Biology subjects

Nair, N.

Publications and source records attributed to Nair, N..

13 recordsLinked to original sources

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2026

A double-blinded, placebo-controlled field trial of an OspA-based oral reservoir targeted vaccine against Borrelia burgdorferi

Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes scapularis ticks, remains a significant vector-borne illness in the United States. Small mammal reservoirs, particularly Peromyscus leucopus, play a critical role in B. burgdorferi maintenance. Here we conducted a five-year, randomized, double-blinded, placebo-controlled field trial deploying an oral OspA-based reservoir targeted vaccine (RTV) across seven Maryland sites. Bayesian modeling provided estimates of vaccine impact on mouse anti-OspA antibody levels, nymphal tick infection prevalence (NIP), mouse infection rates, and seroconversion to B. burgdorferi in hunting dogs. RTV sites exhibited an estimated 10.5% proportional increase in protective murine anti-OspA antibody levels and a 15.4% reduction in NIP by year five. We also found a lower infection prevalence in mouse blood fed nymphal ticks (9.8%). RTV sites exhibited modest decreases in mouse infection prevalence and dog seroconversion rates were similar between groups. Our results indicate that anti-OspA antibody in vaccinated-infected P. leucopus reduced B. burgdorferi summertime larval infection prevalence, measured as NIP reductions the following spring. This suggests that OspA-based oral RTV reduces B. burgdorferi transstadial transmission within tick populations. Our findings advance development of reservoir targeted solutions for Lyme disease prevention. Further evaluation of impacts on incidental hosts is needed.

microbiology↗

bioRxiv2026

Human lung explants as a predictive platform for evaluating the on-target, off-tumor toxicity of T cell bispecifics

T cell bispecifics (TCBs) are potent immunotherapies with proven efficacy in hematological cancers but limited success in solid tumors, where on-target, off-tumor toxicity has restricted their therapeutic index. Clinical discontinuation of TCB formulations against epithelial cell adhesion molecule (EpCAM TCB, Solitomab) and preclinical termination of a TCB against folate receptor alpha (FolR1-TCB) highlight the urgent need for predictive preclinical models to evaluate such toxicities. Conventional models, including cell lines and organoids, lack the immune and stromal complexity of the tumor microenvironment (TME), and while patient-derived explants preserve native tissue architecture and heterogeneity, quantification of TCB-mediated target cell killing has not been previously achieved in this system. Here, we establish a human lung explant model to assess TCB activity in matched tumor and normal adjacent tissues. Using a multi-modal approach combining flow cytometry, cytokine profiling, and multiplexed immunofluorescence, we show that EpCAM and FolR1 TCBs drive robust T cell activation and, critically, quantifiable epithelial cell killing above background levels. Normal lung explants exhibited consistently higher levels of killing than tumor counterparts, reflecting the on-target, off-tumor toxicities observed preclinically and clinically with the tested TCBs. In contrast, colon explants displayed poor viability ex vivo, limiting their suitability for assessing TCB-induced killing despite measurable immune activation. Our findings establish lung explants as a predictive and clinically relevant preclinical model that uniquely enables simultaneous quantification of TCB-mediated T cell activation and target cell killing. This model captures key features of TCB mechanism of action and recapitulates clinically observed toxicities, supporting its application for preclinical evaluation of TCB drug candidates and advancing the development of immunotherapies for solid tumors.

cancer biology↗

bioRxiv2025

Magellon - an extensible platform for cryo-EM data visualization, management, and processing

Single particle cryo-electron microscopy (cryo-EM) has revolutionized structural biology by enabling high-resolution determination of macromolecular structures. However, the field faces challenges in data management, processing workflow integration, and software extensibility. We present Magellon, an innovative cryo-EM software platform that addresses these challenges through a modern microservices architecture. Magellon consists of an extensible backend with a web-based front end that we call Magellon Viewer. Together, these combine high-performance computing capabilities with an intuitive user interface, enabling researchers to efficiently process and analyze cryo-EM data. The platforms distinguishing features include a plugin-based architecture, distributed processing capabilities, comprehensive monitoring systems, and a novel approach to data organization and visualization. A key philosophy of the approach is that the Magellon backend provides a platform that uses robust industry-standard libraries to orchestrate computational tasks while offering users and developers flexibility in selecting the computational resources for performing calculations. Magellon represents a significant advancement in cryo-EM software infrastructure, offering flexibility, scalability, and extensibility while maintaining ease of use.

