Biology subjects

Ganesh, S.

Publications and source records attributed to Ganesh, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Patient-Derived Organoids as a Model to Understand Tumor Microenvironment-Driven Nano-Bio Interactions - A Framework Towards Improved Nanomedicine Translation

Nanomedicines that perform well in conventional cell cultures often fail to translate into patients, in part due to the inability to reproduce the protein corona, and hence the biological identity, that nanoparticles acquire within the tumor microenvironment (TME). Here, we establish patient-derived colonic organoids (PDCOs) as a platform for profiling nano-bio interactions under physiologically tumor-relevant conditions using graphene quantum dots (GQD) and Silicon Quantum Dots (SiQD) as material-distinct probes. By combining spectral flow cytometry, confocal imaging, dynamic light scattering, and multi-spectral dimension-reduction analysis of single-cell uptake, we resolve how nanoparticle identity, uptake, and intracellular fate diverge between conventional culture and patient tissue. Conventional two-dimensional culture overestimated internalization by two-fold relative to ex vivo PDCOs, while TME-specific proteins directed nanoparticles to distinct organoid subpopulations. Exploiting this, we engineer the protein corona with tumor-specific proteins to redirect SiQDs to chemoresistant cells, from 3.8% to 70%, an 18-fold increase in targeted delivery to the cells that drive therapy resistance. Internalization was also model-dependent. PDCOs and fibroblasts favored clathrin/dynamin (DNM1)-mediated endocytosis into lysosomes, whereas cancer cells favored caveolae (CAV1)-mediated entry that bypasses lysosomal degradation. This distinction determines whether a nanocarrier is degraded or delivered intact. Collectively, these findings turn the protein corona into a programmable design tool and establish PDCOs as a next-generation platform for precision nano-oncology.

bioengineering↗

bioRxiv2026

State-dependent aperiodic EEG dynamics track cortical network reorganization in chronic epilepsy

Aperiodic (1/f-like) EEG activity has rapidly become a popular noninvasive marker of cortical network state, proposed to index excitation-inhibition (E/I) balance and increasingly applied across neurological and psychiatric disorders. However, whether this approach remains reliable in the pathological brain, where disease progressively reorganizes neural networks, alters signal morphology, and drives continuous transitions between cortical states has yet to be systematically established.Using a medication-free genetic model of chronic epilepsy (Lafora disease; Epm2a-- mice), we tracked the aperiodic component of the cortical EEG across resting wakefulness, isoflurane anesthesia, and PTZ-induced seizures of graded severity, asking how a single spectral marker behaves as the brain moves between states. Epileptic mice exhibited systematically steeper aperiodic exponents than controls, an effect that persisted after removal of interictal epileptiform discharges and was replicated using independent time-resolved spectral parameterization. Slopes steepened predictably under GABAergic anesthesia, supporting the interpretation that aperiodic activity captures biologically meaningful state transitions beyond simple contamination by pathological waveforms. Across seizure phases, the aperiodic exponent varied systematically, however, the exponent flattened during ictal activity in step with the dominant discharge morphology, revealing that pathological waveform shape itself is a substantial contributor to seizure-state exponent changes. Together, these findings indicate that aperiodic EEG dynamics reflect a combination of chronic network-state reorganization and waveform-shape-driven spectral distortion, with their relative contributions varying across brain states. These results support spectral parameterization as a sensitive approach for tracking pathological neural activity in chronic epilepsy while delineating its interpretive boundaries in the presence of pathological waveforms.

neuroscience↗

bioRxiv2026

Decoupled phenology and PSII thermal plasticity in seasonally dry tropical forest trees

