Biology subjects

Nair, D.

Publications and source records attributed to Nair, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Gram-negative-dominated polymicrobial microbiome of necrotizing soft tissue infections from North India: an integrated culture and 16S rRNA metagenomics prospective cohort study

Necrotizing soft tissue infections (NSTIs) carry 10 to 30% mortality. Current empirical antimicrobial guidance derives almost entirely from Western cohorts dominated by Streptococcus pyogenes and aerobic-anaerobic consortia, yet whether this microbial paradigm applies to tropical, high-antimicrobial-pressure settings has not been tested with culture-independent methods. We did a prospective cohort study of 169 patients with intraoperatively confirmed NSTI at a North Indian tertiary center (2021 to 2024). Wound tissue underwent aerobic and anaerobic culture, QIIME2-based 16S rRNA gene amplicon sequencing (V3-V4), and targeted SYBR Green quantitative PCR (qPCR) for Acinetobacter baumannii and S. pyogenes. The wound microbiota was overwhelmingly Gram-negative and polymicrobial, anchored by A. baumannii (culture, 33.7%; metagenomics, 49.1%; qPCR, 37.9%), Escherichia coli (32.0%), and Klebsiella pneumoniae (20.7%); S. pyogenes contributed only 4.7% of culture-positive cases. Polymicrobial wounds had higher Shannon diversity (2.59 versus 2.33; P = 0.048) and discrete community composition (PERMANOVA R2 = 0.511; P = 0.010). Culture-metagenomics agreement ranged from almost perfect for Escherichia ({kappa} = 0.849) to slight for Streptococcus ({kappa} = 0.131). North Indian NSTIs present a microbial picture distinct from the Western paradigm, with implications for empirical therapy. IMPORTANCENecrotizing soft tissue infections kill rapidly, and physicians must choose antibiotics before laboratory results are available. Globally, treatment guidelines assume the dominant pathogen is Streptococcus pyogenes, a Gram-positive organism, because nearly all molecular evidence comes from Western countries. We show that in a large Indian cohort, the infection is instead dominated by Gram-negative bacteria, especially Acinetobacter baumannii, with S. pyogenes rarely present. Polymicrobial status, not wound location or injury mechanism, most strongly determines community composition. These findings challenge the one-size-fits-all antibiotic approach and argue for region-specific empirical regimens prioritizing Gram-negative coverage in tropical, high-antimicrobial-pressure settings.

microbiology↗

bioRxiv2026

A novel preclinical mouse model recapitulates progressive phenotypes of Bryant-Li-Bhoj Syndrome

Bryant-Li-Bhoj Syndrome (BLBS; OMIM: 619720, 619721) is a Mendelian neurogenetic condition, first described in 2020, with a mixed neurodevelopmental/neurodegenerative phenotype and variable systemic features. To date, 100 affected individuals with 74 unique causative variants have been published. Clinical data and prior functional work in multiple model systems have emphasized the utility of interrogating the pathogenesis of multiple causal variants to identify a convergent, therapeutically targetable mechanism. Additionally, the ability to evaluate the efficacy of future therapeutics relies on the availability of a robustly validated preclinical model. Here, we characterize the developmental and neurobehavioral phenotypes of a novel BLBS mouse model harboring one of the most recurrent causative variants (h3-3a p.T45I). H3.3T45I mice recapitulate the BLBS natural history: perinatal growth restriction, delayed developmental milestones, and progressive motor and gait impairments. Adult mice additionally display craniofacial differences, impaired nest building, hyperactivity in a social context, and male-specific elevated aggression. The non-invasive, clinically translatable endpoints established here provide a validated preclinical platform for evaluating therapeutics for a community whose current standard of care is symptom management. Summary StatementA new mouse model mirrors the developmental delays, motor decline, and behavioral changes seen in individuals with this rare, progressive genetic brain disorder, providing a foundation for testing future therapies.

genetics↗

bioRxiv2026

The bacterial swarming factor SwrD forms hexameric rings reminiscent of DNA binding proteins.

