Biology subjects

Mallick, S.

Publications and source records attributed to Mallick, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Spatial Biology and Organoid Technologies Reveal a Potential Therapy-Resistant Cancer Stem Cell Population in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a 5-year survival rate of less than 10%. Chemotherapy is the current standard-of-care (SOC) for advanced PDAC; however, treatment resistance driven by a complex and immunosuppressive tumor microenvironment (TME) limits its effectiveness. To address mechanisms of resistance, we studied cabozantinib (cabo), a multi-kinase inhibitor approved for several solid tumors. Cabo has shown promise in preclinical PDAC models and clinical trials, particularly when combined with immunotherapy, but its mechanisms of action within the human PDAC TME and its potential to overcome therapy resistance remain unclear. Using CosMx Spatial Molecular Imaging (CosMx SMI) and Orion Multiplex Immunofluorescence (MxIF), we analyzed PDAC tissues collected after first line systemic chemotherapy and the Whipple surgical procedure, as well as from liver or lung metastatic sites from patients with PDAC. To functionally model the TME, we established matched patient-derived organoid (PDO) co-cultures harboring cancer associated fibroblasts (CAFs), and autologous immune cells (IMM) (PDO/CAF/IMM). These models were used to evaluate the effects of cabo and pembrolizumab, an anti-PD1 immune checkpoint inhibitor, with benchmarking of findings to the patients TME. Spatial analysis of post-chemotherapy and metastatic PDAC tissues revealed heterogeneous cellular neighborhoods within the TME, including enrichment of Schwann cells, CAFs, T regulatory cells, and cancer stem cells (CSCs). Distinct niches were observed in metastatic liver tissues, characterized by mesenchymal stem cells, fibroblasts, including myCAFs and iCAFs, and CSCs expressing CD44 and TROP2. In PDO/CAF/IMM co-cultures, treatment with cabo in combination with pembrolizumab enhanced cancer cell death by depleting myeloid-derived suppressor cells (MDSCs) and promoted cytotoxic T lymphocyte proliferation. Across both patient tissues and treated co-cultures, a persistent SOC-resistant cancer stem cell population emerged that expressed CD44 variant 9 (CD44v9). Taken together, these integrative spatial and organoid-based studies demonstrate that cabo can remodel the PDAC TME and potentiate PD-1 immunotherapy in preclinical models, while resistance associates with a CD44v9+ CSC population, revealing a potential therapeutic target.

cancer biology↗

bioRxiv2025

Hematopoietic Stem Cells Modulate Tumor Immune-Environment to Target Triple-Negative Breast Cancer via Altering Mitochondrial Bioenergetics

Ontogenic development of Hematopoietic stem cells (HSCs) takes place at diverse anatomical niches. Moreover, during embryonic development, HSCs migrate from the aorta-gonad mesonephros (AGM) to the fetal liver and finally to the bone marrow immediately after childbirth. Hence, the primary residence of adult HSCs in the bone marrow continues replenishing the hematopoietic lineage pool. In vivo, the HSC niche is significant and might be harnessed in regenerative medicine. HSCs in various niches have exhibited their respective tropism and proliferations based on the growth factors secreted by the niche. Accordingly, in this work, we hypothesized HSCs tropism towards cancer and stem cell niche of triple-negative breast cancer (TNBC) and HER2+, having a high relapse rate for possible cell therapy development. Our results indicate that HSC exclusive tropism towards breast cancer stem cells (CSC) and interaction with the cancer milieu lead to HSC differentiation into T-lymphocyte cells (CD4 & CD8). Moreover, the single-cell type proteomics of the migrated HSCs towards TNBC-CSCs and HER2+ cells indicated upregulation of IL-7 and Notch protein and several other upregulated proteins primarily involved in T cell activation and migration-related pathways. Likewise, the metabolomics from HSCs-derived conditioned media-treated CSCs, and HER2+ cells showed the capability of HSC-CM in arresting the growth and cell cycle of TNBC-CSC via altered mitochondrial bioenergetics. Hence, this study paves the way toward harnessing the potential of both HSCs and HSC-CM for personalized medicine against TNBC CSCs. HighlightsO_LIHematopoietic stem cells exhibited tumor tropism towards triple negative breast cancer stem cells and HER2+ cancer cells. C_LIO_LIUpon migration in the tumor milieu, HSCs differentiated into T cells, targeted CSCs, and modulated the upregulation of interleukin-7 and notch proteins. C_LIO_LIHSCs-CM inhibited the cell cycle in TNBC-CSCs by downregulating CDK1, disrupting mitochondrial bioenergetics via upregulated Drp1, and inducing CSC apoptosis. C_LIO_LIParacrine signaling from HSCs via conditioned media induced metabolic stress and disrupted key metabolic pathways in TNBC-CSCs. C_LI SummaryHematopoietic stem cells (HSCs) are known for their regenerative potential in the blood system. This study reveals the novel therapeutic potential of hematopoietic stem cells (HSCs) in combating triple-negative breast cancer stem cells (TNBC-CSCs). HSCs exhibited tropism towards TNBC-CSCs, themselves differentiated into T cells within the tumor microenvironment, leading to targeted cell killing of TNBC-CSCs. In addition, paracrine signaling from HSC-conditioned media (CM) induced metabolic stress in TNBC-CSCs and disrupted key metabolic pathways. HSC-CM also disrupted mitochondrial dynamics and function, leading to DNA damage and apoptosis. Critically, HSC-CM impaired TNBC-CSC stemness by downregulating stemness genes, leading to the inhibition of 3D spheroid formation. Hence, our study highlights HSCs as a promising therapeutic strategy for targeting TNBC-CSCs via disrupted metabolic homeostasis and self-renewal.