biophysics↗

bioRxiv2024

Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and cone function in retinal organoids

Retinal dehydrogenase 12 (RDH12) is a photoreceptor NADPH-dependent retinal reductase enzyme, converting all-trans-retinal to all-trans-retinol. Heterozygous variants in RDH12 cause a rare autosomal dominant (AD) retinitis pigmentosa. As no disease models exist, we generated human induced pluripotent stem cell derived retinal organoids (RO) from a RDH12-AD patient (with pathogenic c.759del p.(Phe254Leufs*24) variant), alongside a healthy control (WT). RDH12-AD RO exhibited correct localisation of RDH12 to the photoreceptor inner segments up to week 44; transmission electron microscopy at week 37 showed photoreceptors were less abundant and shorter in length compared to WT. Visual cone function, retinol biosynthesis and the vitamin A pathway were also highly disrupted at week 44. Our study is the first to describe a RDH12-AD disease model with pathology at later stages of photoreceptor differentiation, in keeping with the milder disease course seen in humans. It provides insights into the aetiology and possible targets for future therapeutic development.

pathology↗

bioRxiv2024

The toxic effects of lead nitrate on human keratinocytes (HaCaT).

This study investigated the cytotoxicity, genotoxicity, oxidative stress, and mitochondrial toxicity in human keratinocytes (HaCaT) caused by lead nitrate. An increase in lead nitrate concentration (50-800 {micro}M) showed a decrease in cell viability and the IC50 concentration was found to be 385.7 {micro}M. Lead nitrate at 250 {micro}M was also found to decrease the clonogenic potential, produce an increased number of binucleated cells with a micronucleus, increase the olive tail movement, reduce the thiol protein content, increase the intracellular and mitochondrial ROS levels, increase the mitochondrial mass and mitochondrial membrane potential. Which showed that Lead nitrate does indeed show cytotoxic, genotoxic effects as well as increase oxidative stress and alter mitochondrial functions. HIGHLIGHTSO_LILead nitrate causes cytotoxicity in keratinocytes with an IC50 conc. of 385.7 {micro}M. C_LIO_LIExposure to lead nitrate showed a significant increase in DNA damage. C_LIO_LILead nitrate increased the mitochondrial membrane potential and mass. C_LI

cell biology↗

bioRxiv2023

Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues

Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to target tissues is challenging. To address this, we assessed whether primary and metastatic tumors resemble their tissue of origin or target tissue in terms of gene expression. We analyzed gene expression profiles from various cancer types, including single-cell and bulk RNA-seq data, in both paired and unpaired primary and metastatic patient cohorts. We quantified the transcriptomic distances between tumor samples and their normal tissues, revealing that primary tumors are more similar to their tissue of origin, while metastases shift towards the target tissue. Pathway-level analysis highlighted critical transcriptomic changes during metastasis. Notably, primary cancers exhibited higher activity in cancer hallmarks, including Activating Invasion and Metastasis, compared to metastatic cancers. This comprehensive landscape analysis provides insight into how cancer tumors adapt to their metastatic environments, providing a transcriptome-wide view of the processes involved.

cancer biology↗

bioRxiv2022

Infected I. scapularis nymphs maintained in prolonged questing under optimal environmental conditions for one year can transmit B. burgdorferi to uninfected hosts

