Biology subjects

Goldstein, J.

Publications and source records attributed to Goldstein, J..

17 recordsLinked to original sources

bioRxiv2026

Flow-Induced Yap/Taz Signaling Balances Endothelial and Hematopoietic Stem Cell Fates

Mechanical forces from blood flow are essential for production of hematopoietic stem and progenitor cells (HSPCs) during embryogenesis, but the molecular mechanisms by which hemodynamic cues are sensed and orchestrate endothelial-to-hematopoietic (EHT) transition remain incompletely defined. We previously identified YAP mechanotransduction as a key integrator of physical forces with EHT. Here we show that hemodynamic forces can activate YAP signaling via the mechanoresponsive ion channel Piezo1 in human iPSC-derived hemogenic endothelium (HE) and zebrafish embryos. Investigation of the Piezo1/YAP axis revealed shared and unique roles of YAP and its paralogue TAZ in EHT. Mechanistically, we find a requirement for the Tead DNA-binding co-factor in YAP/TAZ-dependent control of HSPC number, and note that TAZ uniquely augments transcriptional output of the hematopoietic master regulator Runx1 via direct protein-protein interactions. By comprehensive scRNA-sequencing of YAP/TAZ gain-of-function (GOF) and yap-deficient cells from zebrafish, we reveal that YAP/TAZ promotes HSC production by positively regulating gene programs for hematopoietic self-renewal, cell cycle, and glycolysis-to-oxidative phosphorylation switching, while preventing reversion to endothelial identity. Importantly, comparison of GOF transcriptomes and functional analyses suggest decoupling of metabolic/proliferative and endothelial gene regulatory modules between YAP and TAZ: while either can functionally compensate for loss of the other in EHT, indiscriminate overactivation of TAZ enhances an endothelial program over pro-hematopoietic fate, ultimately blunting progression of HSPC production. Given that hemodynamic cues are integrated simultaneously by arterial and HE cells in embryonic vessels in which EHT occurs, these findings have strong implications for strategies designed to introduce biomechanical cues to in vitro hematopoietic differentiation systems to drive HSC production.

Cell Biology↗

bioRxiv2025

Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade

Immune exclusion remains a major barrier to effective immunotherapy in solid tumors. Given the abundance and plasticity of tumor-associated macrophages (TAMs) in many tumors, including pediatric tumors, we investigated whether TLR3 activation could reprogram them to facilitate immune access. Single-cell and spatial profiling in a mouse model of rhabdoid tumors showed that they are dominated by TLR3-expressing TAMs, whose depletion delays tumor growth. Treatment with the TLR3 agonist poly(I:C) promotes immune cell infiltration, including progenitor-exhausted CD8+ T cells, by multiple mechanisms including the reduction and reprogramming of immunosuppressive TAMs, promoting nitric-oxide production by peritumoral macrophages, and inducing CXCL9/10 production. Combined poly(I:C) and PD-1 blockade elicited durable, complete tumor rejection. Human macrophages from tumor biopsies showed conserved TLR3 responsiveness, underscoring translational potential. These findings uncover a mechanism by which TLR3-driven myeloid reprogramming transforms immune-excluded tumors into checkpoint-responsive ones, revealing a therapeutic path to overcome resistance to PD-1 blockade.

immunology↗

bioRxiv2025

Dual PD-L1/TIGIT blockade induces PNAd+ HEV-like vessels and CD62L+ lymphocyte recruitment, driving rhabdoid tumor rejection

Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis and limited immunotherapy options. Here, we investigate the therapeutic potential of combined PD-L1 (Programmed cell death ligand 1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) immune checkpoint blockade in RTs using a preclinical murine model that recapitulates key features of human ATRT (Atypical teratoid rhabdoid tumors) subtypes. Transcriptomic analyses of human and murine RTs reveal co-expression of TIGIT and PD-1 (Programmed cell death 1) pathway components and their ligands, particularly in immune-infiltrated subtypes, supporting a rationale for dual blockade. Combination therapy induces complete tumor regression, prolongs survival, and reprograms the tumor immune microenvironment by enriching CD62L naive and central memory T cells and promoting selective T-cell clonal expansion. Notably, dual blockade initiates PNAd (Peripheral node addressin) high endothelial venule (HEV)-like structures, associated with focal lymphocyte clustering and enhanced immune cell recruitment. These findings reveal a mechanistic link between vascular remodeling and immune infiltration and support dual TIGIT and PD-L1 inhibition as a promising immunotherapeutic strategy for RTs.

immunology↗

bioRxiv2025

Diurnal rhythms with sunrise-induced oscular contractions suggest photosensitivity in the demosponge Halichondria panicea