cancer biology↗

bioRxiv2025

Long-term hunter-gatherer continuity in the Rhine-Meuse region was disrupted by local formation of expansive Bell Beaker groups

The first phase of the ancient DNA revolution painted a broad-brush picture of European Holocene prehistory, whereby 6500-4000 BCE, farmers descending from western Anatolians mixed with local hunter-gatherers resulting in 70-100% ancestry turnover, then 3000-2500 BCE people associated with the Corded Ware complex spread steppe ancestry into north-central Europe. We document an exception to this pattern in the wider Rhine-Meuse area in communities in the wetlands, riverine areas, and coastal areas of the western and central Netherlands, Belgium and western Germany, where we assembled genome-wide data for 109 people 8500-1700 BCE. Here, a distinctive population with high hunter-gatherer ancestry ([~]50%) persisted up to three thousand years later than in continental European regions, reflecting limited incorporation of females of Early European Farmer ancestry into local communities. In the western Netherlands, the arrival of the Corded Ware complex was also exceptional: lowland individuals from settlements adopting Corded Ware pottery had hardly any steppe ancestry, despite a characteristic early Corded Ware Y-chromosome. The limited influx may reflect the unique ecology of the regions river-dominated landscapes, which were not amenable to wholesale adoption of the early Neolithic type of farming introduced by Linearbandkeramik, making it possible for previously established groups to thrive, and creating a persistent but permeable boundary that allowed transfer of ideas and low-level gene flow. This changed with the formation-through-mixture of Bell Beaker using populations [~]2500 BCE by fusion of local Rhine-Meuse people (9-17%) and Corded Ware associated migrants of both sexes. Their expansion from the Rhine-Meuse region then had a disruptive impact across a much wider part of northwest Europe, including Britain where its arrival was the main source of a 90-100% replacement of local Neolithic peoples.

genomics↗

bioRxiv2025

Magnetized Cellbots to Spatiotemporally Control Differentiation of Human-Induced Pluripotent Stem Cells

Precise spatiotemporal control of gene expression and cellular differentiation is essential for engineering native-like multicellular structures. Current cell differentiation approaches typically rely on externally provided inputs whose effects are not targeted to distinct cells in the appropriate state and hence cannot spatially organize and mature tissue structures as needed. Our work introduces a magnetically controlled microrobot (MR) platform for guiding mammalian cells to desired locations that, combined with synthetic biology, delivers biological signals at precise locations and times, enabling spatiotemporal control of cell-fate decision-making. We use synNotch, a cell-cell contact-based biological signaling that induces relevant gene expression in receivers when the receiver cells contact sender cells through ligand-receptor binding. Magnetically driven MRs are then allowed to be internalized by sender cells, resulting in magnetized sender cellbots. Using a 3-pair orthogonal Helmholtz coil system, we guided magnetized sender cellbots to precise locations in a receiver cell culture, activating desired fluorescent protein expression in target Chinese Hamster Ovary (CHO) receiver cells. Next, we engineered Human-Induced Pluripotent Stem Cells (hiPSC) to function as receivers that can be instructed by senders to differentiate into endothelial cells (ECs) via overexpression of ETV2 (ETS variant transcription factor 2), a master transcriptional regulator of endothelial cell development. Using our magnetic platform, we guided multiple sender cellbots to target locations on a monolayer of hiPSC receivers, resulting in differentiation of receivers into ECs and possible onset of vascular formation. Our approach provides a foundation for the engineering spatial patterns by activating conditional triggers based on MR location and cell state at multiple time points, enabling several applications such as control of organoid architecture.

