Biology subjects

Mehta, M.

Publications and source records attributed to Mehta, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Identifying the source population of naturally recolonised rhinoceros (Rhinoceros unicornis) in Laokhowa-Burhachapori Wildlife Sanctuary, Assam, through multidisciplinary methods

Megaherbivore population recovery largely depends on restoring connectivity between fragmented protected areas to facilitate natural dispersal, gene flow, and range expansion. The Indian rhinoceros (Rhinoceros unicornis) has recovered from severe population decline in the past, but several populations remain spatially restricted. Recent conservation efforts and the expansion of protected areas in Assam have coincided with natural rhino recolonization in Laokhowa-Burhachapori Wildlife Sanctuary (WLS). This has occurred from nearby regions of Orang NP and Kaziranga NP after the species was locally extinct in the 1980s. Identifying the source population of these recolonised rhinos is crucial for managing this emerging metapopulation. We used non-invasive genetic sampling, genetic assignment and a landscape connectivity model to investigate the origin and potential movement routes of the recolonising rhinos. We identified eight unique individuals from Laokhowa-Burhachapori WLS and assigned them to the potential source population using Bayesian and frequency-based approaches against a reference dataset of 365 individual rhinos across the rhino-bearing areas of Assam. Habitat suitability was modelled using 161 spatially thinned presence points and eight environmental variables. We applied least-cost path (LCP) analysis to assess landscape resistance between protected area nodes. All eight recolonising rhinos were assigned to Orang NP with high Bayesian assignment probabilities (q = 0.97-0.99). The connectivity model identified two least-cost pathways, with the Orang NP-Laokhowa-Burhachapori WLS linkage showing lower landscape friction than the Kaziranga NP linkage. These findings provide genetic evidence that the recolonisation occurred through natural dispersal, most likely from Orang NP, and indicate that recent landscape restoration has re-established the structural connectivity across this floodplain. Maintaining these linkages will be essential to promote natural range expansion and the long-term persistence of Indian rhinoceros in Assam.

ecology↗

bioRxiv2026

Unbiased Long-Read Whole-Genome Sequencing Enables High-Resolution Mapping of Transgene Concatenation and Off-target Genomic Disruption in a Mouse Model

Transgenic mouse models are indispensable for dissecting disease mechanisms; yet, their interpretability is frequently compromised by cryptic genomic alterations introduced during transgenesis. Thus, robust quality control strategies are needed to elucidate integration architecture and evaluate model performance when such unintended events occur. Here, we applied unbiased whole-genome long-read sequencing using the PacBio Revio to investigate a mouse model exhibiting unexpected transgene silencing, originally designed to recapitulate autosomal-dominant hereditary macular dystrophy driven by upregulation of a ZZEF1-ALOX15 fusion gene. Long-read sequencing analysis revealed a [≥]29-kb head-to-tail concatemer containing more than three copies of the transgene vector. Reconstruction of transgene-genome junctions revealed off-target integration of the concatemer into the calcium-sensing receptor gene (Casr), along with exogenous E. coli DNA, that together defined final transgene architecture. 5-methylcytosine profiling identified hypermethylation of the transgene promoter and additional phenotyping indicated disruption of endogenous Casr function resulting from the rearrangement. Our workflow enabled direct detection of transgene concatenation and off-target mapping. These findings establish long-read sequencing as a powerful and scalable quality control standard for genetically engineered animal models, uniquely capable of uncovering hidden genomic complexity, resolving aberrant phenotypes, and enhancing the reliability of in vivo disease modelling.

genomics↗

bioRxiv2026

A multi-species toolkit of TOP2 hypercleavage mutants for studying topoisomerase II-mediated DNA damage

