BRAF mutation as a prognostic factor in clinical studies of first-line treatment of metastatic CRC.
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The RAS/RAF/MEK/ERK signalling cascade, also known as the MAPK (mitogen-activated protein kinase) pathway, is involved in cell proliferation, differentiation, survival and apoptosis [1]. It receives input from multiple sources including internal metabolic stress and DNA damage pathways and altered protein concentrations as well as through signalling from external growth factors, cell-matrix interactions and communication from other cells [2]. This allows for a nodal point for therapeutic targeting, however, dysregulation of this pathway can also increase malignant behaviour [3].
Multiple signals activate RAS (KRAS, NRAS and HRAS), a family of GTPases. This, in turn, activates downstream RAF protein kinases (ARAF, BRAF and CRAF). The dominant substrates of RAF kinases are the MAPK/ERK kinases, MEK1 and MEK2. ERKs phosphorylate a variety of substrates, including multiple transcription factors that regulate several key cellular activities (Figure 1).
The MAPK pathway [
Mutations in RAS and RAF are the most common oncogenes in human cancer [4]. The focus of this chapter will be on BRAF mutations in colorectal cancer, in particular the V600E mutation, the clinical significance, molecular and clinical pathogenesis as well as treatment, now and into the future.
The RAF protein is made of three conserved regions: CR1, CR2 and CR3. CR1 and CR2 are situated in the N terminus. CR1 acts as the main binding domain for RAS; CR2 is the regulatory domain. CR3 is situated in the C terminus and functions as the catalytic kinase domain. CR3 contains two regions important for RAF activation: the activation segment and the regulatory region [5]. Of the RAF family of protein kinases, BRAF is the most frequently mutated and remains the most potent activator of MEK.
The BRAF protooncogene, which encodes for the BRAF protein kinase, is located on chromosome 7 (q34) and is composed of 18 exons. There have been more than thirty BRAF mutations identified to date, occurring in various frequencies. The most common is BRAF V600E mutation (MT), which corresponds to a thymine to adenine transversion at position 1799, resulting in the substitution of valine by glutamate at position 600 of the protein [5]. This lies within the activating segment of the kinase domain. It renders BRAF constitutionally active, increasing kinase activity relative to BRAF wild-type (WT) by 10 times [6]. Because of this, co-mutations in the MAPK signalling cascade offers no selective advantage for developing tumours and therefore BRAF mutations are mutually exclusive with KRAS or NRAS mutations [7].
The V600E mutation accounts for more than 85% of BRAF mutations in melanoma, more than 50% of the mutations in non-small cell lung cancer and more than 95% of mutations in cholangiocarcinoma and hairy cell leukaemia. It accounts for more than 90% of BRAF mutations in colorectal cancer (CRC) [8]. Other BRAF mutations include R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E (V600E), V599K, V599R, V600K, and A727V [9].
BRAF mutations have been found in 7–10% of patients with metastatic CRC [7, 10]. BRAF MT CRC has been associated with a particular phenotype in multiple studies and meta-analysis and specifically pertaining to the BRAF V600E mutation. BRAF tumours are more prevalent in women and in patients >70 years of age. BRAF is not associated with age at diagnosis of less than 60 years [11]. BRAF mutation is more prevalent in proximal colon tumours and is rarely found in the left colon [7]. Histopathology also differs, with 60% of BRAF MT tumours being poorly differentiated and a higher rate of mucinous pathology [12]. There is an association with larger primary tumours. BRAF MT CRC is also associated with a high rate of peritoneal metastases and less lung and liver-limited disease [13, 14, 15]. In contrast, most non-V600 mutations were more likely to be lower grade and left-sided tumours with a greater overall survival [16, 17], except for codon 601/597 mutations which behave similarly to V600E MT CRC [18].
The pathogenesis of CRC is a heterogeneous and complex process. The classic model of adenoma-carcinoma sequence was initially described by Vogelstein and accounts for approximately 80% of sporadic CRC [19]. Mutation of the tumour suppressor gene, APC, occurs early in the process and additional mutations and chromosomal instability leads to neoplastic progression [20].
The serrated neoplastic pathway is an alternative model of CRC pathogenesis with distinct morphologic and molecular characteristics. It is estimated about 20% of CRC develop via this pathway. These lesions develop from aberrant crypt foci and hyperplastic polyps (HP) into traditional serrated adenoma (TSA) and sessile serrated adenoma (SSA), with malignant potential. BRAF mutation occurs early in the pathway, shown to be present in HP, hyperplastic adenomas and SSA [21].
SSA are also characterised by the CpG island methylator phenotype (CIMP) [22]. A cytosine nucleotide followed by a guanine nucleotide (CpG dinucleotide) can be found in dense clusters (CpG islands) in the promoter regions of approximately half of all genes [23]. Aberrant hypermethylation of these CpG islands can lead to silencing of tumour suppressor genes that, in turn, lead to carcinogenesis. CIMP can be described as high, low or negative. Hypermethylation of the mismatch repair gene
MSI is implicated in 15% of sporadic CRC and >95% of Hereditary Non Polyposis Colorectal Cancer (HNPCC), also known as Lynch syndrome. It is caused by deficiency of the DNA mismatch repair (MMR) system, composed of multiple interacting proteins including MSH2, MLH1. The majority of sporadic MSI high CRC is due to the hypermethylation of the mismatch repair gene
BRAF MT CRC is strongly associated with inferior survival compared with BRAF WT disease. Randomised control trials of first line treatment of metastatic CRC demonstrate differences in OS of up to 12 months, shown in Table 1. Venderbosch et al. reported a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies examining mismatch repair and BRAF status [29]. BRAF MT was associated with a poor prognosis with OS of 11.4 vs. 17.2 months, and PFS of 6.2 vs. 7.7 months compared with BRAF WT. This analysis also found dMMR to indicate poor prognosis, despite significant evidence to show that MSI-high tumours confer a better prognosis. However, it is concluded that as there is no interaction between BRAF MT and dMMR, the poor prognostic value of dMMR is likely driven by BRAF MT. There was no difference in OS or PFS between dMMR BRAF MT and pMMR BRAF MT tumours. In a study examining RAS and BRAF mutations, BRAF patients had the worst overall survival. The median OS for WT, KRAS, NRAS and BRAF patients were 49.2, 36.2, 30.1 and 22.5 months, respectively [30].
Study | Treatment regimen | Key outcomes in BRAF MT disease | Prognostic finding |
---|---|---|---|
MRC FOCUS [76] | 5-FU/irinotecan or 5-FU/oxaliplatin | HR for OS 1.82 (P = 0.0002) | BRAF predicts poor OS but no difference in PFS |
MRC COIN [43] | Fluoropyrimidine/oxaliplatin ± cetuximab | OS 8.8 vs. 20.1 months | Median OS was significantly shorter in patients with BRAF, KRAS or NRAS mutations than in patients with WT KRAS, NRAS, and BRAF tumours, irrespective of treatment (P < 0.0001) |
OPUS [77] | FOLFOX ± cetuximab | Median OS, 20.7 months with cetuximab + FOLFOX | Small numbers precluded definitive conclusions |
CRYSTAL [78] | FOLFIRI ± cetuximab | Median PFS (cetuximab + FOLFIRI vs. FOLFIRI), 8.0 vs. 5.6 months (HR, 0.934; P = 0.87) Median OS, 14.1 vs. 10.3 months (HR 0.908; P = 0.74) | BRAF MT was strong indicator of poor prognosis |
NORDIC-VII [48] | FLOX ± cetuximab | BRAF MT had lower ORRs than BRAF WT (20 vs. 50%; P < 0.001) | BRAF mutations was a strong negative prognostic factor |
PRIME [42] | FOLFOX ± panitumumab | Median PFS: Panitumumab + FOLFOX vs. FOLFOX, 6.1 vs. 5.4 months Median OS: Panitumumab + FOLFOX vs. FOLFOX, 10.5 vs. 9.2 months | BRAF mutation was a negative prognostic factor |
CAIRO2 [10] | Capecitabine + oxaliplatin + bevacizumab vs. CAPOX + bevacizumab + cetuximab | Lower median PFS, 5.9 and 6.6 months in BRAF-MT vs. 12.2 and 10.4 months in BRAF WT tumours with CAPOX + bevacizumab and CAPOX + bevacizumab + cetuximab, respectively Lower median OS, 15.0 and 15.2 months in BRAF MT vs. 24.6 and 21.5 months in BRAF WT with CB and CBC, respectively | BRAF mutation was a negative prognostic marker |
AGITG MAX [79] | Capecitabine ± bevacizumab | Median OS, 20.8 months in BRAF WT vs. 8.6 months in BRAF MT tumours | BRAF mutation was a marker of poor prognosis irrespective of treatment |
BRAF mutation as a prognostic factor in clinical studies of first-line treatment of metastatic CRC.
Similarly, BRAF MT has been shown to be a negative prognostic factor in stage II and III disease. Data from the PETACC-3 was extracted, with KRAS, BRAF and MSI status examined [31]. MSI-high tumours were associated with better prognosis. BRAF MT was not prognostic of PFS. The MSI-high status appeared to attenuate the negative prognostic effect of BRAF MT on OS; BRAF MT is a negative prognostic factor in MSS CRC. However, more recently, a meta-analysis of 1164 patients with MSI-high non-metastatic CRC has shown that BRAF V600E mutation does correlate with adverse overall survival, but not disease recurrence [32].
Survival following metastasectomy is also worse for BRAF MT mCRC as demonstrated in a meta-analysis of patients undergoing resection of liver metastases. It showed the BRAF mutation was negatively associated with OS (HR 3.055, P = 0.00004) [33].
In contrast, non-V600E BRAF mutations have a different prognosis. BRAF codons 594 and 596 mutations, when compared with V600E BRAF mutations, are more frequently rectal, non-mucinous with no peritoneal spread. In a study of 10 patients, all BRAF 594 and 596 tumours were microsatellite stable. OS was significantly longer (62 vs. 12.6 months, P = 0.002) [34]. Jones et al. identified 208 metastatic CRC patients out of 9643 with non-V600E mutations. When compared with V600E BRAF mutation patients, those with non-V600E mutations were found to be younger, more likely male, and had lower grade tumours. In addition, median OS was significantly longer compared with both V600E BRAF mutant and BRAF wild-type patients (60.7 vs. 11.4 vs. 43 months respectively) [35]. This has also been demonstrated in a retrospective study of 98 patients, 6 of whom had non-V600E BRAF mutations. Although only a small sample size, OS was significantly better compared with V600E BRAF MT patients (P = 0.38) [17].
