Target protein related to nCoV-19, SARS-CoV and MERS-CoV and possible drug proposed for prevention (data taken from reference [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51]).
\r\n\tThe book aims to provide useful information to electrical engineers, system engineers, communication engineers, mechanical engineers and researchers.
",isbn:"978-1-83968-337-4",printIsbn:"978-1-83968-336-7",pdfIsbn:"978-1-83968-338-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"1de858f7edccd1bfc9374d96bd867aa1",bookSignature:"Dr. Albert Sabban",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10508.jpg",keywords:"UWB Systems Development, Electronic Devices, Communication Systems, Fabrication Technologies, Fabrication Cost, UWB Integration, Analysis Methods, Computer-Aided Design, UWB Filter, UWB Radar, UWB Imaging, UWB Location Tracking",numberOfDownloads:202,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 6th 2020",dateEndSecondStepPublish:"July 27th 2020",dateEndThirdStepPublish:"September 25th 2020",dateEndFourthStepPublish:"December 14th 2020",dateEndFifthStepPublish:"February 12th 2021",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in wideband communication systems, wearable communication systems, WBAN systems, antennas, editor of three books, author of five books, IEEE senior member and holder of registered patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"16889",title:"Dr.",name:"Albert",middleName:null,surname:"Sabban",slug:"albert-sabban",fullName:"Albert Sabban",profilePictureURL:"https://mts.intechopen.com/storage/users/16889/images/system/16889.jpeg",biography:"Dr. Albert Sabban holds a Ph.D. in Electrical Engineering from the Faculty of Electrical and Computer Engineering, University of Colorado at Boulder, USA (1991), and an MBA from the Faculty of Management, Haifa University, Israel (2005). He is currently a Senior Lecturer and researcher at the Department of Electrical and Electronic Engineering at Kinneret and Ort Braude Engineering Colleges. From 2007 to 2010, Albert Sabban was an RF and Antenna specialist at biomedical hi-tech companies where he designed wearable compact systems and antennas for medical systems. In 1976 he joined RAFAEL in Israel where he worked as a senior researcher, group leader, and project leader in the electromagnetic department until 2007. From 2008 to 2010 he worked as a RF Specialist and project leader at hi-tech biomedical companies. He has published over 100 research papers and holds a patent in the antenna area. He wrote four books on wearable compact systems and antennas for communication and medical systems. He wrote a book on electromagnetics and microwave theory for graduate students, and a book on wide band microwave technologies for communication and medical applications. 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Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"9882",title:"Advanced Radio Frequency Antennas for Modern Communication and Medical Systems",subtitle:null,isOpenForSubmission:!1,hash:"e7860667e982eca635e65b494680a598",slug:"advanced-radio-frequency-antennas-for-modern-communication-and-medical-systems",bookSignature:"Albert Sabban",coverURL:"https://cdn.intechopen.com/books/images_new/9882.jpg",editedByType:"Edited by",editors:[{id:"16889",title:"Dr.",name:"Albert",surname:"Sabban",slug:"albert-sabban",fullName:"Albert Sabban"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9271",title:"Innovation in Global Green Technologies 2020",subtitle:null,isOpenForSubmission:!1,hash:"2b283802db94fab806ba5ffc1d48bb5b",slug:"innovation-in-global-green-technologies-2020",bookSignature:"Albert Sabban",coverURL:"https://cdn.intechopen.com/books/images_new/9271.jpg",editedByType:"Edited by",editors:[{id:"16889",title:"Dr.",name:"Albert",surname:"Sabban",slug:"albert-sabban",fullName:"Albert Sabban"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"67039",title:"The Microvine: A Versatile Plant Model to Boost Grapevine Studies in Physiology and Genetics",doi:"10.5772/intechopen.86166",slug:"the-microvine-a-versatile-plant-model-to-boost-grapevine-studies-in-physiology-and-genetics",body:'\nAs a perennial fruit crop, the grapevine (Vitis vinifera) needs a long juvenile period before the reproductive cycle starts. Even vine cuttings from adult plants allow the production of fruits only from the second year. Moreover, during the adult phase, common cultivars produce reproductive organs only once per growing cycle (generally once per year) and per proleptic axis. These biological features, together with the large size of an adult vine, represent major drawbacks for precise physiological, ecophysiological, and omics experiments on the plant and fruit development under well-controlled conditions. Furthermore, those characteristics of normal vines slow down advances in genetics and breeding.
\nThe microvine ML1 is a somatic variant obtained though somatic embryogenesis from Pinot Meunier cultivar. This phenotype results from a somatic mutation in the Vvgai1 gene involved in gibberellin signaling. The mutation is originally present at the heterozygous state in the epidermal cells of Pinot Meunier, being responsible for its well-known hairy phenotype. However, the introduction of the mutation in all cell layers resulted in a miniaturization of all vegetative organs and in a conversion of tendrils into inflorescences, which leads to a continuous flowering and fruiting along vegetative axes.
\nThe small size of the microvine renders this grapevine model very convenient for experiments in usual growth chambers, where a tight control of environmental factors (radiation, vapor pressure deficit (VPD), temperature, water and nutrient supplies) is possible, in contrast with experiments under vineyard conditions. Indeed, it is possible to grow the vines up to densities of 15–30 plants/m2 and to limit their height to 1.2 m. Under such conditions, the most advanced fruits are mature 5–6 months after plantation of cuttings or seedlings, and the vegetative axis displays all developmental stages from young inflorescences (distal phytomers) to flowering, berry growth, and ripening (proximal phytomers). Under stable controlled conditions, the spatial gradients of vegetative and reproductive development of the microvine mimic well the temporal development of each phytomer, which allows to infer kinetic data from one-off spatial information along the proleptic axis.
\nIn controlled conditions, microvine allows to experiment on berry development all year long, which greatly accelerates studies on physiology and molecular biology. Furthermore, by reducing the time lag between two generations and by increasing the precision of phenotyping, genetic approaches are much more efficient than the ones generally performed with macrovines. In the first section of the paper, we describe the genetic and molecular mechanisms underlying the phenotypes of the microvine and derived lines. Then, we review typical experimental designs that can be designed with the microvine. In the last section, we review recent project using this model to study grapevine development and fruit physiology and to identify quantitative trait loci (QTLs) of agronomic traits.
\nThe meristem of higher plants is organized in several cell layers. The outermost, which corresponds to epidermal cells, results from anticlinal divisions (i.e., following a plane of division perpendicular to the surface). This tissue which covers all the organs of the shoot system develops as a single cell layer [1]. Underneath, a multicellular zone, called L2 cell layer, is at the origin of all subepidermal tissues, following multidirectional divisions (i.e., primary structures but also lateral meristems, vascular cambium, phellogen, and their derivative tissues). No further, deeper cell layer (L3 cell layer), which forms in some species the core of shoot organs (pith), has been clearly identified in the grapevine yet [2].
\nIn general, these cell lines that derive from initial cells located at the tip of the apical dome do not mix, unless there is an accident during cells multiplication. The organization in L1 and L2 cell layers is found in the various organs that derive from the shoot apical meristem (SAM) and in particular in the axillary meristems at the origin of caulinar organs. Because a somatic mutation is initially a single cellular event, it leads to the setting of chimeric tissues or organs, i.e., composed of cells of different genotypes and potentially displaying some phenotypic diversity [2]. When a somatic mutation appears laterally to a meristem, changes can only be distributed in the sector of the mutated organ. If the mutation occurs in an initial cell of a meristem, it can spread to all the tissues derived from the mutated cell. The resulting structure is a chimeric and periclinal genotype, i.e., including cell layers that are not all genetically identical. Periclinal chimeras can be stabilized by vegetative propagation, i.e., by cuttings or by grafting.
\nA somatic mutation can invade all the cell layers and spread uniformly to all derivative tissues, provided that the three following conditions are fulfilled: (i) the mutation is not lethal for the plant, (ii) the mutation appears in an initial cell within a meristem, and (iii) the mutation is established, by cell substitution in both L1 and L2 cell layers [2]. The probability of simultaneous occurrence of these three conditions being very low, most of the mutations therefore develop sectorially or periclinally and give rise to chimeric tissues and organs.
\nIn the 1990s, thanks to the use of codominant genetic markers (microsatellites, RFLP), the existence of genetic chimerism has been demonstrated in several vine varieties. As such, Franks et al. [3] showed that Pinot Meunier can display up to three alleles for some loci, whereas a vine, having a diploid genome, can theoretically only show one allelic form per homozygous locus and two allelic forms for a heterozygous locus. Boss and Thomas [4] were able to de-chimerise Pinot Meunier by somatic embryogenesis. They characterized the resulting L1 and L2 genotypes and studied the associated phenotypes. This work showed that Pinot Meunier carries a mutation in VvGAI1 gene in the L1 layer which confers the hairy phenotype to the variety (Figure 1).
\nGenetic structures of pinot noir and pinot Meunier and their respective apex phenotypes. Pinot Meunier is a somatic variant of pinot noir, which carries the mutation (Vvgai1) at heterozygous status. Localized in the epidermal cells (L1 cell layer), the mutation exacerbates the hairiness of vegetative organs of this variety (http://plantgrape.plantnet-project.org/en), without any other significant phenotypic change.
Plants regenerated from L1 or L2 cells exhibited very different phenotypes. The plants obtained from the deepest cell layer (L2) no longer had a mutation at VvGAI1 locus and presented phenotypic traits very close to Pinot Noir. Conversely, the plants derived from L1 cells that retained a mutated version of Vvgai1 associated with a wild-type allele VvGAI1 were dwarf and hairy and displayed a full conversion of all tendrils into inflorescences (Figure 2). This phenotype has been called microvine, due to the small size of the mutant.
\nBy somatic embryogenesis from anthers of pinot Meunier, it is possible to obtain two types of plants. One, which no longer carries the mutation of VvGAI in the L1 and L2 cell layers, has a phenotype similar to pinot noir (large size, juvenility period, main production of clusters from proleptic axes, i.e., winter buds). The other, which carries the mutation of VvGAI in all the tissues, displays a miniaturized phenotype and extreme hairiness and produces inflorescences both in the winter buds and from the conversion of tendrils in inflorescences. In the figure, the numbers associated with VvGAI allele correspond to the nucleotide base length (bp) of the VVS2 microsatellite marker [4].
Thus, the microvine has the Vvgai1 mutation present in both cell layers that confers a very different phenotype from the Pinot Meunier from which it derives and which only bears the mutation in the L1 cell layer. Another interesting feature is related to the genetic status of the mutation in the microvine. Although it is present in both cell layers, the VvGAI locus is heterozygous, i.e., each cell is carrying a mutated allele Vvgai1 is associated with a wild-type allele VvGAI1. Because Vvgai1 is not a lethal mutation nor for the sporophyte or the gametophyte, this status can be rearranged by selfing in three genotypes:
Homozygous VvGAI1/VvGAI1, which corresponds to a vine without any mutation at the locus. The phenotype associated with this genetic status is non-dwarf, similar to classical macrovine varieties.