DNA topoisomerase II (TOP2) generates transient DNA double-strand breaks that are trapped as TOP2-DNA covalent complexes (TOP2cc) by antibiotic and chemotherapy drugs. Here, we characterize tools for study of cellular responses to TOP2cc, exploiting a Saccharomyces cerevisiae TOP2 mutant (TOP2-F1025Y,R1128G) that generates spontaneous and inhibitor-induced covalent complexes at elevated frequencies. This Top2-hc (for "hypercleavage") mutant protein inhibits yeast cell growth when expressed alone or with endogenous Top2, and growth defects are exacerbated in DNA-repair-deficient genetic backgrounds and/or in the presence of low doses of the Top2 poison mAMSA. We generated analogous mutations in human and mouse TOP2A and TOP2B that gave increased TOP2cc, hypersensitization to topoisomerase poisons, increased DNA damage, and decreased cell survival in cultured cells. We further established knock-in mouse models with inducible, tissue-specific expression of each TOP2-hc isoform, demonstrating overt organismal toxicity and cellular markers of DNA damage responses. To illustrate the potential of these genetic tools, we carried out proof-of-principle screens in yeast and cultured human cells for sensitivity to TOP2-hc. The yeast screen revealed strong requirements for homologous recombination, moderate roles for sister chromatid cohesion and kinetochore function, and dependencies on vesicle and vacuolar functions. The pilot shRNA screen in human cells revealed shared requirements for resistance to expression of either TOP2A-hc or TOP2B-hc as well as examples of isoform specificity. These findings establish hypercleavage mutant proteins as effective tools for studying topoisomerase isoform-specific DNA damage and offer a foundation for exploring TOP2cc toxicity and tolerance in vivo. Significance statementDNA topoisomerase II enzymes untangle chromosomes by cutting DNA, but incomplete resealing creates toxic damage that is the basis of antibacterial and chemotherapy drugs. Here we describe toolkits in yeast, mammalian cells, and mice that take advantage of mutant topoisomerase II enzymes that trap on DNA without drugs, creating powerful genetic systems to better study how cells deal with this type of DNA damage. We provide benchmarking data to validate these tools and to illustrate how they can be used for screens in cultured cells or tissue-specific experiments in vivo. These toolkits overcome longstanding technical barriers and enable new ways to study topoisomerase II-mediated DNA damage.

genetics↗

bioRxiv2026

Linking human brain functional connectivity to underlying neurotransmission

The human brain is organized into interacting functional systems. Their underlying neurobiological mechanisms remain difficult to study in vivo. Here, we adopt a topological framework to quantify the association between neurobiology and brain functional connectivity derived from both resting-state fMRI and MEG. Across six healthy adult cohorts (n = 19-112), regional variation in fMRI connectivity robustly aligns with the distribution of neurotransmitter receptors and transporters. These patterns are present in every single subject, replicate across all cohorts, and are mirrored in MEG. Most prominently, noradrenergic modulation of connectivity in a sensorimotor-insular network is consistently detected across individuals and linked to autonomic arousal. In pharmacological and clinical samples, associations are sensitive to neurotransmitter system manipulation and are altered in early psychosis, aligning with clinical symptomatology. These findings provide biological insight into typical and atypical functional organization of the human brain using a framework linking underlying neurobiology to the functional connectome (NEOFC).

neuroscience↗

bioRxiv2026

Ultrasound Activated Nanobubbles Induce Durable Systemic Antitumor Immunity

Clinical outcomes in aggressive breast cancer vary widely, in part because the tumor microenvironment is structured to exclude immune infiltration. Low antigen load, dysfunctional antigen-presenting cells, T cell exclusion and exhaustion, and a stiff extracellular matrix that physically restricts immune cell trafficking work together to form a suppressive barrier that current immunotherapies struggle to overcome. We addressed this barrier using ultrasound (US)-activated nanobubbles (NBs), a drug-free intervention based on perfluoropropane-filled nanoparticles. The size and deformable phospholipid shell enable NBs to achieve deep tumor penetration and a uniform distribution throughout the entire tumor. Upon ultrasound activation, NBs generate localized mechanical forces that restore extracellular matrix elasticity, disrupt tumor transport barriers, and drive HMGB1 release, re-engaging endogenous antitumor immunity without pharmacological agents. In a syngeneic triple-negative breast cancer model, US-NB treatment depleted immunosuppressive myeloid cells 3-fold within 3 hours, followed by a greater than 5-fold increase in the ratio of antigen-experienced to suppressive T cells at 48 hours. US-NB drives rapid infiltration of CD4+ and CD8+ T cells within 48 hours. US-NB treatment achieved an 85% cure rate in the D2A1 model; cured animals maintained durable systemic immune memory, rejecting both local and systemic tumor rechallenge. Consistent therapeutic benefit was observed in a luminal B-like mammary tumor model (E0771), supporting activity across breast cancer subtypes. These results establish US-NB mechanical immunomodulation as a drug-free therapeutic strategy capable of generating robust and durable antitumor immunity, acting through biophysical tissue properties rather than tumor-specific molecular targets. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/714247v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@8f274eorg.highwire.dtl.DTLVardef@5da575org.highwire.dtl.DTLVardef@19defborg.highwire.dtl.DTLVardef@7e630e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