synthetic biology↗

bioRxiv2025

Ancient DNA reveals diverse community organizations in the 5th millennium BCE Carpathian Basin

Little is known about the genetic connection system and community organization of Late Neolithic and Early Copper Age populations of the Carpathian Basin. Here, we present a comprehensive genetic investigation of these populations, leveraging whole genome data from 125 individuals. Using population genetics, kinship analyses and the study of networks of identity-by-descent haplotype segment sharing, we elucidate the social and genetic dynamics of these communities between 4800-3900 calibrated years BCE. Despite changes in settlement patterns, burial practices, and material culture, we document a high degree of genetic continuity. While one set of individuals from a large community cemetery is genetically diverse, another site is more homogenous and closed, with numerous consanguineous relationships and evidence of patrilineality and patrilocality. In this work, we document important differences in kinship systems in contemporaneous Early Copper Age communities using similar material culture and living only about 100 km apart.

genomics↗

bioRxiv2024

Pervasive findings of directional selection realize the promise of ancient DNA to elucidate human adaptation

We present a method for detecting evidence of natural selection in ancient DNA time-series data that leverages an opportunity not utilized in previous scans: testing for a consistent trend in allele frequency change over time. By applying this to 8433 West Eurasians who lived over the past 14000 years and 6510 contemporary people, we find an order of magnitude more genome-wide significant signals than previous studies: 347 independent loci with >99% probability of selection. Previous work showed that classic hard sweeps driving advantageous mutations to fixation have been rare over the broad span of human evolution, but in the last ten millennia, many hundreds of alleles have been affected by strong directional selection. Discoveries include an increase from [~]0% to [~]20% in 4000 years for the major risk factor for celiac disease at HLA-DQB1; a rise from [~]0% to [~]8% in 6000 years of blood type B; and fluctuating selection at the TYK2 tuberculosis risk allele rising from [~]2% to [~]9% from [~]5500 to [~]3000 years ago before dropping to [~]3%. We identify instances of coordinated selection on alleles affecting the same trait, with the polygenic score today predictive of body fat percentage decreasing by around a standard deviation over ten millennia, consistent with the "Thrifty Gene" hypothesis that a genetic predisposition to store energy during food scarcity became disadvantageous after farming. We also identify selection for combinations of alleles that are today associated with lighter skin color, lower risk for schizophrenia and bipolar disease, slower health decline, and increased measures related to cognitive performance (scores on intelligence tests, household income, and years of schooling). These traits are measured in modern industrialized societies, so what phenotypes were adaptive in the past is unclear. We estimate selection coefficients at 9.9 million variants, enabling study of how Darwinian forces couple to allelic effects and shape the genetic architecture of complex traits.

evolutionary biology↗

bioRxiv2024

Long shared haplotypes identify the Southern Urals as a primary source for the 10th century Hungarians

During the Hungarian Conquest in the 10th century CE, the early medieval Magyars, a group of mounted warriors from Eastern Europe, settled in the Carpathian Basin. They likely introduced the Hungarian language to this new settlement area, during an event documented by both written sources and archaeological evidence. Previous archaeogenetic research identified the newcomers as migrants from the Eurasian steppe. However, genome-wide ancient DNA from putative source populations has not been available to test alternative theories of their precise source. We generated genome-wide ancient DNA data for 131 individuals from candidate archaeological contexts in the Circum-Uralic region in present-day Russia. Our results tightly link the Magyars to people of the Early Medieval Karayakupovo archaeological horizon on both the European and Asian sides of the southern Urals. Our analyes show that ancestors of the people of the Karayakupovo archaeological horizon were established in the Southern Urals by the Iron Age and that their descendants persisted locally in the Volga-Kama region until at least the 14th century.