Doublet chemotherapy remains the standard of care for metastatic BRAF MT CRC in patients with appropriate performance status [36, 37]. First-line chemotherapy options include 5 fluorouracil, leucovorin and oxaliplatin (FOLFOX), 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and capecitabine plus oxaliplatin. A retrospective study reported no difference in median PFS between irinotecan-based or oxaliplatin-based chemotherapy regimens in the first line for BRAF-MT CRC [38].
A more intensive triplet chemotherapy regime has been proposed based on 5 fluorouracil, leucovorin, oxaliplatin and irinotecan with bevacizumab (FOLFOXIRI+bev). A phase II trial of FOLFOXIRI and bevacizumab in the metastatic CRC population showed a statistically significant benefit to progression free survival and trend towards improved overall survival at the expense of greater incidence of grade three toxicities [39]. An exploratory analysis of the BRAF-MT cohort (25 patients in a pooled population) reported a median PFS of 11.8 months, median OS of 24.1 months and an impressive response rate of 72%, including one patient with complete response [40]. This was followed up by the open label phase III TRIBE study comparing FOLFIRI plus bevacizumab with FOLFOXIRI with bevacizumab [41]. In the molecular subgroup analysis, 28 out of 391 cases were BRAF mutant. There was a trend towards benefit in overall survival (19.0 months in the FOLFOXIRI plus bevacizumab arm vs. 10.7 months in the FOLFIRI plus bevacizumab arm, HR 0.54); however, this was not statistically significant. This was also seen in median PFS (7.5 vs. 9.5 months, HR 0.57) and best overall response (56 vs. 42%). While not statistically significant, this regime has been proposed in the first line setting for BRAF-MT mCRC patients with good performance status given the overall survival data.
ClinicalTrials.gov number | Therapeutic strategy | Agents investigated | Study design | Status |
---|---|---|---|---|
NCT02928224 | BRAF + EGFR + MEK inhibition | Encorafenib + cetuximab ± binimetinib | Phase 3, randomised, open label | Recruiting |
NCT02906059 | Chemotherapy + selective Wee 1 inhibitor | Irinotecan + AZD1775 | Phase 1b | Recruiting |
NCT01351103 | PORCN inhibitor + immunotherapy | LGK974 ± PDR001 | Phase 1 | Recruiting |
NCT01640405 | Antiangiogenesis agent + cytotoxic chemotherapy | FOLFOX + bevacizumab vs. FOLFOXIRI + bevacizumab | Phase 3 open label | Active, not recruiting |
NCT01750918 | BRAF + EGFR + MEK inhibition | Dabrafenib + panitumumab vs. dabrafenib + trametinib + panitumumab Dabrafenib + panitumumab vs. dabrafenib + trametinib + panitumumab vs. 5-fluorouracil-based chemotherapy + monoclonal antibody Trametinib + panitumumab | 4 part phase 1/2, open label | Active, not recruiting |
NCT01719380 | BRAF + EGFR + PI3K inhibition | Encorafenib + cetuximab + alpelisib | Phase 1b/2, open label, dose escalation | Active, not recruiting |
Ongoing studies investigating different treatment strategies for BRAF MT mCRC.
Updated 7th November 2018.
The epidermal growth factor receptor (EGFR) is involved in signalling upstream of the RAS-RAF-MEK-ERK pathway. Monoclonal antibodies directed against EGFR, cetuximab and panitumumab have shown to be effective in metastatic CRC; however, KRAS mutation is a negative predictor of EGFR treatment response and upfront testing is recommended before starting treatment [36, 37].
As previously discussed, KRAS and BRAF mutations are mutually exclusive. Given the common signalling pathway, BRAF mutation has also been proposed to be a negative predictive marker of EGRF antibody treatment response. In the first line setting, the PRIME study evaluated the addition of panitumumab to FOLFOX. In BRAF-MT tumours, panitumumab added no benefit to survival (HR 0.9, P = 0.76) [42]. Similarly, the phase III MRC COIN trial showed no benefit in the addition of cetuximab to first-line oxaliplatin based chemotherapy, irrespective of KRAS or BRAF mutation status [43]. In the second line setting, the PICCOLO study reported no effect of panitumumab in combination with irinotecan on PFS, but a significant negative effect on OS (HR 1.84, P = 0.029). Cetuximab was also evaluated against best supportive care in the phase III CO.17 trial [44]. For BRAF MT tumours, there were no responses and no change to survival in the sample size of 13 (HR 0.84, P = 0.81).
Given the small numbers of BRAF-MT patients in these trials, there have been a number of meta-analyses evaluating the BRAF mutation as a predictive marker of EGFR therapy. Therkildsen et al. reviewed KRAS, NRAS, BRAF, PIK3CA and PTEN mutations in patients with KRAS exon 2 wild-type patients. Of the 1267 patients in 17 studies treated with either cetuximab or panitumumab in both first line and subsequent like therapies, 128 patients had BRAF V600E mutations [45]. There was a significant decrease in overall response rate (17 vs. 45%). BRAF mutation was also linked to shorter PFS (HR 2.95) and OS (HR 2.52) compared to BRAF wild-type tumours.
Pietrantonio et al. examined the impact of cetuximab and panitumumab on PFS, OS and overall response rate (ORR) [46]. This meta-analysis included 9 phase III trials and 1 phase II trial (across first-line, second-line and chemotherapy refractory settings). 463 RAS wild-type/BRAF MT CRC patients were identified. The addition of EGFR antibody therapy did not significantly improve PFS (HR 0.88, P = 0.33), OS (HR 0.91, P = 0.63) and ORR (relative risk 1.31, P = 0.25).
A further meta-analysis was published in 2015 but Rowland et al. [47]. It included 8 randomised control trials that had also been included in the analysis by Pietrantonio et al., but differed by excluding 2 trials; 1 by Tveit et al. [48] due to lack of OS and PFS data and Stintzing et al. [49] as the control arm included bevacizumab. In addition, the statistical analysis differed as Rowland et al. compared BRAF MT patients with BRAF wild-type. 351 patients were identified with BRAF mutation, of which 330 with the V600E mutation. The HR for PFS was 0.86 for RAS wild-type/BRAF MT compared with 0.62 for RAS wild-type/BRAF wild-type tumours with a test of interaction that nears but does not reach statistical significance (P = 0.07). There was no difference for OS either, the HR for RAS wild-type/BRAF MT tumours was 0.97 compared with 0.81 for RAS wild-type/BRAF wild-type (test of interaction, P = 0.43). It concluded that there was insufficient evidence to definitively state that RAS wild-type/BRAF MT individuals derive a different treatment benefit from EGFR antibodies compared with RAS wild-type/BRAF wild-type patients.
More recently, the triplet chemotherapy regime, FOLFOXIRI, has been studied in combination with panitumumab in the VOLFI trial [50]. This was a randomised phase II trial of patients with RAS WT, unresectable metastatic CRC. 96 patients were included, of which, 16 patients with BRAF MT disease. The primary endpoint was ORR. The addition of panitumumab significantly improved ORR in the overall population (85.7 vs. 54.5%, P = 0.0013), and in the BRAF MT population, there was trend to improved ORR (71.4 vs. 22.2%, P = 0.1262).
Thus, while there exists a significant body of evidence that suggests minimal clinical benefit of EGFR antibody treatment in BRAF MT metastatic CRC, it is not definitive and therefore remains an option for therapy in discussion with the patient. This primarily relates to anti-EGFR as the sole biological agent however anti-EGFR therapy may have a definite role when combined with additional biological agents such as BRAF inhibitors as discussed below.
BRAF represents a therapeutic target in cancer as, unlike KRAS, it is a relatively unidirectional MEK-ERK effector. Inhibition of BRAF with vemurafenib (PLX4032) has been demonstrated to significantly benefit patients with unresectable or metastatic BRAF V600E MT melanoma, improving progression free survival and OS, with a response rate of 48% [51]. In sharp contrast, BRAF inhibition in mCRC is disappointing. An expansion phase II study examined vemurafenib in patients with BRAF MT mCRC who have had at least one line of prior therapy [52]. Of the 21 patients treated, 1 patient had a partial response and 7 other patients had stable disease by RESIST criteria. The median PFS was only 2.1 months and ORR of 5%. Although there were signs of efficacy, the authors concluded that single-agent vemurafenib did not show any meaningful clinical activity in patients with BRAF V600E MT mCRC.
These results were similar to a histology-independent phase II “basket” trial of vemurafenib. 122 patients with BRAF V600 MT malignancies were enrolled into 7 prespecified cohorts, including 37 with mCRC [53]. Vemurafenib, as a single agent, was given to 10 patients with mCRC. Response was poor, with 50% having stable disease and the rest progressing on therapy. The remaining 27 patients with mCRC received combination of vemurafenib and cetuximab, and the results will be discussed later in the chapter.
There are several mechanisms of resistance identified that reduce the efficacy of BRAF inhibition in mCRC. For example Prahallad et al. identified that BRAF inhibition with vemurafenib in mCRC cells causes a rapid activation of EGFR through an ERK-dependent negative feedback loop [54]. Unlike in melanoma, CRC cell lines express high levels of activated EGFR. Blockade of EGFR with either EGFR monoclonal antibodies or small-molecule kinase inhibitors (gefitinib and erlotinib) was showed to work synergistically with BRAF inhibition.
More recently, it has been showed that BRAF inhibition can also lead to up regulation of other receptor tyrosine kinases including human epidermal growth factor receptor (HER) 2 and HER3 [55].
Activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway has also been implicated in BRAF inhibition resistance [56]. PI3K signalling is activated by direct mutational activation or amplification of PIK3CA and AKT1 or loss of PTEN [57]. Approximately 40% of CRC have been shown to have alterations in 1 of 8 PI3K pathway genes, which are almost always mutually exclusive to each other [58]. Genotyping of BRAF MT CRC has showed concomitant PI3KCA and PTEN mutations [59].
The Wnt/β-catenin pathway is also involved in cell proliferation, differentiation and survival and interacts with the RAS-RAF-MEK-ERK pathway at multiple points. It has been identified as an important step in tumourigenesis and alterations in the Wnt pathway have been identified more frequently in BRAF V600E MT CRC patient samples, potentially representing an alternative pathway of tumour development when BRAF is inhibited [60].
Based on these findings, BRAF inhibition has been combined with a number of different agents in order to attempt to overcome resistance and improve response.
