Biology subjects

Srinivasan, S.

Publications and source records attributed to Srinivasan, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

neuroscience↗

bioRxiv2024

Mitochondrial Raf1 Regulates Glutamine Catabolism

One-Sentence SummaryRaf1 is present within the mitochondrial matrix, where it binds GLS to regulate glutamine catabolism and tumorigenesis. In cancer, Raf1 activation occurs via mechanisms that include mutation of upstream regulators, such as receptor tyrosine kinases and Ras GTPases, as well as by mutations that affect RAF1 itself, including via gene amplification (1-4). Once recruited to the plasma membrane (PM) Raf1 can engage downstream mitogen-activated protein kinase (MAPK) pathway signaling through phosphorylation of the MEK kinases (5). In addition to Raf1, A-Raf and B-Raf can also activate MEK and these other two Raf isoforms can compensate for MAPK activation in the event of Raf1 loss (6, 7). Despite this, Raf1 remains essential for the development and maintenance of some tumors through mechanisms independent of MAPK activity (7, 8). In this regard, Raf1 has well-described interactions outside the canonical MAPK pathway, including several with outer mitochondrial membrane (OMM) proteins (9, 10), although Raf1 has not been previously identified inside mitochondria. Mitochondria comprise a hub for various metabolic processes modulated in cancer cells to accommodate rapid proliferation. One such process is glutaminolysis, which involves the catabolism of glutamine to generate both ATP as well as precursors for the synthesis of fatty acids, nucleotides, and nonessential amino acids (11-13). Glutaminase (GLS) proteins, which catalyze the first and rate-limiting step of this process by converting glutamine to glutamate, are often upregulated in cancer (14-16). GLS activation has been previously associated with tumors driven by Ras, upstream regulators of Raf kinases (13, 17). Here we identify Raf1 protein inside mitochondria where Raf1 associates with GLS in the mitochondrial matrix to enable glutamine catabolism and tumorigenic growth. Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

cancer biology↗

bioRxiv2024

Association of Macular Pigment Density with Plasma Macular Carotenoids levels, And lipids in Indian patients with early Age-Related Macular Degeneration

PurposeThe objective of the present study was to investigate the relationship of macular pigment optical density (MPOD) with plasma carotenoids [(L) and (Z)] and serum lipids in South Indian young healthy volunteers and patients with early AMD. MethodsTwo hundred and fourteen (N= 214) study participants (Healthy control group (N) = 178; Early AMD group (N) = 36) were enrolled after getting their written informed consent. The MPOD of the study participants was assessed using MPS II (Electron Technology, UK) after completing their routine ocular examination. Serum lipids were measured by the standard technique. Plasma levels of L, Z, lycopene and beta-carotene were estimated by HPLC with PDA detector. Statistical analysis usedCorrelations among variables in serum, plasma and the MPOD were established using Spearmans rho correlation coefficient. ResultsThe overall mean MPOD in healthy control group and early AMD group was found to be 0.47 {+/-} 0.16 (N= 178; 317 eyes) and 0.35 {+/-} 0.22 (N=36; 38 eyes) at 1{degrees} eccentricity respectively and was found to be significantly low as compared to healthy control group (p<0.001). A strong positive association was found between plasma L, Z and L+Z and MPOD. Serum HDL showed a strong negative association with MPOD and other lipids showed very weak association. MPOD was unaffected by BMI. ConclusionsMPOD is positively associated with plasma L,Z and L+Z, adding further evidence that additional intake of L/Z may be beneficial in delaying the risk of AMD in our population

pharmacology and toxicology↗

bioRxiv2024

CREB activation drives acinar to ductal reprogramming and promote pancreatic cancer progression in animal models of alcoholic chronic pancreatitis

