Biology subjects

Rai, N.

Publications and source records attributed to Rai, N..

16 recordsLinked to original sources

bioRxiv2026

Hierarchical control of remyelination by heparan sulfate sulfation

Efficient myelin regeneration requires coordinated signaling between oligodendrocyte progenitor cells (OPCs) and the extracellular matrix, yet how specific heparan sulfate sulfation patterns regulate this process remains poorly understood. The extracellular endosulfatases Sulf1 and Sulf2 selectively remove 6-O-sulfate groups from heparan sulfate proteoglycans (HSPGs). We previously demonstrated that these enzymes are highly expressed by OPCs following demyelination and inhibit OPC recruitment, differentiation, and remyelination through activation of BMP and WNT signaling. We investigated whether sulfotransferases that establish 2-O and 6-O sulfation during HSPG biosynthesis regulate remyelination. Using OPC-specific conditional knockout models, deletion of the 2-O sulfotransferase Hs2st1 enhanced OPC recruitment, oligodendrocyte differentiation, and remyelination through suppression of BMP and WNT signaling. Loss of 2-O sulfation induced compensatory remodeling of the heparan sulfate glycome, with a marked enrichment of 6-O-sulfated HS species. Conversely, deletion of 6-O sulfotransferases impaired OPC recruitment and differentiation and reversed the Hs2st1 phenotype, identifying 6-O sulfation as the dominant functional determinant of remyelination. Together, these findings establish hierarchical control of remyelination by heparan sulfate sulfation, demonstrating that compensatory remodeling of the heparan sulfate glycome governs regenerative signaling following demyelination.

neuroscience↗

bioRxiv2026

A widespread gut bacterial lineage distinguished by redox metabolism and phage defense

Genomic variation within gut microbial species can have consequences for host health and disease. However, for low abundance species, these variations can be difficult to capture by both culture-dependent and -independent approaches. Here, we focus on the prevalent but low abundance gut Actinomycetota Eggerthella lenta. We developed a selective media for sensitive and specific isolation of E. lenta from human stool. Genomes from 87 new E. lenta isolates were combined with prior high-quality assemblies, shedding light on within-species functional diversity. Phylogenetic analysis revealed a broadly distributed subclade, which we refer to as E. lenta Group B. This lineage was differentiated by its metabolic potential and bacteriophage defense, though mobile elements were shared broadly across the species. Notably, Group B was positively associated with intestinal inflammation in subjects with inflammatory bowel disease. Overall, these results emphasize the importance of bacterial population structure in host-microbiome interactions and provide a framework to study low-abundance gut taxa. HIGHLIGHTSO_LISelective media enables E. lenta isolation and reveals high prevalence in humans C_LIO_LIDiscovery of a distinctive lineage within E. lenta undergoing genome reduction C_LIO_LIE. lenta Group B has altered metabolism, phage defense, and disease associations C_LIO_LIA widespread conjugative plasmid could enable improved genetics C_LI

microbiology↗

bioRxiv2026

Ancient human genomes from Ladakh reveal Tibetan, South Asian, and Central Asian admixture over the last three millennia

The trans-Himalayan region of Ladakh occupies a strategic position at the crossroads of South Asia, the Tibetan Plateau, and Central Asia, with archaeological evidence pointing to long-term cultural exchanges across these regions. However, the human genetic history of Ladakh remains largely unexplored. We generated paleogenomic data from seven individuals recovered from two sites in Western Ladakh - the Old Lady Spider Cave and Hanu - of which six are dated to 531-585 CE and one to the 19th century CE. The older individuals share substantial genetic ancestry with Tibetan groups but also harbor major contributions from two additional sources: one corresponding to the currently-oldest observation of the Ancestral North Indian genetic component that characterizes several present-day populations in North India and Pakistan, and another related to ancient Central Asian groups, with admixture events occurring between [~]2,100-2,500 years ago. In contrast, the later individual falls within a previously described ancient northern Himalayan genetic cline based on [~]1,100-1,300-year-old individuals from Himachal Pradesh, with ancestries related to ancient Tibetan and Steppe-related sources. Stable isotope analysis suggests that these individuals were local to Ladakh in late life and practiced an agro-pastoralist subsistence. Our study establishes that Ladakhs central role in Eurasian economic and socio-cultural networks was shaped by dynamic and sustained gene flow linking high-altitude Himalayan groups with both lowland South Asia and Inner Asia.

