Biology subjects

Dash, S.

Publications and source records attributed to Dash, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by oncogenic KRAS signaling and sustained by a desmoplastic, immunosuppressive microenvironment limiting therapeutic response. CD73 mediated adenosine signaling supports this immune-excluded, tumor supportive microenvironment. Whether dual targeting of KRAS-MAPK and CD73 signaling creates a therapeutic opportunity to improve tumor control remains unexplored. Analysis of KRAS mutant cancer cell lines revealed increased expression of NT5E and adenosine receptor ADORA2B. Pharmacologic and genetic suppression of oncogenic KRAS inhibited CD73 expression through a MAPK-dependent program. In syngeneic KPC tumors, conversely, CD73 inhibition with quemliclustat increased ERK phosphorylation in vivo, suggesting adaptive MAPK activation following CD73 blockade. Combined CD73 and RAS(ON) inhibition in vivo produced the strongest antitumor response, reducing endpoint tumor volume beyond either monotherapy. This combination significantly suppressed tumor proliferation and SMA-positive stroma and resulted in a substantial reduction in CD163-positive macrophage infiltration. RAS-MAPK targeted therapy was also associated with increased CD8-positive T cell infiltration and granzyme B-positive staining. As therapeutic responses in PDAC have been linked to the gut microbiome, we further examined treatment-associated changes in the microbiome. RAS-MAPK inhibition produced the most pronounced microbial alterations, which correlated with tumor volume and immune markers. Together, these findings identify KRAS-MAPK driven CD73 signaling as a therapeutic vulnerability in PDAC and support combined CD73 and RAS(ON) inhibition as a strategy to suppress tumor growth, remodel stroma, and alleviate tumor-associated immune suppression.

cancer biology↗

bioRxiv2026

Pulsed Field Ablation Enables Stromal Manipulation and Tumor Reduction in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic microenvironment that promotes therapeutic resistance and disease progression. Here, we investigated the impact of pulsed field ablation (PFA), a non-thermal electroporation-based therapy, on tumor and stromal remodeling in a syngeneic murine PDAC model. PFA induced rapid apoptotic and necrotic tumor cell death, transient neutrophil infiltration, and durable suppression of tumor growth. Single-cell RNA sequencing following repeated PFA treatments revealed enrichment of a classical secretory tumor cell state associated with complement and stress-response pathways and reduced epithelial-to-mesenchymal transition (EMT) programs. Although overall immune composition was largely unchanged, PFA markedly remodeled the stromal compartment, decreasing SMA-positive activation and shifting cancer-associated fibroblasts (CAFs) from tumor-promoting myofibroblastic CAFs toward Dpp4+ complement-secreting CAFs. This transition was accompanied by increased IL-1 signaling potential, reduced Tgfb1 expression, and diminished tumor cell TGF-{beta} response signatures. Serial PFA treatments further suppressed EMT-associated programs, identifying stromal reprogramming as a potential mechanism through which PFA enhances tumor control.

bioengineering↗

bioRxiv2026

Variational Autoencoder-enabled High-throughput Drug Screening for HIV Latency Modulators predicted through Noise in Gene Expression

Due to its ability to establish a pool of undetectable and latently infected cells that can initiate viral production through random reactivation, a cure to human immunodeficiency virus (HIV) infections has remained elusive. Many approaches have been proposed, including the "shock and kill" method where latency reversing agents (LRAs) are administered to reactivate latently infected cells out of latency and remove them through immune targeting and clearance, and the "block and lock" method where latency promoting agents (LPAs) are administered to inhibit reactivation and potentially induce a "deep latency" state where infected cells can no longer reactivate. Previous large scale drug screen studies have demonstrated a correlation between a compounds capability to modulate the fluctuations (or "noise") in HIV gene expression and its potential to modulate HIV latency. However, measurements of gene expression noise are labor-and cost-intensive. To circumvent these drawbacks, we trained a variational autoencoder (VAE) on a previously published large scale time-lapse fluorescence microscopy dataset, and performed an in silico screening of [~]175,000 compounds for HIV latency modulators. Out of the top 113 predicted modulators that were experimentally tested, 16 latency reversing agent (LRA) synergizers and 2 latency promoting agents (LPAs) were confirmed, yielding an overall experimental hit rate of 15.9%. Our work demonstrates that in silico drug screening modalities, guided by existing large-scale experimental datasets, can yield high experimental hit rates, reducing costs incurred from labor-intensive wet lab-focused methodologies.