BACKGROUND & AIMSChronic alcoholism often leads to pancreatitis, which exacerbates pancreatic damage through acinar cell injury, fibrotic inflammation and activates AKT/mTOR/cyclic adenosine monophosphate response element binding protein 1 (CREB) signaling axis. However, the molecular interplay between oncogenic KrasG12D/+(Kras*) and CREB in promoting pancreatic cancer progression under chronic inflammation remains poorly understood. METHODSExperimental alcoholic chronic pancreatitis (ACP) induction was established in multiple mouse models, with euthanasia during the recovery stage to evaluate tumor latency. CREB was selectively deleted (Crebfl/fl) in Ptf1aCreERTM/+;LSL-KrasG12D/+(KC) genetic mouse models (KCC-/-). Pancreata from Ptf1aCreERTM/+, KC, and KCC-/- mice were analyzed using histological profiling, western blotting, phosphokinase array, and quantitative PCR. Single-cell RNA sequencing was performed in ACP-induced KC mice. Lineage tracing analysis in YFP reporter mice and acinar cell explant cultures analysis were also conducted. RESULTSACP induction in KC mice significantly impaired pancreas repair mechanism. Acinar cell-derived ductal lesions demonstrated sustained CREB hyperactivation in acinar-to-ductal metaplasia (ADM)/pancreatic intraepithelial neoplasia (PanIN) lesions associated with pancreatitis and pancreatic cancer. Persistent CREB activity reprogrammed acinar cells, and increased profibrotic inflammation. Notably, acinar specific Creb deletion in ACP induced models suppressed high grade PanIN development, restrained tumor progression, and improved acinar cell function. CONCLUSIONSOur findings demonstrate that CREB and Kras* promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB may present a promising strategy to mitigate inflammation-driven pancreatic tumorigenesis.

cancer biology↗

bioRxiv2023

Targeting PKC alleviates iron overload in diabetes and hemochromatosis

Diabetes is one of the most prevalent chronic diseases worldwide. Iron overload increases the incidence of diabetes and aggravates diabetic complications that cause mortality. Reciprocally, diabetes potentially promotes body iron loading, but the mechanism remains not well understood. In this study, we demonstrated systemic iron excess and the upregulation of iron exporter ferroportin (Fpn) in the enterocytes and macrophages of multiple diabetic mouse models. Increased Fpn expression and iron efflux was also seen in the enterocytes of type 2 diabetic human patients. We further showed that protein kinase C (PKC), which is activated in hyperglycemia, was responsible for the sustained membrane expression of Fpn in physiological and in diabetic settings. For the first time, we identified that PKCs were novel binding proteins and positive regulators of Fpn. Mechanistically, hyperactive PKC promoted exocytotic membrane insertion while inhibited the endocytic trafficking of Fpn in the resting state. PKC also protected Fpn from internalization and degradation by its ligand hepcidin dependent on decreased ubiquitination and increased phosphorylation of Fpn. Importantly, the loss-of-function and pharmacological inhibition of PKC alleviated systemic iron overload in diabetes and hemochromatosis. Our study thus highlights PKC as a novel target in the control of systemic iron homeostasis.

cell biology↗

bioRxiv2023

Unbiased MD simulations characterize lipid binding pockets in lipid transfer proteins

The molecular characterization of lipid binding to lipid transfer proteins (LTPs) is fundamental to the understanding of several aspects of their mechanistic mode of action. However, obtaining lipid-bound structures of LTPs is not straightforward owing to caveats in current experimental structural biology approaches. As a result, several structures of LTPs, and most notably almost all of those that have been proposed to act as bridges between membrane organelles, do not provide the precise location of their endogenous lipid ligands. To address this limitation, computational approaches are a powerful alternative methodology, but they are often limited by the high flexibility of lipid substrates. In this work, we develop an in silico protocol based on unbiased coarse grain molecular simulations in which lipids placed in bulk solvent away from the protein can spontaneously bind to LTPs. This approach accurately determines binding pockets in LTPs and provides a working hypothesis for the pathway via which lipids enter LTPs. We apply this approach to characterize lipid binding to bridge-like LTPs belonging to the Vps13-Atg2 family, for which the lipid localization inside the protein is currently unknown. Overall, our work paves the way to determine binding pockets and entry pathways for several LTPs in an inexpensive, fast, and accurate manner.

biophysics↗

bioRxiv2023

Assembly reactions of SARS-CoV-2 nucleocapsid protein with nucleic acid

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-) protein into ribonucleoprotein particles (RNPs), 38{+/-}10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to mutant proteins binding different nucleic acids in an in vitro assay for RNP formation, and by examining mutant proteins in a viral assembly assay. We find that nucleic acid-bound N-protein dimers oligomerize via a recently described protein-protein interface presented by a transient helix in its long disordered linker region between NTD and CTD. The resulting hexameric complexes are stabilized by multi-valent protein-nucleic acid interactions that establish crosslinks between dimeric subunits. Assemblies are stabilized by the dimeric CTD of N-protein offering more than one binding site for stem-loop RNA. Our study suggests a model for RNP assembly where N- protein scaffolding at high density on viral RNA is followed by cooperative multimerization through protein-protein interactions in the disordered linker.

