Biology subjects

Jain, V.

Publications and source records attributed to Jain, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Genome-wide within-host evolution during prolonged SARS-CoV-2 infection in a person with advanced HIV infection

Within-host evolution during prolonged SARS-CoV-2 infection can be extensive in immunocompromised individuals, but the consequences of mutations that emerge and change in frequency over time remain difficult to predict. We characterized an XBB.1.5.10 infection lasting nearly 90 days in a person with advanced human immunodeficiency virus (HIV) infection. Genome-wide tracking of allele frequencies in samples collected on study days 43, 48, and 70 revealed a Spike N-terminal domain (NTD) deletion spanning residues 138-145 at frequencies of 33%, 80%, and 96%, respectively. A receptor-binding domain (RBD) deletion-insertion spanning residues 373-378 was detected on days 43 and 48 but not on day 70, while nsp12 C464Y was detected at approximately 8% on day 48 and 86% on day 70. We reconstructed representative Spike and non-Spike mutation profiles from the longitudinal samples and tested their effects on cell entry and viral RNA replication. The representative Spike construct for days 43 and 48 increased entry relative to XBB.1.5. Comparison with a matched construct lacking the receptor-binding domain deletion-insertion showed that the deletion-insertion enhanced entry, although it was not detected in the day 70 sample. The day 48 non-Spike profile supported the highest RNA replication among the tested replicons. Together, allele-frequency tracking revealed both transient mutations and mutations detected at progressively higher frequencies across the sampled time points. Functional testing showed that increased entry or RNA replication in vitro did not necessarily predict persistence in vivo.

microbiology↗

bioRxiv2026

WHAT IS NORMAL? MULTIMODAL CHARACTERIZATION OF NON-DISEASED PEDIATRIC DUODENAL BIOPSIES USING MACHINE LEARNING IMAGE ANALYSIS AND TRANSCRIPTOMICS

Pediatric endoscopy is performed only when clinically indicated, limiting access to healthy duodenal tissue. Biopsies with duodenal no pathologic abnormality (NPA) are often used as controls despite the presence of symptoms or inflammatory disease found elsewhere in the gastrointestinal (GI) tract. We characterized pediatric duodenal NPA tissue across clinical, histologic, cellular, and transcriptomic domains. Methods Archival duodenal NPA biopsies were obtained with clinical metadata and hematoxylin-and-eosin whole-slide images (WSIs). Duodenal mRNA-seq data were analyzed from a subset of patients with duodenal NPA. Clinical metadata and WSIs underwent machine-learning analysis, cell populations were quantified from WSIs, and RNA-seq data underwent differential expression and pathway-enrichment analyses. Results The primary cohort included 195 patients with duodenal NPA. Comparisons between patients with non-duodenal GI disease and those with no GI disease showed differences in inflammatory biomarkers and follow-up utilization. Unsupervised clinical clustering identified three clusters with partial enrichment for IBD with colonic inflammation and Eosinophilic Esophagitis (EoE) with esophageal inflammation. Supervised clinical classification showed modest discrimination. WSI clustering showed limited disease-status discrimination, and cell quantification showed no significant group differences. In the separate RNA-seq cohort of 43 patients, differential-expression and pathway-enrichment analyses identified transcriptional and pathway-level differences between disease-status groups. Conclusions This multi-level characterization indicates that pediatric duodenal NPA tissue should not be treated as a uniform control category. Clinical metadata and transcriptomics revealed clinical and molecular heterogeneity, while histologic and cell analyses showed limited disease-status separation, supporting a refined definition of control tissue.

physiology↗

bioRxiv2026

From planktonic to sedentary lifestyle: Molecular dissection of the establishment and maintenance of mycobacterial biofilm

