The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we ...show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.
Thymically derived Foxp3(+) regulatory T cells (tTregs) constitute a unique T cell lineage that is essential for maintaining immune tolerance to self and immune homeostasis. However, Foxp3 can also ...be turned on in conventional T cells as a consequence of antigen exposure in the periphery, under both non-inflammatory and inflammatory conditions. These so-called peripheral Tregs (pTregs) participate in the control of immunity at sites of inflammation, especially at the mucosal surfaces. Although numerous studies have assessed in vitro generated Tregs (termed induced or iTregs), these cells most often do not recapitulate the functional or phenotypic characteristics of in vivo generated pTregs. Thus, there are still many unanswered questions regarding the T cell receptor (TCR) repertoire and function of pTregs as well as conditions under which they are generated in vivo, and the degree to which these characteristics identify specialized features of pTregs versus features that are shared with tTregs. In this review, we summarize the current state of our understanding of pTregs and their relationship to the tTreg subset. We describe the recent discovery of unique cell surface markers and transcription factors (including Neuropilin-1 and Helios) that can be used to distinguish tTreg and pTreg subsets in vivo. Additionally, we discuss how the improved ability to distinguish these subsets provided new insights into the biology of tTregs versus pTregs and suggested differences in their function and TCR repertoire, consistent with a unique role of pTregs in certain inflammatory settings. Finally, these recent advances will be used to speculate on the role of individual Treg subsets in both tolerance and autoimmunity.
Salinity severely limits wheat production in many parts of the world. Development of salt tolerant varieties represents the most practical option for enhancing wheat production from these areas. ...Application of marker assisted selection may assist in fast tracking development of salt tolerant wheat varieties. However, SSR markers available in the public domain are not specifically targeted to functional regions of wheat genome, therefore large numbers of these need to be analysed for identification of markers associated with traits of interest. With the availability of a fully annotated wheat genome assembly, it is possible to develop SSR markers specifically targeted to genic regions. We performed extensive analysis to identify candidate gene based SSRs and assessed their utility in characterizing molecular diversity in a panel of wheat genotypes.
Our analysis revealed, 161 SSR motifs in 94 salt tolerance candidate genes of wheat. These SSR motifs were nearly equally distributed on the three wheat sub-genomes; 29.8% in A, 35.7% in B and 34.4% in D sub-genome. The maximum number of SSR motifs was present in exons (31.1%) followed by promoters (29.8%), 5'UTRs (21.1%), introns (14.3%) and 3'UTRs (3.7%). Out of the 65 candidate gene based SSR markers selected for validation, 30 were found polymorphic based on initial screening and employed for characterizing genetic diversity in a panel of wheat genotypes including salt tolerant and susceptible lines. These markers generated an average of 2.83 alleles/locus. Phylogenetic analysis revealed four clusters. Salt susceptible genotypes were mainly represented in clusters I and III, whereas high and moderate salt tolerant genotypes were distributed in the remaining two clusters. Population structure analysis revealed two sub-populations, sub-population 1 contained the majority of salt tolerant whereas sub-population 2 contained majority of susceptible genotypes. Moreover, we observed reasonably higher transferability of SSR markers to related wheat species.
We have developed salt responsive gene based SSRs in wheat for the first time. These were highly useful in unravelling functional diversity among wheat genotypes with varying responses to salt stress. The identified gene based SSR markers will be valuable genomic resources for genetic/association mapping of salinity tolerance in wheat.
A genome-wide association study (GWAS) was conducted using six different multi-locus GWAS models and 35K SNP array to demarcate genomic regions underlying reproductive stage salinity tolerance. ...Marker-trait association analysis was performed for salt tolerance indices (STI) of 11 morpho-physiological traits, and the actual concentrations of Na+ and K+, and the Na+/K+ ratio in flag leaf. A total of 293 significantly associated quantitative trait nucleotides (QTNs) for 14 morpho-physiological traits were identified. Of these 293 QTNs, 12 major QTNs with R2 ≥ 10.0% were detected in three or more GWAS models. Novel major QTNs were identified for plant height, number of effective tillers, biomass, grain yield, thousand grain weight, Na+ and K+ content, and the Na+/K+ ratio in flag leaf. Moreover, 48 candidate genes were identified from the associated genomic regions. The QTNs identified in this study could potentially be targeted for improving salinity tolerance in wheat.