In the fore-mentioned phase II “basket” trial, the effect of vemurafenib and cetuximab evaluated in 27 patients with BRAF V600 MT mCRC. The result was marginally improved compared to single-agent treatment. One patient had a partial response (4% ORR) and 69% had stable disease. Median PFS was 3.7 months and median OS was 7.1 months. A pilot trial with combination panitumumab and vemurafenib included 15 patients with BRAF V600E mCRC who had received at least 1 prior line of therapy [61]. 2 patients had confirmed partial response and 6 patients had stable disease, including 2 patients with stability lasting over 6 months. The treatment was well tolerated with fatigue and rash being the most frequently observed adverse events.
Other combinations of BRAF and EGFR inhibitors have also been investigated including vemurafenib plus erlotinib [62], encorafenib (LGX818, a highly selective ATP-competitive small molecule RAF kinase inhibitor) plus cetuximab [63] and dabrafenib (a small molecule kinase BRAF inhibitor) plus panitumumab [64]. Response rates in these trials range from 4 to 23%. To improve this outcome, the combination has been combined with chemotherapy in the randomised phase 2 SWOG 1406 study [65]. Interim results of this trial were presented in 2017. The combination of irinotecan and cetuximab with or without vemurafenib was examined in 106 patients. Median PFS was significantly improved with the addition of vemurafenib (4.4 vs. 2.0 months, P < 0.001). Response rate increased from 4 to 16% (P = 0.09). However, there was an increase in grade 3 and 4 adverse events including neutropenia, anaemia and nausea. It was noted that no new safety signals. The data on median OS was immature. Based on these findings, this treatment regime has been included in treatment guidelines [36].
BRAF and MEK inhibition has been combined in melanoma with greater efficacy and so has been evaluated in the BRAF MT mCRC population. 43 patients were treated with dabrafenib and trametinib [66]. 1 patient achieved a complete response and 4 patients had a partial response (ORR 12%). 24 patients achieved stable disease (56%). During-treatment biopsies in 9 patients showed reduced levels of ERK compared with pre-treatment biopsies. It is suggested that combination BRAF and MEK inhibition could be a potential therapeutic backbone for the addition of other agents including EGFR inhibitors.
Given the role of MEK and ERK in EGFR activation leading to BRAF inhibitor resistance, the triplet combination of BRAF, MEK and EGFR inhibitors have been investigated. Corcoran et al. reported on a trial involving 3 cohorts, dabrafenib and panitumumab (n = 20), dabrafenib, trametinib and panitumumab (n = 91), and trametinib and panitumumab (n = 31) [67].
The ORR for triplet therapy was 21%, compared with 0% with trametinib and panitumumab and 10% with dabrafenib and panitumumab. With the increase in response rate, there was also a corresponding increase in adverse events. 70% of patients on triplet therapy had a grade 3 or 4 adverse event. 18% of patients had an adverse event resulting in study discontinuation, 54% had an adverse event that resulted in dose reduction, and 71% of patients had an adverse event that led to dose interruption or delay. Skin toxicity including rash and dermatitis acneiform occurred in 90% of patients, with 21% having grade 3 or 4 adverse events. Paired pre-treatment and on-treatment biopsies demonstrated that triplet combination produced greater inhibition of ERK than the dabrafenib and panitumumab doublet or the dabrafenib and panitumumab doublet.
It has been suggested that BRAF inhibitors may offset the dermatologic toxicity resulting from MEK or EGFR inhibitors. Mondaca et al. reported on a case of BRAF V600E MT metastatic CRC on clinical trial with dabrafenib, trametinib and panitumumab [68]. Dabrafenib dose reductions for neutropenia were associated with increased skin toxicity, which subsequently improved with increasing the dose. This case highlights the importance of dose intensity of BRAF inhibitors with used in combination regimens.
Current therapeutic investigations in the BRAF MT mCRC field involve multiple targeted therapies aimed at overcoming acquired resistance to MAPK pathway inhibition.
One such combination is encorafenib, cetuximab and alpelisib. Alpelisib (BYL719) specifically inhibits the alpha subunit of PI3K. A phase 1b dose escalation study included 2 arms, encorafenib plus cetuximab vs. triplet therapy with encorafenib, cetuximab and alpelisib [69]. Triplet therapy was showed to be active with an ORR of 18% and impressively a disease control rate of 92.8%. This combination has been investigated further in a phase 2 trial [63]. 102 patients with refractory BRAF MT CRC were randomised to doublet or triplet therapy. Progression free survival was the primary endpoint. Interim data following 73 events were released and showed no statistical difference between doublet and triplet therapy with HR 0.69 (P = 0.064) and median PFS of 4.2 vs. 5.4 months. Grade 3 and 4 adverse events were higher in the triplet arm, including anaemia and hyperglycaemia. Further investigations with other PI3K inhibitors are currently underway; however, the efficacy of PI3K inhibition remains unclear (NCT01337765, NCT01363232).
Other potential targets include BRAF and AKT inhibition [70], BRAF, EGFR and HER2 inhibition [55], ERK inhibition alone or in combination with BRAF inhibition [71] and Wnt/β-catenin pathway inhibition (NCT02278133) Table 2.
Immunotherapy also plays a role in the management of metastatic CRC [36]. Pembrolizumab and nivolumab are immune check point inhibitors against programmed death 1 (PD-1) that have demonstrated significant activity against MSI-high mCRC [72, 73]. Given the strong association between MSI-high and BRAF MT CRC, this represents a possible therapeutic option. The initial trial of pembrolizumab in MSI-high CRC did not include BRAF MT cases; however, a case report does suggest activity in the MSI-high BRAF MT population [74].
Nivolumab and combination nivolumab with ipilimumab (cytotoxic T-lymphocyte associated protein 4 inhibitor) in MSI-high/dMMR CRC was examined in the phase 2 CheckMate 142 study [73, 75]. 12 of the 74 patients receiving nivolumab harboured a BRAF mutation. An objective response was seen in 3 patients (25%) and 9 patients achieved disease control for greater than 12 weeks. The ORR for combination immunotherapy was greater at 55% in patients with MSI-high BRAF MT CRC, and disease control rate of 79%. Safety data was not reported by mutation status, however, appeared manageable, with 32% experiencing a grade 3 or 4 adverse event, most commonly raised AST. Discontinuation due to a treatment related adverse event was 13%.
BRAF V600E mutations are present in 7–10% of CRC. It represents a population with poor prognosis and a particular clinical phenotype, being more prevalent in women, older than 70 years of age, associated with poorly differentiated histology and right-sided tumours. Chemotherapy with the addition of anti-angiogenesis agent remains the current standard of care in the first line metastatic setting. More aggressive, triplet chemotherapy (FOLFOXIRI) may be appropriate in the selected patient. BRAF inhibition has been extensively investigated for second line therapy and beyond and when in combination with EGFR, MEK and PI3K inhibitors have increased response rates, however, PFS and OS remains poor. Ongoing research remains important to improve outcomes in BRAF MT CRC.
For sustainable food production, it is an absolute requirement that nutrients removed with the harvest of crops are replaced to prevent nutrient depletion and soil degradation. Achievement and maintenance of high nutrient use efficiency (NUE) together with high crop productivity have become a major challenge in both developed and developing countries with an increasing growing population, depletion of natural resources, and deteriorating environmental conditions. This is occurring at the same time as society becomes ever more concerned about resource management practices and the environment, especially when it comes to nutrient management [1]. Fertilizer nutrients applied that are not taken up by the crop are also vulnerable to losses from leaching, erosion, and denitrification or volatilization in the case of N, or they could be temporarily immobilized in soil organic matter to be released at a later time, all of which impact apparent use efficiency [2].
Improving nutrient use efficiency (NUE) in plants is vital to enhance the yield and quality of crops, reduce nutrient input cost and improve soil, water, and air quality [3]. Higher NUE by plants could reduce fertilizer input costs, decrease the rate of nutrient losses, and enhance crop yields. Improving crop nutrient use efficiency ideally requires an understanding of the whole system, from the macro (agro-ecosystem) to the molecular level [4]. Nutrient uptake and their internal utilization efficiencies are the two central cores for improving crop NUE [5]. This can be achieved through optimizing agronomic strategies (soil-rhizosphere management) and breeding nutrient-efficient cultivars. Plant genetics and physiological mechanisms and their interaction with best agronomic practice are also a tool that can be used to increase efficiency of cropping systems [3]. Thus, it needs involvement of integrated nutrient management strategies that take into consideration improved fertilizer along with soil and crop management practices are necessary [6]. Sustainable nutrient management must be both efficient and effective to deliver anticipated economic, social, and environmental benefits.
Plants experience nutrient deficiency when soil nutrient availability is either an inherently low amount or low mobility of nutrients in the soil, or poor solubility of certain chemical forms of soil nutrients [7]. Of the various nutrients essential for plants, nitrogen (N), phosphorus (P), and potassium (K) are required in the largest quantities, and their deficiency severely limits crop yield [8]. The dynamic nature of N and P in soil-plant systems creates a unique and challenging environment with nitrate and phosphate contamination of surface and/or groundwater, which can be attributed in large part to low efficiency in plant nutrient uptake. The main challenge for improving P and K use efficiency at the farm level is to apply the existing knowledge in a practical manner [9]. Hence, the best management practice for N, P, and K must consider the specific characteristics of crops, cropping systems, environments, and soils is application of 4R nutrient stewardship. Therefore, this chapter tries to summarize the concept of NUE and recent strategies for enhancing use efficiency of N, P, and K. These approaches consider economic, social, and environmental dimensions essential to sustainable agricultural systems and afford a suitable context for specific NUE indicators.
The variations in defining nutrient efficient plants and methods used in calculating nutrient use efficiency make it difficult to compare results of different studies [10, 11, 12, 13]. Understanding the terminology and the context in which it is used is critical to prevent misinterpretation and misunderstanding and determination of NUE in crop plants is an important approach to evaluate the fate of applied chemical fertilizers and their role in improving crop yields. In order to develop a common framework for NUE, scientists started to formulate concepts and definitions that should serve as a basis for comparison and discussion of research. Nutrient use efficiency in its broadest sense indicates how effectively a plant is able to capture and utilize nutrients to produce biomass. It is simply a measure of how well plants use the available mineral nutrients [10]. The earlier definition of NUE by [14] is simply increment of yield per applied nutrient (Eq. (1)).