Biofilm represents a complex aggregation of bacteria embedded within a self-produced extracellular polymeric substance (EPS). We investigated the characteristics of mycobacterial biofilm using Mycobacterium smegmatis (Msm) as model organism. By combining transcriptomic (RNA-seq) and proteomic (LC-MS) analyses, the research captures dynamic changes during the establishment and maturation of the biofilm. Transcriptomics analysis showed a distinct gene expression profile as compared to its planktonic form. Interestingly, clear differences were seen between initial ([~]2-day old) and mature ([~]5-day old) biofilm stages, highlighting phasic gene expression throughout biofilm development. Marked alteration in oxidative stress-related genes and energy metabolism from ATP to NADH was observed. Furthermore, quantitative mass spectrometry-based proteome examination of EPS showed an abundance of cytoplasmic proteins present differentially between initial and mature biofilm stages. Pathway enrichment revealed enhanced oxidative stress responses and metabolic shifts in mature biofilms, including upregulation of NADH dehydrogenase and downregulation of ATP synthase, indicating altered energy metabolism. Our findings thus provide insights into the molecular adaptations, including production of mycofactocin, occurring during mycobacterial biofilm establishment and maturation, and advance our understanding of mycobacterial biofilm physiology.

microbiology↗

bioRxiv2026

Mycobacteriophage D29-Derived LysB Enhances Anti-Tubercular Therapy in Experimental Pulmonary Tuberculosis

Adjunctive therapies that enhance the efficacy of existing antitubercular drugs are needed for drug-resistant tuberculosis. We evaluated the efficacy of intranasally administered recombinant D29 LysB, a mycobacteriophage-derived mycolylarabinogalactan esterase, in murine and guinea pig models of pulmonary tuberculosis. BALB/c mice and guinea pigs were aerosol-infected with Mycobacterium tuberculosis H37Rv and treated for 4 weeks with LysB alone or with standard antitubercular therapy (ATT: rifampicin, isoniazid, pyrazinamide). Outcomes included pulmonary and extrapulmonary bacterial burden (CFU), lung and spleen histopathology, cytokine profiling, and humoral immune responses. LysB monotherapy produced modest pulmonary CFU reductions. When given adjunctively with ATT, LysB produced an additional 0.6-0.7 log10 reduction in lung CFU compared with ATT alone and decreased splenic dissemination in both species. Combination therapy improved tissue pathology, reducing granulomatous involvement and preserving pulmonary architecture. LysB treatment increased TNF- with a moderate rise in IL-10, a profile consistent with enhanced antibacterial immunity without excessive inflammatory damage. Repeated intranasal administration was well tolerated; no IgE-mediated hypersensitivity was detected. LysB-specific IgG developed but did not diminish therapeutic efficacy. These results show that intranasal D29 LysB augments the bactericidal and histopathological effects of standard ATT in vivo and support further development of inhaled phage-derived lysins as adjunctive therapies for drug-resistant tuberculosis. ImportanceTuberculosis remains a major cause of infectious mortality worldwide, and the increasing burden of multidrug-resistant and extensively drug-resistant disease continues to challenge effective treatment. New therapeutic approaches that complement conventional antibiotics are urgently needed. In this study, intranasally delivered recombinant mycobacteriophage-derived LysB was well tolerated and enhanced treatment efficacy in experimental pulmonary tuberculosis. Adjunctive LysB improved bacterial clearance, reduced tissue pathology, and modulated host immune responses in both murine and guinea pig models. These findings highlight phage-derived endolysins as promising inhalable adjunctive therapeutics for drug-resistant tuberculosis.