The effect of psychedelics on associative learning: a systematic review

IntroductionPsychedelics are emerging as potential treatments for neuropsychiatric conditions, with evidence suggesting a single administration can lead to enduring behavioural changes. While the underlying putative mechanism(s) remain unclear, there is evidence supporting altered learning as a key candidate. AimThis systematic review examined studies assessing the effects of psychedelics on associative learning in both humans and animals. MetodsElectronic databases were searched up until 13/01/2025 for studies investigating any difference in learning after psychedelic administration. Results31 studies were included (29 in animals, 2 in humans). Classical and operant conditioning paradigms were employed, including fear extinction, conditioned avoidance, and reversal learning. Studies assessed acute and post-acute effects, however repeated dosing paradigms often obscured this distinction. There was considerable heterogeneity in study designs, paradigms, drug administration timings and doses, and behavioural effects appeared to be influenced by dose, timing, training intensity, and sex. Due to between-study heterogeneity, a meta-analysis was not possible. Evidence suggests that psychedelic administration enhances associative learning in animals across paradigms, although findings were not entirely consistent. Possible mechanisms identified were increased prediction error sensitivity, serotonin receptor agonism, and structural plasticity. Learning enhancements may extend into the post-acute phase and appear to depend on active environmental engagement during this window. ConclusionStudies suggest that psychedelics enhance associative learning in animals; however, these findings are yet to be translated into humans. Understanding whether a period of enhanced learning follows the psychedelic experience may have important implications for psychedelic-assisted psychotherapy, where behavioural changes must generalise and persist beyond the drug-induced state.

neuroscience↗

bioRxiv2025

Enhanced delivery of lipid nanoparticle-based immunotherapy by modulating the tumor tissue stiffness using ultrasound-activated nanobubbles

Tumors often exhibit an extracellular matrix with elevated stiffness due to excessive accumulation and crosslinking of proteins, particularly collagen. This elevated stiffness acts as a physical barrier, impeding the infiltration of immune cells and the effective delivery of various immunotherapeutic agents, such as lipid nanoparticle-based RNA therapeutics. Here, we investigate the ability of ultrasound-activated nanobubbles (US-NBs) to increase the permeability and immunogenicity of tumors. Our results show that US-NBs physically remodel the tumor tissue by decreasing its stiffness by 60% five days after a single treatment. US-NB-treated tumors display randomly oriented collagen with a 5.47-fold lower deposition compared to untreated tumors. This leads to the effective delivery and widespread distribution of lipid nanoparticles (LNPs) in the tumor. When LNPs are assisted by US-NB, they have higher gene-transfection across pan-immune cells relative to LNPs alone. Notably, US-NB enables LNPs to genetically modify T cells directly in vivo. By effectively engaging both arms of the immune system, US-NB-assisted LNPs enhance the tumor immunogenicity and infiltration of cytotoxic cells by 4-fold when compared to LNPs alone. These results indicate that gentle mechanical stimulation of the tumor using US-NB offers a promising strategy to augment the delivery and efficacy of existing immunotherapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/648512v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@da7fborg.highwire.dtl.DTLVardef@8f5f27org.highwire.dtl.DTLVardef@b002f6org.highwire.dtl.DTLVardef@19265da_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity

The RNA-binding protein IGF2BP3 is an oncofetal protein overexpressed in B-acute lymphoblastic leukemia and is critical for leukemogenesis in experimental models. With cancer-specific expression, functional dispensability for normal development, and an unleveraged pro-oncogenic function in mRNA homeostasis, IGF2BP3 represents an excellent target. With no small molecule inhibitors of IGF2BP3 in clinical use, we undertook an effort to identify new IGF2BP3 inhibitors using biochemical methods. A biochemical screen, followed by a cell-based counter screen, led to the identification of compounds with protein-RNA interaction inhibition and leukemic cell growth-inhibitory activity. One of these compounds, designated I3IN-002, shows consistent cell growth-inhibitory activity, altered cell cycle and increased apoptosis in multiple leukemia cell lines, and is the most potent inhibitor of IGF2BP3 reported to date. I3IN-002 was tolerated in mice when administered intraperitoneally and showed potent anti-leukemic activity in a syngeneic transplantation model of MLL-Af4 leukemia. I3IN-002 inhibits the function of IGF2BP3, disrupting in situ binding of IGF2BP3 to target mRNAs, and altering IGF2BP3-dependent gene expression regulation. Furthermore, cell-free and cellular thermal shift assays as well as drug affinity responsive target stability assays support on target activity of I3IN-002 for IGF2BP3. Thus, the identification of I3IN-002 paves the way for the discovery of potent and selective small molecule inhibitors of IGF2BP3.

cancer biology↗

bioRxiv2024

The Autonomic Nervous System (ANS)-Immune Network in People Living With HIV

PurposePre-clinical studies have demonstrated direct influences of the autonomic nervous system (ANS) on the immune system. However, it remains unclear if ANS-immune connections delineated in pre-clinical studies underlie the relationship between autonomic dysregulation and chronic inflammatory diseases in patients with HIV. This study had three aims: 1.) Examine the relationship between IL-6 and the parasympathetic/vagal component of baroreflex sensitivity (BRS-V) in people with HIV; 2.) Determine if the subtype and severity of HIV-autonomic neuropathy (AN) would predict distinct immunotypes; 3.) Compare the burden of non-AIDS-related co-morbidities between immunotypes. Methods79 adults with well-controlled HIV underwent a standard battery of autonomic function tests summarized as the Composite Autonomic Severity Score and vagal and adrenergic baroreflex sensitivity (BRS-V and BRS-A).1 Levels of immune biomarkers were measured in all participants using the Target 96 Inflammation Panel on the Olink proteomics platform and immunotypes were identified using unbiased, non-negative matrix factorization. Mass cytometry (CyTOF) was completed on a subset of participants with and without autonomic neuropathy (N = 10). ResultsReduced BRS-V predicted higher levels of IL-6 (p=0.002). A pro-inflammatory immunotype defined by elevations in type 1 cytokines (IL-6, IL-17) and increased numbers of CD8+ T-cells was associated with autonomic neuropathy characterized by deficits in sympathetic nervous system activity (aOR=4.7, p=0.017). This pro-inflammatory immunotype was older with a greater burden of co-morbidities. ConclusionDeficits in the parasympathetic/cardiovagal and the sympathetic nervous system are associated with inflammation and disease burden in people living with HIV. Future longitudinal research is needed to examine causality.

immunology↗

bioRxiv2024

Multiparametric grading of glaucoma severity by histopathology can enable post-mortem substratification of disease state

Neurodegeneration in glaucoma patients is clinically identified through longitudinal assessment of structure-function changes, including intraocular pressure, cup-to-disc ratios from fundus images, and optical coherence tomography imaging of the retinal nerve fiber layer. Use of human post-mortem ocular tissue for basic research is rising in the glaucoma field, yet there are challenges in assessing disease stage and severity, since tissue donations with informed consent are often unaccompanied by detailed pre-mortem clinical information. Further, the interpretation of disease severity based solely on anatomical and morphological assessments by histology can be affected by differences in death-to-preservation time and tissue processing. These are difficult confounders that cannot be easily controlled. As pathogenesis and molecular mechanisms can vary depending on the stage and severity of glaucoma, there is a need for the field to maximize use of donated tissue to better understand the molecular mechanisms of glaucoma and develop new therapeutic hypotheses. Further, there is a lack of consensus around the molecular RNA and protein markers that can be used to classify glaucoma severity. Here, we describe a multiparametric grading system that combines structural measurements of the retinal nerve fiber layer with linear regression and principal component analyses of molecular markers of retinal ganglion cells and glia (RBPMS, NEFL, IBA1 and GFAP) to stratify post-mortem glaucoma eyes by the severity of disease. Our findings show that a quantitative grading approach can stratify post-mortem glaucoma samples with minimal clinical histories into at least three severity groups and suggest that this type of approach may be useful for researchers aiming to maximize insights derived from eye bank donor tissue.