While the most recent and complicated one used in crop modeling formula is (Eq. (2)) [12].
where
Generally, nutrient use efficiency comprises both yield as a function of inputs and percentage of nutrient recovered respectively, contributing to yield and quality [15]. The NUE is based on (a) uptake efficiency (acquire from soil, influx rate into roots, influx kinetics, radial transport in roots are based on root parameters per weight or length, and uptake is also related to the amounts of the particular nutrient applied or present in soil), (b) incorporation efficiency (transports to shoot and leaves are based on shoot parameters), and (c) utilization efficiency (based on remobilization, whole plant, i.e., root and shoot parameters) [4].
Phosphorus use efficiency can be divided into (i) P acquisition efficiency [the capacity of a cultivar to extract P from soil] and (ii) P internal utilization efficiency [the capacity of a cultivar to transform the acquired P into biomass/grain yield] [16, 17, 18].
Phosphorus uptake or acquisition efficiency (PACE)
Uptake efficiency or the ability of the plant to extract the nutrient from the soil is calculated as [19] (Eq. (3)).
Phosphorus utilization efficiency (PUTE)
Phosphorus utilization efficiency is defined as a crop’s ability to convert the absorbed P into grain yield [19] (Eq. (4)) can be calculated as:
Utilization efficiency can also be calculates as suggested by [20], (Eqs. (5) and (6)) and expressed as follows:
Generally, if P supply is limited or in more acidic and calcareous soil, P acquisition could be more important than P utilization and high fertilizer application necessary in order to provide sufficient plant-available P. On the other hand, with adequate P supply, PUTE could be considered more important than PACE for crop P efficiency [17]. Therefore, the improvement of both PACE and PUTE in the given species under different P supply conditions in the different soil types seems to be the perfect breeding approach (Figure 1) [17].
Schematic representation of the possible mechanisms of P acquisition and utilization for better growth of modern crops grown in intensive cropping systems
Hence, Nutrient use efficiency = Uptake efficiency × Utilization efficiency. All unit dry weights are in g m−2 [19].
For nitrogen use efficiency in their various definitions and components (Figure 2) [21].
Illustration of nutrient use efficiency parameters exemplified by NUE in wheat. Key process contributing to the NUE trait: nitrogen uptake efficiency, NUpE; nitrogen utilization efficiency, NUtE; nitrogen harvest index, NHI (adopted form [
Apparent recovery efficiency is one of the more complex forms of nutrient use efficiency (NUE) expressions and is most commonly defined as the difference in nutrient uptake in above-ground parts of the plant between the fertilized and unfertilized crop relative to the quantity of nutrient applied. It is often the preferred NUE expression by scientists studying the nutrient response of the crop [22]. Reference [23] proposed that the balance method be used to assess fertilizer P efficiency (Eq. (7)). The balance method is described mathematically as:
Phosphorus use efficiency has become burning issues in recent times due to several reasons [24]. Unlike N, the amount of P is less-abundant, finite resource, less-available, and poor mobility in the soil, being one of the most inaccessible elements for plants. Its deficiency is a major constraint to agricultural production, and it affects an area of over 2 billion hectares worldwide that is on about 70% of the world’s arable land [25]. Remarkably, usually only about 10–30% of the P fertilizer applied in the first year is taken up by the roots, with a substantial part accumulated in the soil as residual P not readily available for plants [26]. This may be due to nature of P that can bound to calcium in alkaline soils and readily complexed to charged Al and Fe oxides and groups hydroxyls on clay surfaces in acidic soils [23]. In addition, agricultural phosphorus (P) run-off is a primary factor in the eutrophication of aquatic and marine ecosystems and has also led to blooms of toxic cyanobacteria [27] and can contain heavy metals such as cadmium that may accumulate in arable soils. Moreover, organic material present in the soil (e.g., from manure or crop residues) can also bind phosphate ions as well as phytate (inositol compounds). In order to avoid a future food-related crisis, phosphorus scarcity needs to be recognized and addressed in contemporary discussions on global environmental change and food security, alongside water, energy, and nitrogen [28].
Selection and breeding nutrient-efficient species or genotypes within a species are justified in terms of reduction in fertilizer input cost of crop production and also reduced risk of contamination of soil and water. Many plants have evolved morphological, physiological, biochemical, and molecular adaptive systems to cope with P-deficiency stress, such as altered root architecture to explore more soil volume and increased carboxylate exudation containing phosphatases, nucleases, and various organic acids [29]. These mechanisms and strategies are necessary to liberate or solubilize Pi from organic and other insoluble pools [30], enhance Pi uptake capacity [31], recycle internal Pi remobilize/retranslocate P from mature to young developing organs [32, 33], and reprioritize metabolic P utilization [34]. Under the current situation, farmers need P-efficient genotypes that perform better than other genotypes with equivalent P inputs. Therefore, selection/identification of cultivars that can absorb and use P efficiently is a promising strategy to cope with environments deficient in bio-available P. Due to the diverse functional and structural roles of P in plants, P-use efficiency (PUE) is a complex trait to dissect [24].
The root morphological factors such as length, thickness, surface area, and volume have profound effects on the plant’s ability to acquire and absorb nutrients in soil [35]. These parameters are influencing the ability of the roots to penetrate high density soil layers, to extremes tolerate temperature, moisture, toxicities, and deficiencies of elements. Additionally, they have the ability to modify the rhizosphere pH and the nutrient uptake kinetics. Efficient acquisition will depend first on root architecture in terms of transporters and exudates and often the presence of symbiotic associations such as mycorrhiza. Hence, improving early root establishment, high-affinity transporter systems, association of microorganisms (mycorrizha), proliferation of roots, and enhanced mechanisms for increasing bio-availability of nutrients and then enhancing NUE [5]. Improvement of transporters plays essential roles particularly in conjunction with effective root proliferation in contributing to nutrient use efficiency. The other important attribute for uptake efficiency is having adequate sinks to store acquired nutrients, which will prevent negative feedback regulation on the initial acquisition/assimilatory processes and should provide important remobilizable storage [5]. The second component of uptake efficiency is root physiological activity such as differing uptake kinetics, i.e., maximum net influx (Imax), affinity of the transporter
A recent study further showed that root tips also play an important role and, despite their small size, accounted for approximately 20% of the total seedling Pi uptake [37], mainly increasing organic acid exudation strategies [38]. Plants increase total soil exploration by increasing root length, increasing root branching, increasing specific root length (i.e., roots with smaller diameter), and modifying branching angle [39, 40, 41]. The findings of Bates and Lynch [39] suggested that increased root growth is associated with improved plant performance under low P by exploring a larger volume of soil. Consequently, root: shoot ratio increases significantly in low-P environments and is an excellent index for partitioning photosynthesized carbon between above- and below-ground plant parts. Root density and root: shoot ratio generally increased under P deficiency, thus favoring P acquisition by plants [29].
Genetic variation for root hair traits, particularly root hair length, can be exploited in breeding for improved P uptake efficiency and P fertilizer use efficiency in crops. Moreover, a deeper root with more aerenchyma tissues in the cortex of the roots can also be an important trait that contributes to efficient N uptake with lower carbon input in root growth [42]. This root architecture may also be efficient in the uptake of deep water and therefore help to increase drought resistance [43]. However, Miguel et al. [44] showed in field trials that shallow and hairy root traits are synergistic in their effects on Pi uptake by bean. However, modifying root growth in response to nutrient deficiency, it is a challenge and complex to identify key regulators that are sufficiently upstream and robust to be suitable for developing plants with optimized root systems for nutrient uptake [8].
Levels of fertilizer applications influence the total dry matter accumulation, thereby affecting the nutrient demand (uptake/utilization) [9]. Improved nutrient utilization efficiency from agrochemicals through PGPR and (or) AMF can contribute to the protection of water resources against agro-pollution and reduce the growing cost of fertilizers [10]. After inorganic phosphate (Pi) acquisition from rhizosphere, Pi should be efficiently transported to shoot for the requirement of plant growth by phosphate transporters (
Another promising area for improvement of crop NUE is to enhance the efficiency of nutrient remobilization from senescing organs to young, developing organs, particularly immature leaves, and developing seeds [47]. The senescence process, that is, the dying-off of vegetative plant parts during seed maturation, is at the core of the nutrient use efficiency issue, as the nutrients need to be remobilized from these parts and translocated into the developing seed [48]. Maximizing the effectiveness of P-remobilization from senescing organs could make an important contribution to the development of crops that can tolerate Pi deficiency, because senescing organs of most “modern” crop varieties exhibit low P-remobilization efficiencies of <50% [30]. An integral understanding of P remobilization would facilitate development of effective biotechnological strategies to improve crop PUE, thereby reducing the rate of depletion of nonrenewable rock P reserves [30, 47]. Therefore, mobilization and redistribution of P from the old tissues to the young tissues will also contribute to high P use efficiency. Better distribution of nutrients in parts of plant (root, shoot, and grain) reflects their use efficiency [11].
In the plant, uptake and utilization efficiency of nutrients are governed by different physiological mechanisms and their response to deficiency, tolerance, and toxicity of element(s) and climatic variables [49]. Efficient internal utilization of nutrient is generally attributed because of high photosynthetic activity per unit of nutrient (P) and more efficient P remobilization from older to young leaves [47]. Acid phosphatase contributes to the increased P utilization efficiency in bean through P remobilization from old leaves [50]. Therefore, improving higher total chlorophyll concentration [51], enhancing phosphorylase stimulation [52], and improving partitioning of carbon between glycolytic and pentose phosphate pathways [53] also provide an effective approach to improve phosphorus use efficiency and crop productivity simultaneously.
P-utilization efficient cultivars produce high yield per unit of absorbed P under P deficient conditions, since they have low internal P demand for normal metabolic activities and growth. Hence, they have low requirement for mineral P fertilizer inputs to produce reasonably high yield. Moreover, they remove less P from soil during growth and therefore the quantity of P removed along with the harvestable parts of the crop would obviously be less, consequently reducing the quantity of mineral P fertilizer inputs required for maintenance fertilization [54].