Heterozygote VvGAI1/Vvgai, which corresponds to the same genotype and (dwarf) phenotype than the original microvine ML1.
Homozygotous Vvgai1/Vvgai1, which corresponds to plants carrying both alleles in a mutated version. The phenotype associated with this status, called picovine, corresponds to an extreme dwarfism, with plants displaying very miniaturized shoot organs [4] (Figure 3).
The three genotypes/phenotypes that can be obtained by selfing from the microvine (VvGAI1/Vvgai1): left, extremely miniaturized vines that carries the homozygous locus Vvgai1/Vvgai1, called picovines; middle, individuals with the same phenotype as the microvine, heterozygous for the mutation (VvGAI1/Vvgai1); and right, normal-sized plants that no longer carry mutated alleles, homozygous for the non-mutated form of the gene (VvGAI1/VvGAI1).
Another interesting feature, linked to the heterozygous status VvGAI/Vvgai1, is the possibility to return to non-dwarf phenotype. Indeed, by crossing a microvine (VvGAI1/Vvgai1) with a classic grapevine variety, i.e., a macrovine (VvGAI1/VvGAI1), it is possible to recover 50% of individuals with a microvine phenotype and 50% of individuals with the characteristics of a non-dwarf grapevine.
\nThe comparison of the allelic VvGAI forms present in Pinot Meunier and the microvine [4, 5] showed that the mutation corresponds to a modification of a single nucleotide in the DELLA motif of the protein, which is important for gibberellin signaling.
\nAfter transient transformation of epidermal onion cells, green fluorescent protein (GFP) fusions to VvGAI1 and Vvgai1 sequences responded differently to gibberellin applications. The GFP signal of the GAI1::GFP fusion disappears rapidly from the nucleus under the effect of gibberellins, which indicates its degradation following the hormonal stimulus. On the contrary, the gai1::GFP translational protein fusion remains insensitive to hormonal signaling, which indicates that the mutation in the DELLA motif abolishes the property of the protein to be degraded when triggered by gibberellins [5].
\nThe GAI gene is known to be an important regulator of vegetative growth and reproductive development [6]. In grapevine, gibberellins, produced under shade, stimulate growth and inhibit the formation of inflorescences [7]. This effect is mediated by the nuclear protein GAI1, which, in its mutated form gai1, no longer transmits the hormonal signaling [5]. Thus, vegetative growth and the inhibition of the conversion of tendrils into inflorescences are no longer maintained which explains the dwarf phenotype and the continuous fructification along the stems. The characterization of the expression profiles of different isogenes of VvGAI revealed that Vvgai1 is mainly expressed in vegetative organs such as buds and young leaves, while other forms are expressed in reproductive organs (unpublished data). For instance, Vvgai2, which does not have any mutation in the DELLA protein motif, is expressed in reproductive organs from flowering to ripening [5]. This explains why Vvgai1 mutation does not interfere directly with berry developmental program which is similar to non-dwarf varieties.
\nSeveral experiments have been conducted outdoor and in controlled environments to characterize the vegetative development of the proleptic axis of the microvine [8]. Different day/night temperature treatments were applied (22/12, 25/15, 30/15, 30/20, 30/25°C), while VPD was maintained constant (about 1 kPa). These experiments showed that the vegetative organogenesis rhythm of the microvine is similar to that of non-dwarf vines. Indeed, its phyllochron (leaf emission rate) is around 24°C, similarly to other varieties of V. vinifera such as Grenache [10], and it fluctuates only slightly with temperature and radiation variations between experiments (photosynthetically active radiation (PAR) has been experimented from 19 to 25 mol.m−2d−1).
\nThe duration of leaf and internode growth of the microvine is also similar to that of non-dwarf vines, lasting ca. 220°C (i.e., 20 days at 25/15°C) for leaves and ca. 150°C (i.e., 14 days under the same conditions) for internodes [9, 10]. The most significant phenotypic difference, induced by Vvgai1, is the size limitation of vegetative organs. The leaf area is reduced by half in the microvine compared to non-dwarf vines, and internodes are five times shorter. The dwarf phenotype is thus very valuable to conduct experiments under very well-controlled conditions in small growth chambers. Such property permits to study the impacts of single or combined abiotic factors (radiation, temperature, VPD, CO2) on plant growth and development while minimizing uncontrolled biases arising from environmental fluctuation in field studies on perennial vines.
\nHowever, the shortening of the internodes increases leaf shading and promotes the development of fungal diseases as compared to non-dwarf vine. The control of powdery mildew (Erysiphe necator) on leaves and green berries or gray mold (Botrytis) on ripening fruits requires a strict phytosanitary management. To improve the microclimate of the clusters, it is recommended to systematically remove the lateral branches to reduce the plant to a single proleptic axis and to systematically eliminate one leaf out of three, e.g., removing the leaves of all P0 phytomers which do not bear any inflorescence. Also, for the most fertile lines, it is necessary to control the number of ripening berries to avoid source/sink unbalance that could be prejudicial to the growth and the formation of new inflorescences as well as the accumulation of metabolites in the fruits. Because the microvine displays several levels of cluster at ripening stages, a good balance is achieved by limiting the number of ripening berries to 8–15 per cluster.
\nThe reproductive development of the microvine is divided into two distinct and simultaneously occurring patterns: (i) the fructification of proleptic shoots from preformed inflorescence primordia within winter buds and (ii) the continuous fruiting of proleptic and sylleptic axes resulting from the conversion of tendrils into inflorescences.
\nIn the grapevine, as for many other perennial fruit crops, fruit formation occurs during 2 consecutive years. The first step starts with the initiation and differentiation of inflorescence primordia in the winter buds prior to endo-dormancy until approximately the end of summer or beginning of autumn. During the subsequent cycle after the break of dormancy, approximately 2 weeks before budburst, the inflorescences resume their development and complete flower organogenesis and subsequently flowering in spring [6]. The level of differentiation of microvine winter buds (i.e., the number of preformed phytomers and inflorescence primordia) was analyzed during 80 days of growth under controlled environmental conditions (25/15°C day/night temperature, VPD 1 kPa, photoperiod 12 h). Two imaging methods were compared, the classic microscopy dissection and the noninvasive X-ray micro-tomography [11], with a resolution of 9 𝝁m. These observations showed that winter buds of the microvine harbor a complex formed of primary, secondary, and tertiary buds of decreasing fertility, as non-dwarf vines [12]. The maximum fertility of the primary buds is two inflorescences in the microvine, whereas it can reach three or even four in some non-dwarf varieties. These inflorescences are inserted into phytomers n°4 to n°6 with an acropetal development as for macrovines [12, 13]. The lignification of the stem which develops from the vegetative axis base is concomitant with the slowdown of bud development and probably its entry into endo-dormancy, similarly as for non-dwarf vines [14].
\nThe microvine has the particularity to develop inflorescences from tendrils along proleptic and sylleptic axes (Figure 4), which result in a continuous flowering and fruiting processes. A gradient of reproductive development stages is thus present simultaneously along the proleptic axis from the differentiation of inflorescences until maturity. This characteristic offers the opportunity to evaluate abiotic or biotic stress impacts on all reproductive stages of development along the proleptic axis simultaneously.
\nVegetative and reproductive development of the ML1 somaclone n°7, a microvine line regenerated from pinot Meunier cl. ENTAV 8 according to the method described by Torregrosa [15]. Top left, longitudinal section of an apex showing the preformation of 7–9 phytomers before emergence of caulinar organs. Upper middle, emergence of young inflorescences just below the apex. We note the very hairy appearance of the apex of the microvine ML1. On the middle, an 8-month-old ML1 microvine displaying all the sequences of the reproductive development from flowering to fruit ripening. Bottom left, a focus on the phytomers carrying bunches shifting from green to ripening stages and the concomitant lignification of the shoot (leaves have been removed for the clearness of the photograph). Top right, section of a winter bud analyzed by tomography. Bottom right, a longitudinal section of a winter bud exhibiting a lateral inflorescence primordium (IP) on the primary bud axis and a secondary preformed vegetative axis on the left side.
Top right, section of a winter bud analyzed by tomography. Bottom right, a longitudinal section of a winter bud exhibiting a lateral inflorescence primordium (IP) on the primary bud axis and a secondary preformed vegetative axis on the left side.
\nThe synchronism between vegetative development and fruiting of the microvine also simplifies the study of their interactions compared to macrovines. The impact of contrasted source/sink balance on fruiting can be easily studied by manipulating shoot or fruit load (number of growing axes and/or number of leaves/inflorescence per axis). The continuous fruiting was found to be stable under standard environmental conditions (25/15°C day/night temperature, VPD 1 kPa, photoperiod 12 h) and when the leaf area to fruit fresh weight was less than 1 m2.kg−1. On the contrary, the capacity of flowering is strongly altered in the presence of abiotic or biotic stresses. High temperature (> 33°C), low radiation levels (PAR < 15 mol.m−2.j−1), or high VPD (>3 kPa) can induce inflorescences abortion and disrupt the continuity of the reproductive gradient along stem axes. The sensitivity of inflorescence development was found higher when the C reserves (starch) were reduced, in particular, in young plants. Thus, although it is possible to obtain fruiting organs from 5-month-old microvine cuttings, it is advisable to use 1-year-old or older plants that are much less susceptible to inflorescence abortion [16]. In experiments conducted in our lab, we obtained successive cycles of fruiting for at least 5 years without repotting.
\nThe size of inflorescences of microvines is smaller (10–50 berries per cluster in average) than that of macrovines [17, 18, 19]. However, flowers and young fruits of the microvine do not display a very high abscission rate as observed in non-dwarf varieties. The development of flowers and berries is identical to non-dwarf vines. Flowering (50% of open flowers) occurs 320°C GDD (growing degree days) after the phytomer emission (i.e., 30 days at 25/15°C), which is comparable to the duration between budburst and flowering in the non-dwarf vines [18]. Ripening (onset of sugar loading) starts at ca. 500°C GDD (i.e., 47 days at 25/15°C) after flowering, and the physiological ripening (when metabolite loading stops) is reached at ca. 900°C GDD (i.e., 80 days at 25/15°C) after flowering or 30 days after the start of sugar loading. This behavior is similar in macrovines [18, 20]. Thus, berries of the ML1 microvine reach a final individual size of 1.2 g, comparable to that of cv. Pinot meunier, from which this line derives. At physiological ripening, berries contain about 0.8 mmol berry-1 of soluble sugars in non-limiting water supply conditions which is similar to other varieties of V. vinifera (Figure 5).
\nSpatiotemporal distribution of the reproductive developmental stages from flowering to ripening. On the abscissa, the calendar time in DAF (days after flowering) was recalculated for each phytomer converting the corresponding plastochron index in thermal time and inferred in calendar time with the phyllochron. Kinetics of fresh fruit weight and the contents of major primary metabolites and potassium are presented in quantity per fruit unit.