genetics↗

bioRxiv2026

Distinct trajectories of urbanization shape the human gut microbiome across South Asia

Human gut microbiomes respond to lifestyle transitions, yet the extent to which these responses are conserved across spatio-cultural contexts remains undercharacterized. We present the South Asian MicroBiome ARray (SAMBAR), a population-scale 16S gut microbiome study of 575 adults from ten geographically and socio-culturally diverse South Asian communities. Each community was sampled in ancestral villages and urban centers, enabling controlled comparisons of geography and lifestyle. Relative to global cohorts, SAMBAR microbiomes occupy a distinct compositional space with stronger correlation to geography and community membership than lifestyle. Although urbanization is consistently associated with increased abundance of disease-linked taxa, microbiome responses to lifestyle transitions are largely community-driven, including the acquisition of wheat- and dairying-associated microbial modules in some communities that may facilitate non-genetic adaptation to lactase non-persistence. Microbiome responses to urbanization are heterogeneous even at regional scales, reflecting local culture and geography and underscoring the need for community-specific investigations of health impacts.

microbiology↗

bioRxiv2025

Comparative proteomics uncovers distinct biomarkers, protein networks and defense responses in tomato during beneficial and pathogenic microbial interactions

The molecular mechanisms underlying plant responses to beneficial and pathogenic microbial interactions has been uncovered in tomato at the proteomic level. Our study employed LC-MS- based proteomics to investigate differential protein regulation in tomato plants during interactions with beneficial bacteria (Bacillus subtilis BV7) versus pathogenic fungus (Alternaria solani). Comparative analysis revealed distinct protein signatures characterizing each interaction: 232 unique proteins in BV7-treated plants versus 96 in pathogen-infected plants, with 54 proteins shared between treatments. BV7 inoculation enhanced proteins involved in photosynthesis and primary metabolism, with PSI-K emerging as the top biomarker (score 2.53), while pathogen infection triggered focused defense responses with Cytochrome b559 (score 2.38) as the key biomarker. Metabolic pathway analysis demonstrated that BV7 uniquely enhanced vitamin metabolism (thiamine, riboflavin, folate) and energy production pathways, while pathogen infection activated defense-related phenylpropanoid biosynthesis. Analysis of defense enzymes showed pathogen infection induced highest activities of PAL (39.4{+/-}0.46 U h-1 g-1 fw), SOD (29.9{+/-}0.94 U mg-1 protein), POD (3.18{+/-}0.07 g g-1 fw min-1), APx (15.58{+/-}0.23 U mg-1 protein), and GPx (71.51{+/-}0.7 U mg-1 protein), while BV7 maintained moderate enzyme levels, suggesting balanced growth-defense responses. The shared proteins between treatments indicate a common molecular framework potentially contributing to induced systemic resistance. These findings provide novel insights into plant-microbe interactions at the molecular level, identifying specific protein biomarkers and metabolic pathways that could be targeted for enhancing crop productivity and disease resistance. The results have significant implications for developing biological control strategies and improving sustainable agricultural practices.

plant biology↗

bioRxiv2025

Protection of photosynthesis by UVR8 and cryptochromes in Arabidopsis under blue and UV radiation

Photosynthesis in plants is negatively affected by high light intensity and UV radiation. The photoreceptors UV RESISTANCE LOCUS 8 (UVR8) and CRYPTOCHROMES (CRYs) mediate perception and acclimation of plants to UV-B/UV-A2 (290-340 nm) and UV-A1/blue light (350-500 nm), respectively. However, their roles in photoprotection of photosynthesis across different wavebands of the spectrum remain unclear. Using chlorophyll fluorescence and LED lighting we studied the roles of UVR8 and CRYs in maintaining photosynthetic capacity in Arabidopsis exposed to UV-B, UV-A1, and blue light. Analysis of quantum yield of Photosystem II, non-photochemical quenching, and LHCII phosphorylation demonstrated that CRYs preserve photosynthetic performance in plants exposed to UV-B, UV-A1, and blue light. UVR8 and CRYs exhibit partially redundant functions in maintaining photosynthetic activity under UV-B, UV-A1, and blue light, and in preventing photodamage under high UV-A1 irradiance. Impaired UVR8 and CRY signaling reduced epidermal flavonol accumulation in leaves, which further compromised photoprotection. These findings provide valuable insights into how UV and blue light perception contribute to photoprotection, with broad implications for plant performance both in natural and managed environments.