Agronomic practices can change soil physicochemical properties and biological characteristics. As a result, a number of agronomic practices have been proposed to enhance nutrient availability under diverse climatic conditions [55, 56]. The rhizosphere (root-soil interface) is the most important area for plant–soil-microorganism interactions and is the hub for controlling nutrient transformation and plant uptake [7]. This modification is paramount to increase nutrient availability and to minimize losses in surface runoff. Possible management strategies options for improving NUE through optimizing agronomic practice or rhizosphere modification [57] are the following:
The 4R Nutrient Stewardship framework promotes the application of nutrients using the right source (or product) at the right rate, right time, and right place. The framework was established to help convey how fertilizer application can be managed to ensure alignment with economic, social, and environmental goals [58]. Nutrient Stewardship defines the right source, rate, time, and place for fertilizer application as those producing the economic, social, and environmental outcomes desired by all stakeholders of the plant ecosystem (Figure 3). This 4R techniques applies (1) right rate—supplying growing crops with the right amount of nutrients for healthy growth and development based on experimentation under various environmental conditions; (2) right time—matching nutrient availability to with the timing of plant peak nutrient uptake and demand; (3) right placement adding nutrients to the soil at a place where crops can easily access them related to volume of roots.; (4) right source—applying the correct fertilizer and organic resources that provide growing crops with all nutrients required for good growth and maturity [58]. The 4R concept was established to help convey how fertilizer application can be managed to ensure alignment with economic, environmental, and social goals [22, 59].
The 4R nutrient stewardship concept (adopted from [
Soil testing remains one of the most powerful tools available for determining the nutrient supplying capacity of the soil, but to be useful for making appropriate fertilizer recommendations good calibration data is also necessary [2]. As P is less mobile, less soluble, and highly prone to soil fixation; effectiveness of applied P depends on the properties of soil being fertilized, fertilizer itself, and time and method of its application [60]. To enhance phosphorus use efficiency (PUE) of applied P fertilizer, time and method of its application are critically important, because different P application methods differ in PUE [61]. In highly sandy soils, P may need to be managed like N, by splitting applications and applying small amounts at sowing and topdressing later in the crop growth cycle [62]. Studies of Jing et al. [63] suggested that localized supply of superphosphate combined with ammonium-N (NH4+-N) significantly stimulated root proliferation, especially of fine roots, and thus improved maize growth in a calcareous soil. Further studies indicated that localized supply of P and NH4+-N at both seeding and later growth stages increased maize yield by 8–10%, P uptake by 39–48%, and localized increases in root density and length of 50% [64]. Rehim et al. [65] also reported that the fixation of broadcasted P is much greater than the fertilizer applied in bands because of less contact with P fixing ingredients. At higher P application, the adsorption of P increased because the plants readily utilize only 8–33% of applied P in the first growing season and remaining portion remained fixed that consequently resulted in higher Olsen P. So, at higher P application rates, plants used smaller proportion of fertilizer P that resulted in low PUE [61].
In principle, N deficiency increases root growth, resulting in longer axial roots (primary roots, seminal roots, and nodal roots), and this helps maize roots to explore a larger soil volume and thus increases the spatial N availability [66]; however, long-term N deficiency stunts root growth due to insufficient N. But also, root elongation can be inhibited if the N supply is too high. Excessive application of N-P fertilizers may lead to high concentrations of soluble nutrients in the root zone, which can also restrict root growth and rhizosphere efficiency [67], even small amounts of P lost can be a cause of the adverse effects of eutrophication of surface waters. Therefore, judicious application of fertilizer best management practices (BMP) [22] that includes the right rate [68], right time [69], right source, right place, and balanced fertilization (4RB) is the best management practice for achieving optimum nutrient efficiency [2, 22].
Cereal-legume intercropping is a crop production system utilized to improve productivity and sustainability under diverse environmental conditions. It can also improve nutrient use efficiency and crop productivity [7]. Intermingling of maize and faba-bean roots increased N acquisition by both crop species by about 20% compared with complete or partial separation of the root systems. Further studies indicate that N2 fixation can be improved by yield maximization in the intercropping system. The improved productivity observed in this production system has been associated with increased levels of available phosphorus (P) in the root rhizosphere. Hinsinger et al. [70] reported more stable yield, superior land resource utilization or conservation, and enhanced pest or weed control [71, 72, 73]. Furthermore, cereal-legume intercropping can also enhance the phosphatase enzyme activity and available P in the soil due to rhizosphere acidification by the legumes in the cropping system [74].
The possible mechanism that increases PUE in intercropping is the increased rhizosphere soil acid phosphatase (RS-APase) activity observed in intercropping due to the fact that large amounts of acid phosphatase are known to be released from their roots into the root rhizosphere. The (RS-APase) activity was significantly higher (26–46%) in the intercropping and occurred concomitant with a significant increase in available phosphorus (RS-Pavailable) in the rhizosphere on podzols in cool climate boreal ecosystem [75]. Another mechanism could be secreting H+ into the soil that acidifiies the rhizosphere [57, 76] and improves dissolution of phosphorus and then enhances P-availability [70]. Additional possible mechanism that improves of plant growth and P uptake in mixed planting was due to root interspecific complementation or facilitation. The complementarity between root morphological and physiological traits of neighboring plants underpins the interactive facilitation, which was the main underlying mechanism improving nutrient-use efficiency, particularly of P, in mixed cropping system [77, 78]. The complementary niches of maize and faba bean significantly reduce interspecific nutrient competition and thus improve nutrient-use efficiency [79]. The presence of maize increased the secretion of carboxylates from alfalfa roots, suggesting that the root interactions between maize and alfalfa are crucial for improving P-use efficiency and productivity in intercropping [80]. Subsequently, Sun et al. [76] reported that decreasing rhizosphere pH and increasing organic anion exudation played key roles in soil P mobilization of maize and alfalfa, with little contribution of acid phosphatase.
The mycorrhizal symbiosis particularly, arbuscular mycorrhizal fungi (AMF), is arguably the most important symbiosis on earth [81]. AMF colonize the roots of many agriculturally important food and bioenergy crops form (approximately 80–90% of all known land plant species) [81] and could serve as “biofertilizers and bioprotectors” in environmentally sustainable agriculture [82]. In AMF associations, two pathways for plant P uptake exist: the direct pathway (P uptake by roots) and the AM fungal pathway [83]. AMF facilitates the uptake and transfer of mineral nutrients, such as phosphorus, nitrogen, sulfur, potassium, calcium, copper, and zinc, from the soil to their host plants by means of the extraradical mycelium extending from colonized roots into the soil [84]. The contribution of AMF to P uptake reaches up to 77% under low P supply compared with only 49% under high P supply [85]. Furthermore, the commercial inoculum Mycobiol, consisting of Glomus spp.,
Various mechanisms have been suggested for the increase in the plant uptake of P. These include: exploration of larger soil volume; faster movement of P into mycorrhizal hyphae; and solubilization of soil phosphorus [88]. Exploration of larger soil volume by mycorrhizal plants is achieved by decreasing the distance that P ions must diffuse to plant roots and by increasing the surface area for absorption. Faster movement of P into mycorrhizal hyphae is achieved by increasing the affinity for P ions and by decreasing the threshold concentration required for absorption of P [88]. Solubilization of soil P is achieved by rhizospheric modifications through the release of organic acids, phosphatase enzymes, and some specialized metabolites such as siderophores [55].
The composition and amount of root exudates affect the composition of microbes in the rhizosphere and the structure of the rhizosphere microbiome, affecting plant growth and nutrient uptake [81]. For precision rhizosphere management, plant-microbe interactions must be finely tuned to improve P use efficiency by crops [57]. Figure 4 illustrates the main structural differences between AM (more for P absorption) and ectomycorrhizal (more for N and few for P absorption) associations of angiosperms or gymnosperms [81].
Phosphorus acquisition efficiency related traits of wheat and barley roots affected by arbuscular mycorrhizal symbiosis in comparison to a non-colonized counterpart (adopted from [
Among the soil bacterial communities, ectorhizospheric strains from Pseudomonas and Bacilli and endosymbiotic rhizobia have been described as effective phosphate solubilizers [90]. Phosphate-solubilizing bacteria (PSB) are also capable of making P available to plants from both inorganic sources and organic ones and increasing P-fertilizer-use efficiency by different mechanisms [91]. They are rhizobacteria that convert insoluble phosphates into soluble forms through acidification, chelation, exchange reactions, and the production of organic acids [92]. Therefore, combined application of AMF and P solubilizers [93] and N fixers are the best inoculants. AM fungi together with PSMs could be much more effective in supplementing soil P. Understanding AM-plant symbiosis, developing AM fungi that could be cultured in vitro, and developing P-solubilizing AM will help realize their potential as phosphate biofertilizer [94].
Soil pH is one of the most important chemical properties influencing nutrient solubility and hence availability to plants. Large amount of P applied as fertilizer enters in to the immobile pools through precipitation reaction (fixation) with highly reactive Al3+ and Fe3+ in acidic and Ca2+ in calcareous or normal soils [94]. Acidic, highly weathered, iron (Fe)-rich soils rapidly bind phosphates at mineral surfaces, limiting access to plant roots. Furthermore, applied Pi (inorganic P) is quickly fixed into insoluble inorganic or organic forms due to its high reactivity and microbial action [95].
Soil pH markedly limits plant growth and P chemistry in soils through its effect on P adsorption and through interactions that affect precipitation of P into solid forms in soil [62]. Consequently, about 80–90% soil P becomes unavailable depending on soil composition and pH [96], 50–70% of the total applied conventional fertilizers are lost to the environment. This level of loss in agricultural nutrients not only leads to the loss of valuable resources but also causes the severe reduction of yield [97]. The pH of a calcareous soil is reduced by the presence of gypsum (CaSO4·2H2O) due to the concentration of Ca2+, which would be expected to decrease the sorption of P, if followed by leaching to removed much of the soluble Na+ and Ca2+ [98]. Thus, adjusting soil pH and base saturation are methods to reduce the amount of P that is bound by Al, Fe, and Ca, further reducing the effects of Al toxicity to plants, which can inhibit uptake, and use of P by the plant (Figure 5) [23, 99].
Soil P availability as affected by soil pH (adopted from Havlin et al. 1999).
Lime acidic soil is widely used in agriculture to create and maintain a soil pH optimal for plant growth in acid soils. Lime reduces toxic effects of hydrogen, aluminum, and manganese, improves soil biological activities, cation exchange capacity (CEC), P, Ca, and Mg availability and soil structure, promotes N2 fixation, stimulates nitrification, and decreases availability of K, Mn, Zn, Fe, boron (B), and Cu [11]. An increase in soil pH, as a result of liming, was due to an increase in hydroxide ions, which increases microbial activity and communities, hence, increasing decomposition of soil organic matter and release of Fe and Al [100]. The decrease in Al-P and Fe-P could be due to their precipitation as insoluble Al(OH)3 and Fe(OH)3 after increased addition of liming material [101]. In addition, Al and Fe oxides become more negatively charged with an increase in pH contributing to an increase in available P [102].