microbiology↗

bioRxiv2026

A VERSATILE LIBRARY OF TETRACYCLINE-INDUCIBLE AND REPRESSIBLE VECTORS FOR FINE-TUNED GENE EXPRESSION

The genus Mycobacterium is increasingly recognized as a major clinical concern due to diseases such as tuberculosis, along with the emergence of antimicrobial-resistant strains, underscoring the urgent need for advanced genetic tools to study mycobacterial biology and pathogenesis. Progress in this area relies heavily on the functional characterization of previously unannotated genes, which necessitates tightly regulated expression systems. Here, we report the development of an improved tetracycline-regulated vector platform, comprising the episomal pM(R)T2 and integrative pMI(R)T2 series, which builds upon the previously described pMT vector system. The T2 vector series incorporates a fine-tuned TetRO system for enhanced transcriptional control. The pMT2 vectors function as tetracycline-inducible systems, whereas the pMRT2 variants utilize a reverse tetracycline repressor (RevTetR) to enable tetracycline-repressible gene regulation. Additionally, the integrative variant, pMI(R)T2 switches the oriM element with the integrase and attP sites derived from mycobacteriophage L5, facilitating stable genomic integration and controlled expression of concentration-sensitive genes, including toxins. To expand the selection flexibility, the pAN(R)Tet series replaces the kanamycin resistance cassette with a hygromycin resistance cassette. Functional validation of gene regulation in M. smegmatis and M. bovis BCG shows that both TetR and RevTetR systems provide reliable inducible and repressible controls, respectively, upon anhydrotetracycline addition. Taken together, these vectors constitute a versatile, tightly regulated genetic toolkit with significant potential to accelerate research and therapeutic development in mycobacterial systems.

synthetic biology↗

bioRxiv2026

Non-canonical histone H3.3 and its chaperones HIRA and DAXX participate in the regulation of KSHV latency

Kaposis sarcoma-associated herpesvirus (KSHV), also named HHV-8, is the etiological agent of Kaposi sarcoma (KS), Primary effusion lymphoma (PEL), and Multicentric Castlemans disease. After de novo infection, KSHV genomes rapidly circularize and acquire a chromatin state that favors latency. During latency, the KSHV episome is decorated with distinct epigenetic marks that segregate the viral genome into transcriptionally active and repressed domains, enabling persistent silencing of lytic genes while retaining the capacity for reactivation. Transcription activity of chromatin is regulated at multiple levels, including the incorporation of histone variants such as H3.3, by a specific set of histone chaperones such as HIRA and DAXX. The interaction between LANA and these interphase active chaperones suggests that H3.3 deposition is a critical driver of early chromatinization and the long-term stability of KSHV latency. We detected rapid H3.3 deposition on KSHV episomes and on episomes within long-term infected cells. Moreover, we demonstrated that genetically disrupting the host H3.3 chaperone HIRA pathway by CRISPR/Cas9-mediated knockout impacted the regulation of LANA and maintenance of viral latency that was not altered in DAXX knockout cells. Collectively, these results support a role for HIRA-mediated H3.3 deposition in the regulation of KSHV latency.

molecular biology↗

bioRxiv2026

A minimally invasive floating-wire interface for transcranial deep brain stimulation

BackgroundNon-invasive neuromodulation technologies have advanced considerably. Yet, precise and focal activation of deep brain regions remains challenging due to the rapid attenuation of electric fields across the scalp, skull and brain surface. ObjectiveWe present FLOATES (FLOAting Transcranial Electrical Stimulation), a novel approach that employs an untethered wire implanted in the brain which passively relays currents injected transcranially from the brain surface to deep brain regions, achieving focused stimulation deep within the brain. MethodsWe validated FLOATES through a combination of simulations, benchtop testing, and in vivo rodent studies. The benchtop experiments confirmed the ability to relay the field across the floating wire. Rodent studies demonstrated capability to stimulate deep brain regions in vivo. ResultsOur simulation and benchtop testing results indicate that FLOATES can deliver significantly higher electric fields to subcortical regions compared to conventional transcranial stimulation approaches. Further in-vivo results demonstrated deep subthalamic nuclei stimulation to evoke limb motor responses and demonstrated a significantly lower motor threshold compared to transcranial stimulation. Finite element simulations reveal that the efficiency of FLOATES depends on several key parameters including input field strength, wire length and diameter, exposed electrode area, impedance, and tip geometry. Simulations using a human-sized head model suggest that electric fields sufficient for brain stimulation can be obtained with reasonable currents injected to the scalp. ConclusionTogether, these results establish a theoretical and experimental foundation for FLOATES as a minimally invasive and spatially precise brain stimulation platform in modulating deep neural circuits implicated in neuropsychiatric and movement disorders.

bioengineering↗

bioRxiv2026

Oxytocin treats respiratory depression and reduces mortality from fentanyl and the combination of xylazine-fentanyl