Prokaryotic swarming is a collective surface-associated behavior that supports rapid colonization, biofilm formation, and host interactions. Swarming requires enhanced flagellar motor (FM) torque generation under high-load conditions. In many bacteria, this adaptation is achieved through increased stator unit recruitment and coordinated transcriptional regulation of motility genes. Genetic studies have implicated several relatively poorly characterized proteins in swarming, including SwrD, a component of the fla-che operon whose loss impairs torque generation in Bacillus subtilis. Intriguingly, SwrD is conserved in spirochetes that experience high viscous loads but do not exhibit canonical swarming, suggesting a broader functional role in FM regulation. Here, we structurally and biophysically characterize SwrD from B. subtilis and the spirochete Borrelia burgdorferi. In both cases, we show that SwrD assembles into a hexameric ring-like structure featuring a highly charged, disordered peripheral tail. Whereas SwrD displays structural similarities to DNA-binding proteins, key DNA interaction motifs are not conserved in SwrD. Deletion of swrD in B. subtilis results in pronounced swarming defects and altered expression of fla-che operon transcripts. In silico interaction analyses further identify the stator protein MotA as a high-confidence SwrD interactor, but this interaction could not be validated biochemically. Conserved SwrD residues mediate subunit interactions or locate to the hexamer periphery where they may mediate functionally important interactions.

biochemistry↗

bioRxiv2026

A novel mouse model of rare neurodevelopmental disorder, TBCK Syndrome

TBCK Syndrome is a rare Mendelian disorder caused by variants in the TBCK gene. Although symptoms affect multiple organ systems, hallmark features include intellectual and developmental disability, craniofacial differences, hypotonia, and premature death. At the cellular level, TBCK has been implicated in mTOR signaling, autophagy, mitophagy, and mRNA trafficking; however, the mechanisms underlying disease onset and progression remain unclear. To address this gap, we characterized a mouse model of TBCK Syndrome. These mice lack exon 5 of the TBCK gene, resulting in a whole-body knockout of Tbck, modeling the most severe known variant. We performed a comprehensive battery of developmental assays, along with microcomputed tomography and histological analyses, which revealed systemic alterations consistent with those observed in affected individuals. Notably, phenotypic changes arising from Tbck loss emerge early and are detectable in the brain, indicating a primary neurodevelopmental origin of disease pathology. Rigorous characterization of this Tbck-deficient mouse establishes the first in vivo platform to investigate disease mechanisms and provides a foundation for preclinical evaluation of gene and targeted pharmacological therapy strategies. Summary StatementThis study establishes a rigorously validated animal model recapitulating systemic features of TBCK Syndrome, enabling targeted investigation of disease biology and preclinical assessment of candidate therapies.

genetics↗

bioRxiv2026

Biological control of ion transport, redox activity, and nucleation during biogenic synthesis of CdS nanoparticles

Cells have the potential to utilize biological pathways to synthesize semiconductor nanomaterials, such as CdS quantum dots. As in chemical reaction schemes, biogenic synthesis requires control of the concentration and redox state of starting materials during the nucleation and growth of nanoparticles. Biological pathways regulate these key processes of particle synthesis, and manipulation of such pathways enables biological control of multiple aspects of nanoparticle synthesis. Here, strains of Escherichia coli were engineered to biosynthesize cadmium sulfide (CdS) quantum dots through the coordinated action of three pathways controlling sulfide generation, cadmium uptake, and nanoparticle nucleation. When exposed to low, micromolar concentrations of external cadmium, strains combining all three pathways produced CdS quantum dots. The synthesis of nanoparticles, nanoparticle yield, and nanoparticle size depended on the combination of pathways found in each strain. Cells lacking all three pathways produced no detectable nanomaterials, cells with specific combinations of one or two pathways produced small particles in the range of 1.95 to 7.9 nm, and cells with all three pathways produced the largest particles with average diameters of 11.78 nm. These results demonstrate that cells can be engineered to control multiple aspects of biogenic nanoparticle synthesis and that these pathways act together to tune the biosynthesis of semiconductor nanomaterials within cells. ImportanceMicrobes synthesize materials, including metallic and semiconductor nanomaterials. This capability stems from the natural ability of microbes to interact with and precisely manipulate metal atoms. Here, multiple biological pathways were combined within a single strain of Escherichia coli, creating a cell capable of producing CdS nanoparticles. This engineered cell controls multiple steps of particle synthesis, including metal uptake, reduction of starting materials, and binding cadmium and sulfide ions to initiate particle formation. Metal uptake by the cells was improved through the modification of a metal ion transport protein, improving cadmium uptake across the outer membrane and creating higher concentrations of cadmium within the cell. Cells with all three pathways were able to produce CdS nanoparticles, called quantum dots, even when exposed to low concentrations of external cadmium. This biotechnology enables nanomaterial synthesis under environmentally friendly conditions and may improve technologies using bacteria to clean up toxic metals.