The microvine provides different advantages over non-dwarf vines to speed up or facilitate genetics. Since the mutation is transmissible by hybridization and has a codominant effect, it is possible to cross microvines (VvGAI1/Vvgai1) or picovines (Vvgai1/Vvgai1) with non-dwarf genotypes, i.e., without the mutation (VvGAI1/VvGAI1), to create microvine segregating populations. In the first case, 50% of individuals will display the microvine phenotype, while using picovines as parent, 100% of the progeny exhibit a dwarf behavior.
\nThe VvGAI1 gene is located on chromosome n°1, while the QTL determining grapevine flower sex is located on chromosome n°2. That means both loci segregate independently, and it is therefore possible to use female microvines or picovines, which facilitates crosses by avoiding the time-consuming emasculation and reducing the risk of selfing [19]. On the other hand, when a female microvine (f/f) is crossed with a hermaphrodite genotype (H/f, the most common genotype in V. vinifera varieties), the population will be composed of 50% of female plants and 50% of hermaphroditic plants. For instance, by crossing between the PV00C001V0008 [19] and the fleshless berry mutant of the ugni blanc [21], a range of genotypes and phenotypes can be obtained [5].
\nThis progeny is composed of 100% microvines (since the female parent has a Vvgai1/Vvgai1 genotype) and a very small proportion of individuals with both hermaphrodite flowers and pigmented berries. Indeed, these two characters are present at the homozygous recessive state in one parent (f/f and n/n) and in the heterozygous dominant state in the other (H/f and N/n). It should be noted that since ugni blanc is heterozygous at the sex locus (H/f), while the picovine is f/f, selecting hermaphrodite individuals leads to a segregation distortion in the progeny of the genetic traits determined on the chromosome n°2.
\nAs the microvine produces inflorescences as long as vegetative growth is maintained, it becomes possible to cross all year around without being hampered by seasonality. Under standard thermal and photoperiodic conditions (25/15°C day/night temperature, VPD 1 kPa, photoperiod 12 h), the microvine produces two to three new inflorescences per week, which enables to make hybridizations during long periods in repeating the crosses on the same plants. This also reduces the number of plants required for crosses and therefore experimental space while spreading the hybridization effort over selected and potentially long periods.
\nOne to two months after a cross, it is possible to start harvesting seeds [22] to rescue zygotic embryos, which makes possible to establish a population maintained and amplifiable by micropropagation or microcuttings [23]. After a few micropropagation cycles, in vitro plants can be acclimatized to greenhouse conditions, and the first grapes are obtained within 12 months after the crosses. Thus, in less than a year, it is possible to start the study of the characteristics of the fruits and to proceed to new crossings to recover F2 populations. These speed up genetic mapping studies because it becomes possible to link a genotype and a phenotype in either F1 or F2 progenies in a few months instead of several years when using macrovines [23, 24].
\nMoreover, if a trait can be inherited through such crosses, it is possible to recover non-dwarf phenotypes (GAI1/GAI1) that can be directly proposed as breeding material. Indeed, 50% of the individuals from a cross between a microvine (VvGAI1/Vvgai1) and a macrovine (VvGAI1/VvGAI1) exhibit the same biological properties as conventional non-dwarf varieties. Thus, the microvine can be used both for the identification of QTLs of interest and also to combine or pyramid characters of interest in a pre-breeding perspective.
\nThe biological properties of the microvine are also of great interest for functional genomics [26]. Indeed, grapevine, as other perennial plants, is a difficult plant model to study the genes regulating the development of reproductive organs. The difficulty comes from its long juvenile period, its discontinuous fructification from winter buds, and the handling of large plants. The genetic transformation of classical varieties [28] requires several years to obtain adult plants and study the phenotypes linked to the ectopic expression of candidate genes.
\nWith microvine, starting from embryogenic tissues compatible to Agrobacterium tumefaciens-mediated transformation (Figure 6), it is possible to recover transgenic fruiting plants in less than 1 year [19]. As for classical genetics, it is then easy to derive F2 lines to establish transgenic loci at homozygous state for further studies. In addition, the microvines have a very good aptitude for transformation by Agrobacterium rhizogenes, allowing to obtain transgenic organs stabilizable in axenic culture in a few weeks [25, 29, 30].
\nFrom competent embryogenic tissues (top left), it is possible to regenerate transgenic plants in a few months and obtain reproductive organs in less than a year. This allows the study of the regulation of flower and fruit development within shorter delays than with the non-dwarf vines. On the right, a microvine line V9 overexpressing the gene VvHB was identified as a major regulator of the development of the flesh in grapevine fruit [27]. Using genetically modified microvines, it is possible to segregate the transgenes in different genotypic configurations or combine them with various other transgenic traits or not.
We have tested the possibility of converting spatial observations (along the proleptic axis) into temporal dynamics at a given stage of vegetative or reproductive development.
\nUnder controlled and stable environment (25/15°C day/night temperature, VPD 1 kPa, photoperiod 12 h), the development of the proleptic axis of the microvine is stable. The phyllochron is constant reaching ca. 24°C. The growing dynamics of leaves (surface) and berries (volume) from continuous fructification was found to be constant at a given level of phytomer, regardless of the date of bud break [20]. The growth durations of leaves and berries (herbaceous phase) are ca. 220°C after the emission of the phytomer and 500°C after flowering, respectively, as mentioned in Section 2.2. The development of these organs is also spatially stable: the dynamics of leaf area and berry volumes (herbaceous phase) for all levels of phytomer are superimposed when they are represented as a function of cumulative thermal time after the emission of the corresponding phytomer.
\nBased on these outcomes, the conversion of spatial dynamics of leaf and berry development along the stems into time profiles was tested (Figure 7). For this purpose, the positions of the phytomers along the axis were converted into cumulated thermal time after their emission by multiplying their plastochron index (or rank position from the apex) by the phyllochron. The temporal profiles of leaf area and berry volume (green growth phase) resulting from this spatiotemporal conversion are similar to the real temporal profiles obtained at a given level of phytomer [8, 20, 31]. This property makes it possible to reconstruct temporal dynamics of development from a single spatial observation of the axis at a given stage. The flow of biomass or metabolites within the organs and their responses to environmental constraints were then addressed using those calculated temporal profiles (Section 5.1).
\nConversion of leaf and young berry growth data collected from the position along the microvine main shoot (plastochron index) into cumulated thermal time after phytomer emergence.
The spatiotemporal conversion approach presented above can also be used to characterize the evolution of winter bud development along the proleptic axis of the microvine [12]. Bud development was analyzed on microvines grown under standard environmental conditions (25/15°C day/night temperature, VPD 1 kPa, photoperiod 12 h), as explained in Section 3.2.1. The number of preformed phytomers initiated by primary axes within buds increases linearly as a function of the plastochron index (PI) of the proleptic axis in the non-lignified zone (PI < 25). The temporal dynamics of bud development were calculated from the spatial profiles using the proleptic axis PI x phyllochron. The primary axis of the bud displayed a maximum of six phytomers from IP 25 (lignified zone), i.e., 625°C or 57 days after its initiation (phyllochron of 24°C). A maximum of two inflorescence primordia was observed in this zone. The primordia of the first and second inflorescences, located between the preformed phytomers n°4 and n°6 of the primary axis, were initiated from IP 13 and 26 of the proleptic axis, respectively, corresponding to 325°C (or 30 days) and 650°C (or 60 days) after bud initiation. The timing of inflorescence primordium development in winter buds in non-dwarf vines [32] is similar to our observations on microvines. This pattern of winter bud development parameterized for the microvine can be used to evaluate, and potentially predict, the environmental stress impacts during the season 1 on the fructification potential of the season 2.
\nThe primary characterization of fruit development along a microvine axis showed that the microvine berry displays the two classical growth phases as observed for berries of macrovines [32, 33]. Microvine berry growth and metabolite accumulation were analyzed in details [34]. Ten microvines were grown under controlled conditions in a climatic room (30/22°C day/night temperature, photoperiod 14 h, VPD 1 kPa, PAR 400 mmol.m−2 s−1). Sampling was performed when proximal fruits attained physiological maturity and when maximum berry volume was reached. Sampling of the present reproductive organs from fruit set to maturity was performed at the same time for each plant. Analysis of the main berry compounds (malic acid, tartaric acid, glucose, fructose, proline) has been carried out. To normalize the stages of development between plants, the spatiotemporal conversion described above was applied using the individual phyllochron of each plant.
\nThe data presented in Rienth et al. [35, 36] shows that microvine fruit accumulates malic acid during the green growth stage for about 40 days after fruit set, until it ceases when the lag phase (herbaceous plateau), which separates the two growth phases, is reached. At the end of the herbaceous phase, at the 24 hours lasting véraison phase, the degradation of malic acid is triggered simultaneously with the accumulation of sugars and proline, which is often used as an indicator of ripening. These processes proceed throughout the second growth or ripening phase. With regard to tartaric acid, we found that it is also accumulated only during the first growth phase as for macrovines and that its amount remains quasi-constant during the ripening phase. The slight decreases in tartaric observed during ripening might be attributed either to enhanced tartaric precipitations as shown by Rosti et al. [37] or variations of microenvironment depending on bunche rank. At the end of green growth stage, the two major organic acids represent approximately 500 mEq, which is comparable to the acidity of the fruit of macrovines. The accumulation of sugars, triggered from the veraison, continues until the moment when the phloem unloading is slowed down (maximum volume of the fruit). From this point, the amount of sugars per berry remains constant, but the concentration increases due the loss of berry volume during over-ripening.
\nThe impact of elevated temperature on growth and carbon distribution between vegetative and reproductive organs was investigated. Two contrasting thermal regimes with a difference of 8° C (30/20°C vs. 22/12°C day/night temperature) were imposed during a period of 450°C GDD. The VPD was 1 kPa and the PAR 19 mol.m−2.d−1 for the two thermal regimes. The biomass, size, and carbon contents of the leaves, internodes, and berries were characterized from spatial observations at harvest and converted into temporal profiles according to the method described in Section 4. Only the organs that developed during heat treatments, i.e., vegetative phytomers younger than 450°C GDD at harvest and the reproductive phytomers, which were at pre-flowering stage at the beginning of experiments, were retained for analysis. Luchaire et al. [20, 36] have shown that high temperature accelerates the growth and the accumulation of biomass in vegetative organs (leaves and internodes) in thermal time, at the expense of the accumulation of sugars in internodes and the surface area to mass of the leaves (thinner leaves).
\nUnder high temperature, the growth and accumulation of biomass of the fruit slowed down on a thermal time basis. Sugar loading of proximal phytomers (from the post-flowering stage to onset of heat treatment) was also delayed by ca. 400°C GDD at high temperatures. High temperatures increased inflorescence abortion rate (+ 20%) at pre-flowering stages, concomitantly with the beginning of sugar loading in the proximal clusters ripening [20, 36, 38]. These results suggest that high temperature decouples vegetative and reproductive development, increasing the total biomass of vegetative organs while reducing the accumulation of carbon reserves and hampering continuous fruiting.