Opioid addiction and misuse are a serious national crisis that affects public health, as well as social and economic welfare. Mortality due to opioid misuse is further exasperated by the combination of opioids with non-opioid respiratory depressants such as xylazine that are resistant to mu opioid receptor antagonists such as naloxone. This study tested the hypothesis that oxytocin can mitigate the severe opioid induced respiratory depression (OIRD) and mortality induced by high doses of fentanyl or the combination of fentanyl with xylazine. Our results show OXT can improve survival and respiratory function in both male and female rats with opioid induced respiratory depression caused by fentanyl, as well as a combination of fentanyl and xylazine. The improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone. Chemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD. These results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine, a situation where naloxone is only partially effective. Additional translational benefits of OXT include it can be repurposed as it is already a FDA approved drug for other uses, has a high safety profile, and is unlikely to induce the withdrawal or reversal of analgesia that occurs with naloxone. Key PointsO_LIOxytocin (OXT) improves survival and respiratory function in both male and female rats with opioid induced respiratory depression (OIRD) caused by fentanyl C_LIO_LIOXT also reverses OIRD induced by the combination of fentanyl and xylazine C_LIO_LIThe improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone C_LIO_LIChemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD C_LIO_LIThese results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine C_LI

pharmacology and toxicology↗

bioRxiv2026

A platform-agnostic evaluation of non-formalin fixed single cell RNA technologies

The rapidly advancing field of single cell RNA sequencing (scRNAseq) offers numerous options for transcriptome profiling. However, questions remain as to which chemistry is appropriate for individual experimental goals. Preceding single cell benchmarking studies included previously available methods and involved a mixture of fresh and fixed samples or probe- and non-probe-based capture methods. However, the inherent differences in sample types and methods limited the conclusions to be drawn between analogous technologies. Here, we present a novel, systematic comparison of four widely used non-probe-based, non-formalin fixed scRNAseq assays. We build upon past comparisons that used varied computational pipelines by applying both platform-specific and agnostic cell calling algorithms for an unbiased comparison of biological and technical replicates from healthy human PBMCs. Our approach evaluates 10x Genomics, Parse Biosciences (QIAGEN), Scale Biosciences (10x Genomics), and Illumina scRNAseq assays to examine data based on accuracy, sensitivity, precision, power, and efficiency using agnostic and platform-specific cell calling. While metrics vary between assays, there are clear advantages and limitations to each technology, including experimental time and financial costs. In summary, our study highlights the need for carefully considered project design of non-formalin fixed scRNAseq assays, which is determined by many factors and dependent on an investigators specific research aims and available resources. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/702057v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@19d9a17org.highwire.dtl.DTLVardef@1ef650aorg.highwire.dtl.DTLVardef@1d27484org.highwire.dtl.DTLVardef@1df8c2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2026

Tau-induced ribosomal collisions impair memory through the activation of the integrated stress response

The formation of new long-term memories is reliant upon the spatial and temporal regulation of mRNA translation. Translational control has been demonstrated to be disrupted in neurodegenerative diseases, which exhibit impairments in both homeostatic translation and memory formation, such as Alzheimers disease (AD) and frontotemporal dementia (FTD). However, the precise mechanisms by which this dysregulation occurs, as well as the pathogenic consequences of this dysregulation have yet to be described. Here we establish that FTD-associated tau mutations impair protein synthesis prior to the onset of memory impairments by slowing ribosomal elongation speed, causing ribosomes to collide upon mRNAs. We reveal that this tau-induced ribosomal collision ultimately impairs memory-associated translation through activation of the integrated stress response (ISR) via GCN2. Pharmacological prevention of this ISR activation not only rescues memory formation in the PS19 mouse model of FTD, but also attenuates neuronal death, decreases tau phosphorylation and accumulation, and improves survival. Collectively, our data elucidates a novel mechanism by which mRNA translation is impaired early in neurodegeneration, identifies several pathological phenotypes which are traceable to impairments in mRNA translation, and highlights the therapeutic potential of rescuing these translational impairments.

neuroscience↗

bioRxiv2025

Antigen-specific CD8 T cells are generated and reactivated in the bone marrow following viral brain infections and impact the bone marrow niche