We tested whether seasonal plasticity in photosystem II (PSII) heat tolerance aligns with leaf phenology in tropical trees, comparing evergreen and deciduous species across the wettopostwet transition in a seasonally dry tropical forest of the central Western Ghats, India. This transition, preceding droughtinduced senescence, represents the key window to assess true unstressed thermal plasticity. PSII thermal traits: damage onset (T5), damage midpoint (T50), and temperature between damage onset to full loss (T95-T5), decline width (DW) were quantified in 27 cooccurring species during the wet (27.5{square}{degrees}C) and postwet (31.6{square}{degrees}C) periods. Contrary to phenologybased predictions, PSII plasticity was not structured by leaf habit or successional status. Both T5 (+1.7{square}{degrees}C) and T50 (+0.9{square}{degrees}C) increased significantly across seasons, but responses were speciesspecific, with evergreen and deciduous trees acclimating similarly. The preventionversusforbearance tradeoff (T5 - DW relationship) remained conserved, though leaf habits diverged under postwet conditions. Thermal safety margins based on T50 were large, but T5 revealed vulnerable latesuccessional evergreens (Saraca asoca, Ficus spp.) and Careya arborea. These results show that PSII thermotolerance regulation operates largely independently of droughtavoidance phenology, indicating species identity and not leaf habit drives plasticity in PSII thermal response in seasonally dry tropical forests.

physiology↗

bioRxiv2026

Safety and Feasibility of Infusing Ex Vivo Expanded Allogeneic Canine Natural Killer Cells for the Treatment of Metastatic Solid Tumors

BackgroundCompanion canines need advances in therapeutic options for solid tumor malignancies. Prior studies established feasibility of autologous natural killer (NK) cell infusions in canines with solid tumors; however, autologous products are limited by dysfunctional immunity and a manufacturing process that delays care. Allogeneic NK cells offer the possibility of "off-the-shelf" therapy to be administered from healthy donors. MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from healthy canine donors via density gradient separation. NK cells were expanded with recombinant human IL-2 and canine IL-21 with the addition of K562 feeder cells transfected with CD137 ligand and membrane bound human IL-15. Additional experiments included IL-12 in the expansions. In vitro potency was assessed via co-culture with the D17-mKate2 canine osteosarcoma cell line. Three canines were enrolled in a phase 1 trial infusing ex vivo expanded allogeneic NK cells after lymphodepletion. ResultsFlow cytometric analysis confirmed successful expansion of canine NK cells with up to 50% of cells demonstrating NKp46+ after 14 days of expansion. Residual T cell numbers varied based on donor. The addition of IL-12 led to increased NK cell expansion. Incucyte demonstrated potency with increasing osteosarcoma cell death at higher effector to target ratios. Three canines with metastatic/refractory solid tumors were successfully lymphodepleted and infused with allogeneic NK cell products. The canines tolerated the infusions well. ConclusionsCanine allogeneic NK cells were successfully expanded and activated ex vivo, demonstrated potency in vitro, and safety in vivo. Further studies will optimize the NK cell product and escalate dosing to reach the maximal tolerable dose.

cancer biology↗

bioRxiv2026

Aging associated RNA loss impairs the dynamics of RNA and protein condensates

Altered biomolecular condensate dynamics are increasingly implicated in age-associated neurodegenerative disorders, yet the molecular principles governing these changes remain incompletely understood. Here, we demonstrate that aged cells across diverse cellular and organismal models harbor pre-formed, viscous, and persistent stress granules (SGs), which we term alt-SGs. These persistent condensates confer protection to senescent cells under fluctuating stress conditions. Comparative analyses reveal that alt-SGs exhibit elevated RNA-binding protein (RBP)-to-RNA ratios, underscoring a shift in condensate stoichiometry. By quantifying SG composition and dynamics in live cells and in vitro, we establish that RNA concentration is a key determinant of condensate material properties, molecular composition, and dissolution capacity. Importantly, aging cells display diminished absolute RNA concentrations due to reduced RNA metabolic activity. Reactivation of RNA metabolism restores RNA/RBP ratios within SGs and alleviates aging-associated phenotypes. Together, our findings highlight RNA metabolism as a central regulator of condensate stoichiometry and function, linking metabolic decline to altered phase behavior and cellular aging. Key findingsO_LIAging and senescence have Alt-SGs with increased protein/RNA Ratio C_LIO_LIAlt-SGs are persistent after stress removal in aging C_LIO_LIAging is associated with reduced total cellular RNA C_LIO_LIReactivating RNA metabolism rescues SG phenotypes C_LIO_LIAlt-SGs are protective for senescent cell C_LI

cell biology↗

bioRxiv2025

Rapid fluorescence lifetime sensor development of LifeCamp enables transient and baseline absolute calcium measurements