bioengineering↗

bioRxiv2025

Epo and hypoxia accelerate a pattern of gradual cell cycle shortening in BFU-e and CFU-e erythroid progenitors in vivo

Regulation of the earliest erythroid progenitors is not well understood, yet it is relevant to some types of anemia that are refractory to treatment with Erythropoietin (Epo). Recent work shows that early erythroid BFU-e and CFU-e progenitors form a developmental continuum characterized by gradual increase in the proportion of cells in S phase of the cycle. Here we proposed two distinct hypotheses to explain this finding, either the presence of quiescent progenitors or the gradual shortening of G1 and the cycle with differentiation. Using a mouse expressing a timer -protein transgene that reports cell cycle duration, we determined that, in vivo, early erythroid progenitors undergo orderly gradual shortening of the cycle as they mature and approach terminal differentiation. There was no evidence of quiescent BFU-e or CFU-e progenitors in tissue. We found that BFU-e and CFU-e progenitors are highly responsive to hypoxic stress and to its Epo and glucocorticoid mediators. Epo and hypoxia accelerated the pattern of gradual cell cycle shortening throughout early erythropoiesis, while conversely, dexamethasone prolonged the cycle specifically in proerythroblasts. Further, Epo and hypoxia generated rapid increase in early progenitor cell size and dynamic changes in cell surface marker expression. Our data suggest that high Epo or hypoxic stress promote rapid increase in the rate of growth in biomass across the entire erythroid trajectory including in the earliest BFU-e progenitors, and indicates that stress progenitors are of the same type and lineage as those sustaining basal erythropoiesis. Key PointsO_LIA maturational process of gradual cell cycle shortening and increasing cell size in BFU-e and CFU-e is accelerated by Epo and hypoxia C_LIO_LIThere are no quiescent BFU-e and CFU-e in tissue. Stress CFU-e arise from the same cell type and lineage as CFU-e in the basal state. C_LI

cell biology↗

bioRxiv2025

SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signaling

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major signalling pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting to ameliorate muscle atrophy. SIRT2 is a mammalian Sirtuin isoform known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. Our study found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. Interestingly, SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy in mice. SIRT2 depletion exacerbates glucocorticoid-induced reduction in myotube diameter and atrophy gene expression. In contrast, SIRT2 overexpression ameliorates myotube atrophy in primary myotubes. Our findings indicate that SIRT2 knockout mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds to the glucocorticoid receptor to negatively regulate its activity, possibly via deacetylation of critical residues in its DNA-binding domain. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy and serve as a potential therapeutic target for treating muscle atrophy.

pathology↗

bioRxiv2025

Palmitoylation of PSD95 flips the bilayer juxtaposed domain and drives cluster formation on membrane