\nTranscriptomic studies are difficult to run with macrovines grown outdoor because of the seasonality of fruiting and the day-to-day environment fluctuations. Thus, while transcriptomics is a very common approach today to understand the genetic mechanisms regulating grape development, no work has attempted to describe the circadian evolution of the grape transcriptome. The results published by Rienth et al. [39] were the first for a perennial fleshly fruit that addressed this topic. For this experiment microvines were grown in climatic growth chambers [40] under controlled environments (30/20°C day/night temperature, photoperiod 14 h, VPD 1kPA) for 3 months to encompass a complete reproductive cycle from flowering to ripening. When most proximal grapes reached physiological maturity, berry samples from two green and two ripening developmental stages were collected at different periods of the photo and nyctiperiod, and a whole genome transcriptomic analysis was carried out by Nimblegen® Vitis 12x microarrays.
\nAll genes modulated during the day also showed some variation of expression at night, with 1843 genes that are only regulated at night. The detection of this very large number of specifically regulated genes during the night emphasized the importance of the regulatory mechanisms associated with the nocturnal fruit development. The comparison of differentially modulated transcripts between day and night at different stages showed that circadian regulation was very specific to the stage of development with only nine commonly deregulated genes between day and night at all stages. With respect to activated or deactivated functional categories, genes related to photosynthesis appear strongly repressed at night, in particular in young green berry, and several functional categories related to secondary metabolism (phenylalanine) and abiotic stress have shown strong overexpression at night at all developmental stages.
\nUntil recently, the studies on the effect of temperature on grape development have only been performed using non-dwarf varieties, with the experimental limits associated with this model. Rienth et al. [41, 42] were the first to perform temperature experiments using microvines grown under tightly controlled environmental factors (photoperiod, light intensity, temperature, VPD, water, and mineral supply). This study was carried out with the ML1 microvine applying temperature gradients ranging from 12 to 35°C during 2 h to 4 weeks.
\nA first series of experiments focused on short-term stress effects (2 h, 35°C) of microvine fruits at different stages between green growth and ripening sampled during day and night. Nimblegen® Vitis 12x microarray assays revealed that a large number of genes (5653) respond to the increase in temperature, at all stages of development (Figure 8). Temperature effect was time and mainly development stage specific, with berries close to veraison being the most reactive to temperature elevation, especially for some categories such as anthocyanin synthesis which was specifically heat repressed at this stage. Furthermore, various genes of secondary metabolism (phenylalanine, anthocyanins) are repressed at the veraison, by high temperature with a larger number of genes regulated during the nocturnal phase.
\nSchema of the expression changes induced by temperature elevation for some genes of the central metabolism during the grapevine fruit development.
Long-term thermal stresses (> 30 days) were also experimented using various temperature charts to several stages of grape development, taking into account circadian variations of the transcriptome [41]. In these studies, we used high-throughput transcriptomic analysis through RNA-seq (Illumina technology). A total of 10,788 genes could be detected as a function of stage, temperature regime, and photoperiod. The importance of “heat shock”-type genes with highly variable expression patterns as a function of the duration of the stress, the circadian cycle, and the stage of development of the fruit has been highlighted. The rise in temperature led to an acceleration of fruit growth during the green growth phase. In fruit at the onset of ripening, the temperature increased the respiration of malic acid and delayed the accumulation of sugars and downregulating key genes of the flavonoid pathway. For the first time, a decoupling of sugar accumulation and malic acid respiration during ripening could be observed and related to the change in carbohydrate status of the plant as a function of temperature [9].
\nA number of genes known to display an induction at veraison and thereafter were confirmed in microvines displaying a remarkably stable expression pattern with respect to temperature (SPS1, sucrose phosphate synthase 1; XET, xyloglucanendotransglucosidase; thaumatin; MRIP, ripening-induced protein1-like precursor (proline-rich cell wall). However, other well-known ripening-induced proteins were induced in the cold in green stage (GRIP3/4, grape ripening-induced protein ¾, ethylene-responsive 1B, putative extensin proline-rich, cell wall chitinase). During the long-term low T° treatment, fruit transcriptomic analyses showed an overexpression of key enzymes linked to both glycolysis (PK, pyruvate kinase) and malic acid synthesis (PEPce, phosphoenolpyruvate carboxylase; MDH, malate dehydrogenase). Temperature variation also impacted posttranscriptional regulation mechanism such as the PPCK (phosphoenol pyruvate carboxylase kinase) which is overexpressed under heat. This gene expression pattern confirmed physiological observations of sugar-acid decoupling and suggests that under cool condition, where the plant energetic status is more comfortable due to lower vegetative growth and cellular respiration rate, malic acid respiration, as a supplemental energy source in the fruit, is not compulsory. In cool climate, the allocation of carbon to the fruit can support glycolysis, malate synthesis, and sugar accumulation into the vacuole. Conversely, under hot climate, cytoplasmic sugars could be limiting when the cell starts to accumulate sugar in the vacuole at the onset of ripening. Thus, the malate would be drained from the vacuole to supply energy through respiration and/or through H+/sugar exchange at the tonoplast.
\nAir temperature elevation combined with the shift of all phenological stages to warmer period is causing critical changes on vine yield and grape composition. Plant breeding has the potential to offer new cultivars with stable yield and quality under warmer conditions, but this requires the identification of stable genetic traits. The investigation about the stability of developmental QTLs with regard to abiotic factors is complicated with the non-dwarf varieties, because of its biological properties (long juvenile period, big size of the plants). Most of previous studies were carried out outdoors, in uncontrolled environmental conditions and with a relatively low experimental flow.
\nHouel et al. [25] reported the first experiment performed with microvines, to identify QTLs of vegetative and reproductive development, testing their stability under fluctuating environments. A F1 mapping population consisting of 129 microvines derived from the PV00C001V0008 x ugni blanc fleshless berry mutant was genotyped using an Illumina® 18 K SNPs chip (single-nucleotide polymorphism). Forty-three vegetative and reproductive traits were phenotyped over four vegetative cycles in the field, and a subset of 22 characters were measured over two climatic chamber culture cycles under two contrasting temperature regimes. Ten stable QTLs were identified for the development and composition of the berry and the leaf area on the parental genetic maps. A new major QTL accounting for up to 44% of variance of the berry weight was identified on the chromosome 7 in the ugni blanc parent. This QTL co-locates with QTLs of number of seeds per berry (accounting for up to 76% of the total variance), QTLs of fruit acidity before maturation (up to 35% of explained variance), and yield components such as the number of clusters and berries per cluster (up to 25% explained variance). In addition, a minor leaf surface QTL was found on the chromosome 4 in the same parent. This study which combined the use of microvine population to boost and facilitate the phenotyping with high-throughput genotyping technologies was innovative in grapevine genetics and also for perennial fruit crops. It allowed the identification of 10 stable QTLs, including the first QTLs of V. vinifera berry acidity detected in an intraspecific cross.
\nThis progeny was also included in a study addressing the diversity for fruit volume, main sugar, and organic acid amounts in V. vinifera [43]. A panel of 33 genotypes, including 12 grapevine varieties and 21 microvine offspring, were characterized. Fruit phenotyping focused on two critical stages of fruit development: the end of green growth phase when organic acidity reaches a maximum and the physiological ripe stage when sugar unloading and water uptake stop. To determine the date of sampling for each critical stage, fruit texture and growth were carefully monitored. Analyses at both stages revealed large phenotypic variation for malic and tartaric acids as well as for sugars and berry size. At ripe stage, fruit fresh weight ranged from 1.04 to 5.25 g and sugar concentration from 751 to 1353 mmol.L−1. The content in organic acids varied both in quantity (from 80 to 361 meq.L−1) and in composition, with malic to tartaric acid ratio ranging from 0.13 to 3.62. At the inter-genotypic level, data showed no link between berry growth and osmoticum accumulation per fruit unit, suggesting that berry water uptake is not only dependent on fruit osmotic potential. The report showed that diversity for berry size, sugar accumulation, and malic to tartaric acid ratio could be exploited through crossbreeding.
\nThese studies which (i) identified genotypes with contrasted fruit composition for compounds controlled by environmental factors and (ii) mapped QTLs of development, including for berry composition, provide interesting prospects to mitigate some adverse effects of climate warming on viticulture.
\nMethoxypyrazines are a family of volatile compounds found in many fruits and vegetables and especially in grapes, providing herbaceous flavors (green capsicum aroma) to the wines of some varieties such as Cabernet Sauvignon or sauvignon blanc. While several methoxypyrazine biosynthetic pathways have been proposed, none of the metabolic steps have been genetically confirmed. Dunlevy et al. [24] used a F2 population derived from a F1 microvine obtained by crossing the Cabernet Sauvignon and a picovine. The Cabernet Sauvignon variety is capable of producing the molecule 3-isobutyl-2-methoxypyrazine (IBMP), the major compound associated with capsicum flavors, while the microvine that derives from Pinot Meunier produces very little amount of this compound. In F1 offspring, all individuals produced IBMP, suggesting a homozygote dominant genotypic status for this trait in Cabernet Sauvignon. The phenotyping of the F2 individuals identified 43 lines able to accumulate IBMP, while 21 individuals lacked this compound confirming the dominant homozygous genotype for Cabernet Sauvignon and the homozygous recessive genotype for picovine progenitor.
\nAfter genotyping and phenotyping, the entire F2 progeny, a 2.3 Mb locus determining IBMP accumulation in grape berries, was found on chromosome n°3. Of the 261 genes identified in the corresponding QTL, two candidate methyltransferase genes have been identified, VvOMT3 and VvOMT4. Screening a collection of 91 grapevine genotypes differentially accumulating IBMP into the grapes indicated VvOMT3 as the most likely candidate to explain the genetic determinism of the green capsicum trait in grapevine fruits. Moreover, the data suggested that the low level of methoxypyrazines found in most cultivated grape varieties resulted from human selection for mutations in methyltransferase. The markers identifying this locus are valuable tools for the selection of grape varieties that are aromatically typified by IBMP and recalling Cabernet wines.
\nThe microvine plant model which displays unique reproductive organ behavior offers new experimental options for grapevine fruit physiological studies, not only because of the size of the plants which facilitate experimental handling in greenhouse or growth cabinet but also because it is possible to study several developmental stages at once. Taking advantage of the biological properties of the microvine, two studies were recently performed to study the impact of exogenous compound application to the ML1 microvine grapes on the aroma accumulation during ripening. The first study was about the impact of vine-shoot aqueous extracts, which have been proposed as bio-stimulants to be sprayed to the canopy to modify wine aromatic profile. Sanchez-Gomez et al. [44] experimented the effect of vine-shoot extract foliar application on the composition of the grapes at 21 stages of development. The application was carried out from BBCH53 (detached inflorescences) to BBCH85 (berry softening) to reveal stage-specific responses of the accumulation of glycosylated aroma precursors at BBCH89 (ripe stage). Fifty grape sampling time points spreading to 86 days were established and normalized using the cumulative growing degree days parameter. The results confirmed that vine-shoot extract treatment had a positive impact on the accumulation of glycosylated compounds [45], especially aglycones such as alcohols, terpenes, and C13-norisoprenoids, with a higher impact when the treatment was applied at grape ripening stage.