Genetically encoded calcium sensors (GECIs) have been instrumental for studying neuronal activity and intracellular signaling. GECIs are typically fluorescence-intensity sensors that change brightness upon calcium binding. Iterative improvements in GECIs have yielded indicators that report action potential-evoked calcium entry with high sensitivity and temporal resolution, enabling measurement of network activity across thousands of neurons. However, fluorescence intensity-based measurements generally cannot report baseline or absolute calcium levels and may confound neuromodulatory regulation of calcium handling with changes in action potential firing. Fluorescence lifetime sensors are insensitive to many artifacts that plague intensity-based measures and report absolute substrate levels, including those at rest. However, relatively few lifetime sensors for neuronal signals exist, and developing new sensors is typically difficult and low-yield. Here, we introduce a new rapid lifetime sensor development (RALISED) platform, which we use to build a new GCaMP8m-based high-speed lifetime calcium sensor, termed LifeCamp. We show that LifeCamp enables comparison of baseline calcium signals in cell culture, brain slices, and mice. In addition, we show that LifeCamp enables the detection of fast action potential-evoked calcium transients in single neurons from brain slices and in behaving mice. Using LifeCamp, we discovered calcium baseline changes associated with neuronal activity in brain slices and behaving mice, as well as slow average calcium changes in neuronal populations of freely moving mice. Altogether, this study highlights the utility of the RALISED method to rapidly develop new lifetime sensors and the application of the LifeCamp calcium lifetime sensor to study fast and slow calcium signaling. Significance statementWe developed a new high-speed, sensitive calcium lifetime sensor (LifeCamp) using a novel rapid lifetime sensor development (RALISED) platform. LifeCamp has high sensitivity and a large substrate-dependent lifetime change (<1ns), allowing for the capture of baseline calcium levels, transient calcium changes, and neuronal firing in vitro and behaving animals. LifeCamp lifetime measurement is insensitive to artifacts that plague conventional intensity imaging and enables absolute comparison of baseline and transient calcium changes across cells, brain regions, and experimental conditions. Hence, LifeCamp is a powerful tool that enables a more accurate and in-depth understanding of neuronal activity and calcium signaling.

neuroscience↗

bioRxiv2025

A silent Kv channel subunit shapes PV neuron action potential waveform and short-term synaptic plasticity during high-frequency firing

Fast-spiking parvalbumin-positive (PV) neurons provide precisely timed, context-dependent inhibition within cortical circuits. PV neuron firing properties are specialized among cortical neurons, suggesting that they express a unique complement of ion channels. Here, we identify the PV-specific silent voltage-gated potassium (Kv) channel subunit Kv6.4 (encoded by Kcng4), whose role in cortical PV neuron physiology was previously unknown, as a modulator of both intrinsic and synaptic properties. Kv6.4 does not form functional channels on its own but, as shown in prior work, assembles with Kv2 subunits to create heterotetrameric channel complexes, effectively reducing Kv2-mediated delayed rectifier current. We find that Kcng4 expression is enriched within a distinct Pvalb-expressing subclass in primary somatosensory (S1) and motor (M1) cortex and emerges during postnatal development. In PV neurons, Kv6.4 loss reduces action potential (AP) height and width, hyperpolarizes the threshold and interspike potential, and accelerates AP upstroke particularly during repetitive firing. Kv6.4 loss, potentially due to the changes in AP waveform, also alters GABA release and paired-pulse depression at synapses made by PV onto pyramidal (PYR) neurons. The effects of Kv6.4 loss are amplified during high-frequency firing, within the physiological range of fast-spiking PV neurons, likely due to altered repolarization dynamics that accumulate across successive APs. These findings are thus consistent with the function of Kv6.4 in modifying Kv2-mediated delayed rectifier currents. Hence, Kv6.4 tunes the temporal precision of PV inhibitory output, a feature that may be critical for stable excitation-inhibition ratios and adaptive circuit function underlying learning and behavior. Significance StatementVoltage-gated ion channels are broadly expressed yet serve cell-type-specific functions. We demonstrate that the Kv6.4 silent subunit is selectively expressed by fast-spiking parvalbumin-positive (PV) inhibitory neurons among cortical neurons. In PV neurons, Kv6.4 modulates action potential (AP) waveform and GABA release onto excitatory neurons in a frequency-dependent manner, well within the physiological range of PV firing. This mechanism is likely important for preserving the temporal precision of inhibition, which is particularly critical for fast-spiking interneuron output. By shaping short-term synaptic plasticity during high-frequency firing, Kv6.4 provides a molecular and cell-type-specific mechanism for context-dependent tuning of inhibition within cortical circuits. This function may be especially relevant for sensory processing, experience-dependent plasticity, and the maintenance of excitation-inhibition ratios in vivo.