pathology↗

bioRxiv2023

PPP1R3B is a metabolic switch that shifts hepatic energy storage from lipid to glycogen

Obesity is a growing worldwide epidemic that carries numerous metabolic complications including increased risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). Multiple genome-wide association studies (GWAS) have associated the PPP1R3B locus with cardiometabolic traits including fasting glucose and insulin levels (T2D traits), plasma lipids (CVD traits), and indications of hepatic steatosis and liver damage (NAFLD traits)1-5. The PPP1R3B gene encodes the glycogen regulatory protein PPP1R3B (also known as GL) which has an established role in liver glycogen metabolism and plasma glucose homeostasis6,7. The metabolic and NAFLD GWAS single nucleotide polymorphisms (SNPs) in this region, which are all in high linkage disequilibrium, result in increased liver PPP1R3B expression and hepatic glycogen accumulation, but have provided conflicting results on the impacts on hepatic steatosis and liver damage. Here we investigate the consequences of both Ppp1r3b overexpression and deletion in mouse and cell models and find that dysregulated Ppp1r3b expression in either direction promotes metabolic dysfunction and liver injury. Hepatocyte overexpression of Ppp1r3b increases hepatic glycogen storage, prolongs fasting blood glucose levels, and confers protection from hepatic steatosis, but increases plasma ALT in aged animals. Conversely, deletion of hepatocyte Ppp1r3b eliminates hepatic glycogen, causes impaired glucose disposal, and results in hepatic steatosis with age or high sucrose diet. We investigated the metabolic pathways contributing to steatosis and found that Ppp1r3b deletion and diminished glycogenesis diverts the storage of exogenous glucose to hepatic triglycerides (TG), and stored liver lipids are preferentially used for energy during fasting through lipid oxidation and ketogenesis. Further, we interrogated two large human biobank cohorts and found carriers of SNPs associated with increased PPP1R3B expression have increased plasma glucose, decreased hepatic fat, and lower plasma lipids, while putative loss-of-function (pLoF) variant carriers have increased hepatic fat and elevated plasma ketones and lipids, consistent with the results seen in our mouse models. These findings suggest hepatic PPP1R3B serves as a metabolic switch favoring hepatic energy storage as glycogen instead of TG.

molecular biology↗

bioRxiv2022

Mega-scale movie-fields in the mouse visuo-hippocampal network

Natural experience often involves a continuous series of related images while the subject is immobile. How does the cortico-hippocampal circuit process this information? The hippocampus is crucial for episodic memory1-3, but most rodent single unit studies require spatial exploration4-6 or active engagement7. Hence, we investigated neural responses to a silent, isoluminant, black and white movie in head-fixed mice without any task or locomotion demands, or rewards, from the Allen Brain Observatory. The activity of most neurons (97%, 6554/6785) in the thalamo-cortical visual areas was significantly modulated by the 30s long movie clip. Surprisingly, a third (33%, 3379/10263) of hippocampal -dentate gyrus, CA1 and subiculum- neurons showed movie-selectivity, with elevated firing in specific movie sub-segments, termed movie-fields. Movie-tuning remained intact when mice were immobile or ran spontaneously. On average, a tuned cell had more than 5 movie-fields in visual areas, but only 2 in hippocampal areas. The movie-field durations in all brain regions spanned an unprecedented 1000-fold range: from 0.02s to 20s, termed mega-scale coding. Yet, the total duration of all the movie-fields of a cell was comparable across neurons and brain regions. We hypothesize that hippocampal responses show greater continuous-sequence encoding than visual areas, as evidenced by fewer and broader movie-fields than in visual areas. Consistent with this hypothesis, repeated presentation of the movie images in a fixed, scrambled sequence virtually abolished hippocampal but not visual-cortical selectivity. The enhancement of continuous movie tuning compared to the scrambled sequence was eight-fold greater in hippocampal than visual areas, further supporting episodic-sequence encoding. Thus, all mouse-brain areas investigated encoded segments of the movie. Similar results are likely to hold in primates and humans. Hence, movies could provide a unified way to probe neural mechanisms of episodic information processing and memory, even in immobile subjects, across brain regions, and species.