Bone marrow is the primary immune organ responsible for stem cell maintenance and hematopoiesis. However, the contribution of the bone marrow niche for the generation of adaptive immune responses is less well-understood. We therefore assessed the capacity of virus antigen-specific CD8 T cells to be generated and expanded in bone marrow following acute neurotropic virus infection. Intracranial infection with the neurotropic Theilers Murine Encephalomyelitis Virus (TMEV) results in an acute infection in the C57BL/6 mouse which is cleared within 4 weeks post infection due to the generation of an antigen-specific CD8 T cell response against the immunodominant epitope VP2121-130. We determined that 1-10% of CD8 T cells present in the femoral, and sternal bone marrow were virus antigen-specific 5-7 days after intracranial TMEV infection. We determined that antigen-specific CD8 T cells were generated in the bone marrow with similar kinetics to that of conventional responses in the secondary lymphoid organs. Importantly, continuous treatment with FTY720, which sequesters T cells outside of the blood, did not eliminate antigen-specific CD8 T cells in the bone marrow compartment indicating generation within the bone marrow niche. Similarly, injection of Poly I:C admixed with fluorescently labeled ovalbumin into the brain generated a similar antigen-specific CD8 T cell response in the bone marrow indicating these responses occur following various brain insults. This model also identified the likely antigen presenting cell (APC) responsible for scavenging antigens from the brain and trafficking into the bone marrow as a migratory myeloid-derived APC. Moreover, following clearance of TMEV infection, CD8 T cells in the bone marrow established durable memory. Antigen-specific memory CD8 T cells in the bone marrow reactivated and expanded upon cognate antigen reencounter. Antigen-specific reactivation of memory CD8 T cells within the bone marrow caused a concurrent increase in Lineage-, Sca-1+, c-Kit+ (LSK) and CD11b+ MHCII+ myeloid cells. This increase in the LSKs and myeloid cells in the bone marrow niche was abrogated with CD8 T cell depletion. We conclude that brain viral infections induce in situ effector and memory T cell responses within the bone marrow compartment. Memory recall CD8 T cell responses induce niche dysregulation by expanding LSK cells and lead to an influx of MHCII+ myeloid cells. Our data pave the way for crucial studies of bone marrow resident antigen-specific CD8 T cells in health and diseases.

immunology↗

bioRxiv2025

The songbird basal ganglia connectome

The basal ganglia (BG) play an essential role in shaping vertebrate behavior, ranging from motor learning to emotions, but comprehensive maps of their canonical synaptic architecture are missing. In mammals, three main neuronal pathways through the BG have been described - the direct, indirect, and hyperdirect pathways - which together orchestrate many aspects of learning and behavior. In songbirds, cell types associated with striatal and pallidal components appear intermingled in a single basal ganglia nucleus, Area X, essential for song learning. This allows for the dense reconstruction of the entire circuit within a compact volume. Here, we introduce the first vertebrate basal ganglia connectome, comprising over 8,500 automated neuron reconstructions connected by about 20 million synapses. High image quality and automated reconstruction allowed analysis with minimal manual proofreading. Based on direct anatomical measurement of synaptic connectivity, we confirm that a direct, indirect and hyperdirect pathway can be traced through Area X. However, detailed morphological and connectomic analysis revealed no clearly distinct direct and indirect medium spiny neuron subpopulations, and a dominance of the direct and hyperdirect pathway. In addition to previously identified neuron types in Area X, we could distinguish three novel GABAergic neuron types, two of which are major output targets of GPe neurons, leading to novel feedback circuitry within Area X. We further found unexpectedly strong neuronal interconnectivity and recurrency between neurons associated with all pathways. Our data thus challenge the universality of the view of the basal ganglia as an information processor organized into discrete feedforward pathways.