•Fifty consistent genomic regions were demarcated for 13 morpho-physiological traits using six multi-locus GWAS models.•Four highly consistent QTNs/genomic regions, one each for flag leaf Na+ content (Q.Na-6AL), flag leaf K+ content (Q.K-1AS), above ground biomass (Q.STI-BM-1BL) and Na+/K+ Ratio (Q.NaK-1BS) were identified.•Wheat chromosome 5B harbored the maximum number of genomic regions for yield contributing traits.•The identified QTN regions contained some important stress responsive candidate genes encoding for cytochrome 450 (CYP) family protein, detoxification protein, auxin responsive protein, MYB family transcription factor and peptidylprolyl isomerase (PPI).•ISIS EM-BLASSO is the most efficient model for multi-trait mapping of reproductive stage salinity tolerance.
Cultivars with efficient root systems play a major role in enhancing resource use efficiency, particularly water absorption, and thus in drought tolerance. In this study, a diverse wheat association ...panel of 136 wheat accessions including mini core subset was genotyped using Axiom 35k Breeders' Array to identify genomic regions associated with seedling stage root architecture and shoot traits using multi-locus genome-wide association studies (ML-GWAS). The association panel revealed a wide variation of 1.5- to 50-fold and were grouped into six clusters based on 15 traits. Six different ML-GWAS models revealed 456 significant quantitative trait nucleotides (QTNs) for various traits with phenotypic variance in the range of 0.12-38.60%. Of these, 87 QTNs were repeatedly detected by two or more models and were considered reliable genomic regions for the respective traits. Among these QTNs, eleven were associated with average diameter and nine each for second order lateral root number (SOLRN), root volume (RV) and root length density (RLD). A total of eleven genomic regions were pleiotropic and each controlled two or three traits. Some important candidate genes such as Formin homology 1, Ubiquitin-like domain superfamily and ATP-dependent 6-phosphofructokinase were identified from the associated genomic regions. The genomic regions/genes identified in this study could potentially be targeted for improving root traits and drought tolerance in wheat.
Bread wheat (
L.) is widely grown in sub-tropical and tropical areas and, as such, it is exposed to heatstress especially during the grain filling period (GFP). Global warming has further affected ...its production and productivity in these heat-stressed environments. We examined the effects of heatstress on 18 morpho-physiological and yield-related traits in 96 bread wheat accessions. Heat stress decreased crop growth and GFP, and consequently reduced morphological and yield-related traits in the delayed sown crop. A low heat susceptibility index and high yield stability were used for selecting tolerant accessions. Under heatstress, the days to 50% anthesis, flag-leaf area, chlorophyll content, normalized difference vegetation index (NDVI), thousand grain weight (TGW), harvest index and grain yield were significantly reduced both in tolerant and susceptible accessions. The reduction was severe in susceptible accessions (48.2% grain yield reduction in IC277741). The plant height, peduncle length and spike length showeda significant reduction in susceptible accessions, but a non-significant reduction in the tolerant accessions under the heatstress. The physiological traits like the canopy temperature depression (CTD), plant waxiness and leaf rolling were increased in tolerant accessions under heatstress. Scanning electron microscopy of matured wheat grains revealed ultrastructural changes in endosperm and aleurone cells due to heat stress. The reduction in size and density of large starch granules is the major cause of the yield and TGW decrease in the heat-stress-susceptible accessions. The most stable and high-yielding accessions, namely, IC566223, IC128454, IC335792, EC576707, IC535176, IC529207, IC446713 and IC416019 were identified as the climate-smart germplasm lines. We selected germplasm lines possessing desirable traits as potential parents for the development of bi-parent and multi-parent mapping populations.
Wheat, an important cereal crop globally, faces major challenges due to increasing global population and changing climates. The production and productivity are challenged by several biotic and ...abiotic stresses. There is also a pressing demand to enhance grain yield and quality/nutrition to ensure global food and nutritional security. To address these multifaceted concerns, researchers have conducted numerous meta-QTL (MQTL) studies in wheat, resulting in the identification of candidate genes that govern these complex quantitative traits. MQTL analysis has successfully unraveled the complex genetic architecture of polygenic quantitative traits in wheat. Candidate genes associated with stress adaptation have been pinpointed for abiotic and biotic traits, facilitating targeted breeding efforts to enhance stress tolerance. Furthermore, high-confidence candidate genes (CGs) and flanking markers to MQTLs will help in marker-assisted breeding programs aimed at enhancing stress tolerance, yield, quality and nutrition. Functional analysis of these CGs can enhance our understanding of intricate trait-related genetics. The discovery of orthologous MQTLs shared between wheat and other crops sheds light on common evolutionary pathways governing these traits. Breeders can leverage the most promising MQTLs and CGs associated with multiple traits to develop superior next-generation wheat cultivars with improved trait performance. This review provides a comprehensive overview of MQTL analysis in wheat, highlighting progress, challenges, validation methods and future opportunities in wheat genetics and breeding, contributing to global food security and sustainable agriculture.