genetics↗

bioRxiv2024

Janus Mazebots and Cellbots Navigating Obstacles in Dense Mammalian Environment

The field of microrobotics has immensely grown in the last few decades, exhibiting several challenges as new features such as shapes, sizes, and actuation mechanisms are explored. Two of the biggest challenges faced in microrobotics are the development of a control system suited for precise microrobotic manipulation, and the ability to navigate microrobots in densely populated environments. In this paper, we fabricate the Mazebot microrobots using silica spheres and ferromagnetic coating, and we use them to create cellbots with genetically modified Chinese Hamster Ovary (CHO) cells. Subsequently, we navigate both the Mazebots and the cellbots through a dense environment populated by CHO cells. The Mazebots navigation is done with a control system that allows the Mazebots to swim on their own, or guide a specific cell from a given origin to a target location while avoiding cell obstacles. The control system operates in open and closed-loop modes, where the first one allows the microrobot to reorient the cell using self-induced fluid vortices, and the second one closely follows a predefined trajectory along the origin and destination. On the other hand, the cellbots navigation is done in closed-loop operation. This enables cell manipulation for potential applications in cell and tissue engineering when in a confined space. Biocompatibility of the Mazebots is confirmed through the exposure of CHO cells to the robots for 24 hours. Experimental results demonstrate the functionality of our algorithm and its potential for biomedical applications, showcasing our system as a powerful and efficient solution for precise cellular manipulation.

bioengineering↗

bioRxiv2024

A genomic history of the North Pontic Region from the Neolithic to the Bronze Age

The north Black Sea (Pontic) Region was the nexus of the farmers of Old Europe and the foragers and pastoralists of the Eurasian steppe1,2, and the source of waves of migrants that expanded deep into Europe3-5. We report genome-wide data from 78 prehistoric North Pontic individuals to understand the genetic makeup of the people involved in these migrations and discover the reasons for their success. First, we show that native North Pontic foragers had ancestry not only from Balkan and Eastern hunter-gatherers6 but also from European farmers and, occasionally, Caucasus hunter-gatherers. More dramatic inflows ensued during the Eneolithic, when migrants from the Caucasus-Lower Volga area7 moved westward, bypassing the local foragers to mix with Trypillian farmers advancing eastward. People of the Usatove archaeological group in the Northwest Pontic were formed ca. 4500 BCE with an equal measure of ancestry from the two expanding groups. A different Caucasus-Lower Volga group, moving westward in a distinct but temporally overlapping wave, avoided the farmers altogether, and blended with the foragers instead to form the people of the Serednii Stih archaeological complex7. A third wave of expansion occurred when Yamna descendants of the Serednii Stih forming ca. 4000 BCE expanded during the Early Bronze Age (3300 BCE). The temporal gap between Serednii Stih and the Yamna expansion is bridged by a genetically Yamna individual from Mykhailivka in Ukraine (3635-3383 BCE), a site of uninterrupted archaeological continuity across the Eneolithic-Bronze Age transition, and the likely epicenter of Yamna formation. Each of these three waves propagated distinctive ancestries while also incorporating outsiders during its advance, a flexible strategy forged in the North Pontic region that may explain its peoples outsized success in spreading their genes and culture across Eurasia3-5,8-10.

genetics↗

bioRxiv2024

Understanding feeding competition under laboratory conditions: Rohu (Labeo rohita) versus Amazon sailfin catfish (Pterygoplichthys spp.)

Competitive interactions between species is widely prevalent within the animal world. In this manuscript, we attempted to understand feeding competitions between the Amazon sailfin catfish, an invasive species introduced globally, and rohu, a keystone species native to several countries within southeast Asia. We used two different size classes of each species, large-size having total length (TL, from snout tip to caudal fin) of 15-20 cm and fingerling having TL <6 cm, and feeding duration was used as a proxy to understand competition. Our results demonstrated that feeding durations of large-size rohu were either similar or significantly (P<0.05) higher in presence of catfish when compared to trials in presence of conspecifics, indicating that large-size rohu is not a weak competitor. However, feeding durations of fingerling rohu was significantly (P<0.05) reduced in presence of both large-size and fingerling catfish, when compared to trials in presence of conspecifics. Moreover, fingerling rohu also displayed freeze (alarm) behavior in presence of the catfish. Interestingly, presence of rohu had no significant (P>0.05) impact on feeding durations of catfish. Overall, the study demonstrated that invasive catfish may behaviorally outcompete fingerling rohu, thus, threatening the sustenance of a species that is native to several freshwaters around the globe.

ecology↗

bioRxiv2023

Prognostic relevance of correlated co-expression of coding and noncoding RNAs in cervical cancers