\nThe same approach was carried out to characterize the behavior of glycosylated aroma precursors in microvine fruits after foliar application of guaiacol. Previous outdoor experiments have showed that spraying guaiacol on vines could modify the contents of aroma compounds in grape and grape-derived wines. It was shown that such treatments could increase guaiacol glycoconjugates in leaves, shoots, and fruits of Monastrell variety, where there was a release of aglycone compounds during wine processing. However, the effect of such application and its timing on glycosylated aroma precursor pool remained unstudied. Sanchez-Gomez [46] studied the effect of guaiacol sprays when applied at several fruit developmental stages on glycosylated compound accumulation. The applications were carried out from phenological stage BBCH71 (fruit set) to BBCH85 (berry softening), to reveal stage-specific responses of the accumulation of glycosylated aroma precursors at BBCH89 (ripe stage). Data confirmed that guaiacol is an elicitor of the accumulation of glycosylated aromatic compounds in the microvine fruit, with a higher efficiency of application during ripening stages of the fruits. Geraniol, a terpene compound, exhibited the higher increase increment with up to 50-fold high concentration after guaiacol spraying than in the control.
\nThe studies summarized here have shown that at a given phytomer level, the development of the vegetative and reproductive organs of the microvine exhibits comparable kinetics to those of non-dwarf vines grown outdoor. Given its original biological properties (small size, continuous fructification, possibility of inferring temporal observations from spatial data), this model can be used in fundamental studies on vine response to abiotic constraints or on fruit physiology under well-controlled environments. Thus, the microvine has already been used as a model in several scientific experiments on the effect of temperature on the vegetative and reproductive development, on changes in gene expression in grapes, and their plasticity under high temperature. This model has also shown its potential to accelerate conventional and reverse genetic approaches, including the identification of genetic determinants of developmental traits stable under fluctuating thermal conditions or major loci controlling the composition of the grapes. Studies are underway to use this model to study the impact of physical factors (drought, CO2 concentration, temperature, etc.) on the development of the vine and the quality of the grapes but also to develop tools (markers of QTLs, pre-breeding lines pyramiding several agronomic traits of interest) for the selection of new varieties displaying original properties, i.e., traits of adaptation to climate changes.
\nThese studies were supported by fundings from the following agencies or institutions: National Research Agency—Genopole (DURAVITIS project ANR-2010-GENM-004-01), Montpellier SupAgro, the departments EA (Environment-Agronomy) and BAP (Plant Biology and Improvement) of INRA, the Poupelain Foundation, the European Eurasia 2 thesis mobility programs, EulaLink, and the Brazilian CNPq scientific cooperation program. Special thanks to Mark Thomas, Pat Corena, Don MacKenzy, and Ian Dry from CSIRO Agriculture (Adelaide) for mentoring and helping during some important steps of these experiments.
\nEmergence of COVID-19 threatens human health and economy around the globe. Possibly, world populations have ever faces such crisis and will remain the witness of such incident. Each new day experiences number of new cases with increasing death toll since its first identification. However, suggested name of corona virus comes from Latin word corona, signifies crown or halo. Electron microscopy of corona virus reveals encapsulation of crown like fringe at outer surface [1]. Novel Corona virus known as different name such as COVID-19, COVID-19, HCoV-19 was outbreak in Wuhan, Capital of Hubei province, China in month of December-2019 and later become pandemic by quick spreading into the major countries in the globe [2, 3]. Outbreak has very high risk with potentiality of human to human transmission. Experts around the globe suggest that, the average incubation period of COVID-19 is ~5 days with a range of 2–14 days [2]. Symptom includes high fever, dry cough to severe respiratory acute disease and death (in some cases) [2]. Average fatality rate reported to be ~1–2% [1, 2]. Scientific community and researchers are at the midst of COVID-19 pandemic and have struggling to find out how much similarity with SARS-CoV. The study reveals that, COVID-19 is similar like SARS corona virus which is believed to be originated from either bats or civet cats or raccoon dogs [2, 3]. However, due to lack of evidence many scientific communities ruled out such report. As per WHO officials, COVID-19 is ten times more infectious than the 2009 pandemic H1N1 influenza virus. There is no effective drug or vaccine against the corona virus or similar infectious agents so far and it is still unknown how many more month require to develop. However, one needs to understand the priority and treatment protocol based on the severity of the disease.
COVID-19 is the seventh coronavirus which infect humans like earlier reported coronavirus SARS-CoV, MERSCoV, HKU1, NL63, OC43 and 229E. [4]. For an enveloped virus, primary mode of transmission is close contact with the infected individual. Transmission is appeared to be silently enter into the host body and no immediate onset symptoms have been evident. Therefore, before infected host tested positive, he/she already transmitted virus to many others (provided infected person does not maintaining isolation/social distancing). In most cases, human to human transmission occurs, though human to human transmission has been ruled out at the very early stage of the outbreak. However, probability of getting infectious becomes higher when an infected person or person in incubation stage comes closer to the healthy person. Alternative transmission medium might be via contact surfaces i.e. skin to skin touching or touching objects having COVID-19 particles. Then direct or indirect entrance of that surface particles into one’s body through mouth, nose, or eyes. The other forms of transmission possibly through inhalation of particle aerosols emanated from exhaled breathe of infected person or via droplet due to cough/sneezes [4]. A recent study reveals that, COVID-19 may survive in aerosols (size <5 μm) for at least three long hour in an open air ambient [1, 2]. Relative humidity, fomite material, and air temperature possibly are the factors for prolonging virus life. Long time survival at the outside of its host organism (surfaces such as aluminum, sterile sponges, or latex surgical gloves) will increase the opportunity to produce new host via touching or breathing [2, 4]. Facal transmission is another transmission path where COVID-19has been found in stool specimen like aluminum, sterile sponges, or latex surgical gloves etc. [2]. The surface stability of S-protein of COVID-19found to be more on plastic, stainless steel than the copper and card board [2]. It is worth mentioning that, some positive COVID-19 cases were also reported due to the nosocomial transmission. Recent study of Wang et al. reflects 29% health professionals and 12% hospitalized patient (associated with other disease history) becomes infectious due to nosocomial transmission [5]. It is worth to mention that, urine of infected one does not contain any COVID-19 particles and therefore does not have any role for transmission [6]. Study of Casanova et al. suggest that, corona virus may remain active even in pure water and pasteurized settled sewage for few days to one week [7]. Airborne dust particles or microorganisms or particulate matter (PM) are the potential transmitter [6]. Some study finds the virus can transmit through air up to 1 m whereas another recent study find virus particles can transmit up to 13 ft. [6]. However, COVID-19 particles combined with airborne dust particles or microorganisms or particulate matter (PM) enters into the deeper alveolar and tracheobronchial regions of the host.
The transmission, survival and characteristics of COVID-19 directly influenced by environment factors like temperature, pressure, pollution level [8]. In addition, outbreak further involved with the reproduction number (R0). The reproduction number (R0) defined as the number of healthy people getting infected from a single infectious living in a susceptible populated environment. Reproduction no (R0) mainly governed by the factors like (i) stage of infection, (ii) transmissible strength of the pathogen, and (ii) the number of susceptible contacts. It is meaningless to set the exact value of R0 until otherwise the surrounding environment clearly specified. For example, Li et al. reported R0 value for COVID-19 as 2.2 (95% confidence interval, 1.4–3.9) [9]. However, in reality R0 for COVID-19 might be very higher than expected if one does not obey the rule of social distancing or home quarantine. Few governing factor are crucial for reproduction rate or newly infected cases in a particular area viz.; (i) isolation of infected person from the day of infection, (ii) availability of general needs for ones to remain in isolation like food and other necessities and (iii) availability of sufficient diagnosis tools in the area. Based on the above facts, a mathematical model proposed by Tang et al. [10] determines the reproduction rate or spreading rate by individual infected host per day. If the above factors favor in a particular region, then contact rate C(t) (assuming reproduction rate proportional to the number of new contact) in a certain period of time follows Eq. (1) leading to decreasing reproduction rate [10].
Where C0 initial contact rate, Cb is minimum contact rate under current control strategies, r1 is coefficient of contact factor, t is investigated time period. However, reproduction rate further depends on the diagnosis rate as shown in Eq. (2) [10].
Where δI (t) diagnosis rate and, δI0 is initial diagnosis rate with δI(0) = δI0, δIf is fastest diagnosis rate with
Showing simulation data of (A) contact rate C (t) and diagnosis rate (B) effective daily reproduction ratio for the period of 30 days somewhere in Wuhan [10].
Many infectious remains asymptomatic and silently affected so many. Most of the mild cases symptoms such as, fever (83–100%), myalgia (11–35%), diarrhea (2–10%), fatigue, headache (7–8%) and cough (59–82%), and dyspnoea have been found predominantly [11]. However, severe infection outcome includes drastic reduction in average circulating lymphocyte and platelet counts etc. Other abnormalities are on chest radiographic imaging, lymphopenia, leukopenia, and thrombocytopenia [2]. Respiratory system is highly affected. Though age is still not be a proven critical risk factor for COVID-19 infection, but it was observed that, mortality rate were prominent for elderly having some previous disorder like hypertension, chronic obstructive pulmonary disease, diabetes, cardiovascular disease. Such prior disorder with COVID-19 particles in body quickly developed some dangerous malfunction like coagulation dysfunction, septic shock, metabolic acidosis and acute respiratory distress syndrome which are hard to correct eventually leading to the death. Further, few other malfunction like decrease in neutrophil count, D-dimer, blood urea, and creatinine levels etc. were prominent in severe infected patient [2]. However, all effects (including inhaled particulate matter combined with an immune response or cytokine storm induced by COVID-19 infection) together exacerbate severe ill effect on respiratory system and increase the risk of patient life. In order to investigate the different organ disorder due to COVID-19, human protein database and distribution of antigiotensin converting enzyme 2 (ACE2) has been correlated. It would be appropriate to mention that, an ACE2 is a transmembrane enzyme, act as a receptor function in host body and help to enter COVID-19 in host cell [8, 9, 10, 11]. Figure 2(b) and (c) shows the detection of ACE2 receptors over neurons and glial cells, further, how COVID-19 binds to ACE2 receptor in brain cell. Figure 2(a) and (e), ensure presence of COVID-19 in general blood circulation with abundant number of virus in cerebral circulation. The presence of such virus possibly is the reason of slowing the blood circulation mechanism in capillary endothelium which results in higher interaction probability of COVID-19 spike protein with the ACE2 [3]. Hence, there is a possibility of neuronal damage or endothelial rupture of cerebral capillaries in association with bleeding in cerebral tissue which increases the life risk of patient infected with COVID-19. Few evidence of neurotropic mortality caused by COVID-19 has been reported but proper explanation is yet to be established [12]. A study of 218 patients from recent outbreak reveals 78 patient (36.4%) having neurological malfunctions due to the COVID-19. Rest of the patients is either losing control over breathing or suffering from acute respiratory failure [3, 12]. However, evidence of virus in cerebrospinal fluid is still under debate. Apart from blood circulation, entry of COVID-19 through cribriform plate close to the olfactory bulb can be an alternative pathway to the brain. Further, indirect consequences of multi organ failure (pulmonary, renal, cardiac, and circulatory damage) caused in patient having COVID-19appears to be more dangerous than expected. The study reveals that COVID-19 severely damages leucocytes which possibly are the reason of multi organ failure [13]. Older infected people having diabetes mellitus-2 are at more risk to mortality due to the uncontrolled glycaemia [14]. COVID-19 infection in diabetes patient raises the stress level and hence blood glucose levels and abnormal glucose variability. Increase in blood glucose possibly due to the release of hyperglycemic hormones (glucocorticoids and catecholamines) [14].