Postsynaptic density protein 95 (PSD95) is a highly abundant scaffolding protein at excitatory synapses, where it organizes the molecular architecture of the postsynaptic density (PSD) by anchoring neurotransmitter receptors, ion channels, adhesion molecules, and signaling enzymes. Emerging evidence indicates that PSD95 forms transient "nanodomains" essential for the fidelity of synaptic transmission and plasticity, and disruptions in its clustering are linked to neuropsychiatric disorders. Palmitoylation, a reversible post-translational modification involving the covalent attachment of palmitate to Cysteine residues, has been implicated in the localization and clustering of the PSD95 at the plasma membrane, but its structural and mechanistic role remains unclear. Here, we use a multiscale molecular dynamics approach that combines all-atom and coarse-grained simulations to investigate how palmitoylation regulates PSD95 conformational dynamics, membrane association, and self-assembly. Our results show that palmitoylation promotes an open conformation in solution and stabilizes an extended assembly-primed state at the membrane. In the unmodified state, the PDZ1 domain remains distal while PDZ2 preferentially engages with the membrane; palmitoylation reverses this arrangement, anchoring PDZ1 to the membrane and enhancing clustering propensity. Membrane lipid composition further modulates this behavior, with negatively charged lipids influencing favorable domains orientation through electrostatic interactions. Finally, coarse-grained simulations reveal that palmitoylated PSD95 forms stable dimers on the membrane surface, whereas unmodified molecules fail to associate persistently. Together, these findings provide a mechanistic model for how palmitoylation facilitates the early stages of PSD95 clustering, offering nanoscale insights into synaptic organization that complement experimental observations. Significance StatementPSD95 is a key scaffolding protein that organizes synaptic components essential for neuronal communication. Its ability to cluster at the membrane is critical for postsynaptic architecture, yet the molecular determinants of this process remain unclear. Using multiscale molecular dynamics simulations we reveal how palmitoylation, a reversible lipid modification, acts as a molecular switch that anchors PSD95 to the membrane and reorients its domains to favor self-association. We further demonstrate that membrane lipid composition modulates these effects through electrostatic interactions. Our work offers a mechanistic model for the initial steps of PSD95 clustering, highlighting how post-translational modifications and membrane environment together regulate synaptic protein organization. These insights bridge molecular structure with synaptic function and are not easily accessible through current experimental methods. Graphical Abstract Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/679381v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1411deaorg.highwire.dtl.DTLVardef@132cddorg.highwire.dtl.DTLVardef@e69aa6org.highwire.dtl.DTLVardef@1b34753_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

sEEG-Suite: An Interactive Pipeline for Semi-Automated Contact Localization and Anatomical Labeling with Brainstorm

Stereoelectroencephalography (sEEG) is a critical tool for mapping epileptic networks in patients with drug-resistant epilepsy. Accurate localization and labeling of sEEG contacts are essential for identifying the seizure onset zone (SOZ) and ensuring optimal resective surgery. Traditional methods for localizing and labeling sEEG contacts rely on manual processing, which is prone to human error and variability. To address these challenges, we developed and integrated a semi-automatic sEEG contact localization and labeling pipeline within Brainstorm1, an open-source software platform for multimodal brain imaging analysis2-8, widely adopted in the neuroscience community with over 50,000 registered users and an active online user forum. The software has been supported by the National Institute of Health (NIH) for over two decades. The pipeline presented in this paper performs three key steps: (1) import and apply rigid co-registration of post-implantation Computed Tomography (CT) or post-CT with pre-implantation Magnetic Resonance Imaging (pre-MRI), (2) post-CT image segmentation and semi-automatic detection of sEEG contacts using GARDEL9, which has been integrated as a Brainstorm plugin, and (3) automatic anatomical labeling of contacts using standard and commonly used brain anatomy templates and atlases. Integrating this pipeline into Brainstorm brings the best of both worlds: GARDELs automation and Brainstorms multimodal data compatibility, and rich library of visualization and advanced analysis tools at both sensor and source level6. This sEEG-Suite tool facilitates reproducible research, supports clinical workflows, and accelerates sEEG-based investigations of invasive brain recordings.