plant biology↗

bioRxiv2024

A minimally invasive thrombotic stroke model to study circadian rhythm in awake mice

Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively impacting their translational relevance. Here we aimed to develop a minimally invasive thrombotic stroke model through magnetic particle delivery that does not require craniotomy, is amenable to reperfusion therapy, can be combined with in vivo imaging modalities, and can be performed in awake mice. We found that the model results in reproducible cortical infarcts within the middle cerebral artery (MCA) with cytologic and immune changes similar to that observed with more invasive distal MCA occlusion models. Importantly, the injury produced by the model was ameliorated by tissue plasminogen activator (tPA) administration. We also show that MCA occlusion in awake animals results in bigger ischemic lesions independent of day/night cycle. Magnetic particle delivery had no overt effects on physiologic parameters and systemic immune biomarkers. In conclusion, we developed a novel stroke model in mice that fulfills many requirements for modeling human stroke.

neuroscience↗

bioRxiv2024

The genetic landscape, gene flow and adaptation in Ladakh highlanders of trans-Himalayas

Trans-Himalayan Ladakh has witnessed complex cultural movements and demographic changes since the Neolithic period, which is still continue despite the harsh, inhospitable and cold climate. Although geographically isolated from mainland South Asia, Ladakh has historic trade routes and is well connected and accessible to travelers from Tibet and Central Asia. Despite its rich cultural heritage, a detailed description of the genetic landscape of the Ladakh region is completely lacking, particularly with regard to genome-wide analysis and larger sample sizes. Therefore, in the current study, we genotyped 80 individuals from Kargil and Leh districts of the Union Territory of Ladakh, India. Here, we performed a comprehensive genetic analysis based on allele frequency and haplotype sharing. Our analysis revealed the presence of two distinct genetic lineages in the region with quite distinct genetic composition. The population of Leh Region is more similar to East Asian and Southeast Asian populations. In contrast, the population of the Kargil Region (LDKLA) is more similar to Indo-European populations. Demographic modeling suggests that the Leh group shares a genetic history with Tibetans, while the Kargil group showed great affinities with Kashmiri Muslims, Gujjars and Nepalese Brahmins, and both showed recent admixture. Both groups have experienced a founder event around during 11th to 22nd generations ago, the duration of which coincided with the Mughal invasion. The genome-wide scan for a signal of positive selection revealed genetic signatures of high-altitude adaptation (EPAS1 and ELMO2) in the Leh population, while in the Kargil population the key gene signatures were associated with immunity and female fertility.

genetics↗

bioRxiv2023

Development and clinical validation of molecular subgrouping in medulloblastoma by targeted methylation sequencing

BackgroundThe WHO classification of CNS tumors confers promising prognostic value to the molecular classification of medulloblastoma (MB). Next-generation sequencing (NGS) has been the primary method employed for molecular classification through transcriptomic, genomic, or methylation profiling. However, due to cost and infrastructural needs, particularly in developing countries, we propose a relatively simple, rapid, and economical Sanger sequencing-based targeted methylation sequencing method for MB classification and prognostication. MethodsEleven epigenetic targets were amplified using optimized primers and bisulfite-converted DNA for Sanger sequencing. Chromas software was used for low-quality data trimming and NCBIs Needleman Wunsch alignment tool was used for sequence alignment to reference. The developed method was applied to tissues from twelve cases of medulloblastoma. ResultsSuccessful interpretation of methylation status in ten out of eleven targets was achieved which was sufficient for classification according to the latest WHO classification of Medulloblastoma tumors. Twelve medulloblastoma cases were classified into WNT (n=2), Group 3 (n=5), and Group 4 (n=5). ConclusionThe developed Sanger sequencing method is a cost-effective, in-house solution that can be used for molecular subgrouping of medulloblastoma. It offers an alternative to NGS, can be done on a case-to-case basis, and does not require high-end infrastructure, sample pooling, or extensive bioinformatics knowledge. Impact statementMolecular classification is imperative for determining the prognosis of medulloblastoma and is recommended by WHO. However, NGS proves to be an expensive option in developing countries. This study has come up with an affordable targeted methylation Sanger sequencing method requiring minimal bioinformatic skills, by utilizing epigenetic targets, for prognostication and risk stratification in medulloblastoma patients. The molecular subgroups of all recruited cases were successfully determined according to WHO classification which is crucial information that, when combined with clinical findings, will enable the clinicians to determine effective treatment strategies.