Human papillomavirus (HPV) drives cervical cancer (CaCx) pathogenesis and viral oncoproteins jeopardize global gene expression in such cancers. We aimed to identify differentially expressed coding (DEcGs) and long noncoding (sense intronic and Natural Antisense Transcripts) RNA genes (DElncGs) in HPV16-positive CaCx patients (N=44) compared to HPV-negative normal individuals (N=34). Thereby, employing strand-specific RNA-seq, we determined the relationships between DEcGs and DElncGs and their clinical implications. Gene set enrichment and protein-protein interaction analyses of DEcGs revealed enrichment of processes crucial for abortive virus life cycle and cancer progression. The DEcGs formed 16 gene clusters, portraying cancer-related functions. We recorded significantly correlated co-expression of 79 DElncGs with DEcGs at proximal genomic loci, and 24 such pairs portrayed significantly altered correlation coefficients among patients, compared to normal individuals. Of these, 6 DEcGs belonged to 5 gene clusters, one of which was survival-associated. Out of the 24 correlated DEcG: DElncG pairs, 3 pairs were identified, where expression of both members was significantly associated with patient overall survival. Besides being prognostically relevant, disruption of the significant correlative relationships of such gene pairs in CaCx bears immense potential for patient-targeted therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/573593v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@19091c8org.highwire.dtl.DTLVardef@52fbeaorg.highwire.dtl.DTLVardef@18ecf3org.highwire.dtl.DTLVardef@6c5e30_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO A schematic representation of the analyses undertaken to draw insights on the biological relevance of joint analysis of co-expressed and significantly correlated DElncGs and DEcGs considering the ncNATs and sense intronic DElncGs, in HPV16-positive CaCx patients compared with HPV-negative normal individuals. C_FIG

cancer biology↗

bioRxiv2023

Ecological assessment of the Amazon sailfin catfish (Pterygoplichthys species) within the Indian freshwaters: a mesocosm-based approach

Amazon sailfin catfish is relatively a recent invader to the open waters of India, and studies on ecological assessment of the species within the Indian freshwaters are lacking. In the present study, to assess the ecological impact of catfish, we established mesocosms mimicking the Indian freshwaters within natural ponds of eastern India using three species of native fish, rohu, catla and mrigal, and for two size classes, small (10-20 cm length) and large (20-30 cm length) native fishes. Mesocosms were maintained with (test) and without the catfish (control), and length and weight of native fish, zooplankton abundance, and several hydrological and soil parameters were measured at a monthly interval for a period of 120-days. The catfish had a significant (P<0.05) negative impact on growth of small-size rohu only. However, we found no significant (P>0.05) differences in abiotic parameters and zooplankton abundance between control and test ponds for the small-size class. We speculate that reduced growth of rohu could be due to competition from catfish in the context of feeding, and not due to modification of abiotic environment. Thus, we emphasize upon the need for behavioral studies to further assess the impact of the catfish.

ecology↗

bioRxiv2023

Social and genetic diversity in first farmers of central Europe

The Linearbandkeramik (LBK) Neolithic communities were the first to spread farming across large parts of central Europe, settling fertile regions from Ukraine to France during the second half of the 6th millennium BCE. The LBK had a high degree of material culture uniformity, albeit with regional differences in settlement patterns, subsistence, and mortuary practices. To date, ancient DNA data from LBK individuals have been generated for a limited number of locations and often in small sample sizes, making it challenging to study variation within and across sites. We report genome-wide data for 178 LBK individuals, from the Alfold Linearbankeramik Culture (ALPC) eastern LBK site of Polgar-Ferenci-hat in Hungary, the western LBK site of Nitra in Slovakia, and the enclosed western LBK settlement and massacre site of Schletz in Austria, as well as 42 LBK individuals from 18 other sites. We also report genome-wide data for 28 Early Neolithic Koros and Star[c]evo individuals from 13 sites, viewed as the predecessors of the LBK. We observe a higher percentage of western hunter-gatherer (WHG) admixture among individuals in the eastern LBK than in the far more widely distributed western LBK, showing that these two archaeologically distinct cultures also had different genetic trajectories. Most WHG-farmer mixture occurred just before the dawn of the LBK culture and there is no evidence that the WHG ancestry came systematically more from males or females. However, we do find strong genetic evidence for patrilocality among the LBK, extending previous findings based on isotopic analysis, with more genetic structure across sites on the male than on the female line, and a higher rate of within-site relatives for males. At Schletz we detect almost no first-degree relatives despite reporting data from almost every skeleton present at the site, showing that this massacre involved people from a large population, not a small community.

