Biology subjects

Silverman, J.

Publications and source records attributed to Silverman, J..

10 recordsLinked to original sources

bioRxiv2026

Dietary fiber-type-specific gut microbiome preconditioning drives differential susceptibility to sporadic colon cancer development

Background: Dietary fiber intake is broadly associated with reduced colorectal cancer (CRC) risk, yet processed fiber supplements exert inconsistent and occasionally opposing effects on colon tumorigenesis. How structurally distinct dietary fibers differentially shape the gut microbiome-metabolome axis to influence carcinogenic susceptibility remains poorly understood. Objective: To determine whether structurally distinct dietary fibers differentially modulate colon tumor development and characterize the underlying gut microbiome and metabolic mechanisms. Design: Four-week-old male mice were maintained on low-fiber control or fiber-supplemented diets (7.5%w/w: cellulose, agar, pectin, or inulin) for 28 weeks and received eight intraperitoneal azoxymethane injections (AOM; 7.5 mg/kg). Temporal fecal microbiomes were profiled by 16S-rRNA sequencing, cecal metabolites quantified by H-NMR spectroscopy, and microbiome-metabolome interactions assessed by co-occurrence networks. Results: Refined inulin supplementation markedly elevated colon tumor incidence (~70%) compared with all other groups (~10-20%), and cecal extracts from inulin-fed mice promoted HT29 cancer-cell proliferation. Longitudinal microbiome profiling identified 36 inulin-specific microbial signatures converging on two axes: depletion of SCFAs and fermentation cross-feeding taxa and reprogramming of amino acid and nitrogen metabolism. Metabolomics confirmed succinate, fumarate, and lactate accumulation alongside propionate and amino acid depletion exclusively under AOM conditions, with no differences in carcinogen-naive animals. Two stable co-occurrence hubs were identified exclusively in AOM-treated animals, structurally integrating both functional axes. Conclusion: Inulin supplementation preconditions the gut microbiome toward functional vulnerability, characterized by disrupted fermentation throughput and reprogrammed amino acid metabolism, that is amplified by carcinogen exposure into a tumor-promoting ecosystem, providing a mechanistic basis for the disproportionately higher tumor prevalence in inulin-fed animals.

microbiology↗

bioRxiv2026

Scale-Aware Compositional Inference Improves Reproducibility and Uncovers Convergent Aging Programs in Spatial Transcriptomics

Spatial transcriptomics enables analysis of molecular organization with anatomical context. Existing spatial differential expression methods are restricted to within-sample inference, forcing between-sample comparisons to rely on approaches adapted from single-cell RNA-seq. Here, we establish a scale-aware inference framework for spatial differential expression by modeling compositional constraints and variation in total RNA abundance rather than removing them through normalization, enabling calibrated between-sample inference at cell-level resolution. Our method produces more reliable results in simulated data and different spatial platforms. When applied to aged mouse brains, the analysis reveals converging aging-associated programs involving cellular signaling, membrane homeostasis, and neurovasculature across independent datasets.

genomics↗

bioRxiv2026

Label-free 3D virtual histology of human formalin-fixed paraffin-embedded (FFPE) prostate needle biopsies with propagation-based phase-contrast micro-CT (PBCT)

For over a century, the goal of estimating clinical outcome from tumor biopsies has been based on histomorphology of 2D tissue slices that represent a small fraction of collected samples. Its power derives from histologys 1) unbiased representation of cell types, 2) subcellular resolution that allows the characterization of health and disease states across cell types, and 3) multi-millimeter fields of view that allow assessment of tumor heterogeneity. Histologys dependence upon physical slices, however, limits assessment of 3-dimensional cellular volumes and tissue architecture. Here, we used propagation-based phase-contrast micro-CT (PBCT) to create 3D histological images of residual formalin-fixed, paraffin-embedded (FFPE) prostate needle biopsies. The resulting isotropic, grey-scale, 0.5 micron voxel matrices were used to explore the potential of for the 3D virtual histology to distinguish diagnostic categories including benign prostatic tissue and prostatic adenocarcinoma of Gleason patterns 3, 4, and 5. Maximum intensity projections of stacks of digital slices totaling 5 microns "slices" allowed the study of virtual sections corresponding to actual serial H&E-stained sections of tissue cut after micro-CT imaging. Like histology, our PBCT reconstructions allowed us to distinguish between non-infiltrative and undulating glands of benign prostatic tissue, infiltrative round glands of Gleason pattern 3, cribriform structures of Gleason pattern 4, and comedonecrosis of Gleason pattern 5. Unlike histology, micro-CT allowed us to further probe 3D tissue architecture in volumetric context. User-friendly exploration of sample volumes was achieved using a customized Neuroglancer multiplanar and 3D rendering interface. Sparsely trained cycleGAN produced plausible virtual H&E staining from the unstained micro-CT reconstructions. Unlike tissue-section based histology, micro-CT-based virtual histology yields nondestructive 3D characterization of cancer cell and tissue architecture, including glandular spaces, without the undersampling or cutting artifacts of histology. These findings demonstrate the feasibility of PBCT-based 3D virtual histology of prostate cancer and suggest the exploration of derived quantitative analyses of tumor properties for potential contributions to patient care.