biophysics↗

bioRxiv2023

Modulation of Biophysical Properties of Nucleocapsid Protein in the Mutant Spectrum of SARS-CoV-2

Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also exhibiting functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.

biophysics↗

bioRxiv2023

A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss

In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion increases during fasting, and acts as a bona fide gut-to-brain homeostatic signal that attenuates neuronally induced fat loss during food shortage. INS-7 functions as an antagonist at the canonical DAF-2 receptor in the nervous system, and phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cell with enteroendocrine functions suggests that much remains to be learned about the intestine and its role in directing neuronal functions.

physiology↗

bioRxiv2023

Bamboozling Interactions: Interspecific associations within mixed-species bird flocks in bamboo in the Eastern Himalayas

O_LIBamboo, although widespread, is a globally understudied habitat, but supports significant biodiversity, including specialist bird species. Mixed-species bird flocks (flocks) are an important and regular feature of forest bird communities worldwide and have been well-studied. However, how and why flocks might differ between bamboo and non-bamboo habitats is unknown. C_LIO_LIWe studied flocks and their arthropod prey in rainforest and bamboo stands across two seasons in the Eastern Himalaya. Using network analysis, we compared interspecific associations within flocks, and asked if resource availability (arthropod abundance) drives flocking. C_LIO_LIBamboo and rainforest flocks were significantly different, with bamboo flocks being more cohesive, less modular and their species more interconnected. Further, bamboo flocks were more consistent in their composition across seasons whereas rainforest flocks partially disintegrated in spring, probably because of increased arthropod abundance. In bamboo, the loss of arthropods in an entire substrate and the increase in other substrates was potentially insufficient to cease flocking in spring. C_LIO_LIResource availability and the unique foraging behaviour of the bamboo specialists likely drive flocking in the Eastern Himalaya bamboo. Our study is among the few to describe bamboo flocks and we emphasise conserving bamboo stands to ensure persistence of this unique flock in the Eastern Himalaya. C_LI

ecology↗

bioRxiv2023

SurvBal: Compositional Microbiome Balances for Survival Outcomes

Identification of balances of bacterial taxa in relation to continuous and dichotomous outcomes is an increasingly frequent analytic objective in microbiome profiling experiments. SurvBal enables the selection of balances in relation to censored survival or time-to-event outcomes which are of considerable interest in many biomedical studies. The most commonly used survival models - the Cox proportional hazards and parametric survival models are included in the package, which are used in combination with step-wise selection procedures to identify the optimal associated balance of microbiome, i.e., the ratio of the geometric means of two groups of taxas relative abundances. Availability and implementationSurvBal is available as an R package and a Shiny app: https://github.com/yinglia/SurvBal, https://yinglistats.shinyapps.io/shinyapp-survbal/.

bioinformatics↗

bioRxiv2023

EX VIVO GENE EDITING AND CELL THERAPY FOR HEREDITARY TYROSINEMIA TYPE 1

Background & AimsWe previously demonstrated the successful use of in vivo CRISPR gene editing to delete 4-hydroxyphenylpyruvate dioxygenase (HPD) to rescue mice deficient in fumarylacetoacetate hydrolase (FAH), a disorder known as hereditary tyrosinemia type 1 (HT1). The goal of this study was to develop an ex vivo gene editing protocol and apply it as a cell therapy for HT1. MethodsWe isolated hepatocytes from wild-type (C57BL/6) and Fah-/- mice and then used an optimized electroporation protocol to deliver Hpd-targeting CRISPR-Cas9 ribonucleoproteins (RNP) into hepatocytes. Next, hepatocytes were transiently incubated in cytokine recovery media that we formulated to block apoptosis, followed by splenic injection into recipient Fah-/- mice. ResultsWe observed robust engraftment and expansion of transplanted gene-edited hepatocytes from wild-type donors in the liver of recipient mice when transient incubation with our cytokine recovery media was used after electroporation and negligible engraftment without the media (mean 46.8% and 0.83%, respectively, p = 0.0025). Thus, the cytokine recovery media was a critical component of our electroporation protocol. When hepatocytes from Fah-/- mice were used as donors for transplantation, we observed 35% and 28% engraftment for Hpd-Cas9 RNPs and Cas9 mRNA, respectively. Tyrosine, phenylalanine, and biochemical markers of liver injury normalized in both Hpd-targeting Cas9 RNP and mRNA groups independent of drug induced-inhibition of Hpd through nitisinone, indicating correction of disease indicators in Fah-/- mice. ConclusionsThe successful liver cell therapy for HT1 validates our protocol and, despite the known growth advantage of HT1, showcase ex vivo gene editing using electroporation in combination with liver cell therapy to cure a disease model. These advancements showcase the impacts of electroporation combined with transplantation as a cell therapy.

