Biology subjects

Henry, J.

Publications and source records attributed to Henry, J..

7 recordsLinked to original sources

bioRxiv2026

Novel neonatal hypoxic-ischemic model demonstrates neuroinflammation-associated memory deficits without neuronal loss

BackgroundNeonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. MethodsRat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 minutes. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. ResultsTwelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. ConclusionThis novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. ImpactO_LIThis study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. C_LIO_LInGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. C_LIO_LINeonatal CA/CPR induces global cerebral ischemia which uniquely allows investigation of hindbrain structures, such as cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia. C_LI

neuroscience↗

bioRxiv2025

Energy-guided combinatorial co-optimization of antibody affinity and stability

Affinity maturation is an essential process in antibody engineering. Although powerful, it is iterative, time-consuming, and can result in trade-offs, where affinity is gained at the cost of important properties, such as specificity and stability. We present a scalable strategy, called LAffAb, that starts from a crystallographic structure of the antibody-antigen complex and introduces combinations of mutations to optimize its energy. A combinatorial library comprising 7,000 variants with up to nine mutations results in gains of up to 30-fold in affinity while co-optimizing stability. Surprisingly, the library does not converge on a single solution, instead favoring diverse variants with a high mutational load. Small-scale screening of 10 designs against a potential drug target results in an order-of-magnitude improvement in affinity while maintaining high developability. We also apply LAffAb to improve the developability of a therapeutic antibody without degrading affinity. We envision that LAffAb can be used to design stable, specific, and high-affinity binders and to improve our understanding of sequence, structure, and function relationships in antibodies.

synthetic biology↗

bioRxiv2025

Metagenomes and Metagenome-Assembled Genomes from Tidal Lagoons at a New York City Waterfront Park

We report the sequencing and analysis of 15 shotgun metagenomes, including the reconstruction of 129 high-quality metagenome-assembled genomes, from tidal lagoons and bay water at Bush Terminal Piers Park in Brooklyn, NY sampled from July to September 2024.. Our metagenomic database for this site provides an important baseline for ongoing studies of the microbial communities of public parks and waterfront areas. In particular, we provide rich functional and taxonomic annotations that enable the use of these metagenomes and metagenome-assembled genomes for a wide variety of downstream applications.

microbiology↗

bioRxiv2025

Cell type-specific associations with Alzheimer's Disease conserved across racial and ethnic groups

Genomic studies at single-cell resolution have implicated multiple cell types associated with clinical and pathological traits in Alzheimers Disease (AD), but have not examined common features across broad, multi-ethnic populations, and across multiple regions. To bridge this gap, we performed single-nucleus RNA-seq and ATAC-seq profiling of cortical and subcortical brain regions from post-mortem samples across Non-Latin White, African American, and Latin donors (the latter of any race). Using discrete and continuous dissection of molecular programs, we elucidate cell-type-specific glial and neuronal signatures associated with AD across multiple population groups. Notably, we found that multiple microglial (GPNMB+, CD74+, and CR1+ subgroups) and astrocyte (SERPINH1+ and WIF1+ subgroups) signatures are associated with worse clinical and pathological phenotypes across all three population groups. We also report continuous gene expression factors in oligodendrocytes that are not captured by discrete clusters, yet still show strong associations with disease phenotypes. Finally, we observe these discrete cellular identities and continuous gene programs separate cognitively impaired donors into 6 molecularly distinct subgroups that span racial and ethnic population groups. Overall, our study identifies key cell types and gene programs implicated in AD that are shared across population groups, and provides an initial data set that underscores how representative sampling can capture conserved signatures as well as disease heterogeneity, leading to better prioritization of key cell types for further investigation.

neuroscience↗

bioRxiv2023

Regulatory mechanisms in multiple vascular diseases locus LRP1 involve repression by SNAIL and extracellular matrix remodeling