Showing possible targets of COVID-19 (lungs, heart, kidneys, intestines, brain, and testicles); (a) COVID-19 distribution and ACE2 receptor in human, (b) COVID-19 transmission to brain through upper nasal trancribrial path (c) inset image shows binding mechanism of spike protein at the site of neuron (d) showing COVID-19 distribution through blood circulation at lungs and (e) inset image showing bind of COVID-19with ACE2 receptor at lungs cell (reproduced with permission ref. [3, 12]).
The COVID-19in the infected human body consists of critical virion which is a spike type glycoprotein known as S-protein [15]. The characteristics of spike protein or S-protein solely determine whether host cell is infected by corona virus or not. The spike protein has two subunit referred as S1 and S2 respectively. S1 is responsible for virus-host range and cellular tropism with the help of receptor binding domain (RBD) whereas S2 expedite the virus-cell membrane fusion with help of heptad repeats 1 (HR1) and heptad repeats 2 HR2 [16]. However, a polybasic cleavage site (RRAR) in between S1 and S2 influence the viral infectivity and host range with the effect of furin and other proteases [4]. O-linked glycans created by the proline, which possibly flank the cleavage site and shields epitopes or key residues on the SARS-CoV-2 spike protein [4]. However, the outermost part of critical virion cell is full of spike protein which helps to binding and subsequent fusion of antigiotensin converting enzyme 2 (ACE2) membranes in host cell. ACE2 is a transmembrane enzyme, act as a receptor function in human body and help to enter COVID-19 in host cell [1, 2, 3, 4, 5, 6, 7, 8, 9]. ACE2 exist at almost each organ of the body including arterial smooth muscle cells in the lungs, lymph nodes, stomach, colon, skin, liver bile ducts small intestine, kidney parietal epithelial cells, and the brain [14, 15].
The genome sequence of COVID-19contains ~ 27 no of protein and almost ~30000 nucleotides in length as shown in Figure 3(a) [17]. Open reading frames (ORFs) are found to be variable in COVID-19 gene. In first ORFs (ORF1a/b), almost 2/3 viral RNA have been found which encodes 16 non-structural protein (NPS) and translates two polyproteins (pp1a and pp1ab). Accessory and structural proteins encoded by remaining 1/3 ORFs. Most essential proteins are RNA dependent polymerase (RdRP) and four structural proteins viz.; matrix protein (M), nucleocapsid protein (N), small envelope protein (E) and spike surface glycoprotein (S) [17]. The function of S protein is to binding and fusion of ACE2 membrane in host cell. On the other hand, M, N and E protein helps to budding, envelope formation, assembled, pathogenesis and RNA encasing in host cell [15, 16, 17]. Upper part of the respiratory tract has lower ACE2 results in less infection by S-protein whereas lower parts of the lungs have more amount of ACE2 consequently higher tendency of getting infected by S-protein as confirmed by higher opacity in CT image as shown in Figure 4. ACE2 has high binding capability with COVID-19 spike protein and its initiates the infection process as shown in Figure 3(b) [5]. The interaction of S-protein and ACE2 in the host cell is as follows; COVID-19genome encodes many structural protein (glycosylated spike (S) protein) and non-structural protein (RNA-dependent RNA polymerase (RdRp), protease (3CLpro), and papain-like protease (PLpro)) for inducing host immune response [19]. 3CLpro and PLpro are responsible for COVID-19genome replication in host cell by proteolytic processing of non-structural proteins. As per National Center for Biotechnology1 (NCBI) database, with ID NC_045512, the COVID-19 genome structure is 29,903 bp single-stranded RNA (+ss-RNA) coronavirus [3]. COVID-19genome at the host cell releases it outer encapsulation and remain as single-stranded positive RNA (having 5′-cap structure and 3′-poly-A tail). RNA translated into viral polyproteins with help of host antigiotensin converting enzyme 2 (ACE2). Cleaving of polyproteins turns it to an effector protein by viral proteinases 3CLpro and PLpro [19]. Such mechanism reduces the host immune response drastically. Monte Carlo simulations by convolution contact maps suggest, receptor binding domain (RBD) area of spike protein shows various conformations with respect to the remaining portion of the protein structure [20]. The identified RBD area were then reassembled using pipeline method which produces a complex structure of spike trimer and the extracellular domain of human ACE2. Cryo-EM structure analysis reveals that, the binding affinity of ACE2 with the S protein of COVID-19spike protein is 10–20 times higher than that of the SARS CoV spike protein [3]. However, corona virus genome sequence study suggests that, RBD in spike protein is the most variable part and determines probability of getting infected based on the binding efficiency with host receptor. From reports of Wan et al. six RBD amino acid of COVID-19viz; L455, F486, Q493, S494, N501 and Y505 found to have high binding affinity with ACE2 receptor of human [21]. Possibly high binding capability of RBD with human ACE2 results in high rate of natural infection in human species.
(a) Genome structure of COVID-19, (b) spike protein structure of COVID-19 constructed from C-I-TASSER, and (c) human antigiotensin converting enzyme 2 (ACE2) (yellow color) and spike protein trimmer (right side multicolor (magenta, cyan and blue)).(reproduced with permission [1]).
CT image of (A) 75 year male patient having fever and cough since 5 days (B) 55 year female patient having fever and cough since 7 days (C) 43 year male patient having fever and cough since 7 days [D] 43 year female patient having fever and cough since 5 days; the abnormalities in axial CT were [a] bilateral subpleural CGO [B] extensive CGO with consolidations [C] small bilateral areas of peripheral CGO with minimal consolidation [d] peripheral consolidation in right lung (reproduced with permission from ref. [18]).
Diagnostics measure can play a major role for the screening of COVID-19 patient from the healthy ones. Initial identification of the COVID-19have been carried out through molecular diagnostic approach viz.; metagenomic next generation sequencing (m-NGS), reverse-transcription PCR (RT-PCR) procedure and CRISPR. Rapid DNA alteration/genome structure of COVID-19makes it difficult to detect by any specific method. Therefore, specific DNA sequence must be developed for early stage detection and subsequent alarming. A paper-based colorimetric assay for DNA detection based on pyrrolidinyl peptide nucleic acid (acpcPNA)-induced nanoparticle aggregation has been reported by Teengam et al. [22]. The oligonucleotide targets were detected by investigating different color measurement of silver nanoparticles (AgNP) with detection limit down to 1.53. Chen et al. followed real-time polymerase chain reaction (RT-PCR) using nucleic acid analysis for detection of COVID-19 [4]. Measurement accuracy reported to be about 71% [4]. Pathogens from bronchoalveolar lavage (BAL) fluid analysis found to be an alternative of finding genetic sequence of corona virus. Swab test possibly have higher accuracy but insufficient kits impose to go for other techniques. In this section few diagnosis process discussed elaborately.
Protein testing: Biomarker like viral protein antigens can be used for detection of infected COVID-19. Variation in infection stages make it hard to find a particular protein antigens or antibody pattern in host cell. Study of Wang et al., confirms viral increases in salivary in the first week of onset symptoms and then decreases gradually with progress in time [23]. Saliva testing possibly show shedding from salivary glands and the upper and lower respiratory tract [23]. Author tested posterior oropharyngeal (deep throat) saliva of 23 COVID-19 infected patients among which 13 were mild disease and 10 were severely affected. The findings reveals that, at initial stage of testing, posterior oropharyngeal saliva was 5·2 log10 copies per mL (IQR 4·1–7·0). The viral load decline to slope − 0·15, 95% CI –0·19 to −0·11; R2 = 0·71. Further, study finds relatively older aged patients having higher viral load of Spearman’s ρ = 0·48, 95% CI 0·074–0·75; p = 0·020. Due to non-invasive and painless procedure, posterior oropharyngeal saliva testing is more acceptable to the patients. Similar study of nasopharyngeal swab or bronchoalveolar lavage fluid testing by CRISPR-nCoV method carried out by Hou et al. [24]. The finding reveals better accuracy of testing with lower turn-around time about ~40 minutes and does not require thermal cyclers. CRISPR-nCoV method composes recombinase polymerase amplification (RPA) step followed by T7 transcription and Cas13 detection step. In a typical process, a mixture of 2.5 μl of tested sample, primer (0.4 μM), reaction buffer, magnesium acetate (14 mM of) and the RT-RPA enzyme have been prepared [25]. The prepared sample was incubated at 42 °C for half an hour. Again mixture of amplification product, 166 nM of ssRNA, 66.7 nM of Cas13, 1 μl T7 RNA polymerase, 5 mM of each NTP, and 33.3 nM of gRNA allow to reacts in CRISPR. The temperature during reaction was maintained about ~42 °C. Finally, Fluorescent signals were collected. The sensitivity of CRISPR were found to be 100%. Results of 52 known infected sample showed positive COVID-19with FC value ranging from 5–66.3 [25].
Metagenomic next-generation sequencing (mNGS): Study of Hou et al. demonstrated 52 confirm positive COVID-19infected cases among 61 patients by mNGS method [25]. The rest are found to be negative. In this method, Qubit Fluorometer (Thermo Fisher Scientific, 99 Carlsbad, CA, USA) can be used to measure RNA concentrations and then transposase-based methodology with ribosomal RNA depletion approach might be useful for creating sequence libraries. 10 million single-end 75 bp reads must be generated for each sample followed by removal of read derived from host genome. The sequence libraries were generated by reverse-transcribed of RNA into cDNA. However, taxonomic classification and identification of sequence read may be performed by comparing with existing database of plasmid, bacteria, fungi, human, protozoa, univec, and virus sequences. It is worth mentioning that, a simultaneous testing of negative sample and its sequence generation must be carried out with each above sequence run for controlling contamination. Further, genetic similarity of all positive cases confirms Orf1ab and N gene are two potential sequences for identification of COVID-19infection. The turnaround time ~ 20 hours (library preparation (8 hours), sequencing (10 hours) and bioinformatic analysis (2 hours)) and high cost makes this method limited use for COVID-19 detection.