bioengineering↗

bioRxiv2023

The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations

Until recently, efforts in population genetics have been focused primarily on people of European ancestry. To attenuate the bias, global population studies, such as the 1,000 Genomes Project, have revealed differences in genetic variation across ethnic groups. How much of these differences would attribute to the population-specific traits? To answer this question, the mutation data must be linked with the functional outcomes. A new "edgotype" concept has been proposed that emphasizes the interaction-specific, "edgetic", perturbations caused by mutations in the interacting proteins. In this work, we performed a systematic in-silico edgetic profiling of [~]50,000 non-synonymous SNVs (nsSNVs) from 1,000 Genomes Project by leveraging our semi-supervised learning approach SNP-IN tool on a comprehensive set of over 10,000 protein interaction complexes. We interrogated functional roles of the variants and their impact on the human interactome and compared the results with the pathogenic variants disrupting PPIs in the same interactome. Our results demonstrated that a considerable number of nsSNVs from healthy populations could rewire the interactome. We also showed that the proteins enriched with the interaction-disrupting mutations were associated with diverse functions and had implications in a broad spectrum of diseases. Further analysis indicated that distinct gene edgetic profiles among major populations could shed light on the molecular mechanisms behind the population phenotypic variances. Finally, the network analysis revealed that the disease-associated modules surprisingly harbored a higher density of interaction-disrupting mutations from the healthy populations. The variation in the cumulative network damage within these modules could potentially account for the observed disparities in disease susceptibility, which are distinctly specific to certain populations. Our work demonstrates the feasibility of a large-scale in-silico edgetic study and reveals insights into the orchestrated play of the population-specific mutations in the human interactome.

bioinformatics↗

bioRxiv2023

Spatially distinct inputs modulate the amount of active Mitotic-phase GAP to locally restrict RhoA signaling for successful cell division

At the end of mitosis a contractile ring consisting of filamentous actin (F-actin) assembles at the cell equator and ring constriction equally partitions the cellular content. Inhibitory and stimulatory signaling cascades spatially limit RhoA activity to a narrow central zone to promote F-actin polymerization only at the cell equator. While the stimulatory signal is well-characterized, the mechanisms by which inhibitory signals restrict active RhoA to a narrow equatorial zone and prevent improper RhoA activity at the cell poles are not known. Here, we identify two regulatory inputs that control the activation and cortical targeting of the Mitotic-phase GTPase activating protein (MP-GAP) for RhoA which limits RhoA activity both at the cell poles and at the cell equator. We show that at cell poles, MP-GAP is a direct phosphorylation target of spindle-pole associated Aurora A kinase. We identify three Aurora A target residues in a region of MP-GAP that binds directly to its catalytic GAP domain suggesting the Aurora A phosphorylation releases MP-GAP autoinhibition. We show that phosphorylation of these sites is required to keep RhoA activity low at the cell poles. At the cell equator, F-actin facilitates MP-GAP enrichment, which opposes RhoA GEF activity and thereby accelerates RhoA flux through the GTPase cycle for the formation of a narrow equatorial zone of active RhoA. Thus, the amount of active MP-GAP is modulated by two distinct regulatory inputs that function in spatially restricted locations: Aurora A phosphorylation relieves MP-GAP autoinhibition to limit RhoA activity at the cell poles, while F-actin polymerization promotes MP-GAP targeting to prevent distribution of active RhoA in a broad zone at the cell equator. By determining the mechanism of spatially confining RhoA activity at the equator and the cell poles during cytokinesis, our work has broad implications to how Rho activity zones are formed and maintained during cytokinesis and how defects in their formation impact animal development and disease.

cell biology↗

bioRxiv2023

A Vibrating Ingestible BioElectronic Stimulator Modulates Gastric Stretch Receptors for Illusory Satiety