biochemistry↗

bioRxiv2026

Serial Thermal Ablation Induces Abscopal Antitumor Immunity and Reveals Targetable CSF1R-Dependent Resistance in Pancreatic Cancer

Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined. Using a bilateral LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) flank tumor model, we show serial radiofrequency ablation (RFA) enhances local tumor control and induces a robust abscopal response. This effect was associated with increased activation of CD8 T cells and natural killer cells, and was abrogated by CD8 T cell depletion. Single-cell RNA sequencing revealed expansion of cytotoxic immune programs alongside induction of a CSF1R-driven myeloid response consistent with adaptive immune resistance. Although combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1R-dependent myeloid resistance program which constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC. STATEMENT OF TRANSLATIONAL RELEVANCERadiofrequency ablation is a local thermal therapy that induces tumor destruction and modulation of the tumor microenvironment used for treatment of many solid tumors, including pancreatic cancer. Serial thermal ablations induce a CD8+ T cells and NK cell antitumor immunological response; however, Nt5e (CD73) is increased in tumor cells, PD-1 is increased in CD8+ T cells, and serial ablations increase a CSF1R+ macrophage cluster in ablated tumors. Combinational targeting of CD73, PD-L1, and CSF1R alleviates CSF1R-dependent therapeutic resistance and enhances local and systemic tumor control. This study identifies targetable countervailing mechanisms to local ablation therapy and provides a rationale for combinatorial strategies integrating serial tumor ablation with systemic immunomodulatory agents. Future prospective studies should evaluate the influence of timing, dosage, and sequence of ablation on immune priming to improve clinical interventions in pancreatic cancer.

cancer biology↗

bioRxiv2026

Low levels of metabolic auxotrophy among environmental Pseudomonas isolates

Auxotrophy, the inability of bacteria to synthesize one or multiple essential metabolites (e.g. amino acids, vitamins, metabolites) is thought to be common among bacteria. However, studies often rely either on bioinformatic tools to predict auxotrophies from genome data or on experiments with low numbers of strains. Here, we combine experimental and bioinformatic approaches to assess amino acid auxotrophy levels among 315 co-isolated natural Pseudomonas strains from pond and soil habitats. Both approaches revealed that Pseudomonas isolates are predominantly prototrophs. We identified one single histidine auxotroph and five non-specific auxotrophs featuring complex growth phenotypes incompatible with single amino acid auxotrophies. While different bioinformatic pipelines vary in the extent to which auxotrophy is over- or underestimated, none of the pipelines could resolve the basis of non-specific auxotrophies. Our analysis further revealed the existence of multiple alternative biosynthesis pathways for methionine, proline, and phenylalanine, with significant enrichments of specific pathways among soil or pond strains. We conclude that combining experiments with bioinformatics is a powerful approach to assess the metabolic potential of environmental bacteria. Moreover, taxa like Pseudomonas can be predominantly prototrophic possibly owing to their generalist lifestyle, thus calling for nuanced ecological concepts predicting auxotrophy levels based on lifestyle and habitat.

microbiology↗

bioRxiv2025

Thermal shifts can override the effects of Transcription-targeting Antibiotics

Bacteria traverse diverse stresses but rarely experience them in isolation. Thermal fluctuations and antibiotic exposure often coincide. Yet, how cells transduce these concurrent cues into gene regulatory programs remains unresolved. Here, we show that in Escherichia coli, cold and heat shocks exert dominance over antibiotic stresses across multiple levels of bacterial physiology. First, combined exposure to antibiotics and thermal shifts produced transcriptomes that consistently converged to temperature-defined transcriptomic states. This dominance emerges through the effects of thermal shifts on metabolism, nucleoid organization, engagement of antibiotic targets with DNA, over-expression of global transcription regulators, drug-target conformational plasticity, and regulatory induction of efflux pathways during combined exposure. Finally, cross-species simulations and phylogenetic analysis revealed that thermal disruption of antibiotic efficiency is conserved across evolutionary distant bacterial species. Together, these results identify temperature as a critical determinant of antibiotic efficacy.

microbiology↗

bioRxiv2025

Vascular Patterning affects Intramembranous Ossification through HIF1α-Vegf Signaling