Despite their quiescent lifestyle, sponges display contraction-expansion behaviours that regulate water flow through their aquiferous system. These behaviours are intrinsically generated but can be modulated by environmental parameters, including light exposure. Some sponges exhibit diurnal contraction-expansion rhythms synchronized with illumination cycles. Since the often-used photopigment opsin is unknown in sponges, the light-induced behaviour is likely mediated by cryptochromes and extra-ocular photoreceptors, as shown in sponge larvae. Previous studies on demosponges reported higher contraction-expansion activity during daylight than at night. Understanding such diurnal behaviours in nerve- and muscle-less metazoans may provide insights into the early evolution of sleep-like states. However, systematic diurnal observations of sponge contraction-expansion rhythms remain scarce. Here, we document the contractile behaviour of single-osculum explants of the marine demosponge Halichondria panicea over six days, maintained under a 12:12 h dark:light cycle with simulated sunrise and sunset. We find a light-induced diurnal rhythm in the contraction-expansion behaviour of their osculum, suggesting photosensitivity. Furthermore, we observe that sunrise triggers the onset of oscular contractions and discuss these results in context with the characteristics of sleep-like states in other metazoans. Summary statementA diurnal rhythm of light-induced oscular contractions suggests photosensitivity in the nerveless demosponge Halichondria panicea. This may offer insights into the early evolution of sleep-like behaviours in metazoans.

animal behavior and cognition↗

bioRxiv2025

Dynamic activity of Erg promotes aging of the hematopoietic system

Hematopoiesis changes to adapt to the physiology of development and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts over the lifespan is unknown. Here, we show that expression of the ETS family TF Erg is adult-biased, and that programmed upregulation of Erg expression during juvenile to adult aging is evolutionarily conserved and required for complete implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs, and persistent juvenile phenotypes in Erg haploinsufficient mice are dependent on deregulation of the fetal-biased TF Hmga2. Finally, Erg haploinsufficiency in the adult results in fetal-like resistance to leukemogenesis. Overall, we identify a mechanism whereby HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases. SUMMARYThe hematopoietic system undergoes a process of coordinated aging from the juvenile to adult states. Here, we find that expression of ETS family transcription factor Erg is temporally regulated. Impaired upregulation of Erg during the hematopoietic maturation results in persistence of juvenile phenotypes.

developmental biology↗

bioRxiv2024

High-fat and high-carbohydrate diets worsen the mouse brain susceptibility to damage produced by enterohemorrhagic Escherichia coli Shiga toxin 2

BackgroundNutrition quality could be one of the reasons why, in the face of a Shiga toxin-producing enterohaemorrhagic Escherichia coli outbreak, some patients experience more profound deleterious effects than others, including unfortunate deaths. Thus, the aim of this study was to determine whether high-fat and/or high-carbohydrate diets could negatively modulate the deleterious action of Shiga toxin 2 on ventral anterior and ventral lateral thalamic nuclei and the internal capsule, the neurological centers responsible for motor activity. MethodsMice were fed a regular, high-fat, high-carbohydrate diet or a combination of both previous to the intravenous administration of Shiga toxin 2 or vehicle. Four days after intravenous administration, mice were subjected to behavioral tests and then sacrificed for histological and immunofluorescence assays to determine alterations in the neurovascular unit at the cellular and functional levels. Statistical analysis was performed using one-way analysis of variance followed by Bonferroni post hoc test. The criterion for significance was p = 0.0001 for all experiments. ResultsThe high-fat and the high-carbohydrate diets significantly heightened the deleterious effect of Stx2, while the combination of both diets yielded the worst results, including endothelial glycocalyx and oligodendrocyte alterations, astrocyte and microglial reactivity, neurodegeneration, and motor and sensitivity impairment. ConclusionsIn view of the results presented here, poor nutrition could negatively influence patients affected by Stx2 at a neurological level. Systemic effects, however, cannot be ruled out.

microbiology↗

bioRxiv2024

The Scalable Variant Call Representation: Enabling Genetic Analysis Beyond One Million Genomes

The Variant Call Format (VCF) is widely used in genome sequencing but scales poorly. For instance, we estimate a 150,000 genome VCF would occupy 900 TiB, making it both costly and complicated to produce and analyze. The issue stems from VCFs requirement to densely represent both reference-genotypes and allele-indexed arrays. These requirements lead to unnecessary data duplication and, ultimately, very large files. To address these challenges, we introduce the Scalable Variant Call Representation (SVCR). This representation reduces file sizes by ensuring they scale linearly with samples. SVCR achieves this by adopting reference blocks from the Genomic Variant Call Format (GVCF) and employing local allele indices. SVCR is also lossless and mergeable, allowing for N+1 and N+K incremental joint-calling. We present two implementations of SVCR: SVCR-VCF, which encodes SVCR in VCF format, and VDS, which uses Hails native format. Our experiments confirm the linear scalability of SVCR-VCF and VDS, in contrast to the super-linear growth seen with standard VCF files. We also discuss the VDS Combiner, a scalable, open-source tool for producing a VDS from GVCFs and unique features of VDS which enable rapid data analysis. SVCR, and VDS in particular, ensure the scientific community can generate, analyze, and disseminate genetics datasets with millions of samples.

bioinformatics↗

bioRxiv2021

N-glycosylation profiles of the SARS-CoV-2 spike D614G mutant and its ancestral protein characterized by advanced mass spectrometry

