Biology subjects

Romero, J.

Publications and source records attributed to Romero, J..

At least 19 recordsLinked to original sources

bioRxiv2026

PhageLysData: an evidence-aware and AI-ready dataset of phage lytic enzymes and depolymerases

Bacteriophage lytic enzymes and depolymerases are relevant to phage biology, antimicrobial development, and protein engineering, but their sequence and annotation data remain dispersed across general databases, specialized resources, genome-centred collections, and prediction-oriented datasets. We present PhageLysData, an evidence-aware and AI-ready resource constructed through reproducible multisource integration, provenance tracking, and exact-sequence consolidation. The release integrates 807,366 source observations from seven primary resources into 759,105 unique exact-sequence entities, comprising an evidence-supported Core of 11,867 entities, a Prediction Extension of 745,092 prediction-only candidates, and 2,146 Context entities retained for provenance and reference. This architecture preserves broad sequence-space coverage while maintaining a clear distinction between non-predictive and prediction-derived support. Core entities are enriched with harmonized biological annotations, physicochemical properties, independent InterProScan-derived functional annotations, mapped PDB and AlphaFold DB structural assets, and reusable numerical representations. For 11,259 eligible Core sequences, PhageLysData provides embeddings from 11 protein language models together with one-hot encoding under a common representation contract. Release-facing examples demonstrate latent-space exploration, unsupervised clustering, supervised classification, and evidence-aware candidate retrieval without defining a universal predictive benchmark. PhageLysData provides a traceable, versioned, and computationally accessible foundation for protein retrieval, comparative analysis, task-specific dataset construction, and machine-learning applications involving phage lytic enzymes and depolymerases.

bioinformatics↗

bioRxiv2026

Glycosylation of anandamide and other bioactive N-acylethanolamines in mammalian cells and tissues

N-acylethanolamines (NAEs), including the endocannabinoid anandamide, are bioactive fatty acid amides that are normally hydrolyzed by fatty acid amide hydrolase (FAAH) or N-acyl acid amidohydrolase (NAAA). Strikingly, when canonical NAE degradation is blocked, NAE levels do not increase indefinitely but instead reach a plateau. This apparent metabolic ceiling suggests that additional, underexplored pathways contribute to NAE homeostasis. Identifying these pathways is essential to determine whether NAEs are converted into inactive metabolites or products with distinct biological properties. Here, we identify NAE glycosylation as a metabolic pathway that links endocannabinoid-related lipid metabolism to glycosphingolipid turnover. We synthesized glycosylated NAEs and their isotope-encoded standards and developed targeted LC-MS/MS assays to monitor their enzymatic processing and quantify their abundance in mouse and human cells, tissues, and plasma. We show that non-lysosomal glucosylceramidase GBA2 transfers glucose or galactose to anandamide, N-oleoylethanolamine and N-palmitoylethanolamine, and lysosomal glucosylceramidase GCase hydrolyses {beta}-Glycosylated-NAEs ({beta}-Glyco-NAE) back to their parent NAEs. {beta}-Glyco-NAEs occur endogenously in macrophages and neuronal cells, increase when canonical NAE degradation is impaired, and accumulate in human samples with GCase deficiency, including Gaucher disease and GBA1-associated Parkinsons disease. {beta}-Glyco-NAEs do not engage the cannabinoid receptors, TRPV1, or PPAR, and potentiate inflammatory cytokine release, including IL6 and TNF, from microglia. Based on these findings, we pose that GBA2-dependent NAE glycosylation may constitute an overflow lipid-remodeling pathway that connects NAE metabolism to lysosomal dysfunction, inflammation and neurodegeneration.

biochemistry↗

bioRxiv2026

NeuroFLAME: A Scalable, Privacy-Preserving Federated Framework for Secure, Reproducible, and Multi-Site Neuroimaging Analysis