Reverse-transcription PCR (RT-PCR): RT-PCR is widely used method using upper respiratory tract samples (including nasopharyngeal swabs, nasopharyngeal washes, nasal aspirates and oropharyngeal swabs) for COVID-19 testing. Probable test sample from lower respiratory tract might be sputum, BAL fluid and tracheal aspirates. However, BAL fluid and tracheal aspirates in general not used as sample for RT-PCR testing, because of aerosol formation from these samples. Mainly two steps followed in RT-PCR process; reverse transcription of viral RNA into cDNA and subsequent amplification of cDNA [26, 27]. Throughout RT-PCR diagnosis, crucial steps followed are sequence alignment, primer selection, optimization of assay (like reagent conditions, incubation times, and temperatures) and finally PCR testing. RNA-dependent RNA polymerase (RdRp) sequence and the open reading frame 1ab (ORF1ab) sequence has been used as gene target for COVID-19 detection. One step real time RT-PCR, where swab of the infected patient were mixed with following ingredients; reverse transcriptase, polymerase, magnesium, nucleotides, nuclease-free water, primers, a fluorophore-quencher probe [26, 27]. Whole mixture then transferred into PCR thermocycler which generates a fluorescent signal with help of fluorophore-quencher probe. Corman et al., uses three types of assay structure (RdRp gene, N gene and E gene) for testing 297 samples [27]. Result reveals that, detection probability ~97% for both assay RdRp gene and N-gene with 3.8 and 5.2 copies per reaction, respectively. The process turnaround time is about ~1.5 hours possibly due to the producing capability of many copies of specific gene sequence. Need of thermo cycler and use of sophisticated instruments hinders this method to use as diagnostic tool in limited resource setting. Accuracy of the method depends on sampling location, quality of RNA extraction and training of operators etc. However, still this method finds its application due to the faster nucleic acid amplification. Lower accuracy in RT-PCR results (negative result in infected sample sometimes) possibly due to the insufficient cellular material and improper extraction of nucleic acid from the specimen [27].
Computed Tomography (CT): Imaging technique like computed tomography offers easy capture of the cross sectional surface of the lung from many angles in non-invasive way. Analysis of such image modality by radiologist can offer insight about abnormal features that may come from COVID-19 infection. However, it should be noted that, abnormalities of pulmonary involvement may arise due to other viral disease as well. Note that, in some asymptomatic patients whose RT-PCR shows negative even he/she have travel history or closure contact to infected person, in that case CT imaging could be good approach of screening. Pattern change in peripheral ground-glass opacification (areas of hazy opacity), consolidations (i.e. fluid or solid material in compressible lung tissue), bilateral involvement, peripheral and diffuse distribution are found to be the responsible factor for abnormalities in pulmonary due to COVID-19infection [28]. Further, it should be noted that, such marker may vary depending on the infected stages of COVID-19. For example, Bernheim et al. reported 56% pulmonary involvement after 2 days of onset symptoms whereas it researches to peak involvement on 10th day [29]. A CT imaging of asymptomatic patients reveals that, at the early stage of no symptoms only lesions in lungs and it gradually bilateral diffuse disease become prominent and then consolidation found on day of first or second week from onset of the symptoms [28]. Xie et al. reported five patients having negative RT-PCR result but their CT imaging confirms positive COVID-19 viral infection [30]. All the positive confirm cases does not had any prior abnormalities in pulmonary. However, same author also demonstrated 155 patients having positive RT-PCR which was found again positive by CT imaging method and 7 other patient who were positive in RT-PCR testing showed negative in CT imaging [30]. CT imaging of the five patients (who were tested RT-PCR negative) showed abnormalities in pulmonary like ground glass opacity (5 patients) and/or mixed CGO and mixed consolidations (2 patients) [30]. A series of 51 patients test by CT imaging and verification of the same by RT-PCR method resulted sensitivity about ~98% for CT and ~ 71% for RT-PCR study, respectively [18]. A CT image of four patients is shown in Figure 4(a)–(d) [18]. The CT investigation of 21 patients (among which 6 male 15 were male) from the onset of initial symptoms to recovery period were carried out by Pan et al. [28]. On an average, CT image capture and analysis of all the patients were carried out after every four days interval and all have been discharge after 17 ± 4 days. In most of the patients, maximum abnormalities were noted on or after 10th day since onset symptoms with R2 = 0.25 and p < 0.001. Based on the progress of infection level during complete hospital stay (~21 day) until recovery has been categorized into four stages viz.; stage 1(0–4 days), stage 2 (5–8 days), stage 3 (9–13 days), and stage 4 (>14 days). The most pulmonary abnormalities reported are (i) CGO in stage 1, in 17 among 24 (75%) patients (b) increased crazy paving pattern in stage 2, in 9 out of 17 (53%) patients (iii) consolidation in stage 3, in 19 out of 21 (91%) patients and (iv) gradual resolution of consolidation with decreased crazy paving pattern in stage 4, in 15 among 20 (75%) patients [28]. The governing factor (ground-glass opacification, bilateral involvement etc.) for detection of COVID-19 employing CT imaging, sometimes became imperceivable due to the low severity or few symptoms in patients making this method more challenging. Use of artificial intelligence for screening the infected patient by CT imaging possibly can increase the sensitivity of the method.
Nucleic Acid Testing. This testing does not require sophisticated laboratory instruments but dyes (malachite green, calcein and hydroxynaphthol blue) that utilize inherent by-products of the extensive DNA synthesis [31]. The testing based on the isothermal amplification at particular temperature for nucleic acid testing. The different isothermal techniques like polymerase amplification, helicase-dependent amplification, and loop-mediated isothermal amplification (LAMP) have been followed in nucleic testing [32]. Reverse transcription LAMP (RT-LAMP) is one of major techniques for detection of COVID-19 based on one-step nucleic acid amplification method [32]. In this method, few primer and DNA polymerase are essential to obtain insight about viral genome sequence. Yu et al. uses six primers to amplify the ORF1ab gene fragment [33]. The primer are as follows; forward inner primer (FIP), outer forward primer (F3), outer backward primer (B3), backward inner primer (BIP), loop forward primer (LF), and loop backward primer (LB) [34, 35]. In a typical process, the mixture of isothermic amplification buffer, dNTPs, manganese sulfate, FIP/BIP, F3/B3, FL/BL primers, Bst 2·0, antarctic thermolabile UDG, and Warm Start Reverse Transcriptase in ddH20 were transferred in ice bath. The ice bath then kept in enclosed room and allows incubation at 63 °C for half an hour. RNA detection started with simultaneous occurrence of reverse transcription and amplification process. The detection can be confirmed by several identification like color change from orange to yellow or laddering pattern of bands after electrophoresis on a gel or by fluorescent light in response to UV excitation [32]. Loop mediated isothermal study of respiratory swabs employing pH-sensitive dyes and five primers for visual and colorimetric detection has been reported by Zhang et al. [31]. In conventional method, patient swabs were mixed with BSA (1%), amphotericin (15 μg/mL), penicillin G (100 units/mL), and streptomycin (50 μg/mL). The mixture sample then deactivated at 56 °C and finally COVID-19RNA was extracted from the deactivated sample. Average detection sensitivity was ~100 copies in each five primer. All the samples were further confirmed through RT-PCR testing. Similar study by Yang et al. [36] reported detection of ORF1ab gene, E gene and N gene employing RT-LAMP method. Testing of 208 samples reveals sensitivity similar to RT-PCR method whereas specificity was 100%. RT-LAMP technique has high sensitivity and specificity. The turnaround time less than one hour and have flexibility to work at various pH level and temperature level. The cost of testing is relatively low compared to other techniques. However, optimum primer selection and producing suitable reaction environment are two major difficulties technician faces during sample testing.
Point-of-Care Testing: In point of care testing sample does not require to send in laboratory rather one can test with smaller device with turnaround time is less than one hour. One can either detect virus genetic content by nucleic acid based probes or by detection of toxin produced by pathogen or by epitopes of pathogen membrane [37]. In later two approaches, antibodies or antibody derivatives can be used for easy diagnosis. However, specificity of the later two (antibody based) approaches is lower than the former (nucleic acid based) approach. Some of reported point of care techniques are (i) biosensors, (ii) gold nanoparticles as antibody for binding virus protein (lateral flow assay), (iii) mirofluidic devices, (iii) electrochemical sensors, (iv) paper based systems, and (v) and surface-enhanced Raman scattering based systems [37]. Lab on chip point of care diagnosis offer portability, rapid detection time, and miniaturization. Further, testing require small sample volume [36, 37, 38]. The smart phone dongle attached with devices like mirofluidic device, electrochemical sensor or lab on chip can also be a point of care strategies for COVID-19detection. Xiang et al. compared COVID detection by (i) ELISA test with IgG and IgM antibodies for 63 patients and (ii) colloidal gold-immunochromatographic assay (GICA) for 91 patients and the sensitivity were found to be 87.3% and 82.4% [37].