genetics↗

bioRxiv2023

Lymphoid tissues contribute to viral clonotypes present in plasma at early post-ATI in SIV-infected rhesus macaques

The rebound-competent viral reservoir (RCVR), comprised of virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after antiretroviral therapy interruption (ATI), remains the biggest obstacle to the eradication of HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop targeted therapeutic strategies for reducing the RCVR. In this study, barcoded SIVmac239M was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood, lymphoid tissues (LTs, spleen, mesenteric and inguinal lymph nodes), and non-lymphoid tissues (NLTs, colon, ileum, lung, liver, and brain) were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX/RNAscope/in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy although plasma viral RNA remained < 22 copies/mL. Among the tissues studied, mesenteric and inguinal lymph nodes, and spleen contained viral barcodes detected in plasma, and trended to have higher cell-associated viral loads, higher intact provirus levels, and greater diversity of viral barcodes. CD4+ T cells were the main cell type harboring viral RNA (vRNA) after ATI. Further, T cell zones in LTs showed higher vRNA levels than B cell zones for most animals. These findings are consistent with LTs contributing to virus present in plasma early after ATI. One Sentence SummaryThe reemerging of SIV clonotypes at early post-ATI are likely from the secondary lymphoid tissues.

immunology↗

bioRxiv2023

The Allen Ancient DNA Resource (AADR): A curated compendium of ancient human genomes

More than two hundred papers have reported genome-wide data from ancient humans. While the raw data for the vast majority are fully publicly available testifying to the commitment of the paleogenomics community to open data, formats for both raw data and meta-data differ. There is thus a need for uniform curation and a centralized, version-controlled compendium that researchers can download, analyze, and reference. Since 2019, we have been maintaining the Allen Ancient DNA Resource (AADR), which aims to provide an up-to-date, curated version of the worlds published ancient human DNA data, represented at more than a million single nucleotide polymorphisms (SNPs) at which almost all ancient individuals have been assayed. The AADR has gone through six public releases since it first was made available and crossed the threshold of >10,000 ancient individuals with genome-wide data at the end of 2022. This note is intended as a citable description of the AADR.

genomics↗

bioRxiv2023

AWC mediated behavioral plasticity in C. elegans against Salmonella Typhimurium infection

Soil-dwelling nematode Caenorhabditis elegans (C. elegans) is widely found in close vicinity with different types of microbes, including bacteria, fungus, viruses, etc. However, sensing environmental stress, they often undergo a dormant state called dauer for better survival. Our current study aims to decipher chemosensory responses of worms under Salmonella Typhimurium (WT-STM) infection and how bacterial gene modulating worms chemosensory system to mediate dauer larvae development. We initially observed the olfactory preference of C. elegans toward the pathogenic WT-STM. Although prolonged exposure showed enhanced lawn occupancy of worms in fepB mutant Salmonella strain with better associative learning response compared to WT-STM counterpart. We also found strong participation of AWC neuron for sensing {Delta}fepB strain and mediating worms behavioral plasticity. Overall out study implying a relationship between chemosensory neurons and bacteria emitted signals alter worms behavioral plasticity which help us to understand complex scenario of host-pathogen interaction.