Federated analysis offers a scalable approach to multi-site neuroimaging research by enabling distributed statistical modeling, machine learning, decomposition, harmonization, and validation without exchanging sensitive individual-level data. However, a significant implementation gap exists, as the majority of federated clinical neuroimaging studies remain technical proofs of concept, struggling to fully navigate the rigorous data-sharing regulations and security constraints of real-world clinical and research environments. Compounding this, existing federated analysis frameworks are typically exposed as command-line tools and configuration files, imposing a considerable setup burden that demands specialized technical expertise from neuroscience researchers. To address these barriers, we present NeuroFLAME, an enterprise-grade, open-source federated neuroimaging platform built upon the NVIDIA FLARE (NVFlare) framework. NeuroFLAME couples a client-outbound-only communication framework with a graphical user interface specifically tailored for neuroscientists. Using certificate-based trust and containerized execution, the platform ensures reproducible analyses with baseline privacy guarantees through data localization and mTLS encryption; advanced protections such as differential privacy and homomorphic encryption are available as optional configurations. By ensuring that clients only need outbound communication and that raw data never leaves each site, NeuroFLAME is designed to support institutional data governance requirements and regulatory frameworks such as HIPAA and GDPR. We demonstrate the platform's utility through three federated analysis workflows, each implemented as a NeuroFLAME computation: multi-site federated closed form voxel-wise regression, decentralized constrained joint independent component analysis (dcjICA) and federated label-based dimensional prediction. Empirical validation of both workflows shows that NeuroFLAME achieves high consistency with established centralized approaches, effectively bridging the gap between experimental federated learning prototypes and production-ready collaborative tools for privacy-preserving, large-scale federated neuroimaging analysis.

neuroscience↗

bioRxiv2025

Hypoxia Imaging as a Radiomics Signature in Tumors Using Novel 19F-Eu-Based Contrast Agents for Magnetic Resonance Imaging

The ability to accurately identify and characterize regions of hypoxia has been an active area of study due to the biological ramifications of low oxygen tension in different pathological conditions, including inflammation, infections, wound healing, cardiovascular conditions, kidney and pulmonary diseases, hepatic and neurological toxicities, and cancer. Although hypoxia contributes a significant role in these conditions, the ability to accurately and instantaneously monitor the presence of hypoxia in vivo and correlate comprehensive analysis of hypoxia-dependent molecular signatures in response to treatments regimens is lacking. With the advent of hypoxia-responsive contrast agents for magnetic resonance imaging (MRI), including the recent development and characterization by our team of a novel probe that involves both 19F and EuII, the capability to integrate direct hypoxia imaging in real-time with new technologies that enable spatial transcriptomic profiling has become a possibility. To assess the capability of this agent for studying hypoxia, we used osteosarcoma as a model. In this preliminary study we demonstrate two major results: First, we show that convection-enhanced delivery (CED) is a reliable and robust methodology to distribute MRI contrast agents throughout a tumor. Second, we show that integration of direct hypoxia-detecting imaging modalities and spatial biology enables real-time in vivo insights into biology and identification of biomarkers directly applicable to disease development and response to therapy. The ability to identify and define hypoxia-mediated biology using direct rather than indirect MRI methods has extremely significant implications in the care of a wide-range of pathological conditions. Consequently, the framework outlined in these preliminary studies is applicable to other pathological conditions and provides the basis for direct in vivo hypoxia detection, monitoring, and biological analyses with translational applications to patient care and management.

cancer biology↗

bioRxiv2025

Cannabinoid CB2R regulates T cell gut-homing in preclinical Crohns model.

Leukocyte trafficking is a critical step in development of chronic intestinal diseases such as Crohns disease. While strategies that block gut-homing have yielded partial success, this disease remains uncurable leaving an unmet clinical need. This is the first paper to describe a role for cannabinoid receptor two (CB2R) signalling in promoting retinoic acid-mediated induction of the gut-homing associated integrin heterodimer 4{beta}7. Using in vitro and in vivo models, we characterised the effects of pharmacological CB2R agonists and inverse agonists on T cell homing receptor expression and transmigration across gut-associated endothelial barriers. This ERK-dependent process coincides with increased T cell adherence in response to CB2R agonism with JWH133. These effects were reversed with an inverse agonist GP-1a in a CB2R dependent manner. Selective deletion of CB2R using CRISPR in vitro or CD4Cre/+ floxed mice in vivo resulted in impaired endothelial cell adherence and decreased diapedesis into the ileal lamina propria. T cell-specific deletion of cnr2, the gene encoding CB2R, attenuated chronic murine ileitis characterised by decreased naive T cell infiltration and loss of tissue architecture in 20wk TNF{Delta}ARE/+mice. This study supports further therapeutic development of CB2R-blocking drugs for the treatment of inflammatory bowel disease.