neuroscience↗

bioRxiv2025

Structure and dynamics of a muti-domain nitric oxide synthase regulated by a C2 domain

Nitric oxide synthase (NOS) is a widely studied multidomain redox enzyme that produces the key signaling molecule and cytotoxic agent nitric oxide (NO) for functions that range from mammalian vasodilation to prokaryotic antibiotic resistance. NOS enzymes from metazoans and cyanobacteria rely on dynamic associations of their oxygenase and coupled di-flavin reductase domains that have largely evaded detailed structural characterization. CryoEM studies of a representative dimeric six-domain Synechococcus NOS reveal the architecture of the full-length enzyme, which contains an unusual regulatory C2 domain, and additional nitric oxide deoxygenase (NOD) and pseudo-globin modules. Five distinct structural states depict how pterin binding couples to tight and loose oxygenase conformations and how the Ca2+-sensitive C2 domain moves over 85 [A] to alternatively regulate either the NOS or NOD heme center. The extended C-terminal tail and its dynamic interactions highlight an added layer of regulation required by multidomain NOSs compared to other di-flavin reductases. TeasersyNOS is a highly dynamic multi-domain oxidoreductase that harnesses a Ca2+-sensitive C2 domain to modulate activity.

biophysics↗

bioRxiv2025

Nanoscale Lattice Organization of Molecular Condensates Drives Compositional Degeneracy in Synaptic Plasticity

Synaptic plasticity is essential for neuronal communication, involving coordinated structural, molecular and functional changes that are shaped by the nanoscale alterations of the active zone and postsynaptic density. Emerging evidence suggests that synapses function as complex information processing machines, where unique molecular assemblies shape transmission properties. Central to this is the organization of voltage-gated calcium channels (VGCCs) and Bassoon within active zones. Utilizing advanced techniques like liquid-liquid phase separation, super-resolution microscopy, and data-driven models of synaptic transmission, we reveal how nanoscale "compositional degeneracy" in Bassoon and VGCCs enables synapses to achieve functional adaptability through multiple molecular configurations. By modulation of local uncertainty and implementing probabilistic inference, synapses fine-tune transmission efficiency by regulating dynamic entropy and free energy. These principles are especially evident during homeostatic scaling, where synaptic scaling mechanisms differ with neuronal maturity. This study highlights how distinct thermodynamic states in VGCC and Bassoon organization optimize information transfer at different plasticity stages. Our findings propose a refined framework for understanding synaptic transmission as an adaptable, entropy-modulated process, balancing resilience and efficiency.

neuroscience↗

bioRxiv2024

Prediction of Post Traumatic Epilepsy using MRI-based Imaging Markers

Post-traumatic Epilepsy (PTE) is a debilitating neurological disorder that develops after traumatic brain injury (TBI). Despite the high prevalence of PTE, current methods for predicting its occurrence remain limited. In this study, we aimed to identify imaging-based markers for the prediction of PTE using machine learning. Specifically, we examined three imaging features: lesion volumes and resting-state fMRI-based measures of functional connectivity and amplitude of low-frequency fluctuation (ALFF). We employed three machine learning methods, namely, kernel support vector machine (KSVM), random forest, and a neural network, to develop predictive models. Our results showed that the KSVM classifier, with all three feature types as input, achieved the best prediction accuracy of 0.78 AUC (Area Under the Receiver Operating Characteristic (ROC) curve) using nested cross-validation. Furthermore, we performed voxel-wise and lobe-wise group difference analyses to investigate the specific brain regions and features that the model found to be most helpful in distinguishing PTE from non-PTE populations. Our statistical analysis uncovered significant differences in bilateral temporal lobes and cerebellum between PTE and non-PTE groups. Overall, our findings demonstrate the complementary prognostic value of MR-based markers in PTE prediction and provide new insights into the underlying structural and functional alterations associated with PTE.