microbiology↗

bioRxiv2023

ancIBD - Screening for identity by descent segments in human ancient DNA

Long DNA sequences shared between two individuals, known as Identical by descent (IBD) segments, are a powerful signal for identifying close and distant biological relatives because they only arise when the pair shares a recent common ancestor. Existing methods to call IBD segments between present-day genomes cannot be straightforwardly applied to ancient DNA data (aDNA) due to typically low coverage and high genotyping error rates. We present ancIBD, a method to identify IBD segments for human aDNA data implemented as a Python package. Our approach is based on a Hidden Markov Model, using as input genotype probabilities imputed based on a modern reference panel of genomic variation. Through simulation and downsampling experiments, we demonstrate that ancIBD robustly identifies IBD segments longer than 8 centimorgan for aDNA data with at least either 0.25x average whole-genome sequencing (WGS) coverage depth or at least 1x average depth for in-solution enrichment experiments targeting a widely used aDNA SNP set ( 1240k). This application range allows us to screen a substantial fraction of the aDNA record for IBD segments and we showcase two downstream applications. First, leveraging the fact that biological relatives up to the sixth degree are expected to share multiple long IBD segments, we identify relatives between 10,156 ancient Eurasian individuals and document evidence of long-distance migration, for example by identifying a pair of two approximately fifth-degree relatives who were buried 1410km apart in Central Asia 5000 years ago. Second, by applying ancIBD, we reveal new details regarding the spread of ancestry related to Steppe pastoralists into Europe starting 5000 years ago. We find that the first individuals in Central and Northern Europe carrying high amounts of Steppe-ancestry, associated with the Corded Ware culture, share high rates of long IBD (12-25 cM) with Yamnaya herders of the Pontic-Caspian steppe, signaling a strong bottleneck and a recent biological connection on the order of only few hundred years, providing evidence that the Yamnaya themselves are a main source of Steppe ancestry in Corded Ware people. We also detect elevated sharing of long IBD segments between Corded Ware individuals and people associated with the Globular Amphora culture (GAC) from Poland and Ukraine, who were Copper Age farmers not yet carrying Steppe-like ancestry. These IBD links appear for all Corded Ware groups in our analysis, indicating that individuals related to GAC contexts must have had a major demographic impact early on in the genetic admixtures giving rise to various Corded Ware groups across Europe. These results show that detecting IBD segments in aDNA can generate new insights both on a small scale, relevant to understanding the life stories of people, and on the macroscale, relevant to large-scale cultural-historical events.

genetics↗

bioRxiv2022

Adaptation of a transmitted/founder simian-human immunodeficiency virus for enhanced replication in rhesus macaques

Transmitted/founder (TF) simian-human immunodeficiency viruses (SHIVs) express HIV-1 envelopes modified at position 375 to efficiently infect rhesus macaques while preserving authentic HIV-1 Env biology. TF SHIV.C.CH505 is an extensively characterized virus shown to recapitulate key features of HIV-1 immunobiology, including CCR5-tropism, a tier 2 neutralization profile, reproducible early viral kinetics, and authentic immune responses. SHIV.C.CH505 is used frequently in nonhuman primate studies of HIV, but viral loads after months of infection are variable and typically lower than those in people living with HIV. We hypothesized that additional mutations besides {Delta}375 might further enhance virus fitness without compromising essential components of CH505 Env biology. From sequence analysis of SHIV.C.CH505-infected macaques across multiple experiments, we identified a signature of envelope mutations associated with higher viremia. We then used short-term in vivo mutational selection and competition to identify a minimally adapted SHIV.C.CH505 with just five amino acid changes that substantially improve virus replication fitness in macaques. Next, we validated the performance of the adapted SHIV in vitro and in vivo and identified the mechanistic contributions of selected mutations. In vitro, the adapted SHIV shows improved virus entry, enhanced replication on primary rhesus cells, and preserved neutralization profiles. In vivo, the minimally adapted virus rapidly outcompetes the parental SHIV with an estimated growth advantage of 0.14 days-1 and persists through suppressive antiretroviral therapy to rebound at treatment interruption. Here, we report the successful generation of a well-characterized, minimally adapted virus, termed SHIV.C.CH505.v2, with enhanced replication fitness and preserved native Env properties that can serve as a new reagent for NHP studies of HIV-1 transmission, pathogenesis, and cure. Author SummaryThe power of the nonhuman primate model of HIV to predict outcomes in people living with HIV (PLWH) depends on authentic virus-host interactions. In pursuit of viruses that generate infection that mirrors the effects of HIV-1 in PLWH, we developed a minimally adapted version of a commonly used virus, SHIV.C.CH505, which has better fitness than the parental virus while retaining important biological properties. First, we studied virus sequences from SHIV.C.CH505-infected rhesus macaques to identify a signature of mutations common to animals with higher viral loads. We then tested viruses containing the various mutations in the lab and in animals to determine the most fit version and to identify the contribution of each mutation. Ultimately, we identified a minimally adapted version of SHIV.C.CH505 with just 5 amino acid substitutions that enhances virus replication and preserves CH505 envelope properties, including sensitivity to clinically relevant broadly neutralizing antibodies. This new virus, called SHIV.C.CH505.v2 replicates well in macaques over time and persists through antiretroviral therapy. SHIV.C.CH505.v2 could be an important component of nonhuman primate studies of HIV prevention, therapy, and cure.

microbiology↗