immunology↗

bioRxiv2025

Cellular characterization of the peritumoral brain zone of glioblastomas: heterogenous nature and clinical relevance.

BackgroundGlioblastoma (GBM) is a highly aggressive cancer with near-universal recurrence, often due to residual tumor cells that persist after aggressive standard of care treatment. This study aimed to characterize tumor infiltration and microenvironment in the GBM periphery. MethodsWe prospectively collected 161 radiologically guided biopsies from 45 GBM patients and conducted an immunohistochemical analysis. We also integrated single-cell RNA sequencing data to select specific markers for immune, glial, and vascular cells. We measured the expression of these genes in samples from contrast-enhancing (CE) and non-enhancing (nCE) tumor areas, vasogenic edema, and radiologically normal tissue. Correlations with resection extent and clinical outcomes were evaluated. ResultsnCE biopsies exhibited neoplastic features similar to those of the tumor core. However, tumor infiltration was also found in regions classified radiologically as edema, particularly in elderly patients. We found important differences in the composition of the peripheral microenvironment between male and female GBM patients. Prognostic associations with specific cell types, such as myeloid cells, showed intertumor heterogeneity, with variations depending on patient sex, age and extent of resection. Furthermore, in our cohort, minimal residual CE tumor following surgery was associated with significantly poorer patient survival. ConclusionsThe GBM periphery includes regions of active tumor growth that are visible on MRI, as well as infiltrated areas that resemble edema radiologically. Tumor infiltration and microenvironmental features are influenced by patient sex and age, which has major implications for recurrence rates, highlighting the need to tailor surgical and therapeutic strategies based on tumor biology and patient subgroup. Key pointsnCE areas show similar neoplastic traits to the CE tumor. GBM infiltrates edema tissue, predominantly in older adult patients. Prognostic value of the peritumoral phenotype depends on resection extent and patient age/sex. Importance of the studyThis study shows that the impact of peripheral and core cellular features on prognosis differs between patients who undergo complete versus incomplete CE tumor resection. Our results suggest a paradigm shift in the classification and management of these patients, encouraging the inclusion of detailed post-surgical MRI analyses to guide the design of future clinical trials according to the nature and extent of the residual disease. Furthermore, our data confirm the presence of tumorigenic features in non-enhancing areas, supporting the benefits of supratotal resections according to the new RANO classification. Our findings also underscore the need to refine surgical and therapeutic strategies based on a more detailed understanding of the tumor microenvironment beyond the GBM core. This understanding may help identify novel targets for more effective and personalized GBM therapies.

cancer biology↗

bioRxiv2024

RWRtoolkit: multi-omic network analysis using random walks on multiplex networks in any species

Leveraging the use of multiplex multi-omic networks, key insights into genetic and epigenetic mechanisms supporting biofuel production have been uncovered. Here, we introduce RWRtoolkit, a multiplex generation, exploration, and statistical package built for R and command line users. RWRtoolkit enables the efficient exploration of large and highly complex biological networks generated from custom experimental data and/or from publicly available datasets, and is species agnostic. A range of functions can be used to find topological distances between biological entities, determine relationships within sets of interest, search for topological context around sets of interest, and statistically evaluate the strength of relationships within and between sets. The command-line interface is designed for parallelisation on high performance cluster systems, which enables high throughput analysis such as permutation testing. Several tools in the package have also been made available for use in reproducible workflows via the KBase web application.

bioinformatics↗

bioRxiv2024

Cannabinoid CB2 receptors in primary sensory neurons are implicated in CB2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance

Cannabinoid CB2 agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB1 receptors. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model. However, the specific cell types involved in this phenomenon have never been investigated and whether this therapeutic profile is observed in female mice remains poorly understood. We used conditional deletion of CB2 receptors from specific cell populations to determine the population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice of either sex. The anti-allodynic effect of the CB2 agonists were absent in conditional knockout (KO) mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f) but preserved in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male mice but absent in female mice of any genotype. In mice with established paclitaxel-induced neuropathy, prior LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the subsequent development of morphine tolerance in male CB2f/f mice but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. LY2828360-induced sparing of morphine tolerance was preserved in male CX3CR1CRE/+; CB2f/f mice, but this effect was not observed in female CX3CR1CRE/+; CB2f/f mice. Similarly, co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed tolerance to the anti-allodynic efficacy of morphine in paclitaxel-treated male CB2f/f mice, but this effect was absent in female CB2f/f mice and AdvillinCRE/+; CB2f/f mice of either sex. Additionally, LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical and cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our studies reveal that CB2 receptors in primary sensory neurons are required for the anti-allodynic effects of CB2 agonists in a mouse model of paclitaxel-induced neuropathic nociception. We also find that CB2 agonists acting on primary sensory neurons produce a sexually-dimorphic sparing of morphine tolerance in males, but not female, paclitaxel-treated mice.

neuroscience↗

bioRxiv2023

25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and in response to different inflammatory stimuli overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimers disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC, an immune-oxysterol primarily produced by activated microglia, is further metabolized to 7,25-dihydroxycholesterol, which is a potent chemoattractant for leukocytes. We have also previously shown that 25HC increases production and secretion of the proinflammatory cytokine, IL-1{beta}, by mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) and Ch25h-knockout (CKO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treated WT mice, Ch25h expression and 25HC levels increased in brain relative to vehicle-treated WT mice. Interestingly, 25HC levels were significantly higher in LPS-treated WT female compared to male mice. Activation of microglia and astrocytes in response to systemic LPS was suppressed in CKO mice relative to WT mice. Proinflammatory cytokine production and intra-parenchymal infiltration of neutrophils strongly correlated with brain 25HC levels and were significantly lower in CKO compared to WT mice. Overall, our results show that 25HC mediates a sex-specific proinflammatory response in the brain characterized by activation of both microglia and astrocytes but also by neutrophil migration into the brain parenchyma presumably due to 7,25-diHC produced from 25HC.

neuroscience↗

bioRxiv2023

MICROGLIAL CELL EXPRESSION OF THE TYPE 2 CANNABINOID RECEPTOR REGULATES IMMUNE-MEDIATED NEUROINFLAMMATION

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.

immunology↗

bioRxiv2023

Clustering the Planet: An Exascale Approach to Determining Global Climatype Zones

We present an exascale approach for producing global scale, high resolution, longitudinally based geoclimate classifications. Using a GPU implementation of the DUO Similarity Metric on the Summit supercomputer, we calculated the pairwise environmental similarity of 156,384,190 vectors of 414,640 encoded elements derived from 71 environmental variables over a 50-year time span at 1km2 resolution. GPU matrix-matrix (GEMM) kernels were optimized for the GPU architecture and their outputs were managed through aggressive concurrent MPI rank CPU communication, calculations, and transfers. Using vector transformation and highly optimized operations of generalized distributed dense linear algebra, calculation of all-vector-pairs similarity resulted in 5.07 x 1021 element comparisons and reached a peak performance of 2.31 exaflops. We demonstrated this method using existing and synthesized climate layers to show how geography can be parsed using high-performance computing. Geoclimate zones are important tools for understanding how environmental variables impact natural systems, particularly for agriculture and conservation with relevance to climate change. Historically, classification systems have been low resolution, based on limited variables, or subjective. To identify climate classes, we clustered DUO outputs at varying stringency, producing 69, 133, 340, and 717 global geoclimate zones. Our approach produced global scale, high resolution, longitudinally informed climate classifications that can be used in precision agriculture, cultivar breeding efforts, and conservation programs.