neuroscience↗

bioRxiv2024

Widespread Neuroanatomical Integration and Distinct Electrophysiological Properties of Glioma-Innervating Neurons

Gliomas are the most common malignant primary brain tumors and are often associated with severe neurological deficits and mortality. Unlike many cancers, gliomas rarely metastasize outside the brain, indicating a possible dependency on unique features of brain microenvironment. Synapses between neurons and glioma cells exist, suggesting that glioma cells rely on neuronal inputs and synaptic signaling for proliferation. Yet, the locations and properties of neurons that innervate gliomas have remained elusive. In this study, we utilized transsynaptic tracing with a pseudotyped, glycoprotein-deleted rabies virus to specifically infect TVA and glycoprotein-expressing human glioblastoma cells in an orthotopic xenograft mouse model, allowing us to identify the neurons that form synapses onto the gliomas. Comprehensive whole-brain mapping revealed that these glioma-innervating neurons (GINs) consistently arise at brain regions, including diverse neuromodulatory centers and specific cortical layers, known to project to the glioma locations. Molecular profiling revealed that these long-range cortical GINs are predominantly glutamatergic, and subsets express both glutamatergic and GABAergic markers, whereas local striatal GINs are largely GABAergic. Electrophysiological studies demonstrated that while GINs share passive intrinsic properties with cortex-innervating neurons, their action potential waveforms are altered. Our study introduces a novel method for identifying and mapping GINs and reveals their consistent integration into existing location-dependent neuronal network involving diverse neurotransmitters and neuromodulators. The observed intrinsic electrophysiological differences in GINs lay the groundwork for future investigations into how these alterations may correspond with the postsynaptic characteristics of glioma cells. SignificanceWe have developed a novel system utilizing rabies virus-based monosynaptic tracing to directly visualize neurons that synapse onto human glioma cells implanted in mouse brain. This approach enables the mapping and quantitative analysis of these glioma-innervating neurons (GINs) in the entire mouse brain and overcomes previous barriers of molecular and electrophysiological analysis of these neurons due to the inability to identify them. Our findings indicate that GINs integrate into existing neural networks in a location-specific manner. Long-range GINs are mostly glutamatergic, with a subset expressing both glutamatergic and GABAergic markers and local striatal GINs are GABAergic, highlighting a complex neuromodulatory profile. Additionally, GINs exhibit unique action potential characteristics, distinct from similarly selected neurons in non-tumor-bearing brains. This study provides new insights into neuronal adaptations in response to forming putative synapses onto glioma, elucidating the intricate synaptic relationship between GINs and gliomas.

cancer biology↗

bioRxiv2023

Polyimide-Based Flexible Multi-Electrode Arrays: Synthesis, Microfabrication, and in-vivo Validation