BackgroundGenome-wide association studies (GWAS) implicate common genetic variations in the low-density lipoprotein receptor-related protein 1 locus (LRP1) in risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown. MethodsFine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells (iPSC) were genome-edited using CRISPR-Cas9 to delete or modify candidate enhancer regions, and generate LRP1 knockout cell lines (KO). Cells were differentiated into smooth muscle cells (SMCs) through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA-sequencing and mass spectrometry. ResultsMulti-trait co-localization analyses pointed at rs11172113 as the most likely causal variant in LRP1 for fibromuscular dysplasia, migraine, pulse pressure and pulmonary function trait. We found rs11172113-T allele to associate with higher LRP1 expression. Genomic deletion in iPSC-derived SMCs supported rs11172113 to locate in an enhancer region regulating LRP1 expression. We found transcription factors MECP2 and SNAIL to repress LRP1 expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele. LRP1 KO decreased iPSC-derived SMCs proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix, connective tissue and lung development. LRP1 KO showed potentiated canonical TGF-{beta} signaling through enhanced phosphorylation of SMAD2/3. Analyses of protein content of decellularized extracts indicated partial extracellular matrix (ECM) remodeling involving enhanced secretion of CYR61, a known LRP1 ligand involved in vascular integrity and TIMP3, implicated in extracellular matrix maintenance and also known to interact with LRP1. ConclusionsOur findings support allele specific LRP1 gene repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreased LRP1 expression in SMCs to remodel the ECM enhanced by TGF- {beta} as a potential mechanism of this pleiotropic locus for vascular diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/539992v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@11926a8org.highwire.dtl.DTLVardef@390a37org.highwire.dtl.DTLVardef@cdad4dorg.highwire.dtl.DTLVardef@12cbf92_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Genomic, transcriptomic and proteomic depiction of iPSC-derived smooth muscle cells as emerging cellular models for arterial diseases

BackgroundVascular smooth muscle cells (VSMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing deep cellular phenotyping, epigenomic and proteomic depiction of SMCs derived from induced pluripotent stem cells (iPSCs) and evaluating their potential as cellular models in the context of complex genetic arterial diseases. MethodsWe differentiated 3 human iPSC lines using either RepSox (R-SMCs) or PDGF-BB and TGF-{beta} (TP-SMCs), during the second half of a 24-days-long protocol. In addition to cellular assays, we performed RNA-Seq and assay for transposase accessible chromatin (ATAC)-Seq at 6 time-points of differentiation. The extracellular matrix content (matrisome) generated by iPSCs derived SMCs was analyzed using mass spectrometry. ResultsBoth iPSCs differentiation protocols generated SMCs with positive expression of SMC markers. TP-SMCs exhibited greater capacity of proliferation, migration and lower calcium release in response to contractile stimuli compared to R-SMCs. RNA-Seq data showed that genes involved in the contractile function of arteries were highly expressed in R-SMCs compared to TP-SMCs or primary SMCs. Matrisome analyses supported an overexpression of proteins involved in wound repair in TP-SMCs and a higher secretion of basal membrane constituents by R-SMCs. Open chromatin regions of R-SMCs and TP-SMCs were significantly enriched for variants associated with coronary artery disease and blood pressure, while only TP-SMCs were enriched for variants associated with peripheral artery disease. ConclusionsOur study portrayed two iPSCs derived SMCs models presenting complementary cellular phenotypes of high relevance to SMC plasticity. In combination with genome-editing tools, our data supports high relevance of the use of these cellular models to the study of complex regulatory mechanisms at genetic risk loci involved in several arterial diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/490058v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1f1002corg.highwire.dtl.DTLVardef@1426fa7org.highwire.dtl.DTLVardef@b05b56org.highwire.dtl.DTLVardef@3c6e88_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2018

A thermo-responsive plasmid for biconditional protein expression

Here we develop a temperature sensitive expression vector that allows the selective production of distinct proteins over different temperature ranges with a single plasmid. We use the E. coli cold shock translational control system (the cspA 5Untranslated Transcribed Region - UTR) to drive the expression of a desired protein below a certain temperature threshold, and the lambda phage pL/cI857 transcriptional repressor system to drive the expression of a different protein above a certain temperature threshold. In this developmental work we use the chromogenic reporter proteins amilCP (blue chromoprotein) and monomeric red fluorescent protein (mRFP) to assess the function of the thermo-sensitive regulatory sequences over the desired temperature ranges. Our results show temperature dependent response of the cold shock regulatory sequence. However, our sequence design for the heat shock regulatory sequence did not give the intended result. The integration of these two temperature sensitive elements into a single plasmid awaits the re-design of the heat shock sequence.

synthetic biology↗