COVID-19 outbreak converges existing reproductive health and economic stability of the women’s and girl’s. The crisis reduced the access of family planning, and increase the unsafe abortion, miscarriage, unintended pregnancies, post traumatic stress disorder, intimate partner violence etc. [39]. Limited resources available for illness prediction of COVID-19infected pregnant women but provide some insight based on the effects one encounter from similar type of corona virus infection (SARS) and MERS). COVID-19can increase the rate mortality for the case of pregnant women and enhances the chance of transmission to new born baby via vertical transmission. A study of 33 new born baby from infected mother reveals vertical COVID-19transmission in 3 babies [39]. US Centers for Disease Control and Prevention (CDC) sets few rule and regulation for women having new born babies are (a) sanitize the hands before touching the baby, (b) wash feeding bottles before and after use, (c) women are allowed to breast feed until evidence suggest otherwise, (d) use mask during breast feeding, (e) use of dexamethasone as an alternative to betamethasone for fetal lung maturation etc. [24]. Study of Liu et al., from January 20, 2020, to February 10, 2020 gives a clear picture of different symptoms and subsequent treatment of infected women having different stage of pregnancies [40]. The entire clinical study reviewed by three radiologist for 15 pregnant infected women (diagnosis with reverse transcription–polymerase chain reaction (RT-PCR) at the time of admission) reveals that, 11 patient gave successful deliver of new born and 4 patient are still under observation (three are in second trimester and one in third trimester). They were not facing any natal asphyxia, neonatal death or abortion up to the end of the study. The CT imaging was carried out for infected women before and after delivery. All patients chest CT imaging shows pulmonary abnormalities. Similar chest diagnosis by CT scan and pulmonary abnormalities of all admitted patient has also been found in the report of Rasmussen et al. [41]. CT imaging reveals ground-glass opacity (GGO) in early stage of the infection and crazy paving pattern (denser, more profuse, and confluent) in patients having more infection than the images of healthy lungs [40, 41]. The most common symptoms were found to be fever (13 among 15 patients) and cough (9 among 15 patients). Lymphocytopenia was the most common abnormality found in 12 patients. CT scanning ensures no evidence of COVID-19provocation after delivery. Among 11 patients. All were given antibiotic treatment before and after delivery whereas 4 patient who were still pregnant till end of the study period were treated only with antibiotics. Another study by Zhu et al., reported nine pregnant women with 10 new born (one twin) babies [42]. The report says onset symptoms of COVID-19 were evident in four patients before 1 to 6 day of delivery, in two patients on the same day of delivery and in three patients after 1to 3 day of delivery. Two among the nine mothers had intrauterine fetal distress and 6 babies were born preterm. No mortality was reported [42]. As far as respiratory acute failure is concern, 40% pregnant women were given mechanical ventilation whereas it was 13% for non-pregnant women [31]. However, what treatment is actually applied is still unknown. Pregnant women’s are more likely to be affected due to the physical changes like diaphragm elevation, edema of respiratory tract mucosa, increased oxygen consumption etc. drive them to more complicated cases. What about the new born babies? Whether there is any vertical transmission of COVID-19 to new born or not? If transmission takes place, then in what mode and is it when fetal is in the mother womb or during delivery time (by means of surface contact)?. This question mark is still in dilemma. Because some evidence proofs that, there is no vertical transmission takes place [41]. On the other hand, few study ensure positive cases in new born babies [43]. Vertical transmission case study of four mother and their new born have been investigated by Chen et al. with different parameters variation in mother as well as in the new born babies [44]. All four mothers were admitted in hospital at their trimester with positive COVID-19. Initial health counseling of mothers was as follows; three among four have fever, two among four have myalgia or fatigue, two among four have cough. The fetal movement was normal except one mother who have dyspnea. Lymphocytes count (<1.1 × 109/L) found to be lower than in normal case and C-response protein was found to be significantly increased in level for all four mothers. Chest CT imaging before delivery confirms abnormalities. However, after antiviral treatment, COVID-19test found negative in three mother and they were released after 3–5 days. One who suffer with dyspnea takes more time to recover from COVID-19. The states of babies are as follows; all four babies were isolated upon birth from their mother. For prevention of COVID-19 perinatal and postnatal transmission, three mothers opted cesarean section and remaining one had vaginal delivery due to the sudden labor pain. The RT-PCR testing were carried out after 72 hour of their birth and only three babies were tested since one among four were not given consent for testing.
Worldwide scientist and physicians started major campaign to understand the emergence of the disease and its possible antiviral treatment by drug development or therapeutic agents or developing vaccines. As of now there is no specific therapeutics agent or vaccine approved to cure COVID-19 patient in clinical procedure. Due to limited clinical and basic research information, most of the clinical trial/manifestation follows basic symptomatic treatment protocol and supportive care which was followed for curing SARS and MERS patients [45]. The strategies of SARS-CoV and MERS-CoV therapy or antiviral drug have been extrapolated for the treatment of COVID-19 (Table 1). Most of the hospitalized infected patient have following status; (i) among the admitted patients, 23%–32% enters into ICU, (ii) 17%–29% feels critical respiratory failure (iii) ~7–8% were discharged and (iii) ~1% reported death. S-protein of COVID-19 has much similarity (in structural as well as replication procedure) with SARS and MERS protein and hence most of the articles reported broad spectrum antiviral activity of remdesivir, baricitinib, and chloroquine as the clinical trial antiviral drug [19] (Figure 5). Remdesivir demonstrated effectiveness for curing COVID-19 in USA [46]. Nucleotide type of remdesivir drug assisted to premature termination of RNA chain in host cell. On the other hand, ribavirin is a guanosine analogue mostly used for treating chronic hepatitis C [47]. However, study finds suitable dosage of ribavirin might stop the replication spike protein RNA [47]. Lopinavir (a viral protease inhibitor) with its pharmacological booster ritonavir (LPV/R) initially proved to be useful for HIV, SARS-CoV, MERS-CoV treatment with the action of protease inhibitors. Recently study in South Korea reveals significant decrease in COVID-19 viral load after treating with (LPV/R) [46, 48]. Similar reduction in viral loading (associated with pneumonia related symptoms) was also observed after treating with arbidol [34]. Chloroquine and its hydroxy-analogue hydroxychloroquine demonstrated to be relevant for patient having diabetes with infected COVID-19 [14]. Researcher and scientific community stress more on 3CLpro, PLpro and RdRp protein target than other target possibly due to the most responsible proteases for COVID-19 replication and hence attractive targets for antiviral therapies. Further, one needs to understand, the possible action mechanism of existing drug on COVID-19 before being used. For example, arbidol can be used for fusion of virus-host cells to prevent virus entry into the host. The clinical trial of arbidol is in process [34]. Clinically approved camostat mesylate a possible inhibitor used (to reduce activity of TMPRSS2) for blocking the COVID-19entry into human body [35]. Combination of tocilizumab and hydroxychloroquine found to be very effective for curing COVID-19patient underwent kidney transplant surgery [49].
structure of viral entry inhibitor (a) remdesivir, (b) ribavirin, (c) IDX-184, (d) chloroquine, (e) hydroxycholoroquine, and (f) camostat mesylate.
Sr No | Target Protein | Possible Drug | Ref |
---|---|---|---|
1 | Angiotensin-converting enzyme 2 (ACE2) | Arbidol | [34] |
2 | Viral spike glycoprotein (S-protein) | Arbidol | [34] |
3 | Transmembrane protease, serine 2 (TMPRSS2) | camostat mesylate | [50] |
4 | Coronavirus main protease 3CLpro (3CLpro) | lopinavir | [46] |
5 | Papain-like protease PLpro (PLpro) | lopinavir | [48] |
6 | RNA-dependent RNA polymerase (RdRp) | remdesivir, ribavirin, favipiravir | [47] |
7 | JAK kinas | baricitinib | [51] |
8 | Endosome/ACE2 | Chloroquine, Hydroxychloroquine | [47] |
8 | RNA-dependent RNA polymerase (RdRp) | IDX-184 | [35] |
Recently nanomaterial used for point of care diagnosis, therapeutics agent, or in vaccine development. Nanomaterial found to be the promising candidate for the modulation of viral infection cycle [4]. Especially, carbon quantum dots having size below 10 nm found to be a promising interferes for the viruses into the cells. Nanomaterial having different nanostructure offers multivalent character due to surface to volume ratio. Such multivalent properties facilitate several ligands to attach with virus. The viral-ligands interface blocks the entry of virus into the host cell [20]. Łoczechin et al. reported function of carbon quantum dot (CQD) as inhibitor for COVID-19 [52]. CQD synthesis itself from different precursor offer different level of inhibition strength to corona virus. Two different study of CQD synthesis from (i) citric acid/ethylenediamine and further conjugated by boronic acid, and (ii) 4-aminophenylboronic acid and phenylboronic acid offer 50% inhibition concentrations of EC50 = 52 ± 8 μg mL−1 and EC50 = 5.2 ± 0.7 μg mL−1, respectively [52]. CQD inhibit growth of s-protein by fusion mechanism and stop replication process of S-protein by signal transduction mechanism or by interaction with cytosolic proteins [52]. Nanomaterial particles as therapeutic agent for stopping viral entry and subsequent replication of S-protein in host membrane may be an alternative of many existing treatment to avoid their side effects. For example, use of ribavirin and IFN as an antiviral drug for COVID-19 spike protein have many side effects including short-term memory loss, confusion, extrapyramidal effects and deficits in executive functions [20, 52].
Plasmonic biosensor working on the cumulative effect of plasmonic photothermal (PPT) and localized surface plasmon resonance (LSPR) transduction principle found to be another potential alternative diagnosis of COVID-19 [53]. Two dimensional (2D) gold nanoislands (AuNIs) functionalized with DNA receptors exploited as sensing of RNA gene sequence. Sensitivity of material can be enhanced to some order by direct thermoplasmonic heating to biosensor chip. The usable plasmonic heat to the chip has been generated by setting a particular plasmonic resonant frequency. Photon generated oscillation frequency modulated the electrons behavior on the surface of plasmon material which might be the crucial factor for detection of selective COVID-19 gene sequence from multi gene mixture. Enhanced plasmonic field at the nanostructures surfaces increases sensitivity of sensor by suppressing local variation like refractive index and molecular binding. Employing field effect transistor as biosensor for fast and accurate spike protein detection through nasopharyngeal swab has recently been reported by Seo et al. [54]. Graphene coated specific antibody has been used as sensing material for spike protein detection [54]. The spike protein directly not attached with graphene surfaces rather 1-pyrenebutyric acid N-hydroxysuccinimide ester was used as probe linker to conjugate protein structure on graphene surfaces. Such attachment of spike protein induced by 1-pyrenebutyric acid N-hydroxysuccinimide ester on graphene surface leading to changes in conductivity and subsequently in current through the FET structure (shown in Figure 6(a) and (b)). The sensitivity which was measured by current fluctuation due to presence or absence of spike protein is shown in Figure 6(c) and (d). The biosensor capable to detect down to 16 pfu/mL in cultural mode and 2.42 × 102 copies/mL in clinical sample [32]. The diagnosis method does not require sophisticated laboratory equipment and provide very high sensitivity with instantaneous measurements employing small volume of nasopharyngeal swab.
(a) showing conjugation of spike protein on to the surface of graphene via 1-pyrenebutyric acid N-hydroxysuccinimide ester (b) model showing spike protein on the surface (covered with graphene) of field effect transistor (c) FET sensor sensitivity in presence of SARS-COV-2 antibody and in absence of SARS-COV-2 antibody and (d) FET sensor sensitivity in MERS-COV and SARS-COV-2 (reproduce with permission [32]).
Like other epidemic, COVID-19 may also become seasonal, but at present one can only predicted about it not for sure. Meanwhile, to reduce the outbreak, it is required to have international collaboration with data sharing policies. Because, of the limited information, one can reuse the existing drugs as clinical trial for curing COVID-19 infection (based on the similarity of target protein with other coronavirus). Further, fight against COVID-19 requires the knowledge of computer science, medicine, health policy, environmental factors and risk management etc. Present situation imposes researcher and scientific community a number of research target viz.; (i) production of rapid point of care diagnosis (ii) enhancement in surveillance and monitoring (iii) design of new therapeutic agents and finally (iv) vaccine development. We can only reduce the transmission level up to certain extent but cannot be demolished completely. For complete cure one has to develop vaccine.
Author declares there is no conflict of interest.
My sincere thanks to the doctor, nurses, and all other professionals for their continuous involvement directly or indirectly to fight against COVID-19.
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