Liming, gypsum application, or mixing of both is an effective practice to improve pH, improve Ca content, and control Al toxicity. Lime has very low mobility in soil, and when surface applied, it does not reduce the acidity of subsurface soil horizons. Contrary to lime, gypsum (CaSO4) has a greater downward movement, and when applied to the surface, it can still impact and reduce the acidity of the subsoil [4]. The pH of a calcareous soil is reduced by the presence of gypsum (CaSO4·2H2O) due to the concentration of Ca2+, which would be expected to decrease the sorption of P, if followed by leaching to removed much of the soluble Na+ and Ca2+. The uptake of nutrients by plants, content of nutrients in plants and in soil were substantially positively influenced by both the wood ash, especially by FGD gypsum [103]. Gypsum application can ameliorate saline-sodic soil, thereby increasing crop yield and NUE [104].
Apart from traditional methods, new techniques have been developed such as site-specific/real-time nitrogen management, slow release/controlled release fertilizer (SR/CRF), site-specific precision nutrient management, and urease/nitrification inhibitor. Those techniques play an important role in decreasing fertilizer loss and increasing NUE [105]. The remote sensing is quicker than the previous two methods, and it obtains continuous data rather than spot data, which is more advantageous. It is becoming the major means of obtaining data for precision farming. GIS (geographic information system) establishes the field management information system by processing, analyzing, and trimming the data of soil and crops [105]. Another approach to synchronize release of N from fertilizers with crop need is the use of N stabilizers and controlled release fertilizers. Nitrogen stabilizers (e.g., nitrapyrin, DCD [dicyandiamide], NBPT [n-butyl-thiophosphoric triamide]) inhibit nitrification or urease activity, thereby slowing the conversion of the fertilizer to nitrate. The most promising for widespread agricultural use are polymer-coated products, which can be designed to release nutrients in a controlled manner.
Agronomic management strategies such as precision P fertilization, polymer coated P-fertilizers, and recycling of P from domestic, agricultural, and industrial wastes can be helpful in improving P use at farm level [106]. Modern concepts for tactical N management should involve a combination of anticipatory (before planting) and responsive (during the growing season) decisions [9]. On soils with moderate P and K levels and little fixation, management must focus on balancing inputs and outputs at field and farm scales to maximize profit, avoid excessive accumulation, and minimize risk of P losses. Improving the internal, on-farm and field recycling is the most important K management issue worldwide. As for N, the primary determinants for REP and REK are the size of the crop sink, soil supply, soil characteristics, and fertilizer rate.
Control release fertilizers with polymer coatings are commonly applied to crops to increase efficiency of nutrients [96]. One way of improving the P availability to crop plant is by coating diammonium phosphate (DAP) with polymer that allows a steady but controlled discharge of phosphorus from the granules for crop plant uptake and improved P recovery percentage. Thus, by the use of polymer, availability of P to plant increased because it has high cation exchange capacity, which holds the divalent calcium (Ca+2) and trivalent cations iron and aluminum (Fe+3 and Al+3) and stop P fixation with these cations. Moreover, polymer absorbs water efficiently and holds more water and keeps P in available form that enhanced the plant growth and yield-contributing factors [97]. This is because polymer-coated diammonium phosphate (DAP) absorbs water many times of its original weight, which increases the availability of phosphorus for longer period of time [107] and creates a diffusion shell around the grain of DAP and directly reduces the fixation and precipitation by reducing the availability of calcium and magnesium (Ca+2/Mg+2) cations [108]. As the result of this mechanism, availability of phosphorus to plants increases and leads to more P uptake, and this uptake indirectly influences the other nutrient absorption by crop plants.
Considering the wide variety of soil types, cropping patterns, and farmers’ resources, several management practices are adopted to reduce the magnitude of soil fertility degradation. Integrated Plant Nutrient Management System (IPNMS) is defined as the package of practices for the manipulation of the plant growth environment to supply essential nutrients to a crop in an adequate amount and proportion for optimum production without degrading the natural resources [3]. Many authors have reported that combining organic and inorganic P can improve and sustain crop yields in low fertility soils [109, 110, 111]. Best management practices (BMPs) such as use of fertilizer and amendment (lime), proper crop rotations, increases in organic matter content, and control of erosion, insects, diseases, and weeds can significantly improve crop yields and optimize nutrient use efficiency [11]. Integrated use of organic manures and fertilizers not only improves efficiency of crops but also significantly increases the availability of P [112, 113].
Organic amendment improves the structure and fertility of the soil by adding nutrients and organic matter and consequently promotes soil microbial biomass and activity. Blockage of P sorption sites by organic acids, as well as complexation of exchangeable Al and Fe in the soil, is potential cause of this mobilization [114]. Organic materials can reduce P fixation by masking the fixation sites on the soil colloids and by forming organic complexes or chelates with Al, Fe, and Mn ions, thereby improving P uptake efficiency of crop plants. Decomposition of organic matter produces organic anions that interact with soil to reduce P sorption via (1) complexation/competition for soil P binding sites such as Fe and Al oxyhydroxides or (2) increased soil PH. Organic materials also increase agronomic efficiency by improving availability of P by promoting soil aggregation, increased soil PH, microbial biomass, and parameters controlling soil-P-sorption [115]. The integration of biochar FYM, poultry manure, and inorganic P sources increases in PUE under both wheat and maize crops, and there is a concomitant increase in crop yields compared with the unamended soil [112, 113]. This increase in PUE with biochar addition could also be the result of the additional nutrients made available by biochar [112]. Similarly, FYM applications increase soil P bioavailability more than applications of triple supper phosphate that enhance P Uptake Efficiency. FYM is also a source of other nutrients used by crops via mineralization, which promotes root development and root area interception and thus increases nutrient uptake including P uptake [116].
Rotating a legume with a cereal can enhance P acquisition by cereals through indirect feedback interactions [117]. A legume crop modifies the rhizosphere through biological and chemical processes, thereby increasing P uptake by the following cereal crop. As reported by [77], legumes are able to mobilize P that is not initially available to cereal species, thereby improving the availability of P for the following crop. The biological processes include the promotion of symbiotic mutualists such as nitrogen-fixing rhizobacteria and mycorrhizal fungi, while the chemical processes are acidification of the rhizosphere and secretion of organic anions [79].
Achievement and maintenance of high nutrient use efficiency (NUE) together with high crop productivity have become a major challenge in both developed and developing countries with an increasing growing population, depletion of natural resources, and deteriorating environmental conditions. Improving nutrient use efficiency (NUE) in plants is vital to enhance the yield and quality of crops, reduce nutrient input cost and improve soil, water, and air quality [3]. Higher NUE by plants could reduce fertilizer input costs, decrease the rate of nutrient losses, and enhance crop yields. Improving crop nutrient use efficiency ideally requires an understanding of the whole system, from the macro (agro-ecosystem) to the molecular level.
The development of nutrient-efficient crop varieties that can grow and yield better with low supply is a key to improving crop production. A prerequisite for nutrient use efficiency for any germplasm will be the optimization of agronomic practice for any given environment and season. Judicious application of fertilizer that includes the right rate, right time, right source, right place, and balanced fertilization (4RB) is the best management practice for achieving optimum nutrient efficiency. By the coordination of the acquisition, root-to-shoot translocation, utilization, and remobilization of internal Pi can be achieved through genetic breeding. Selection and breeding nutrient efficient species or genotypes within a species are justified in terms of reduction in fertilizer input cost of crop production and also reduced risk of contamination of soil and water. Overall NUE in plant is a function of capacity of soil to supply adequate levels of nutrients and ability of plant to acquire, transport in roots and shoot, and remobilize to other parts of the plant. Improvement in NUE will ultimately come from integrating a range of different approaches to develop a more efficient farming system. Use of nutrient efficient crop species or genotypes within species in combination with other improved crop production practices offers the best option for meeting the future food requirements of expanding world populations. Modern tools and resources available to plant scientists and the agronomy and breeding communities should aid further improvements in NUE and hence crop production. Therefore, integrated strategy that seeks to increase phosphorus use efficiency and simultaneously seeks to recover unavoidable phosphorus losses. The nutrient inputs in the intensive farming system should be optimized to achieve both high crop productivity and high nutrient use efficiency through maximizing root/rhizosphere efficiency in nutrient mobilization and acquisition.
The authors are highly thankful to researchers whose findings are included directly or indirectly in preparing this manuscript.
The authors declare no conflict of interest.
The authors received no direct funding for this research.
All data generated are included in this article reference’s part.