Neurological disorders such as epilepsy, Parkinsons disease, are rising globally, with conditions like drug-resistant epilepsy affecting millions of patients for whom traditional pharmacological treatments are ineffective. Implantable neural devices have shown great promise in managing these conditions, but their accessibility is limited due to high costs and the availability of suitable biocompatible materials.Thin film implantable neural interfaces hold immense promise over conventional clinical electrodes, offering higher resolution, flexibility, and improved integration with neural tissue. However, their widespread use, especially for flexible interfaces, is limited by the lack of customizable and medical grade materials. We report a novel synthesis method for ISO 10993-11 compliant polyamic acid that enables the fabrication of biocompatible polyimide films tailored for neural implants. Using this material, we developed 4 and 32 channel depth and surface electrodes, including custom whole brain ECoG arrays. These were implanted in the laforin knockout mice, a validated model of drug-resistant epilepsy, to monitor spontaneous seizures. Both acute and 12 day recordings demonstrated mechanical flexibility, long term stability, and excellent biocompatibility. This study presents a clinically safe material platform and a complete fabrication pathway for building thin film neural interfaces, paving the way for broader clinical use in applications such as epilepsy monitoring and stereo EEG.

bioengineering↗

bioRxiv2023

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

genetics↗

bioRxiv2022

Precision Discovery of Novel Inhibitors of Human Cancer Target HsMetAP1 from Vast Unexplored Metagenomic Diversity

Microbial natural products have long been a rich source of human therapeutics. While the chemical diversity encoded in the genomes of microbes is large, this modality has waned as fermentation-based discovery methods have suffered from rediscovery, inefficient scaling, and incompatibility with target-based discovery paradigms. Here, we leverage a metagenomic partitioning strategy to sequence soil microbiomes at unprecedented depth and quality. We then couple these data with target-focused, in silico search strategies and synthetic biology to discover multiple novel natural product inhibitors of human methionine aminopeptidase-1 (HsMetAP1), a validated oncology target. For one of these, metapeptin B, we demonstrate sub-micromolar potency, strong selectivity for HsMetAP1 over HsMetAP2 and elucidate structure-activity relationships. Our approach overcomes challenges of traditional natural product methods, accesses vast, untapped chemical diversity in uncultured microbes, and demonstrates computationally-enabled precision mining of modulators of human proteins.

microbiology↗

bioRxiv2022

Katnip is required to maintain microtubule function and lysosomal delivery to autophagosomes and phagosomes

The efficient delivery of lysosomes is essential for many cell functions, such as the degradation of unwanted intracellular components by autophagy and the killing and digestion of extracellular microbes within phagosomes. Using the amoeba Dictyostelium discoideum we find that cells lacking Katnip (Katanin interacting protein) have a general defect in lysosome delivery and whilst able to make autophagosomes and phagosomes correctly are then unable to digest them. Katnip is largely unstudied yet highly conserved across evolution. Previously studies found Katnip mutations in animals cause defects in cilia structure. Here we show that Katnip plays a general role in maintaining microtubule function. We find that loss of Katnip has no overall effect on microtubule dynamics or organisation, but is important for the transport and degradation of endocytic cargos. Strikingly, Katnip mutants become highly sensitive to GFP-tubulin expression, which leads to microtubule tangles, defective anaphase extension and slow growth. Our findings establish a conserved role for Katnip in the function of all microtubules, not just cilia as previously reported. We speculate this is via a key function in microtubule repair, required to maintain endosomal trafficking and lysosomal degradation.