MicroRNAs are ~22 nucleotide long non-coding RNAs that regulate gene expression at posttranscriptional level. Genome-wide analysis was performed to identify polycistronic miRNAs from wheat. Total 89 ...polycistronic miRNAs were identified in bread wheat which were distributed on three component sub-genomes (A = 26, B = 33 and D = 30). Except some, most of the identified polycistronic miRNAs were also present in other cultivated and wild wheat species. Expression of 11 identified polycistronic miRNAs could be validated using previously assembled transcriptomes, RNA-seq/s-RNA seq data of cultivated and wild wheats and RT-PCR. Polycistronic miRNAs orthologs were also localized on rice and Brachypodium genomes. As a case study, we also analyzed molecular evolution of miR395 family polycistrons in wheat. Both tandem and segmental duplications contributed to expansion of miR395 family polycistrons. Our findings provide a comprehensive view on wheat polycitronic miRNAs that will enable their in-depth functional analysis in the future.
•Polycitrsonic microRNA (miRNA) loci exist in wheat and these are broadly conserved across the ancestral wheat species.•Expression of 11 polycistronic miRNA loci were validated using previously assembled transcriptomes, deep small RNA sequencing (sRNA-seq) data sets and reverse transcription-polymerase chain reaction (RT-PCR).•miR395 family polycistrons were evolved by duplication and subsequent divergence of an ancestral basic polycitronic unit containing two genes.•Massive loss of nucleotide diversity at majority of the A sub-genome polycistronic miRNA loci during domestication. However, a few polycistronic loci were highly conserved across domesticated and wild wheat.
Wheat (
.) is a staple food crop for the global human population, and thus wheat breeders are consistently working to enhance its yield worldwide. In this study, we utilized a sub-set of Indian wheat ...mini core germplasm to underpin the genetic architecture for seed shape-associated traits. The wheat mini core subset (125 accessions) was genotyped using 35K SNP array and evaluated for grain shape traits such as grain length (GL), grain width (GW), grain length, width ratio (GLWR), and thousand grain weight (TGW) across the seven different environments (E
, E
, E
, E
, E
, E
, E
, and E
). Marker-trait associations were determined using a multi-locus random-SNP-effect Mixed Linear Model (mrMLM) program. A total of 160 non-redundant quantitative trait nucleotides (QTNs) were identified for four grain shape traits using two or more GWAS models. Among these 160 QTNs, 27, 36, 38, and 35 QTNs were associated for GL, GW, GLWR, and TGW respectively while 24 QTNs were associated with more than one trait. Of these 160 QTNs, 73 were detected in two or more environments and were considered reliable QTLs for the respective traits. A total of 135 associated QTNs were annotated and located within the genes, including ABC transporter, Cytochrome450, Thioredoxin_M-type, and hypothetical proteins. Furthermore, the expression pattern of annotated QTNs demonstrated that only 122 were differentially expressed, suggesting these could potentially be related to seed development. The genomic regions/candidate genes for grain size traits identified in the present study represent valuable genomic resources that can potentially be utilized in the markers-assisted breeding programs to develop high-yielding varieties.
The high demand for bone grafts has motivated the development of implants with excellent osteogenic activity, whereas the risk of implant-associated infection, particularly given the rise of ...antimicrobial resistance, has compelled the development of implants with innovative antimicrobial strategies in which a small amount of bactericidal agent can effectively kill a wide range of bacteria. To induce antibacterial property, the surface of Grade-5 bone plate titanium implants used in clinical applications was modified using direct current (DC) sputter coating followed by thermal annealing. The 15 nm silver film-coated implants were thermally annealed in the furnace for 15 min at 750 °C. The modified implant surface's antibacterial efficacy against
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),
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),
, and
bacteria has been assessed using a colony-forming assay. On the modified implant surface, the growth of
and
bacteria is reduced by 99.72%, while highly drug-resistant bacteria are inhibited by 96.59%. The MTT assay was used to assess the cytotoxicity of the modified bone-implant surface against NIH3T3 mouse fibroblast cells. The modified bone-implant surface promoted fibroblast growth and demonstrated good cytocompatibility. Furthermore, the mechanical properties of the implant were not harmed by this novel surface modification method. This method is simple and provides new insight into surface modification of commercial metallic implants to have effective antibacterial properties against various classes of bacteria.
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