neuroscience↗

bioRxiv2022

Dysregulation of mTOR Signaling Mediates Common Neurite and Migration Defects in Both Idiopathic and 16p11.2 Deletion Autism Neural Precursor Cells

Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism defects in controls. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.

neuroscience↗

bioRxiv2022

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function

Deficiency of iron-sulfur (Fe-S) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of Fe-S biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreichs ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, we aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells exhibited a vasoconstrictive phenotype consistent with PH. These data were observed in both primary pulmonary endothelial cells after pharmacologic inhibition of FXN and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study defines FXN as a shared upstream driver of pathologic aberrations in both metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction, suggesting available and future therapies may be beneficial and targeted for PH subtypes with FXN deficiency. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/504849v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@12c5568org.highwire.dtl.DTLVardef@19b5f0borg.highwire.dtl.DTLVardef@17d0157org.highwire.dtl.DTLVardef@1e323a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Understanding spatiotemporal effects of food supplementation on host-parasite interactions using community-based science

O_LISupplemental feeding can increase the overall health of animals but also can have variable effects on how animals defend themselves against parasites. However, the spatiotemporal effects of food supplementation on host-parasite interactions remain poorly understood, likely because large-scale, coordinated efforts are difficult. C_LIO_LIHere, we introduce the Nest Parasite Community Science Project, which is a community-based science project that coordinates studies with bird nest box "stewards" from the public and scientific community. This project was established to understand broad ecological patterns between hosts and their parasites. C_LIO_LIThe goal of this study was to determine the effect of food supplementation on eastern bluebirds (Sialia sialis) and their nest parasite community across the geographic range of the bluebirds from 2018-2021. We received 646 nests from 68 stewards in 26 states in the eastern United States. Nest box stewards reported whether or not they fed their bluebirds mealworms or suet, then followed the nesting success of the birds (number of eggs laid and hatched, percent hatched, number and percent fledged). We then identified and quantified parasites in the nests. C_LIO_LIWe found that food supplementation increased fledgling numbers and proportional fledging success. The main nest parasite taxa were parasitic blow flies (Protocalliphora sialia), but a few nests contained fleas (Ceratophyllus idius, C. gallinae, Orchopeas leucopus) and mites (Dermanyssus spp. and Ornithonyssus spp.). Blow flies were primarily found at northern latitudes, where food supplementation affected blow fly abundance. However, the direction of this effect varied substantially in direction and magnitude across years. More stewards fed bluebirds at southern latitudes than at northern latitudes, which contradicted the findings of other community-based science projects. C_LIO_LIOverall, food supplementation of birds was associated with increased host fitness but did not appear to play a consistent role in defense against these parasites across all years. Our study demonstrates the importance of coordinated studies across years and locations to understand the effects of environmental heterogeneity, including human-based food supplementation, on host-parasite dynamics. Studies during a single year or considering only a single population might not provide the necessary data to develop management strategies for species. C_LI

ecology↗

bioRxiv2022

Properties and computational consequences of fast dendritic spikes during natural behavior