Effective therapies for obesity either require invasive surgical or endoscopic interventions or high patient adherence, making it challenging for the nearly 42% of American adults who suffer from obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. Here we developed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill - an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release as well as yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake ([~]40%, p< 0.0001) and minimized the weight gain rate (p< 0.03) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

pathology↗

bioRxiv2023

Stochastic coding: a conserved feature of odor representations and its implications for odor discrimination

Sparse coding is thought to improve discrimination of sensory stimuli by reducing overlap between their representations. Two factors, however, can offset sparse codings advantages. Similar sensory stimuli have significant overlap, and responses vary across trials. To elucidate the effect of these two factors, we analyzed odor responses in the fly and mouse olfactory regions implicated in learning and discrimination -- the Mushroom Body (MB) and the Piriform Cortex (PCx). In both species, we show that neuronal responses fall along a continuum from extremely reliable across trials to extremely variable or stochastic. Computationally, we show that the range of observed variability arises from probabilistic synapses in inhibitory feedback connections within central circuits rather than sensory noise, as is traditionally assumed. We propose this coding scheme to be advantageous for coarse- and fine-odor discrimination. More reliable cells enable quick discrimination between dissimilar odors. For similar odors, however, these cells overlap, and do not provide distinguishing information. By contrast, more unreliable cells are decorrelated for similar odors, providing distinguishing information, though this requires extended training with more trials. Overall, we have uncovered a stochastic coding scheme that is conserved in vertebrates and invertebrates, and we identify a candidate mechanism, based on variability in a winner-take-all inhibitory circuit, that improves discrimination with training.

neuroscience↗

bioRxiv2023

Differences in Hepatocellular Iron Metabolism Underlie Sexual Dimorphism in Hepatocyte Ferroptosis

Males show higher incidence and severity than females in hepatic injury and many liver diseases, but the mechanisms are not well understood. Ferroptosis, an iron-mediated lipid peroxidation-dependent death, plays an important role in the pathogenesis of liver diseases. We determined whether hepatocyte ferroptosis displays gender difference, accounting for sexual dimorphism in liver diseases. Compared to female hepatocytes, male hepatocytes were much more vulnerable to ferroptosis by iron and pharmacological inducers including RSL3 and iFSP1. Male but not female hepatocytes exhibited significant increases in mitochondrial Fe2+ and mitochondrial ROS (mtROS) contents. Female hepatocytes showed a lower expression of iron importer transferrin receptor 1 (TfR1) and mitochondrial iron importer mitoferrin 1 (Mfrn1), but a higher expression of iron storage protein ferritin heavy chain 1 (FTH1). It is well known that TfR1 expression is positively correlated with ferroptosis. Herein, we showed that silencing FTH1 enhanced while knockdown of Mfrn1 decreased ferroptosis in HepG2 cells. Removing female hormones by ovariectomy (OVX) did not dampen but rather enhanced hepatocyte resistance to ferroptosis. Mechanistically, OVX potentiated the decrease in TfR1 and increase in FTH1 expression. OVX also increased FSP1 expression in ERK-dependent manner. Elevation in FSP1 suppressed mitochondrial Fe2+ accumulation and mtROS production, constituting a novel mechanism of FSP1-mediated inhibition of ferroptosis. In conclusion, differences in hepatocellular iron handling between male and female account, at least in part, for sexual dimorphism in induced ferroptosis of the hepatocytes.

cell biology↗

bioRxiv2023

CyVerse: Cyberinfrastructure for Open Science

CyVerse, the largest publicly-funded open-source research cyberinfrastructure for life sciences, has played a crucial role in advancing data-driven research since the 2010s. As the technology landscape evolved with the emergence of cloud computing platforms, machine learning and artificial intelligence (AI) applications, CyVerse has enabled access by providing interfaces, Software as a Service (SaaS), and cloud-native Infrastructure as Code (IaC) to leverage new technologies. CyVerse services enable researchers to integrate institutional and private computational resources, custom software, perform analyses, and publish data in accordance with open science principles. Over the past 13 years, CyVerse has registered more than 110,000 verified accounts from 160 countries and was used for over 1,600 peer-reviewed publications. Since 2011, 45,000 students and researchers have been trained to use CyVerse. The platform has been replicated and deployed in two countries outside the US, with additional private deployments on commercial clouds for US government agencies and multinational corporations. In this manuscript, we present a strategic blueprint for creating and managing SaaS cyberinfrastructure and IaC as free and open-source software.

scientific communication and education↗