neuroscience↗

bioRxiv2025

Extensive and differential platinum chemotherapy mutagenesis in children

Childhood cancer survivors often develop long-term adverse effects, which may be caused by direct mutagenesis of cytotoxic agents. Some of these agents generate distinctive DNA imprints (mutational signatures), as exemplified by platinum chemotherapeutics. Here, we examined chemotherapy mutagenesis in paediatric tissues by deploying a duplex sequencing method (NanoSeq), which enables mutation calling from single DNA molecules. We surveyed whole genomes of paediatric liver, blood and other tissues, obtained from surgical resections and at post-mortem. Platinum signatures pervaded all tissues extensively, elevating mutation burdens of paediatric tissues to levels seen in adults. Remarkably, we found a tissue-specific mutational signature in the liver. We examined the functional potential of mutations by gene focused NanoSeq, which revealed that platinum agents cause a vast repertoire of cancer causing variants across normal tissues, such as leukaemogenic mutations in blood. This finding may conceivably link cancer treatment in childhood to mutation-driven long term sequelae.

cancer biology↗

bioRxiv2025

Multi-region spatial transcriptomics reveals region specific differences in response to amyloid beta (Aβ) plaque induced changes in Alzheimer's Disease (AD)

Alzheimers disease (AD) is the leading cause of dementia affecting 55 million people worldwide. The pathological hallmarks of AD, beta-amyloid (A{beta}) plaques and neurofibrillary tangles (NFT), follow distinct stereotypical patterns of progression across brain regions and trigger a multicellular response that ultimately leads to neuronal loss and cognitive decline. Despite the uniform spread of A{beta} plaque across the cortex during AD progression, different regions demonstrate varying levels of vulnerability and resilience to temporal A{beta} plaque induced changes, such as NFT accumulation. There is a critical gap in our understanding of the cell types and molecular mechanisms that underlie these region-specific differences in resilience to A{beta} plaque induced changes. In this study, we hypothesized that brain region and cell type specific transcriptional responses within the A{beta} microenvironment, and more broadly within the grey matter, may contribute to this variation. We carried out matched multi-region spatial transcriptomics and A{beta} immunofluorescence staining from the entorhinal, occipito-temporal, dorsolateral prefrontal and striate cortices from two individuals with Braak III and Thal 4 AD. Spatiotemporal comparisons of cell type proportions, gene expression, and cell-cell communication revealed differences in the vulnerability of somatostatin and somatostatin chondrolectin inhibitory neurons and the expression of endosomal and lysosomal trafficking and metallothionein genes within the A{beta} plaque microenvironment. We also observed variations in blood-brain-barrier dysfunction, fibroblast growth factor signaling, and vascular impairment and repair related cell-cell communication networks within the grey matter. Our results demonstrate the value of simultaneously profiling AD-omic and spatial modalities in multiple regions to elucidate how cortical region-specific differences contribute to selective vulnerability and resilience during neurodegeneration.

genomics↗

bioRxiv2025

Connectome analysis of a cerebellum-like circuit for sensory prediction

Stable and accurate perception involves comparing incoming sensory input with internally- generated predictions 1-3. A mechanistic understanding of this process has been elusive due to the size and complexity of the relevant brain regions in mammals. Here we leverage connectomics to comprehensively map the cell types and synaptic connections underlying a well-characterized and ecologically relevant form of predictive sensory processing in the cerebellum-like electrosensory lobe (ELL) of weakly electric fish 4,5. Connectome analysis reveals highly-structured feedforward and recurrent synaptic connectivity mediating the cancellation of predictable electrosensory input. A computational model constrained by prior electrophysiological recordings shows how this connectivity supports the formation of predictions at multiple sites within the network and how the ELL solves a continual learning problem by maintaining fast and accurate predictions despite noise and changes in environmental context. Overall, these findings provide a blueprint for using connectomics to elucidate learning in vertebrate nervous systems.

neuroscience↗

bioRxiv2025

Cerebellum metastasis model of HER2-positive breast cancer unveils key role of IL34-induced Arg1+ macrophages.