Dendritic membrane potential was recently measured for the first time in drug-free, naturally behaving rats over several days. These showed that neuronal dendrites generate a lot of sodium spikes, up to ten times as many as the somatic spikes. These key experimental findings are reviewed here, along with a discussion of computational models, and computational consequences of such intense spike traffic in dendrites. We overview the experimental techniques that enabled these measurements as well as a variety of models, ranging from conceptual models to detailed biophysical models. The biophysical models suggest that the intense dendritic spiking activity can arise from the biophysical properties of the dendritic voltage-dependent and synaptic ion channels, and delineate some computational consequences of fast dendritic spike activity. One remarkable aspect is that in the model, with fast dendritic spikes, the efficacy of synaptic strength in terms of driving the somatic activity is much less dependent on the position of the synapse in dendrites. This property suggests that fast dendritic spikes is a way to confer to neurons the possibility to grow complex dendritic trees with little computational loss for the distal most synapses, and thus form very complex networks with high density of connections, such as typically in the human brain. Another important consequence is that dendritically localized spikes can allow simultaneous but different computations on different dendritic branches, thereby greatly increasing the computational capacity and complexity of neuronal networks.

neuroscience↗

bioRxiv2021

How perception and attention participate in reading skill?

Reading creates accessibility to the outer world information and is an integral skill for academic achievement. It involves visual perception, reasoning at symbolic level (text reading) and phonological processing. But does perception, visuospatial processing at pre-symbolic level affect reading skill? To understand and untangle the mechanism fifty children with reading problem (developmental dyslexia, DDC) and twentyfive age-matched typical readers (healthy controls, HC) were studied. In DDC, the variable-performance of non-symbolic visual search (pictorial-level) was associated with bilateral brain activity (functional MRI) of ventral stream (inferior occipital and fusiform) and greater involvement of frontal-prefrontal regions, suggesting the modified dorsal route-gating for figure-ground filtering. Performance variability in picture-concept reasoning (71.9% and significant group mean difference) and visuospatial-organization (51.3%) of DDC children indicate attentional or executive differences at nonsymbolic level. In symbolic discrimination performance, no significant difference observed for single alphabet or number (digit) reading but significant differences at word level for visual and phonological performance (considering orthographic differences), attributes to distractor-inhibition problems. Nonsymbolic to symbolic coding/decoding speed and writing error (copying) differences are suggestive of execution variability rather than motor coordination in DDC. In HC, the top-down dorsal route gating and hypoactivity induced in right frontal-anterior cingulate cortices, play a major role in reading by allocating spatial attention and inhibiting distractors. It has been elaborated in the "neurobiological model". How perception and attention participate in reading skill?O_ST_ABSResearch HighlightsC_ST_ABSO_LIVisuospatial attention, executive control (nonsymbolic level) and visual discrimination (symbolic level) performance contribute to reading. C_LIO_LIIn children with reading problems (dyslexia) pictorial visual processing task (fMRI) recruited higher activation in right hemispheric frontal, inferior parietal and anterior cingulate regions. C_LIO_LIBilateral activation of occipital-striate, extra-striate, fusiform for nonsymbolic is associated with significantly more errors at bigger-symbol-string, in dyslexia. C_LIO_LIAuditory discrimination differences in shallow-deep orthography. C_LIO_LICorrelation of non-symbolic executive and symbolic performances. C_LIO_LIRole of the prelexical visual perception and dorsal-route gating in reading skill explained as neurobiological model. C_LI

neuroscience↗

bioRxiv2020

Urine single cell RNA-sequencing in focal segmental glomerulosclerosis reveals inflammatory signatures in immune cells and podocytes

The diagnosis of focal segmental glomerulosclerosis (FSGS) requires a renal biopsy, which is invasive and can be problematic in children and in some adults. We used single cell RNA-sequencing to explore disease-related cellular signatures in 23 urine samples from 12 FSGS subjects. We identified immune cells, predominantly monocytes, and renal epithelial cells, including podocytes. Analysis revealed M1 and M2 monocyte subsets, and podocytes showing high expression of genes for epithelial-to-mesenchymal transition (EMT). We confirmed M1 and M2 gene signatures using published monocyte/macrophage data from lupus nephritis and cancer. Using renal transcriptomic data from the Nephrotic Syndrome Study Network (NEPTUNE), we found that urine cell immune and EMT signature genes showed higher expression in FSGS biopsies compared to minimal change disease biopsies. These results suggest that urine cell profiling may serve as a diagnostic and prognostic tool in nephrotic syndrome and aid in identifying novel biomarkers and developing personalized therapeutic strategies.

immunology↗