Organs and tissues develop in close association with vasculature which transports blood and nutrients and helps to remove waste. The vasculature is composed primarily of endothelial cells, which provide structure, form barriers, and are a source of developmental signals. We recently found that the Mediator, a multiprotein complex, which regulates transcription, was essential for proper vascular development. Here, we investigated the specific role of the Mediator tail subunit Med23 in endothelial cells. Endothelial cell-specific knockout of Med23 in mouse embryos using Tek-Cre results in vascular anomalies, including edema, hemorrhage, and mispatterned vasculature, alongside craniofacial defects such as micrognathia and cleft palate. Spatial transcriptomics revealed downregulated expression of key vascular and osteogenic genes in Med23 mutants, including Vegfr1 and Col1a1, with altered signaling dynamics between endothelial and osteoblast populations. Elevated HIF1 expression and reduced VEGF signaling were observed in Med23 mutants, suggesting a hypoxia-driven suppression of neural crest cell derived osteoblast maturation. Consistent with this model, pharmacological inhibition of HIF1, combined with VEGFA supplementation, rescued craniofacial ossification and extended embryonic viability. These findings reveal a critical role for Med23 in coordinating vascular patterning and intramembranous ossification and highlight distinct hypoxic and angiogenic requirements in craniofacial dermal bone versus axial and appendicular endochondral bone development. Thus, the cranial vasculature and more specifically endothelial cells, play an instructive role in neural crest cell and osteogenic differentiation during cranioskeletal development.

developmental biology↗

bioRxiv2025

Explainable AI-Driven Diagnosis Model for Early Glaucoma Detection Using Grey-Wolf Optimized Extreme Learning Machine Approach

Glaucoma is a prominent threat to vision and ranks as the third leading cause of blindness in India. Early detection is crucial to limit its progression. Retinal image analysis, particularly computer-aided diagnosis (CAD), has gained significant attention due to its potential in effectively screening for and managing glaucoma. Nowadays, Artificial intelligence (AI) has achieved significant progress has been made in medical image analysis across various applications. However, the main challenge hindering the widespread adoption of deep neural models in clinical settings is their lack of interpretability. In response to this need, we propose an enhanced CAD model with four key components: image pre-processing, feature extraction, feature dimensionality reduction, and classification. Utilizing the G1020 and ORIGA datasets, we employ a fast discrete curvelet transform with wrapping (FDCT-WRP) for curve-like feature extraction. A combined feature reduction technique, principal component analysis (PCA) and linear discriminant analysis (LDA), is applied to generate relevant features and reduce the feature dimensionality. Incorporating an improved grey wolf Optimization (IMGWO) with an Extreme Learning Machine (ELM) for classification. Then, IMGWO optimizes parameters, enhancing the efficiency of single-hidden-layer feedforward neural networks. Through a 10 x 5-fold stratified cross-validation (SCV) test on standard datasets, our CAD model demonstrates superior performance. The proposed CAD model achieved better classification result i.e., 93.87% and 95.38% on the G1020 and ORIGA datasets respectively. Additionally, we have proposed a framework named as GlaucoXAI (Glaucoma explainable artificial intelligence), which utilizes seven advanced explanation methods to improve the interpretability of deep learning models for medical experts trust. GlaucoXAI has been employed on glaucoma detection using fundus images. GlaucoXAIs adaptable design could aid ophthalmologists and medical professionals in detection of glaucoma. The experimental results demonstrate that the proposed model surpasses other existing models in classification accuracy, while significantly reducing the number of features.

bioengineering↗

bioRxiv2025

Obligate cross-feeding of metabolites is common in soil microbial communities

Many microorganisms are refractory to laboratory cultivation. One possible explanation, known as the great plate count anomaly, is metabolic dependencies among community members. However, systematic studies of these interactions in communities like soil are missing, hindering advances in understanding these ecologically important ecosystems. Here, we address this issue by systematically analysing 6,931 bacterial isolates of 27 soil microbial communities. We find that the growth of up to 50% of all community members depended essentially on supplementation with amino acids, vitamins, or nucleotides. In 73% of cases, supplementation with multiple amino acids was necessary. Genomic analysis of 62 strains revealed that accumulation of insertion sequences and specific gene loss was associated with the observed auxotrophies. Finally, genome-scale metabolic models, computational analyses, and cocultivation experiments demonstrated that other co-occurring genotypes complemented the metabolic needs of auxotrophs, thus facilitating their growth. Our results demonstrate that soil bacteria exist within integrated metabolic networks, which hampers their cultivation.

microbiology↗

bioRxiv2025

Endothelial Sphingosine-1-Phosphate Receptor (S1PR) 1, a Functional S1PR in the Human Cerebrovascular Endothelium, Limits Blood Brain Barrier Permeability and Neuronal Injury following Subarachnoid Hemorrhage in Mice.