pathology↗

bioRxiv2026

Protein-guided RNA barcoding links transcriptomes to synaptic architecture

Mammalian brain function relies on the precise synaptic architecture of diverse cell types, yet scalable methods for linking a neurons transcriptomic profile to its neuroanatomy remain limited. We present Synapse-seq, an in vivo strategy in which cell-identifying barcoded mRNAs are routed to subcellular compartments via targeting proteins and detected by single-cell and spatial genomics. Using AAV delivery for minimal perturbation of gene expression, we directed barcodes to presynaptic terminals (via synaptophysin) in four distinct circuits, or to postsynaptic sites (via nanobodies to endogenous PSD95) of hippocampal excitatory neurons. In the mouse primary visual cortex, presynaptic Synapse-seq recovered known long-range projections and discovered cortical layer subtypes with distinct thalamic innervation. In the anterior cortex, we elucidated simple topographic rules of corticostriatal innervation: intratelencephalic neurons followed a continuous depth-to-target gradient, while extratelencephalic neurons exhibited striatal collaterals that spatially correlated with medullary innervation. Finally, postsynaptic barcoding of excitatory neurons revealed cell type-specific variation in dendritic architectures across and within hippocampal subfields. These data establish Synapse-seq as a versatile, genomics-based approach for the integrated definition of molecular identity and synaptic organization across mammalian brains.

neuroscience↗

bioRxiv2026

Targeting activated IL-23 signaling in Scleroderma by tildrakizumab

The pathogenesis of systemic sclerosis (SSc) involves immune system dysregulation and progressive multi-organ fibrosis. Aberrant interleukin-23 (IL-23) function is linked to many inflammatory conditions. Tildrakizumab, a humanized monoclonal antibody that binds to the p19 subunit of IL-23 to block its interaction with the IL-23 receptor, is FDA-approved for treating psoriasis. IL-23 levels are increased in SSc patients with lung involvement, but the pathogenic role of IL-23 in SSc fibrosis remains unclear. We examined IL-23 expression in SSc skin biopsies and assessed the effects of IL-23 inhibition in an in vivo fibrosis model. We found increased IL-23 expression in SSc compared to healthy skin biopsies. Pharmacological blockade of IL-23 signaling using tildrakizumab reversed experimental skin and lung fibrosis. Our findings support a pathogenic role of IL-23 in SSc and suggest that tildrakizumab could be a novel antifibrotic treatment strategy for SSc and related fibrotic disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/701821v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@777c8aorg.highwire.dtl.DTLVardef@9163f5org.highwire.dtl.DTLVardef@1399a54org.highwire.dtl.DTLVardef@c30ec2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Long-range neural pathways for octopus chemotactile processing revealed from periphery-to-brain by centimeter-field microCT

Understanding how nervous systems mediate responses to sensation requires whole-body maps of periphery-to-brain connections. Octopuses exemplify this challenge with distributed control of eight arms and hundreds of suckers, yet their long-range microanatomical wiring remains elusive due to limitations in microscopy. We extend histotomography (Ding et al. 2019), a form of soft tissue microCT customized for volumetric characterization of cells and tissues, to centimeter range with a custom micro-CT imaging system (Ding et al., 2019). With its 10-mm field of view and 0.7-{micro}m isotropic voxels we created a high-resolution digital intact small octopus. This multi-tissue 3D blueprint enabled us to (i) elucidate previously uncharacterized chemotactile pathways from the suckers to the brain, (ii) discern subdivisions of the nerve ring connecting neighboring arms, and (iii) segment over 300 structures across organ systems at histology-like resolution. We release the labeled interactive digital specimen to facilitate collaborative whole-organism phenotyping as a practical foundation for digital organismal biology. ONE-SENTENCE SUMMARYWhole-body 3D histology reveals neural and organ architecture throughout a small octopus.

