Biology subjects

Sabo, A.

Publications and source records attributed to Sabo, A..

10 recordsLinked to original sources

bioRxiv2026

DigitAb: Domain-Adaptive Cell Type Prediction Method from Light Microscopy Images

Light microscopy imaging with histological stains is central to disease diagnosis and research. It is enhanced with immunostaining to reveal cellular composition and complexity linked to clinical utility and biological mechanisms. Emerging multiplex imaging technologies like Phenocycler markedly increase the coverage to capture the cellular diversity but are costly, technically demanding, and inaccessible to most clinical laboratories. We developed DigitAb, a deep learning framework that classifies cell types directly from hematoxylin and eosin (H&E) stained slides, eliminating the need for specialized assays. Using Phenocycler imaging, we generated highlZlresolution ground truths for [~]3.5 million cells from 29 human kidney samples across four multi-institutional datasets to train a semantic segmentation model for 10 cell types, achieving a balanced accuracy of 0.78. By employing an integrated adversarial domain adaptation module, we tested DigitAb on unlabeled and untested biopsy samples from kidney transplant and diabetic samples. We were able to predict several cell types just from histology images, without using any special technology or immunostains, and demonstrate high concordance with clinical gold-standard Banff schema in kidney transplant rejection, and clinical characteristics of diabetic nephropathy. Our cloudlZlbased tool, DigitAb, provides scalable, accessible, labellZlfree cellular segmentation for research and clinical pathology.

pathology↗

bioRxiv2026

Uromodulin promotes immune zonation and inhibits alternative inflammasome-mediated activation of immune-to-collecting duct inflammatory signaling in early acute kidney injury

Uromodulin, a protein made uniquely by the kidney, is protective against acute kidney injury. An integrated transcriptomic and multiplexed spatial protein imaging was used to uncover early cellular and molecular pathophysiological mechanisms following murine kidney ischemia and reperfusion injury (IRI) and better define the role of Uromodulin at the early stage of injury. Six hours following IRI, there was a pan-nephronal transcriptomic response with activation of common pathways but also unique gene expression signatures for each nephron segment. Cell-cell communications and epithelial-immune spatial interactions most prominently involved thick ascending limbs and distal nephron segments with distinct immune zonation in the inner stripe of the outer medulla. Uromodulin deficiency swayed the tubular transcriptomic signatures towards more severe injury and inflammation with altered macrophage communication. Uromodulin deficiency also caused partial loss of immune zonation and a shift towards broader epithelial-immune interactions in the outer stripe and cortex. Uromodulin inhibited activation of the Nlrc4-dependent alternative inflammasome pathway in macrophages, where the production of IL-1{beta} predominantly targets other immune and collecting duct (CD) cells. Indeed, Uromodulin deficiency induced the expression of CD8 in CD cells which acquire a proinflammatory phenotype linked to spatial niches containing immune cells. The presence of CD8+ CD cells was validated in human kidney biopsies. In conclusion, our findings support a role for Uromodulin in spatially confining the immune system around TAL cells in the inner stripe away from the vulnerable outer stripe in early injury. Uromodulin also inhibits the inflammasome-mediated macrophage-epithelial crosstalk that could induce collecting duct cells towards more inflammatory signaling.

physiology↗

bioRxiv2024

A MEF2C transcripton factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease

The maintenance of a healthy epithelial-endothelial juxtaposition requires cross-talk within glomerular cellular niches. We sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. From 74 human kidney samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular capillary endothelial (EC-GC) and mesangial cells. Data were culled from single nucleus RNA and ATAC sequencing and three orthogonal spatial transcriptomic technologies for correlation with histopathological and clinical trial data. We identified a cellular niche in diabetic glomeruli enriched in a proliferative endothelial cell subtype (prEC) and altered vascular smooth muscle cells (VSMCs). Cellular communication within this niche maintained pro-angiogenic signaling with loss of anti-angiogenic factors. We identified a TF network of MEF2C, MEF2A, and TRPS1 which regulated SEMA6A and PLXNA2, a receptor-ligand pair opposing angiogenesis. In silico knockout of the TF network accelerated the transition from healthy EC-GCs toward a degenerative (injury) endothelial phenotype, with concomitant disruption of EC-GC and prEC expression patterns. Glomeruli enriched in the prEC niche had histologic evidence of neovascularization. MEF2C activity was increased in diabetic glomeruli with nodular mesangial sclerosis. The gene regulatory network (GRN) of MEF2C was dysregulated in EC-GCs of patients with DKD, but sodium glucose transporter-2 inhibitor (SGLT2i) treatment reversed the MEF2C GRN effects of DKD. The MEF2C, MEF2A, and TRPS1 TF network carefully balances the fate of the EC-GC in DKD. When the TF network is "on" or over-expressed in DKD, EC-GCs may progress to a prEC state, while TF suppression leads to cell death. SGLT2i therapy may restore the balance of MEF2C activity.

cell biology↗

bioRxiv2021

Polycomb Group Ring Finger Protein 6 suppresses Myc-induced lymphomagenesis

Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4 and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6 - but not Mga - accelerates Myc-induced lymphomagenesis in E{micro}-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.