Hypoxia-induced blood-brain barrier (BBB) permeability has been identified as a key contributor to the progression of ischemic-hypoxic brain injury and neuronal dysfunction in stroke and other cerebrovascular diseases. Emerging clinical evidence highlights that the vasoprotective signaling properties of high-density lipoprotein (HDL), mediated through its bioactive lipid component sphingosine-1-phosphate (S1P), may be impaired in cardiovascular and inflammatory conditions. Nonetheless, the precise contributions and mechanistic roles of S1P signaling within the cerebral microvasculature remain insufficiently characterized. In this study, we aimed to elucidate the role of S1P signaling via its endothelial receptor S1PR1 in the pathophysiology of early brain injury following subarachnoid hemorrhage (SAH), a particularly severe form of stroke. Additionally, we sought to evaluate the relevance of the endothelial S1PR1 pathway in the human cerebrovascular endothelium, its functional role in hypoxia-induced cerebral endothelial barrier dysfunction, and its underlying molecular mechanisms. To address these objectives, we utilized endothelial-specific S1PR1 knockout mice subjected to the endovascular rupture model of aneurysmal SAH, performed mechanistic studies in primary human cerebral microvascular endothelial cells, and characterized S1PR1 expression in human brain tissue using validated protocols. Our findings reveal robust expression of S1PR1 in the cerebrovascular endothelium of both mice and humans. Functional analyses demonstrated that S1PR1 is critical for maintaining BBB integrity and mitigating neuronal injury in the context of SAH. Mechanistic in vitro studies indicated that S1PR1 exerts a vasoprotective effect by limiting hypoxia-induced BBB dysfunction in human primary brain microvascular endothelial cells through inhibition of Rho-associated kinase (ROCK)-mediated phosphorylation of myosin light chain (MLC), suppression of stress fiber formation and caveolin-1-dependent endosomal trafficking. These results highlight the pivotal role of endothelial S1PR1 signaling in preserving cerebral vascular integrity and provide a strong scientific foundation for developing novel therapeutic approaches targeting the S1P pathway in the endothelium to enhance neurovascular protection.

neuroscience↗

bioRxiv2024

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by MAP3K13) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified MAP3K13. A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules. Inhibition of LZK catalytic activity suppressed tumor growth in HNSCC PDX models with amplified MAP3K13. We found that the kinase activity of LZK stabilized c-MYC and that LZK stabilized gain-of-function (GOF) p53 through a kinase-independent mechanism. Therefore, we designed proteolysis-targeting chimeras (PROTACs) and demonstrate that our lead PROTAC promotes LZK degradation and suppresses expression of GOF p53 and c-MYC leading to impaired viability of HNSCC cell lines. This research provides a strong basis for development of therapeutics targeting LZK in HNSCCs with amplification of the gene. One Sentence SummaryThis study establishes the kinase LZK as a therapeutic target for HNSCC through regulation of c-MYC expression.

cancer biology↗

bioRxiv2024

Molecular and functional alterations in the cerebral microvasculature in an optimized mouse model of sepsis-associated cognitive dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in systemic inflammation-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammatory response. In the acute phase, we identified novel molecular (e.g. upregulation of plasmalemma vesicle associated protein, a driver of endothelial permeability, and the pro-coagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small molecule BBB permeability, elevated levels of PAI-1, intra/perivascular fibrin/fibrinogen deposition and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor suggesting diffuse axonal injury, synapse degeneration and impaired neurotrophism. Our study serves as a standardized model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition. SIGNIFICANCEThe limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.