Brain metastases occur in up to 40% of Stage IV breast cancer patients. The cerebellum is a frequent location for metastases in HER2-positive breast cancer patients, but the mechanisms for this are unknown. Here, we developed a syngeneic, immunocompetent mouse model for breast cancer brain metastases by stereotactically injecting mouse HER2-overexpressing breast cancer organoids into the cerebellum. Growth of these cerebellar metastases was monitored by MRI and trastuzumab optical imaging using a near-infrared fluorophore conjugated to trastuzumab. Spatial transcriptomics identified interleukin-34 production by breast cancer cells inducing ARG1+ macrophages at the invading edge of the metastasis. Treatment with a blocking antibody to interleukin-34s receptor, CSF1R, produced tumor shrinkage. These findings have immediate translation potential as a CSF1R-blocking antibody is FDA-approved. Further, it demonstrates that cancer-associated inflammation bordering the brain metastasis promotes metastatic growth and offers a molecularly targeted strategy to treat inflammation in brain metastasis. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/660224v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9f1a50org.highwire.dtl.DTLVardef@178acc5org.highwire.dtl.DTLVardef@196d803org.highwire.dtl.DTLVardef@3fe631_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Induction of hypoxic response despite normoxic conditions associated with vascular mitochondrial dysfunction in diet induced metabolic syndrome

Reduced mitochondrial function is one of the various cellular pathologies in cardio-metabolic syndrome. Elevated asymmetric dimethyl arginine (ADMA) levels is known to induce hypoxia driven mitochondrial dysfunction in the lungs, despite normoxic conditions. This alteration is known to be caused by interleukin-4 (IL-4). In addition to asthma, IL-4 and ADMA are also known to be elevated in metabolic syndrome (MetS), but the existence of hypoxic response in arterial tissue remains elusive. Since, MetS and asthma are correlated; we explored whether hypoxia exists in vascular tissue and is associated with IL-4 and ADMA levels. To induce MetS, C57BL/6 mice were fed chow, high-fat or high-fructose diets for six months. Interestingly, MetS was associated with the induction of the hypoxic response in aortic tissue. Further, IL-4 and ADMA, which induce aberrant hypoxic response despite normoxia in the lungs, were elevated in the aorta of mice with MetS. Additionally, significant reductions in the levels of mitochondrial biogenesis factors (TFAM, PGC1) and respiratory chain complexes (Complex I and Complex IV) activities were observed in MetS mice. Mitochondrial dysfunction in the aorta of mice with MetS perturbed mitochondrial inner membrane integrity and was associated with the leakage of cytochrome c in the cytosol. These results collectively suggest that elevated levels of IL-4 and ADMA in the aorta of mice with MetS correlates with induced vascular mitochondrial dysfunction and hypoxic response.

molecular biology↗

bioRxiv2024

Paired and solitary ionocytes in the zebrafish olfactory epithelium

The sense of smell is generated by electrical currents that are influenced by the concentration of ions in olfactory sensory neurons and mucus. In contrast to the extensive morphological and molecular characterization of sensory neurons, there has been little description of the cells that control ion concentrations in the zebrafish olfactory system. Here, we report the molecular and ultrastructural characterization of zebrafish olfactory ionocytes. Transcriptome analysis suggests that the zebrafish olfactory epithelium contains at least three different ionocyte types, which resemble Na+/K+-ATPase-rich (NaR), H+-ATPase-rich (HR), and Na+/Cl- cotransporter (NCC) cells, responsible for calcium, pH, and chloride regulation, respectively, in the zebrafish skin. In the olfactory epithelium, NaR-like and HR-like ionocytes are usually adjacent to one another, whereas NCC-like cells are usually solitary. The distinct subtypes are differentially distributed: NaR-like/HR-like cell pairs are found broadly within the olfactory epithelium, whereas NCC-like cells reside within the peripheral non-sensory multiciliated cell zone. Comparison of gene expression and serial-section electron microscopy analysis indicates that the NaR-like cells wrap around the HR-like cells and are connected to them by shallow tight junctions. The development of olfactory ionocyte subtypes is also differentially regulated, as pharmacological Notch inhibition leads to a loss of NaR-like and HR-like cells, but does not affect NCC-like ionocyte number. These results provide a molecular and anatomical characterization of olfactory ionocytes in a stenohaline freshwater teleost. The paired ionocytes suggest that both transcellular and paracellular transport regulate ion concentrations in the olfactory epithelium, while the solitary ionocytes may enable independent regulation of ciliary beating.

neuroscience↗