AMF | arbuscular mycorrhizal fungi |
BMP | best management practice |
DAP | diammonium phosphate |
FYM | farm-yard manure |
NUE | nutrient use efficiency |
PACE | phosphorus acquisition efficiency |
PSB | phosphate solubilizing bacteria |
PUE | phosphorus use efficiency |
PUTE | phosphorus utilization efficiency |
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Jose",middleName:null,surname:"Hernández-Serrano",slug:"maria-jose-hernandez-serrano",fullName:"Maria Jose Hernández-Serrano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10191",title:"Health and Academic Achievement",subtitle:"New Findings",isOpenForSubmission:!1,hash:"7ee3f57e3911318305ac5c2eef39f8ab",slug:"health-and-academic-achievement-new-findings",bookSignature:"Blandina Bernal-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/10191.jpg",editedByType:"Edited by",editors:[{id:"174721",title:"Dr.",name:"Blandina",middleName:null,surname:"Bernal-Morales",slug:"blandina-bernal-morales",fullName:"Blandina Bernal-Morales"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to 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Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:34,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"59705",doi:"10.5772/intechopen.74943",title:"Augmented Reality Trends in Education between 2016 and 2017 Years",slug:"augmented-reality-trends-in-education-between-2016-and-2017-years",totalDownloads:2475,totalCrossrefCites:19,totalDimensionsCites:27,abstract:"The aim of this chapter is to review literature regarding using augmented reality (AR) in education articles published in between 2016 and 2017 years. The literature source was Web of Science and SSCI, SCI-EXPANDED, A&HCI, CPCI-S, CPCI-SSH, and ESCI indexes. Fifty-two articles were reviewed; however, 14 of them were not been included in the study. As a result, 38 articles were examined. Level of education, field of education, and material types of AR used in education and reported educational advantages of AR have been investigated. All articles are categorized according to target groups, which are early childhood education, primary education, secondary education, high school education, graduate education, and others. AR technology has been mostly carried out in primary and graduate education. “Science education” is the most explored field of education. Mobile applications and marker-based materials on paper have been mostly preferred. The major advantages indicated in the articles are “Learning/Academic Achievement,” “Motivation,” and “Attitude”.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Rabia M. Yilmaz",authors:[{id:"225838",title:"Dr.",name:"Rabia",middleName:null,surname:"Yilmaz",slug:"rabia-yilmaz",fullName:"Rabia Yilmaz"}]},{id:"63639",doi:"10.5772/intechopen.81086",title:"Cooperative Learning: The Foundation for Active Learning",slug:"cooperative-learning-the-foundation-for-active-learning",totalDownloads:3427,totalCrossrefCites:17,totalDimensionsCites:24,abstract:"The role of instructors is evolving from the presenter of information to the designer of active learning processes, environments, and experiences that maximize student engagement. The more active a lesson, the more students tend to engage intellectually and emotionally in the learning activities. Cooperative learning is the foundation on which many of the active learning procedures are based. Cooperative learning is the instructional use of small groups so that students work together to maximize their own and each other’s learning. Most of the active learning procedures, such as problem-based learning, team-learning, collaborative learning, and PALS, require that students work cooperatively in small groups to achieve joint learning goals. Cooperative learning is based on two theories: Structure-Process-Outcome theory and Social Interdependence theory. Four types of cooperative learning have been derived: formal cooperative learning, informal cooperative learning, cooperative base groups, and constructive controversy. There is considerable research confirming the effectiveness of cooperative learning. To be cooperative, however, five basic elements must be structured into the situation: positive interdependence, individual accountability, promotive interaction, social skills, and group processing.",book:{id:"6929",slug:"active-learning-beyond-the-future",title:"Active Learning",fullTitle:"Active Learning - Beyond the Future"},signatures:"David W. Johnson and Roger T. Johnson",authors:[{id:"259976",title:"Dr.",name:"David",middleName:null,surname:"Johnson",slug:"david-johnson",fullName:"David Johnson"},{id:"263004",title:"Dr.",name:"Roger",middleName:null,surname:"Johnson",slug:"roger-johnson",fullName:"Roger Johnson"}]},{id:"59468",doi:"10.5772/intechopen.74344",title:"Virtual and Augmented Reality: New Frontiers for Clinical Psychology",slug:"virtual-and-augmented-reality-new-frontiers-for-clinical-psychology",totalDownloads:2339,totalCrossrefCites:13,totalDimensionsCites:21,abstract:"In the last decades, the applied approach for the use of virtual reality (VR) and augmented reality (AR) on clinical and health psychology has grown exponentially. These technologies have been used to treat several mental disorders, for example, phobias, stress-related disorders, depression, eating disorders, and chronic pain. The importance of VR/AR for the mental health field comes from three main concepts: (1) VR/AR as an imaginal technology, people can feel “as if they are” in a reality that does not exist in external world; (2) VR/AR as an embodied technology, the experience to feel user’s body inside the virtual environment; and (3) VR/AR as connectivity technology, the “end of geography’. In this chapter, we explore the opportunities provided by VR/AR as technologies to improve people’s quality of life and to discuss new frontiers for their application in mental health and psychological well-being promotion.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Sara Ventura, Rosa M. Baños and Cristina Botella",authors:[{id:"106036",title:"Dr.",name:"Rosa Maria",middleName:null,surname:"Baños",slug:"rosa-maria-banos",fullName:"Rosa Maria Baños"},{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura"},{id:"229056",title:"Dr.",name:"Cristina",middleName:null,surname:"Botella",slug:"cristina-botella",fullName:"Cristina Botella"}]},{id:"58060",doi:"10.5772/intechopen.72341",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8762,totalCrossrefCites:15,totalDimensionsCites:21,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"64583",doi:"10.5772/intechopen.81714",title:"Evaluating a Course for Teaching Advanced Programming Concepts with Scratch to Preservice Kindergarten Teachers: A Case Study in Greece",slug:"evaluating-a-course-for-teaching-advanced-programming-concepts-with-scratch-to-preservice-kindergart",totalDownloads:1409,totalCrossrefCites:13,totalDimensionsCites:18,abstract:"Coding is a new literacy for the twenty-first century, and as a literacy, coding enables new ways of thinking and new ways of communicating and expressing ideas, as well as new ways of civic participation. A growing number of countries, in Europe and beyond, have established clear policies and frameworks for introducing computational thinking (CT) and computer programming to young children. In this chapter, we discuss a game-based approach to coding education for preservice kindergarten teachers using Scratch. The aim of using Scratch was to excite students’ interest and familiarize them with the basics of programming in an open-ended, project-based, and personally meaningful environment for a semester course in the Department of Preschool Education in the University of Crete. For 13 weeks, students were introduced to the main Scratch concepts and, afterward, were asked to prepare their projects. For the projects, they were required to design their own interactive stories to teach certain concepts about mathematics or physical science to preschool-age students. The results we obtained were more satisfactory than expected and, in some regards, encouraging if one considers the fact that the research participants had no prior experiences with computational thinking.",book:{id:"6936",slug:"early-childhood-education",title:"Early Childhood Education",fullTitle:"Early Childhood Education"},signatures:"Stamatios Papadakis and Michail Kalogiannakis",authors:null}],mostDownloadedChaptersLast30Days:[{id:"58060",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8743,totalCrossrefCites:15,totalDimensionsCites:21,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"61746",title:"Facilitation of Teachers’ Professional Development through Principals’ Instructional Supervision and Teachers’ Knowledge- Management Behaviors",slug:"facilitation-of-teachers-professional-development-through-principals-instructional-supervision-and-t",totalDownloads:3349,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"With the rise of global competition and the focus on teacher quality, teacher professional development is becoming increasingly crucial, and the stress and challenges for principals are more severe than ever. Teachers can improve their professional abilities through principals’ instructional supervision and their own knowledge-management (KM) behaviors to benefit students. Thus, this chapter analyzes the relationship among principals’ instructional supervision, teachers’ KM, and teachers’ professional development. The author believes that principals’ instructional supervision and effective KM can facilitate the professional development of teachers. The author also believes the readers can know the relationships among them, and teachers’ professional development can be improved through principal’s instructional supervision and teachers’ KM behaviors.",book:{id:"6674",slug:"contemporary-pedagogies-in-teacher-education-and-development",title:"Contemporary Pedagogies in Teacher Education and Development",fullTitle:"Contemporary Pedagogies in Teacher Education and Development"},signatures:"Chien-Chin Chen",authors:[{id:"232569",title:"Ph.D.",name:"Chien Chih",middleName:null,surname:"Chen",slug:"chien-chih-chen",fullName:"Chien Chih Chen"}]},{id:"75908",title:"From the Classroom into Virtual Learning Environments: Essential Knowledge, Competences, Skills and Pedagogical Strategies for the 21st Century Teacher Education in Kenya",slug:"from-the-classroom-into-virtual-learning-environments-essential-knowledge-competences-skills-and-ped",totalDownloads:501,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"As teachers in Kenya begin to migrate from the classroom to virtual learning spaces following COVID 19 pandemic, there is pressing need to realign Teacher Education to requisite Knowledge, competences, skills, and attitudes that will support online teaching. This chapter explores these needs using a combination of lived experiences and literature review that captured a meta-analysis of research trends on e-learning. While trends in Teacher Education indicate progression towards adoption of technology, there are disparities between the theory and practice. Evidence from recent research and reports; and the recollected experiences confirmed knowledge, competence, skills and pedagogical gaps in the implementation of online learning, that have been exacerbated by COVID-19. The researcher recommends that teacher education should sensitize and train teacher trainees on how to access, analyze and use new knowledge emerging with technology; they also should be coached on how learners learn with technology and on fundamentals of the communication process. Particularly the course on educational technology, should focus on how to create and manage online courses. The 5-stage E-Moderator Model and Universal Design for Learning (UDL) are recommended as effective pedagogical scaffold for online teaching.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Catherine Adhiambo Amimo",authors:[{id:"333482",title:"Dr.",name:"Catherine Adhiambo",middleName:null,surname:"Amimo",slug:"catherine-adhiambo-amimo",fullName:"Catherine Adhiambo Amimo"}]},{id:"75224",title:"Decoding the Digital Gap in Teacher Education: Three Perspectives across the Globe",slug:"decoding-the-digital-gap-in-teacher-education-three-perspectives-across-the-globe",totalDownloads:552,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"Educational use of technology is regularly assessed, and results often show a gap between educational policies and what is actually practiced. This chapter will help clarify how teacher educators experience the changing educational contexts due to the digital revolution, how their meaning-making shifts, and how outside forces influence those processes. The results are based on comparative international studies. Central for this study is practitioners’ professional digital competence, their attitudes towards digital technology and the use of digital technology in education. We found that the influence and contribution of digital practice is carried out quite differently across the globe. Our research questions were: How do practitioners experience teaching in a rapidly changing context? How do attitudes change due to top-down governing of education? and What motivates teacher educators to implement digital technology?",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Steinar Thorvaldsen and Siri Sollied Madsen",authors:[{id:"332624",title:"Associate Prof.",name:"Siri Sollied",middleName:null,surname:"Madsen",slug:"siri-sollied-madsen",fullName:"Siri Sollied Madsen"},{id:"332626",title:"Prof.",name:"Steinar",middleName:null,surname:"Thorvaldsen",slug:"steinar-thorvaldsen",fullName:"Steinar Thorvaldsen"}]},{id:"75416",title:"Self-Study Research: Challenges and Opportunities in Teacher Education",slug:"self-study-research-challenges-and-opportunities-in-teacher-education",totalDownloads:724,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This article aims to describe what self-study research is, why self-study can be a good approach to teacher educators’ professional development and improvements in practice and highlight some challenges and opportunities in this research approach. In addition, the article will shed light on some methodological aspects related to self-study. Self-study refers to teacher educators who in an intentionally and systematically way examine their practice to improve it, based on a deeper understanding of practice, as well as the context practice takes place. In the article, I argue that engaging in self-study is a learning and development process and an approach to developing personal professionalism, collective professionalism and improvements in practice.