bioinformatics↗

bioRxiv2023

Enhancing Collaborative Neuroimaging Research: Introducing COINSTAC Vaults for Federated Analysis and Reproducibility

Collaborative neuroimaging research is often hindered by technological, policy, administrative, and methodological barriers, despite the abundance of available data. COINSTAC is a platform that successfully tackles these challenges through federated analysis, allowing researchers to analyze datasets without publicly sharing their data. This paper presents a significant enhancement to the COINSTAC platform: COINSTAC Vaults (CVs). CVs are designed to further reduce barriers by hosting standardized, persistent, and highly-available datasets, while seamlessly integrating with COINSTACs federated analysis capabilities. CVs offer a user-friendly interface for self-service analysis, streamlining collaboration and eliminating the need for manual coordination with data owners. Importantly, CVs can also be used in conjunction with open data as well, by simply creating a CV hosting the open data one would like to include in the analysis, thus filling an important gap in the data sharing ecosystem. We demonstrate the impact of CVs through several functional and structural neuroimaging studies utilizing federated analysis showcasing their potential to improve the reproducibility of research and increase sample sizes in neuroimaging studies.

neuroscience↗

bioRxiv2022

GenSLMs: Genome-scale language models reveal SARS-CoV-2 evolutionary dynamics.

We seek to transform how new and emergent variants of pandemiccausing viruses, specifically SARS-CoV-2, are identified and classified. By adapting large language models (LLMs) for genomic data, we build genome-scale language models (GenSLMs) which can learn the evolutionary landscape of SARS-CoV-2 genomes. By pretraining on over 110 million prokaryotic gene sequences and finetuning a SARS-CoV-2-specific model on 1.5 million genomes, we show that GenSLMs can accurately and rapidly identify variants of concern. Thus, to our knowledge, GenSLMs represents one of the first whole genome scale foundation models which can generalize to other prediction tasks. We demonstrate scaling of GenSLMs on GPU-based supercomputers and AI-hardware accelerators utilizing 1.63 Zettaflops in training runs with a sustained performance of 121 PFLOPS in mixed precision and peak of 850 PFLOPS. We present initial scientific insights from examining GenSLMs in tracking evolutionary dynamics of SARS-CoV-2, paving the path to realizing this on large biological data.

bioinformatics↗

bioRxiv2022

Quantum biological insights into CRISPR-Cas9 sgRNA efficiency from explainable-AI driven feature engineering

CRISPR-Cas9 tools have transformed genetic manipulation capabilities in the laboratory. Empirical rules-of-thumb have been established for only a narrow range of model organisms, and mechanistic underpinnings for sgRNA efficiency remain poorly understood. This work establishes a novel feature set and new public resource, produced with quantum chemical tensors, for interpreting and predicting sgRNA efficiency. Feature engineering for sgRNA efficiency is performed using an explainable-artificial intelligence model; iterative Random Forest (iRF). By encoding quantitative attributes of position-specific sequences for E. coli sgRNAs, we identify important traits for sgRNA design in bacterial species. Additionally, we show that expanding positional encoding to quantum descriptors of base-pair, dimer, trimer and tetramer sequences captures intricate interactions in local and neighboring nucleotides of the target DNA. These features highlight variation in CRISPR-Cas9 sgRNA dynamics between E. coli and H. sapien genomes. These novel encodings of sgRNAs greatly enhance our understanding of the elaborate quantum biological processes involved in CRISPR-Cas9 machinery.

systems biology↗

bioRxiv2022

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of neuropathic pain

Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonists, which lack psychoactivity associated with central CB1 activation, on antiretroviral-induced neuropathic nociception and identified cell types expressing CB2 that mediate the antinociceptive efficacy of CB2 agonists. Two structurally distinct CB2 agonists (AM1710 and LY2828360) alleviated antiretroviral-induced neuropathic pain, benefits which were absent in CB2 knockout mice. Conditional deletion of CB2 from peripheral sensory neurons eliminated the antinociceptive efficacy of CB2 agonists. We also asked whether LY2828360 treatment could reverse established morphine tolerance in the ddC-induced neuropathy model and whether CB2 expression on peripheral sensory neurons is necessary for sparing of morphine tolerance by LY2828360. The present studies suggest that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