cell biology↗

bioRxiv2021

Developmental Dynamics of RNA Translation in the Human Brain

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have deeply profiled mRNA dynamics in the developing human brain, there is a fundamental gap in our understanding of accompanying translational regulation. We perform ribosome profiling from more than 70 human prenatal and adult cortex samples across ontogeny and into adulthood, mapping translation events at nucleotide resolution. In addition to characterizing the translational regulation of annotated open reading frames (ORFs), we identify thousands of previously unknown translation events, including small open reading frames (sORFs) that give rise to human- and/or brain-specific microproteins, many of which we independently verify using size-selected proteomics. Ribosome profiling in stem cell-derived human neuronal cultures further corroborates these findings and shows that several neuronal activity-induced long non-coding RNAs (lncRNAs), including LINC00473, a primate-specific lncRNA implicated in depression, encode previously undescribed microproteins. Physicochemical analysis of these brain microproteinss identifies a large class harboring arginine-glycine-glycine (RGG) repeats as strong candidates for regulating RNA metabolism. Moreover, we find that, collectively, these previously unknown human brain sORFs are enriched for variants associated with schizophrenia. In addition to significantly expanding the translational landscape of the developing brain, this atlas will serve as a rich resource for the annotation and functional interrogation of thousands of previously unknown brain-specific protein products.

neuroscience↗

bioRxiv2019

Adverse childhood experiences in families with multiple members diagnosed to have psychiatric illnesses

ObjectiveAdverse Childhood Experiences (ACEs) are linked to the development of a number of psychiatric illnesses in adulthood. Our study examined the pattern of ACEs and their relation to the age of onset (AAO) of major psychiatric conditions in individuals from families that had [≥] 2 first degree relatives with major psychiatric conditions (multiplex families) identified as part of an ongoing longitudinal study.\n\nMethodsOur sample consisted of 509 individuals from 215 families. Of these, 268 were affected i.e diagnosed with bipolar disorder (BPAD) (n=61), obsessive-compulsive disorder (OCD) (n=58), schizophrenia (n=52), substance dependence (SUD) (n=59), or co-occurring diagnoses (n=38); while 241 were at-risk first degree relatives (FDRs) who were either unaffected (n=210) or had other depressive or anxiety disorders (n=31). All individuals were evaluated using the Adverse Childhood Experiences - International Questionnaire (ACE-IQ) and ACE binary and frequency scores were calculated.\n\nResultsIt was seen that affected males, as a group, had the greatest ACE scores in our sample. A cox mixed-effects model fit by gender revealed that higher ACE binary and frequency scores were associated with significantly increased risk for an earlier AAO of psychiatric diagnoses in males. A similar model that evaluated the effect of diagnosis revealed an earlier AAO in OCD and SUD, but not in schizophrenia and BPAD.\n\nConclusionsOur study indicates that ACEs brought forward the onset of major psychiatric conditions in men and in individuals diagnosed with OCD and SUD. Ongoing longitudinal assessments in FDRs from these families are expected to identify mechanisms underlying this relationship.

neuroscience↗

bioRxiv2019

Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans

Delta 9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is also known to modulate immune response in peripheral cells. The mechanisms of THCs effects on gene expression in human immune cells remains poorly understood. Combining a within-subject design with single cell transcriptome mapping, we report that administration of THC acutely alters gene expression in 15,973 human blood immune cells. Controlled for high inter-individual transcriptomic variability, we identified 294 transcriptome-wide significant genes among eight cell types including 69 common genes and 225 cell-type specific genes affected by acute THC administration, including those genes involving not only in immune response, cytokine production, but signal transduction, and cell proliferation and apoptosis. We revealed distinct transcriptomic sub-clusters affected by THC in major immune cell types where THC perturbed cell type-specific intracellular gene expression correlations. Gene set enrichment analysis further supports the findings of THCs common and cell-type specific effects on immune response and cell toxicity. We found that THC alters the correlation of cannabinoid receptor gene, CNR2, with other genes in B cells, in which CNR2 showed the highest level of expression. This comprehensive cell-specific transcriptomic profiling identified novel genes regulated by THC and provides important insights into THCs acute effects on immune function that may have important medical implications.