neuroscience↗

bioRxiv2023

SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration

Reactive astrogliosis is a common pathological hallmark of central nervous system (CNS) injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These SrfGFAP-ERCKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains of Srf knockout mice exhibited neuroprotection against kainic-acid induced excitotoxic cell death. Relevant to human neurodegenerative diseases, SrfGFAP-ERCKO astrocytes abrogate nigral dopaminergic neuron death and reduce {beta}-amyloid plaques in mouse models of Parkinsons and Alzheimers disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Golgi apposition promotes the generation of specialized lysosomes in differentiated keratinocytes

Intracellular organelles support cellular physiology in diverse conditions. In the skin, epidermal keratinocytes undergo differentiation with gradual changes in cellular physiology, accompanying remodeling in lysosomes and the Golgi apparatus. However, the functional significance and the molecular link between lysosome and Golgi remodeling were unknown. Here, we show that in differentiated keratinocytes, the Golgi apparatus redistributes as ministacks leading to a significant increase in total protein secretion. The Golgi ministacks establish contact with lysosomes facilitated by Golgi tethering protein GRASP65, the depletion of which is associated with the loss of Golgi-lysosome contact and malformation of lysosomes defined by their aberrant morphology, size, and function. Strikingly, these lysosomes receive secretory Golgi cargoes, contribute to the protein secretion from the Golgi, and are critically maintained by the secretory function of the Golgi apparatus. We uncovered a novel mechanism of lysosome specialization through unique Golgi-lysosome contact that likely supports high secretion from differentiated keratinocytes. Key pointsO_LICalcium induced differentiation of human keratinocytes accompanies the dispersal of functional Golgi stacks and lysosomes. C_LIO_LIDispersed Golgi stacks establish contact/physical apposition with the lysosomes. C_LIO_LIGolgi tether GRASP65 surrounds keratinocyte lysosomes and facilitates Golgi-lysosome apposition. C_LIO_LIGRASP65 depletion abolishes Golgi-lysosome apposition and accumulates morphologically altered non-degradative lysosomes. C_LIO_LILysosomes of differentiated keratinocytes receive secretory Golgi cargo and contribute to the protein secretion from the Golgi. C_LIO_LISpecialized lysosomes are maintained by the secretory function of the Golgi apparatus. C_LI

cell biology↗

bioRxiv2022

Golgi Fragmentation - One of the Earliest Organelle Phenotypes in Alzheimer's Disease Neurons

Alzheimers disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied Amyloid beta (A{beta}) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD disease phenotypes, such as increased A{beta} secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/519571v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@98a8eeorg.highwire.dtl.DTLVardef@7aa7b7org.highwire.dtl.DTLVardef@991e33org.highwire.dtl.DTLVardef@8dabb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Alterations in gut microbiome composition and function in irritable bowel syndrome and increased probiotic abundance with daily supplementation

BackgroundIrritable bowel syndrome (IBS) is characterized by abdominal discomfort and irregular bowel movements and stool consistency. Because there are different symptoms associated with IBS, it is difficult to diagnose the role of the microbiome in IBS. ObjectiveHere, we present a study that includes metagenomic sequencing of stool samples from subjects with the predominant subtypes of IBS and a healthy cohort. We collected longitudinal samples from individuals with IBS who took daily made-to-order precision probiotic and prebiotic supplementation throughout the study. Materials and MethodsThis study includes a population of 489 individuals with IBS and 122 healthy controls. All stool samples were subjected to shotgun metagenomic sequencing. Precision probiotics and prebiotics were formulated for all subjects with longitudinal timepoints. ResultsThere was significant variation explained in the microbiome between the healthy and IBS cohorts. Individuals with IBS had a lower gut microbiome diversity and reduced anti-inflammatory microbes compared to the healthy controls. Eubacterium rectale and Faecalibacterium prausnitzii were associated with healthy microbiomes while Shigella species were associated with IBS. Pathway analysis indicated a functional imbalance of short chain fatty acids, vitamins, and a microbial component of Gram-negative bacteria in IBS compared to healthy controls. In the longitudinal dataset, there was a significant difference in microbiome composition between timepoints 1 and 3. There was also a significant increase in the overall microbiome score and relative abundances of probiotic species used to target the symptoms associated with IBS. ConclusionsWe identified microbes and pathways that differentiate healthy and IBS microbiomes. In response to precision probiotic supplementation, we identified a significant improvement in the overall microbiome score in individuals with IBS. These results suggest an important role for probiotics in managing IBS symptoms and modulation of the microbiome as a potential management strategy. ImportanceAn estimated 35 million people in the United States and 11.5% of the population globally are affected by IBS. Immunity, genetics, environment, diet, small intestinal bacterial overgrowth (SIBO), and the gut microbiome are all factors that contribute to the onset or triggers of IBS. With strong supporting evidence that the gut microbiome may influence symptoms associated with IBS, elucidating the important microbes that contribute to the symptoms and severity is important to make decisions for targeted treatment. As probiotics have become more common in treating IBS symptoms, identifying effective probiotics may help inform future studies and treatment.