neuroscience↗

bioRxiv2022

Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

Neuroinflammation is a major hallmark of Alzheimers disease and several other neurological and psychiatric disorders and is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol biosynthesis. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via apolipoprotein E (ApoE)-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. 25HC increased extracellular levels of ApoE lipoprotein particles without altering Apoe mRNA expression, due to elevated Abca1 expression via activation of LXRs and decreased ApoE reuptake due to suppressed Ldlr expression via inhibition of SREBP. Astrocytes metabolized 25HC to limit its effects on lipid metabolism via Cyp7b1, an enzyme responsible for 7-hydroxylation of 25HC. Knockdown of Cyp7b1 expression with siRNA prolonged the effects of 25HC on astrocyte lipid metabolism. 25HC also suppressed Srebf2 expression to reduce cholesterol synthesis in astrocytes but did not affect fatty acid levels or the genes required for fatty acid synthesis. We further show that 25HC led to a doubling of the amount of cholesterol esters and their concomitant storage in lipid droplets. Our results suggest an important role for 25HC in regulating astrocyte lipid metabolism.

cell biology↗

bioRxiv2021

#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus ob-scure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized. ACM Reference FormatAbigail Dommer1{dagger}, Lorenzo Casalino1{dagger}, Fiona Kearns1{dagger}, Mia Rosenfeld1, Nicholas Wauer1, Surl-Hee Ahn1, John Russo,2 Sofia Oliveira3, Clare Morris1, AnthonyBogetti4, AndaTrifan5,6, Alexander Brace5,7, TerraSztain1,8, Austin Clyde5,7, Heng Ma5, Chakra Chennubhotla4, Hyungro Lee9, Matteo Turilli9, Syma Khalid10, Teresa Tamayo-Mendoza11, Matthew Welborn11, Anders Christensen11, Daniel G. A. Smith11, Zhuoran Qiao12, Sai Krishna Sirumalla11, Michael OConnor11, Frederick Manby11, Anima Anandkumar12,13, David Hardy6, James Phillips6, Abraham Stern13, Josh Romero13, David Clark13, Mitchell Dorrell14, Tom Maiden14, Lei Huang15, John McCalpin15, Christo- pherWoods3, Alan Gray13, MattWilliams3, Bryan Barker16, HarindaRajapaksha16, Richard Pitts16, Tom Gibbs13, John Stone6, Daniel Zuckerman2*, Adrian Mulholland3*, Thomas MillerIII11,12*, ShantenuJha9*, Arvind Ramanathan5*, Lillian Chong4*, Rommie Amaro1*. 2021. #COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy ofDeltaSARS-CoV-2 in a Respiratory Aerosol. In Supercomputing 21: International Conference for High Perfor-mance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages. https://doi.org/finalDOI

biophysics↗

bioRxiv2021

The emergence of highly fit SARS-CoV-2 variants accelerated by recombination

The SARS-CoV-2 pandemic recently entered an alarming new phase with the emergence of the variants of concern (VOC) and understanding their biology is paramount to predicting future ones. Current efforts mainly focus on mutations in the spike glycoprotein (S), but changes in other regions of the viral proteome are likely key. We analyzed more than 900,000 SARS-CoV-2 genomes with a computational systems biology approach including a haplotype network and protein structural analyses to reveal lineage-defining mutations and their critical functional attributes. Our results indicate that increased transmission is promoted by epistasis, i.e., combinations of mutations in S and other viral proteins. Mutations in the non-S proteins involve immune-antagonism and replication performance, suggesting convergent evolution. Furthermore, adaptive mutations appear in geographically disparate locations, suggesting that either independent, repeat mutation events or recombination among different strains are generating VOC. We demonstrate that recombination is a stronger hypothesis, and may be accelerating the emergence of VOC by bringing together cooperative mutations. This emphasizes the importance of a global response to stop the COVID-19 pandemic.

evolutionary biology↗