cancer biology↗

bioRxiv2023

Dicer deficiency in microglia leads to accelerated demyelination and failed remyelination

Microglia are the resident immune cells of the central nervous system (CNS) and are important regulators of normal brain functions. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Here we probed the impact of microRNA (miRNA)-mediated post-transcriptional gene regulation using a mouse model lacking microglia/macrophage-specific Dicer expression during demyelination and remyelination. Conditional Dicer ablation and loss of miRNAs in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting OL progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, these results highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/562812v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@71b542org.highwire.dtl.DTLVardef@13338b3org.highwire.dtl.DTLVardef@1cfa6c0org.highwire.dtl.DTLVardef@1ccc099_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Integrating genetic and oral histories of Southwest Indian populations

Over the past decade, genomic data has contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 158 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Greats army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Andaman Islanders. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.

genetics↗

bioRxiv2020

The photoreceptor UVR8 mediates the perception of both UV-B and UV-A wavelengths up to 350 nm of sunlight with responsivity moderated by cryptochromes

The photoreceptors UV RESISTANCE LOCUS 8 (UVR8) and CRYPTOCHROMES 1 and 2 (CRYs) play major roles in the perception of UV-B (280-315 nm) and UV-A/blue radiation (315-500 nm), respectively. However, it is poorly understood how they function in sunlight. The roles of UVR8 and CRYs were assessed in a factorial experiment with Arabidopsis thaliana wild-type and photoreceptor mutants exposed to sunlight for 6 h or 12 h under five types of filters with cut-offs in UV and blue-light regions. Transcriptome-wide responses triggered by UV-B and UV-A wavelengths shorter than 350 nm (UV-Asw) required UVR8 whereas those induced by blue and UV-A wavelengths longer than 350 nm (UV-Alw) required CRYs. UVR8 modulated gene expression in response to blue light while lack of CRYs drastically enhanced gene expression in response to UV-B and UV-Asw. These results agree with our estimates of photons absorbed by these photoreceptors in sunlight and with in vitro monomerization of UVR8 by wavelengths up to 335 nm. Motif enrichment analysis predicted complex signaling downstream of UVR8 and CRYs. Our results highlight that it is important to use UV waveband definitions specific to plants photomorphogenesis as is routinely done in the visible region.

plant biology↗

bioRxiv2019

Genetic variation for root architectural traits in response to phosphorus deficiency in mungbean at the seedling stage

Roots enable the plant to survive in natural environment by providing anchorage and acquisition of water and nutrients. In this study, 153 mungbean genotypes were studied to compare root architectural traits under normal and low phosphorus conditions. Significant variations, medium to high heritability, near normal distribution and significant correlations were observed for studied root traits. Total root length (TRL) was positively correlated with total surface area (TSA), total root volume (TRV), total root tips (TRT) and root forks. The first two principal components explained the 79.19 % and 78.84% of the total variation under normal and low phosphorus conditions. TRL, TSA and TRV were major contributors of variation and can be utilized for screening of phosphorus uptake efficiency at seedling stage. Released Indian mungbean varieties were found to be superior for root traits than other genotypic groups. Based on comprehensive phosphorus efficiency measurement, IPM-288, TM 96-25, TM 96-2, M 1477, PUSA 1342 were found to be best five highly efficient genotypes whereas M 1131, PS-16, Pusa Vishal, M 831, IC 325828 were highly inefficient genotypes. These identified highly efficient lines are valuable genetic resources for phosphorus uptake efficiency that could be used in mungbean breeding programme.