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Kåre Hauge",authors:[{id:"332053",title:"Associate Prof.",name:"Kåre",middleName:null,surname:"Hauge",slug:"kare-hauge",fullName:"Kåre Hauge"}]}],onlineFirstChaptersFilter:{topicId:"265",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81937",title:"Socialization Experiences among Undergraduate Students in Higher Learning Institutions (HLI)",slug:"socialization-experiences-among-undergraduate-students-in-higher-learning-institutions-hli-",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.99007",abstract:"This work portrays the problems of socialization among undergraduate students in higher learning institutions. The socialization processes in higher learning institution are significant for the successful navigation of students in the academic programs and university environment in preparing the next generation of professional practitioners and scholars. But the undergraduate student socialization experiences of students at university environment are overlooked. To navigate in the higher learning institutions, students should be socialized effectively to the normative contexts of the higher learning institutions. The normative contexts of the higher learning institutions are generally categorized into social and academic contexts, because these context academic and social context integration have been linked to student retention and success. Social integration involves interpersonal relationships, support, interactions with others, and a sense of belonging at a university, which stems from extracurricular activities, informal dealings with peer groups, and interactions with faculty and staff, whereas academic integration is described through grade performance and intellectual development that reflects an ability to meet the standards of the academic system; intellectual development involves a student valuing their education as a process of development in which they gain knowledge and ideas. Students’ background is also the contributing factor for students’ socialization in the University.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Mulusew Birhanu Ayalew"},{id:"80280",title:"Adoption of Online Learning during the Covid19 Pandemic Lockdown by Universities in Garowe",slug:"adoption-of-online-learning-during-the-covid19-pandemic-lockdown-by-universities-in-garowe",totalDownloads:88,totalDimensionsCites:0,doi:"10.5772/intechopen.99941",abstract:"In response to the Covid-19 outbreak the world closed and therefore countries like Somalia have not been exceptional. The government of Somalia and all higher education institutions adopted crisis intervention measures on implementation of blended learning approaches like online teaching and learning. In this chapter we explore the process and challenges of adopting online learning in response to the world wide lockdown due to the pandemic. Given that this was an abrupt requirement, the survey was interested in finding out whether universities adopted and adapted easily. Researchers compared findings from previous studies and theoretical inclinations on online learning. Results indicate that the adoption of online learning among universities in Garowe was as a matter of crisis management whereby administration, lecturers and students were all not ready and had no prior grounding in this pedagogical learning platform. Just like previous studies online learning implementers have continued to encounter several challenges like intermittent internet network, cost of gadgets and facilities, inadequate skills of both the instructors and students, aspects of communication and satisfaction from stakeholders. With the research survey in Garowe, results show that this is still pervading and therefore need for more rigorous contextualised research on this subject.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Tumwebaze Alicon Auf and Omer Abdi Hamdi"},{id:"78597",title:"Public-Private Participation in Funding University Education in Sub-Saharan Africa: A Nigerian Case-Study for Sustainable Development",slug:"public-private-participation-in-funding-university-education-in-sub-saharan-africa-a-nigerian-case-s",totalDownloads:134,totalDimensionsCites:0,doi:"10.5772/intechopen.99940",abstract:"The developing countries in Africa still cannot withstand the pressure of the highly competitive global education market. Together with the large numbers of people who make a living in various innovative companies, these countries have solved key contemporary issues affecting global education. For this reason, it is necessary to actively respond to current technological innovation and educational challenges and to eliminate new technology graduates who can effectively interact with students through the responsive expansion of education and training. Expansion of education can produce effective expansion that promotes educational development, but due to budget constraints, most African governments cannot successfully and sustainably implement such educational programs. This is difficult. However, public-private partnership efforts provide a way out of this financial dilemma. The Sub-Saharan Africa initiative has achieved important educational objectives, such as: ensuring relevance for quality; secure funding for sustainability and establish resource mobilization partnerships and connections; and promote international cooperation. This discussion is relevant to the basic conditions for a successful public-private partnership with educational institutions and extended education and sheds light on the impact, lessons, and challenges. The public is increasingly concerned about the importance of higher education in the 21st century. This chapter explores some of the key functions of an innovative education system that supports the development of education in Nigeria and enhances people’s ability to use information. Nigeria’s education system re-emphasizes the importance of public and private universities, but the country does not have a sustainable education system and well-equipped educational institutions to support people’s ability to use information, learning, education, and research activities.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Lawrence Jones-Esan"},{id:"79197",title:"University Teachers’ Conceptions of What University Is: Implications for the Future of Higher Education",slug:"university-teachers-conceptions-of-what-university-is-implications-for-the-future-of-higher-educatio",totalDownloads:107,totalDimensionsCites:0,doi:"10.5772/intechopen.100813",abstract:"This chapter presents the perception of university teachers about the university, the most recent changes and how they have influenced their activity. The phenomenographic study was conducted with 10 university teachers, nine females and one male with more than 15 years of professional activity. The perception of the university emerges, in the teachers’ voice, focused on the description of its mission, namely as a context for the production and diffusion of knowledge to society, as a space for creative and critical thinking about the world, as an interdisciplinary space and as a system focused on teaching and research. It also includes characteristics related to its structure and functioning, such as the level of hierarchization, bureaucratization, competitiveness, dehumanization and bibliometrics overvaluation. Regarding the perceived changes, they are related to the structural reforms resulting from the Bologna Process, diverse student populations, research and internationalization, new technologies, institutional cooperation, bureaucratization and relationship with the community. Teachers also revealed some dissatisfaction in the way they are experiencing university life due to the overwork resulting from the multiple tasks required in the four activity strands (teaching, research, management and extension) with an impact on quality and innovation, but in line with what the institution demands.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Elisa Chaleta"},{id:"78595",title:"Globalization and Education: Trends towards Sustainability",slug:"globalization-and-education-trends-towards-sustainability",totalDownloads:58,totalDimensionsCites:0,doi:"10.5772/intechopen.99974",abstract:"Higher Education Institutions (IES) have a very relevant role in the path towards sustainability. The problem of the implementation of curricular sustainability is the disparity of solutions that can be adopted depending on the political and economic situation of each country. The study of a practical case in the south of Honduras allows the student to approach key decisions in a real scenario to bring improvements to a very disadvantaged population, lacking basic services, such as water and electricity, under the premise of sustainability, facing aspects as relevant such as sustainable mobility, water resources management, energy and construction models, in a context where globalization and technological innovation play a very important role. It is essential to know in depth the real context where structural changes will be applied to understand that there is no single reality, that actions are built adapting to specific situations and that the effectiveness of the measures that can be adopted to establish models that prioritize that part of sustainability that best weighs the balance between the environment, society and the economy for each case.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Maria Olga Bernaldo and Gonzalo Fernandez-Sanchez"},{id:"79255",title:"Higher Education Institutions (HEIs) in Africa Embracing the “New Normal” for Knowledge Production and Innovation: Barriers, Realities, and Possibilities",slug:"higher-education-institutions-heis-in-africa-embracing-the-new-normal-for-knowledge-production-and-i",totalDownloads:128,totalDimensionsCites:1,doi:"10.5772/intechopen.101063",abstract:"If Africa is to remain relevant and competitive in today’s knowledge-based economy, it has to rely on higher education institutions (HEIs) as centers of excellence for knowledge production. HEIs nurture and sustain the production of highly-skilled individuals to support Africa’s growing economies. Among all possible ways, this could be achievable through strategic curricula innovation driven by emerging mobile technologies. Consequently, Africa’s HEIs need to embrace the ‘New Normal’ by optimizing online teaching and learning in their pursuit to expand information and communications technology (ICT) literacy as a means to increase students’ opportunities in higher education (HE). However, Africa’s ability to embrace the ‘New Normal’ has been marred by inadequate ICT infrastructures, low connectivity, unreliable power supply, and national budget constraints that may undermine Africa’s HEIs’ potential to augment knowledge production and innovation.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Christopher B. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:45,paginationItems:[{id:"82135",title:"Carotenoids in Cassava (Manihot esculenta Crantz)",doi:"10.5772/intechopen.105210",signatures:"Lovina I. Udoh, Josephine U. Agogbua, Eberechi R. Keyagha and Itorobong I. 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Serves as a peer reviewer for biomedical journals. Military Reserve Officer serving with the 100 Support Command, 100 Troop Command, 40 Infantry Division, CA National Guard.",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"6925",title:"Endoplasmic Reticulum",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6925.jpg",slug:"endoplasmic-reticulum",publishedDate:"April 17th 2019",editedByType:"Edited by",bookSignature:"Angel Català",hash:"a9e90d2dbdbc46128dfe7dac9f87c6b4",volumeInSeries:2,fullTitle:"Endoplasmic Reticulum",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}]},{type:"book",id:"6924",title:"Adenosine Triphosphate in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6924.jpg",slug:"adenosine-triphosphate-in-health-and-disease",publishedDate:"April 24th 2019",editedByType:"Edited by",bookSignature:"Gyula Mozsik",hash:"04106c232a3c68fec07ba7cf00d2522d",volumeInSeries:3,fullTitle:"Adenosine Triphosphate in Health and Disease",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. 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He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN), Kuala Lumpur from 2002 until 2005. He then completed his Fellowship in Cardiothoracic Surgery at Monash Health, Melbourne, Australia in 2008. He has served in the Malaysian army as a Medical Officer with the rank of Captain upon completing his Internship before joining USM as a trainee lecturer. He is now serving as an academic and researcher at Monash University Malaysia. He is a life-member of the Malaysian Association of Thoracic & Cardiovascular Surgery (MATCVS) and a committee member of the MATCVS Database. He is also a life-member of the College of Surgeons, Academy of Medicine of Malaysia; a life-member of Malaysian Medical Association (MMA), and a life-member of Islamic Medical Association of Malaysia (IMAM). Recently he was appointed as an Interim Chairperson of Examination & Assessment Subcommittee of the UiTM-IJN Cardiothoracic Surgery Postgraduate Program. As an academic, he has published numerous research papers and book chapters. He has also been appointed to review many scientific manuscripts by established journals such as the British Medical Journal (BMJ). He has presented his research works at numerous local and international conferences such as the European Association for Cardiothoracic Surgery (EACTS) and the European Society of Cardiovascular Surgery (ESCVS), to name a few. He has also won many awards for his research presentations at meetings and conferences like the prestigious International Invention, Innovation & Technology Exhibition (ITEX); Design, Research and Innovation Exhibition, the National Conference on Medical Sciences and the Annual Scientific Meetings of the Malaysian Association for Thoracic and Cardiovascular Surgery. He was awarded the Darjah Setia Pangkuan Negeri (DSPN) by the Governor of Penang in July, 2015.",institutionString:null,institution:{name:"Monash University Malaysia",country:{name:"Malaysia"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",fullName:"Abdulsamed Kükürt",profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",institutionString:null,institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}},{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/320603",hash:"",query:{},params:{id:"320603"},fullPath:"/profiles/320603",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()