N-glycosylation plays an important role in the structure and function of membrane and secreted proteins. The spike protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is heavily glycosylated and the major target for developing vaccines, therapeutic drugs and diagnostic tests. The first major SARS-CoV-2 variant carries a D614G substitution in the spike (S-D614G) that has been associated with altered conformation, enhanced ACE2 binding, and increased infectivity and transmission. In this report, we used mass spectrometry techniques to characterize and compare the N-glycosylation of the wild type (S-614D) or variant (S-614G) SARS-CoV-2 spike glycoproteins prepared under identical conditions. The data showed that half of the N-glycosylation sequons changed their distribution of glycans in the S-614G variant. The S-614G variant showed a decrease in the relative abundance of complex-type glycans (up to 45%) and an increase in oligomannose glycans (up to 33%) on all altered sequons. These changes led to a reduction in the overall complexity of the total N-glycosylation profile. All the glycosylation sites with altered patterns were in the spike head while the glycosylation of three sites in the stalk remained unchanged between S-614G and S-614D proteins.

biochemistry↗

bioRxiv2020

Naegleria fowleri: protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba

Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brains frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogens high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. N. fowleri genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen.

molecular biology↗

bioRxiv2020

Cognitive deficits found in a pro-inflammatory state are independent of ERK 1/2 signaling in the murine brain hippocampus treated with Shiga toxin 2 from enterohemorrhagic Escherichia Coli

Shiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS) and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. Results demonstrate that systemic administration of a sublethal dose of Stx2 reduced memory index and produced depression like behavior, pro-inflammatory cytokine release and NF-kB activation independent of the ERK 1/2 signaling pathway. On the other hand, LPS activated NF-kB dependent on ERK 1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.

pathology↗

bioRxiv2019

RICOPILI: Rapid Imputation for COnsortias PIpeLIne

MotivationGenome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open sourced Perl-based pipeline was developed to address the challenges of rapidly processing large scale multi-cohort GWAS studies including quality control, imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing (HPC) environments.\n\nSummaryRICOPILI was created as the Psychiatric Genomics Consortium (PGC) pipeline for GWAS and has been adopted by other users. The pipeline features i) technical and genomic quality control in case-control and trio cohorts ii) genome-wide phasing and imputation iv) association analysis v) meta-analysis vi) polygenic risk scoring and vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all of the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work.\n\nAvailability and ImplementationRICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home\n\nContactsripke@broadinstitute.org\n\nSupplementary informationSupplementary data are available.

genetics↗

bioRxiv2017

Common risk variants identified in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.

genetics↗

bioRxiv2017

The iPSYCH2012 case-cohort sample: New directions for unravelling genetic and environmental architectures of severe mental disorders

The iPSYCH consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born 1981-2005 including 1,472,762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3,540), autism (N=16,146), ADHD (N=18,726), and affective disorder (N=26,380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30,000). Within the sample of 86,189 individuals, a total of 57,377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

genetics↗

bioRxiv2017

Discovery Of The First Genome-Wide Significant Risk Loci For ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of school-age children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no individual variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes, as well as around brain-expressed regulatory marks. These findings, based on clinical interviews and/or medical records are supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population. Meta-analyzing these data with our primary scan yielded a total of 16 genome-wide significant loci. The results support the hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits.

genetics↗

bioRxiv2017

Ecological and demographic drivers of jellyfish blooms

O_LIJellyfish blooms are conspicuous demographic events with significant ecological and socio-economic impact. Despite worldwide concern about an increased frequency and intensity of jellyfish mass occurrences, predicting their booms and busts remains challenging. C_LIO_LIForecasting how jellyfish populations may respond to environmental change requires taking into account their complex life histories. Metagenic life cycles, which include a benthic polyp stage, can boost jellyfish outbreaks via asexual recruitment of pelagic medusae. C_LIO_LIHere we present stage-structured matrix population models with demographic rates of all life stages of the cosmopolitan jellyfish Aurelia aurita s. l. for different environments. We investigate the life stage-dynamics of such complex populations to illustrate how changes in medusa density depend on non-medusa stage dynamics. C_LIO_LIWe show that increased food availability is an important ecological driver of jellyfish mass occurrence, as it can shift the population structure from polyp- to medusa-dominated. Projecting populations for a winter warming scenario additionally enhanced the booms and busts of jellyfish blooms. C_LIO_LIWe identify demographic key variables that control the intensity and frequency of jellyfish blooms in response to anthropogenic drivers such as habitat eutrophication and climate change. By contributing to an improved understanding of mass occurrence phenomena, our findings provide perspective for future management of ecosystem health. C_LI

ecology↗

bioRxiv2016

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability [Formula] of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

genomics↗

bioRxiv2016

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by both common polygenic and de novo variation. The purpose of this analysis was to clarify the influence of common polygenic risk for ASDs and to identify subgroups of cases, including those with strong acting de novo variants, in which different types of polygenic risk are relevant. To do so, we extend the transmission disequilibrium approach to encompass polygenic risk scores, and introduce the polygenic transmission disequilibrium test. Using data from more than 6,400 children with ASDs and 15,000 of their family members, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs in two independent samples, but not to their unaffected siblings. These findings hold independent of proband IQ. We find that common polygenic variation contributes additively to risk in ASD cases that carry a very strong acting de novo variant. Lastly, we find evide ...

genetics↗