cancer biology↗

bioRxiv2021

Neptune: An environment for the delivery of genomic medicine

PurposeGenomic medicine holds great promise for improving healthcare, but integrating searchable and actionable genetic data into electronic health records remains a challenge. Here, we describe Neptune, a system for managing the interaction between a clinical laboratory and an electronic health record system. MethodsWe developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis and EHR integration. ResultsNeptune enabled the analysis of data for generation of and delivery to EHR systems of over 15,000 clinical genomic reports. These projects demanded customizable clinical reports that contained a variety of genetic data types including SNVs, CNVs, pharmacogenomics and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. ConclusionsMethods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open and available at https://gitlab.com/bcm-hgsc/neptune.

bioinformatics↗

bioRxiv2020

Technical Note: Quantifying music-dance synchrony with the application of a deep learning-based 2D pose estimator

Dance interventions are more effective at improving gait and balance outcomes than other rehabilitation interventions. Repeated training may culminate in superior motor performance compared to other interventions without synchronization. This technical note will describe a novel method using a deep learning-based 2D pose estimator: OpenPose, alongside beat analysis of music to quantify movement-music synchrony during salsa dancing. This method has four components: i) camera setup and recording, ii) tempo/downbeat analysis and waveform cleanup, iii) OpenPose estimation and data extraction, and iv) synchronization analysis. Two trials were recorded: one in which the dancer danced synchronously to the music and one where they did not. The salsa dancer performed a solo basic salsa step continuously for 90 seconds to a salsa track while their movements and the music were recorded with a webcam. This data was then extracted from OpenPose and analyzed. The mean synchronization value for both feet was significantly lower in the synchronous condition than the asynchronous condition, indicating that this is an effective means to track and quantify a dancers movement and synchrony while performing a basic salsa step.

neuroscience↗

bioRxiv2020

Integrated requirement of non-specific and sequence-specific DNA binding in MYC-driven transcription

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity: how these binding modes are integrated to determine select transcriptional outputs remains unresolved. We designed mutants of the MYC transcription factor bearing substitutions in residues that contact either the DNA backbone or specific bases within the consensus binding motif (E-box), and profiled their DNA-binding and gene-regulatory activities in murine cells. Our data reveal that non-specific DNA binding is required for MYC to engage onto active regulatory elements in the genome, preceding sequence recognition; beyond merely stabilizing MYC onto select target loci, sequence-specific binding contributes to its precise positioning and - most unexpectedly - to transcriptional activation per se. In particular, at any given binding intensity, promoters targeted via the cognate DNA motif were more frequently activated by MYC. Hence, seemingly promiscuous chromatin interaction profiles actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.

molecular biology↗

bioRxiv2019

Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz

Background & AimsActivation of MYC and CTNNB1 (encoding {beta}-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.\n\nApproach & ResultsWe generated a mouse model allowing conditional activation of MYC and WNT/{beta}-catenin signaling (through either {beta}-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Conditional activation of WNT/{beta}-catenin signaling strongly accelerated MYC-driven carcinogenesis in the mouse liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and {beta}-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a \"Myc/{beta}-catenin signature\", composed of a discrete set of Myc-activated genes whose expression increased in presence of active {beta}-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/{beta}-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/{beta}-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/{beta}-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.\n\nConclusionsYap and Taz mediate the cooperative action of Myc and {beta}-catenin in liver tumorigenesis. This warrants efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/{beta}-catenin activity.

cancer biology↗

bioRxiv2019

An early Myc-dependent transcriptional program underlies enhanced macromolecular biosynthesis and cell growth during B-cell activation

Upon activation, lymphocytes exit quiescence and undergo substantial increases in cell size, accompanied by activation of energy-producing and anabolic pathways, widespread chromatin decompaction and elevated transcriptional activity. These changes depend upon prior induction of the Myc transcription factor, but how Myc controls them remains unclear. We addressed this issue in primary mouse B-cells, based on conditional deletion of the c-myc gene, followed by LPS stimulation. Myc was rapidly induced, became detectable on virtually all active promoters and enhancers, but had no direct impact on global transcriptional activity. Instead, Myc contributed to the swift up- and down-regulation of several hundred genes, including many known regulators of the aforementioned cellular processes. Myc-activated promoters were enriched for E-box consensus motifs, bound Myc at the highest levels and showed enhanced RNA Polymerase II recruitment, the opposite being true at down-regulated loci. Remarkably, the Myc-dependent signature identified in activated B-cells was also enriched in Myc-driven B-cell lymphomas: hence, besides modulation of new cancer-specific programs, the oncogenic action of Myc may largely rely on sustained deregulation of its normal physiological targets.

cancer biology↗

bioRxiv2019

Exome sequencing of 457 autism families recruited online provides evidence for novel ASD genes

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. Additionally, we identified variants that are possibly associated with autism in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.2 provides statistical support for 34 ASD risk genes with at least one damaging variant identified in SPARK. Nine of these genes (BRSK2, DPP6, EGR3, FEZF2, ITSN1, KDM1B, NR4A2, PAX5 and RALGAPB) are newly emerging genes in autism, of which BRSK2 has the strongest statistical support as a risk gene for autism (TADA q-value = 0.0015). Future studies leveraging the thousands of individuals with ASD that have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate autism research that incorporates genetic etiology.

genetics↗