systems biology↗

bioRxiv2023

A Cellular Platform for Production of C4 Monomers

Living organisms carry out a wide range of remarkable functions, including the synthesis of thousands of simple and complex chemical structures for cellular growth and maintenance. The manipulation of this reaction network has allowed for the genetic engineering of cells for targeted chemical synthesis, but it remains challenging to alter the program underlying their fundamental chemical behavior. By taking advantage of the unique ability of living systems to use evolution to find solutions to complex problems, we have achieved ~95% theoretical yield of three C4 commodity chemicals, n-butanol, 1,3-butanediol, and 4-hydroxy-2-butanone. Genomic sequencing of the evolved strains identified pcnB and rpoBC as two gene loci that are able to alter carbon flow by remodeling the transcriptional landscape of the cell, highlighting the potential of synthetic pathways as a tool to identify metabolic control points.

synthetic biology↗

bioRxiv2022

Unique features of the gut microbiome characterized in animal models of Angelman Syndrome

A large subset of patients with Angelman syndrome (AS) suffer from concurrent gastrointestinal (GI) issues, including constipation, poor feeding, and reflux. AS is caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. Clinical features of AS, which include developmental delays, intellectual disability, microcephaly, and seizures, are primarily due to the deficient expression or function of the maternally inherited UBE3A allele. The association between neurodevelopmental delay and GI disorders is part of the increasing evidence suggesting a link between the brain and the gut microbiome via the microbiota-gut-brain (MGB) axis. To investigate the associations between colonization of the gut microbiota in AS, we characterized the fecal microbiome in three animal models of AS containing maternal deletions of Ube3A, including mouse, rat, and pig, using 16S ribosomal RNA amplicon sequencing. Overall changes in the microbial composition of all three animal models of AS in both the phylum and genus levels of bacterial abundance were identified. Specific bacterial groups were significantly increased across all animal models, including: Lachnospiraceae Incertae sedis, Desulfovibrios sp., and Odoribacter, which have been correlated with neuropsychiatric disorders. Taken together, these findings suggest that specific changes to the local environment in the gut are driven by a Ube3a maternal deletion, unaffected by varying housing conditions and are prominent and detectable across multiple small and large model species. These findings may begin to uncover the underlying mechanistic causes of GI disorders in AS patients and provide future therapeutic options for AS patients. IMPORTANCEAngelman syndrome (AS) associated gastrointestinal (GI) symptoms significantly impact quality of life in patients. Using AS models in mouse, rat, and pig, AS animals showed impaired colonization of the gut microbiota compared to wild type (healthy) control animals. Unique changes in AS microbiomes across all three animal models may be important in causing GI symptoms and may help to identify ways to treat these comorbidities in patients in the future.

microbiology↗

bioRxiv2021

Scalable estimation of microbial co-occurrence networks with Variational Autoencoders

Estimating microbe-microbe interactions is critical for understanding the ecological laws governing microbial communities. Rapidly decreasing sequencing costs have promised new opportunities to estimate microbe-microbe interactions across thousands of uncultured, unknown microbes. However, typical microbiome datasets are very high dimensional and accurate estimation of microbial correlations requires tens of thousands of samples, exceeding the computational capabilities of existing methodologies. Furthermore, the vast majority of microbiome studies collect compositional metagenomics data which enforces a negative bias when computing microbe-microbe correlations. The Multinomial Logistic Normal (MLN) distribution has been shown to be effective at inferring microbe-microbe correlations, however scalable Bayesian inference of these distributions has remained elusive. Here, we show that carefully constructed Variational Autoencoders (VAEs) augmented with the Isometric Log-ratio (ILR) transform can estimate low-rank MLN distributions thousands of times faster than existing methods. These VAEs can be trained on tens of thousands of samples, enabling co-occurrence inference across tens of thousands of microbes without regularization. The latent embedding distances computed from these VAEs are competitive with existing beta-diversity methods across a variety of mouse and human microbiome classification and regression tasks, with notable improvements on longitudinal studies.

bioinformatics↗

bioRxiv2020

Only 40% of the world's forests are in good health

Many global environmental agendas, including halting biodiversity loss, reversing land degradation, and limiting climate change, depend upon retaining forests with high ecological integrity, yet the scale and degree of forest modification remains poorly quantified and mapped. By integrating data on observed and inferred human pressures and an index of lost connectivity, we generate the first globally-consistent, continuous index of forest condition as determined by degree of anthropogenic modification. Globally, only 17.4 million km2 of forest (40.5%) have high landscape level integrity (mostly found in Canada, Russia, the Amazon, Central Africa and New Guinea) and only 27% of this area is found in nationally-designated protected areas. Of the forest in protected areas, only 56% has high landscape level integrity. Ambitious policies that prioritize the retention of forest integrity, especially in the most intact areas, are now urgently needed alongside current efforts aimed at halting deforestation and restoring the integrity of forests globally.

ecology↗