genetics↗

bioRxiv2018

A network-based model for drug repurposing in Rheumatoid Arthritis

BackgroundThe identification of drug repositioning targets through computational methods has the potential to provide a fast, inexpensive alternative to traditional drug discovery process. Diseases where complicated pathophysiology evolves over time are excellent targets for such methods. One such disease is Rheumatoid Arthritis (RA), a chronic inflammatory autoimmune disease, where the drug survival at 5-years is less than 50% for patients treated with disease-modifying anti-rheumatic drugs (DMARDs).\n\nMethods and FindingsWe have developed a network-based approach for drug repositioning that takes into account the human interactome network, proximity measures between drug targets and disease-associated genes, potential side-effects, genome-wide gene expression and disease modules that emerge through pertinent analysis. We found that all DMARDs, except for hydroxychloroquine (HCQ), were found to be significantly proximal to RA-related genes. Application of the method on anti-diabetic agents, statins and H2 receptor blockers identified anti-diabetic agents - gliclazide, sitagliptin and metformin - that have similar network signatures with the DMARDs. Subsequent in-vitro experiments on mouse fibroblast NIH-3T3 cells validated the findings and the down regulation of six key RA-related inflammatory genes. Our analysis further argues that the combination of HCQ and/or sulfasalazine with methotrexate (MTX) is predicted to have an additive synergistic effect in treatment based on network complementarity. Similarly, leflunomide and tofacitinib were found to be suitable alternatives upon chemoresistance to MTX-based double/triple therapy, given the complementary network signatures and overlapping critical target hubs.\n\nConclusionsOur results corroborate that computational methods that are based on network proximity, among other contextual information can help narrow down the drug candidates for drug repositioning, as well as support decisions for combinatorial drug treatment that is tailored to patients needs.\n\nAuthor summaryThe network-based proximity between drug targets and disease genes can provide novel insights on the repercussion, interplay, and reposition of drugs in the context of disease. Disease-modifying anti-rheumatic drugs (DMARDs) located significantly close to rheumatoid arthritis (RA)-associated genes and RA-relevant pathways. Three anti-diabetic agents were identified to have an anti-inflammatory effect like DMARDs. We built RA disease module encompassing the emerging small-molecule targets and functional neighbors, which better explained the RA pathophysiology. By proximity and network robustness, tofacitinib and tocilizumab were the most potent for RA disease module as a single agent, and this is consistent with clinical observation. Side effects of clinical importance are predictable by measuring network-based proximity between drug targets and side effect protein. Network-based drug-disease proximity offers a novel and clinically actionable information about drugs and opens the new possibility to drug combination and reposition.

systems biology↗

bioRxiv2018

The Genomic Formation of South and Central Asia

The genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia--consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC--and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.\n\nOne Sentence SummaryGenome wide ancient DNA from 357 individuals from Central and South Asia sheds new light on the spread of Indo-European languages and parallels between the genetic history of two sub-continents, Europe and South Asia.

genomics↗

bioRxiv2017

Like Sugar in Milk: Reconstructing the genetic history of the Parsi population

BackgroundThe Parsis, one of the smallest religious community in the world, reside in South Asia. Previous genetic studies on them, although based on low resolution markers, reported both Iranian and Indian ancestries. To understand the population structure and demographic history of this group in more detail, we analyzed Indian and Pakistani Parsi populations using high-resolution autosomal and uniparental (Y-chromosomal and mitochondrial DNA) markers. Additionally, we also assayed 108 mitochondrial DNA markers among 21 ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India.\n\nResultsOur extensive analyses indicated that among present-day populations, the Parsis are genetically closest to Middle Eastern (Iranian and the Caucasus) populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred [~]1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement.\n\nConclusionsWe show that the Parsis are genetically closest to the Neolithic Iranians, followed by present-day Middle Eastern populations rather than those in South Asia and provide evidence of sex-specific admixture from South Asians to the Parsis. Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7thcentury and in agreement with their assimilation into the Indian sub-continents population and cultural milieu \"like sugar in milk\". Moreover, in a wider context our results suggest a major demographic transition in West Asia due to Islamic-conquest.

evolutionary biology↗