microbiology↗

bioRxiv2020

A Hybrid High-Resolution Anatomical MRI Atlas with Sub-parcellation of Cortical Gyri using Resting fMRI

We present a new high-quality, single-subject atlas with sub-millimeter voxel resolution, high SNR, and excellent grey-white tissue contrast to resolve fine anatomical details. The atlas is labeled into two parcellation schemes: 1) the anatomical BCI-DNI atlas, which is manually labeled based on known morphological and anatomical features, and 2) the hybrid USCBrain atlas, which incorporates functional information to guide the sub-parcellation of cerebral cortex. In both cases, we provide consistent volumetric and cortical surface-based parcellation and labeling. The intended use of the atlas is as a reference template for structural coregistration and labeling of individual brains. A single-subject T1-weighted image was acquired at a resolution of 0.547mm x 0.547mm x 0.800mm five times and averaged. Images were processed by an expert neuroanatomist using semi-automated methods in BrainSuite to extract the brain, classify tissue-types, and render anatomical surfaces. Sixty-six cortical and 29 noncortical regions were manually labeled to generate the BCI-DNI atlas. The cortical regions were further sub-parcellated into 130 cortical regions based on multi-subject connectivity analysis using resting fMRI (rfMRI) data from the Human Connectome Project (HCP) database to produce the USCBrain atlas. In addition, we provide a delineation between sulcal valleys and gyral crowns, which offer an additional set of 26 sulcal subregions per hemisphere. Lastly, a probabilistic map is provided to give users a quantitative measure of reliability for each gyral subdivision. Utility of the atlas was assessed by computing adjusted Rand indices between individual sub-parcellations obtained through structural-only coregistration to the USCBrain atlas and sub-parcellations obtained directly from each subjects resting fMRI data. Both atlas parcellations can be used with the BrainSuite, FreeSurfer, and FSL software packages.

bioinformatics↗

bioRxiv2020

Vinculin mediated axon growth requires interaction with actin but not talin

Axon growth requires coordination of the actin cytoskeleton by actin-binding proteins in the extending neurites. Vinculin is a major constituent of focal adhesion but its role in neuronal migration and axon growth is poorly understood. We found that vinculin deletion in mouse neocortical neurons attenuated axon growth both in vitro and in vivo. Using different functional mutants of vinculin, we found that expression of a constitutively active vinculin significantly enhanced axon growth while the head-neck domain had a moderate inhibitory effect. Interesting, we found that vinculin-talin interaction was dispensable for axon growth and neuronal migration. Strikingly, expression of the tail domain delayed migration, increased branching and stunted axon. Inhibition of the Arp2/3 complex or abolishing the tail domain interaction with actin completely reversed the branching phenotype caused by tail domain expression without affecting axon length. Super-resolution microscopy showed increased mobile fraction of actin in tail domain expressing neurons. Our results provide novel insights into the role of vinculin and its functional domains in regulating neuronal migration and axon growth.

neuroscience↗