In recent decades, Lyme disease has been expanding to previous non-endemic areas. We hypothesized that infected I. scapularis nymphs that retain host-seeking behavior under optimal environmental conditions are fit to fulfil their transmission role in the enzootic cycle of B. burgdorferi. To test this hypothesis, we produced nymphal ticks in the laboratory under controlled temperature (22-25{degrees}C), humidity (80-90%) and natural daylight cycle conditions to allow them to retain host-seeking/questing behavior for 1 year. We then analyzed differences in B. burgdorferi infection prevalence in questing and diapause nymphs at 6 weeks post-molting (prime questing) as well as differences in infection prevalence of questing nymphs maintained under prolonged environmental induced questing over 12 months (prolonged questing). Lastly, we analyzed the fitness of nymphal ticks subjected to prolonged questing in transmission of B. burgdorferi to naive mice over the course of the year. Our study shows that B. burgdorferi infected unfed I. scapularis nymphal ticks maintained under optimal environmental conditions in the laboratory not only survived for a year in a developmental state of prolonged questing (host-seeking), as they retained an infection prevalence sufficient to effectively fulfil transmission of B. burgdorferi to uninfected mice after tick challenge. Our study is important for understanding and possibly modeling Lyme disease expansion into former non-endemic regions due to global warming. IMPORTANCELyme disease is rapidly spreading from its usual endemic areas in the Northeast, Midwest and Midatlantic states into neighboring areas which could be due to changing climate patterns. Our study shows that unfed I. scapularis nymphal ticks kept under optimal environmental conditions in the laboratory survived for a year while exhibiting aggressive host-seeking behavior and they maintained a B. burgdorferi infection prevalence which was sufficient to infect naive reservoir hosts after tick challenge. Our study raises important questions regarding prolonged survival of B. burgdorferi infected host-seeking nymphal I. scapularis ticks that can potentially increase the risk of Lyme disease incidence, if conditions of temperature and humidity become amenable to the enzootic cycle of B. burgdorferi in regions currently classified as non-endemic.

microbiology↗

bioRxiv2021

Data-driven discovery of targets for bipotent anticancer drugs identifies Estrogen Related Receptor Alpha

Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at http://bipotentr.dfci.harvard.edu/. One-Sentence SummaryBipotentR identifies targets for bipotent anticancer drugs, as shown by the energy and immune effects of ESRRA inhibition.

cancer biology↗

bioRxiv2021

Maternal transfer of neutralizing antibodies to OspA after oral vaccination of the rodent reservoir

Lyme Disease presents unique challenges for public health efforts. We hypothesized that transfer of protective antibodies between mothers and offspring should occur after oral vaccination of C3H-HeN mice with E. coli overexpressing OspA. We present new evidence for maternal transfer of vaccine induced neutralizing anti-OspA IgG antibodies to mouse pups through ingestion of colostrum. Protective levels of OspA antibodies in pups were present from 2-5 weeks after birth and they persisted in some mice until 9 weeks of age. This was corroborated by detection of neutralizing antibodies in the serum of all pups at 2-3 weeks after birth and in some mice at 9 weeks of age. A clear association was found between robust antibody responses in mothers and the length of antibody persistence in the respective pups using a novel longitudinal Bayesian model. These factors are likely to impact the enzootic cycle of B. burgdorferi when reservoir targeted OspA-based vaccination interventions are implemented.

microbiology↗

bioRxiv2020

Humanized TLR4 immunocompetent mice are more susceptible to kidney disease after infection with Leptospira interrogans than wild-type mice