genetics↗

bioRxiv2018

Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers

PurposeHomeostasis Model Assessment of {beta}-cell function and Insulin Resistance (HOMA-B/-IR) indices are informative about the pathophysiological processes underlying type 2 diabetes (T2D). Data on both fasting glucose and insulin levels are required to calculate HOMA-B/-IR, leading to underpowered Genome-Wide Association studies (GWAS) of these traits.\n\nMethodsWe overcame such power loss issues by implementing Genome-Wide Inferred Statistics (GWIS) approach and subsequent dense genome-wide imputation of HOMA-B/-IR summary statistics with SS-imp to 1000 Genomes project variant density, reaching an analytical sample size of 75,240 European individuals without diabetes. We dissected mechanistic heterogeneity of glycaemic trait/T2D loci effects on HOMA-B/-IR and their relationships with 36 inflammatory and cardiometabolic phenotypes.\n\nResultsWe identified one/three novel HOMA-B (FOXA2)/HOMA-IR (LYPLAL1, PER4, PPP1R3B) loci. We detected novel strong genetic correlations between HOMA-IR/-B and Plasminogen Activator Inhibitor 1 (PAI-1, rg=0.92/0.78, P=2.13x10-4/2.54x10-3). HOMA-IR/-B were also correlated with C-Reactive Protein (rg=0.33/0.28, P=4.67x10-3/3.65x10-3). HOMA-IR was additionally correlated with T2D (rg=0.56, P=2.31x10-9), glycated haemoglobin (rg=0.28, P=0.024) and adiponectin (rg=-0.30, P=0.012).\n\nConclusionUsing innovative GWIS approach for composite phenotypes we report novel evidence for genetic relationships between fasting indices of insulin resistance/beta-cell function and inflammatory markers, providing further support for the role of inflammation in T2D pathogenesis.

genetics↗

bioRxiv2018

Butyrivibrio hungatei MB2003 competes effectively for soluble sugars released by Butyrivibrio proteoclasticus B316T from growth on xylan or pectin

Rumen bacterial species belonging to the genera Butyrivibrio are important degraders of plant polysaccharides, particularly hemicelluloses (arabinoxylans) and pectin. Currently, four distinct species are recognized which have very similar substrate utilization profiles, but little is known about how these microorganisms are able to co-exist in the rumen. To investigate this question, Butyrivibrio hungatei (MB2003) and Butyrivibrio proteoclasticus (B316T) were grown alone or in co-culture on the insoluble substrates, xylan or pectin, and their growth, release of sugars, fermentation end products and transcriptomes were examined. In single cultures, B316T was able to degrade and grow well on xylan and pectin, while B. hungatei MB2003 was unable to utilize either of these insoluble substrates to support significant growth. Co-cultures of B316T grown with MB2003 revealed that MB2003 showed almost equivalent growth to B316T when either xylan or pectin were supplied as substrates. The effect of co-culture on the transcriptomes of B316T and MB2003 was very marked; B316T transcription was largely unaffected by the presence MB2003, but MB2003 expressed a wide range of genes encoding carbohydrate degradation/metabolism and oligosaccharide transport/assimilation in order to compete with B316T for the released sugars. These results suggest that B316T has a role as an initiator of the primary solubilization of xylan and pectin, while MB2003 competes effectively as a scavenger for the released soluble sugars to enable its growth and maintenance in the rumen.\n\nIMPORTANCEFeeding a global population of nine billion people and climate change are the primary challenges facing agriculture today. Determining the roles of rumen microbes involved in plant polysaccharide breakdown is fundamental to understanding digestion and maximizing productivity of ruminant livestock. Butyrivibrio are abundant rumen bacteria and are a substantial source of polysaccharide-degrading enzymes with biotechnological applications for the depolymerization of lignocellulosic material. Our findings suggest that closely related species of Butyrivibrio have developed unique strategies for the degradation of plant fibre and the subsequent assimilation of carbohydrates in order to coexist in the competitive rumen environment. The identification of genes related to their enzymatic machinery by which these bacteria work in concert to degrade these different forms of polysaccharides contributes to our understanding of carbon flow in the rumen.

microbiology↗

bioRxiv2018

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

IntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.\n\nMethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.\n\nResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a private mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.\n\nConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.

neuroscience↗