Toll-Like Receptor (TLR) 4, the LPS receptor, plays a central role in the control of leptospirosis and absence of TLR4 results in lethal infection in mice. Because human TLR4 does not sense the atypical leptospiral-LPS, we hypothesized that TLR4/MD-2 humanized transgenic mice (huTLR4) may be more susceptible to leptospirosis than wild-type mice, and thus may constitute a model of acute human leptospirosis. Therefore, we infected huTLR4 mice, which express human TLR4 but not murine TLR4, with a high but sublethal dose of L. interrogans serovar Copenhageni FioCruz (Leptospira) in comparison to C57BL/6J wildtype (WT) and, as a control, a congenic strain in which the tlr4 coding sequences are deleted (muTLR4Lps-del). We show that the huTLR4 gene is fully functional in the murine background. We found that dissemination of Leptospira in blood, shedding in urine, colonization of the kidney and overall kinetics of leptospirosis progression is equivalent between WT and huTLR4 C57BL/6J mice. Furthermore, inflammation of the kidney appeared to be subdued in huTLR4 compared to WT mice in that we observed less infiltrates of mononuclear lymphocytes, less innate immune markers and no relevant differences in fibrosis markers. Contrary to our hypothesis, huTLR4 mice showed less inflammation and kidney pathology, and are not more susceptible to leptospirosis than WT mice. This study is significant as it indicates that one intact TLR4 gene, be it mouse or human, is necessary to control acute leptospirosis. Contribution to the fieldDifferences of recognition exist between mouse and human TLR4, in that the anchor of LPS in the outer membrane of Leptospira (LipidA) activates murine, but not human TLR4. We hypothesized that if human TLR4 does not sense leptospiral-LPS, then transgenic mice in which murine TLR4 was replaced with human TLR4, should be more susceptible to Leptospira dissemination as compared to congenic wild-type mice, which could result in a more robust inflammatory response and pathology in the kidney. However, we found that impaired sensing of leptospiral-LPS in huTLR4 mice did not affect overall infection in comparison to wild-type mice and does not result in increased pathology of the kidney. Our study indicates that rather than leptospiral-LPS sensing, the presence of a fully functional TLR4 receptor is necessary to control acute leptospirosis.

microbiology↗

bioRxiv2019

Surpassing thermodynamic, kinetic, and stability barriers to isomerization catalysis for tagatose biosynthesis

There are many enzymes that are relevant for making rare and valuable chemicals that while active, are severely limited by thermodynamic, kinetic, or stability issues (e.g. isomerases, lyases, transglycosidase etc.). In this work, we study an enzymatic reaction system - Lactobacillus sakei L-arabinose isomerase (LsLAI) for D-galactose to D-tagatose isomerization - that is limited by all three reaction parameters. The enzyme has a low catalytic efficiency for non-natural substrate galactose, has low thermal stability at temperatures > 40 {degrees}C, and equilibrium conversion < 50%. After exploring several strategies to overcome these limitations, we finally show that encapsulating the enzyme in a gram-positive bacterium (Lactobacillus plantarum) that is chemically permeabilized can enable reactions at high rates, high conversion, and at high temperatures. The modified whole cell system stabilizes the enzyme, differentially partitions substrate and product across the membrane to shift the equilibrium toward product formation enables rapid transport of substrate and product for fast kinetics. In a batch process, this system enables approximately 50 % conversion in 4 h starting with 300 mM galactose (an average productivity of 37 mM/h), and 85 % conversion in 48 h, which are the highest reported for food-safe mesophilic tagatose synthesis. We suggest that such an approach may be invaluable for other enzymatic processes that are similarly kinetically-, thermodynamically-, and/or stability-limited.

bioengineering↗

bioRxiv2018

Transdermal, but not oral mucosa exposure, causes sublethal leptospirosis in mice

The goal of this study was to determine the timing of Leptospira dissemination after infection using natural physiologic routes and its correlation with signs and symptoms of leptospirosis. Groups of C3H-HeJ mice were sub-lethally infected through exposure of a dermis wound and the oral mucosa to L. interrogans serovar Copenhageni, and compared to mice infected via standard laboratory practice of intraperitoneal inoculation. We found that transdermal infection leads to delayed bacterial dissemination in blood and urine when compared to intraperitoneal infection using the same infectious dose, and that the overlapping presence of L. interrogans in both fluids was twice as long as the standard intraperitoneal infection. Furthermore, dissemination of L. interrogans and disease did not occur in mice infected with the same dose of L. interrogans via the oral mucosa. Over the course of these studies we also observed that the timing of exit of Leptospira from blood and establishment of colonization of the kidney in the second week of infection correlated well with weight loss, but not with hypothermia. Thus, a non-invasive sign of leptospirosis such as weigh loss can be used to monitor bacterial dissemination and disease stage in mice. Our findings underline the importance of precise determination of windows of pathogen dissemination in biological fluids and how the route of infection affects the progression of disease. These studies could help focus the development of better treatment strategies and new technologies for diagnostic use.

microbiology↗