neuroscience↗

bioRxiv2023

Transcription attenuation in synthetic promoters in tandem formation

Closely spaced promoters are ubiquitous in prokaryotic and eukaryotic genomes. How their structure and dynamics relate remains unclear, particularly for tandem formations. To study their transcriptional interference, we engineered two pairs and one trio of synthetic promoters in non-overlapping, tandem formation, in single-copy plasmids. From in vivo measurements in E. coli cells, we found that promoters in tandem formation have attenuated transcription rates. The attenuation strength can be widely fine-tuned by the promoters positioning, natural regulatory mechanisms, and other factors, including the antibiotic rifampicin, which hampers RNAP promoter escape. From this, and supported by in silico models, we concluded that the attenuation emerges from premature terminations generated by collisions between RNAPs elongating from upstream promoters and RNAPs occupying downstream promoters. Moreover, we found that these collisions can cause one or both RNAPs to fall-off. The broad spectrum of possible, externally regulated, attenuation strengths in synthetic tandem promoters should make these structures valuable internal regulators of future synthetic circuits.

synthetic biology↗

bioRxiv2023

A library of reporters of the global regulators of gene expression of Escherichia coli

The topology of the transcription factor network (TFN) of E. coli is far from uniform, with 22 global regulator (GR) proteins controlling one-third of all genes. So far, their production rates cannot be tracked by comparable fluorescent proteins. We developed a library of fluorescent reporters for 16 GRs for this purpose. Each consists of a single-copy plasmid coding for GFP fused to the full-length copy of the native promoter. We tracked their activity in exponential and stationary growth, as well as under weak and strong stresses. We show that the reporters have high sensitivity and specificity to all stresses tested and detect single-cell variability in transcription rates. Given the influence of GRs on the TFN, we expect that the new library will contribute to dissecting global transcriptional stress-response programs of E. coli. Moreover, the library can be invaluable in bioindustrial applications that tune those programs to, instead of cell growth, favor productivity while reducing energy consumption. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/568972v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@15d7ef4org.highwire.dtl.DTLVardef@139d856org.highwire.dtl.DTLVardef@aa0517org.highwire.dtl.DTLVardef@344a2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2023

Dynamics of bacterial operons during genome-wide stresses

Bacterial gene networks have operons, each coordinating several genes under a primary promoter. Half of the operons in Escherichia coli have been reported to also contain internal promoters. We studied their role during genome-wide stresses targeting key transcription regulators, RNAP and gyrase. Our results suggest that operons responses are influenced by stress-related changes in premature elongation terminations and internal promoters activity. Globally, this causes the responses of genes in the same operon to differ with the distance between them in a wavelike pattern. Meanwhile, premature terminations are affected by positive supercoiling buildup, collisions between elongating and promoter-bound RNAPs, and local regulatory elements. We report similar findings in E. coli under other stresses and in evolutionarily distant bacteria Bacillus subtilis, Corynebacterium glutamicum, and Helicobacter pylori. Our results suggest that the strength, number, and positioning of operons internal promoters might have evolved to compensate for premature terminations, providing distal genes similar response strengths.

systems biology↗

bioRxiv2023

In silico and in vitro characterization of the mycobacterial protein Ku to unravel its role in non-homologous end-joining DNA repair

Non-homologous end-joining DNA repair is essential for the survival and sustenance of M. tuberculosis (Mtb) in the dormant stage of its life cycle. The ability of Mtb to sustain itself in the inactive form has been reported to be the critical factor for its resilience over the years. To unravel one of the salient features of the Mtbs arsenal, we exploited in silico and in vitro tools to characterize the DNA binding properties of mycobacterial protein Ku (mKu) and its role in mycobacterial NHEJ. Here, we report the strong affinity of mKu for linear dsDNA exhibiting positive cooperativity for dsDNAs ({zeta}40bp). Molecular dynamics complemented with in vitro experiments showed that the DNA binding of mKu provides stability to both mKu homodimer and the DNA. Furthermore, mKu end-capping of DNA was seen to protect the DNA termini against nucleolytic degradation by exonuclease. The DNA-mKu association formed higher-order oligomers probably due to the lodgement of two DNA molecules at opposite ends of the mKu homodimer. The ability of mKu to form continuous filament-like structures with DNA indicated its potential role in mycobacterial NHEJ synapsis.

biochemistry↗

bioRxiv2023

Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer's disease

INTRODUCTIONIn this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODSWe inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels. RESULTSWe found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways. DISCUSSIONOxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

neuroscience↗

bioRxiv2023

BiGPICC: a graph-based approach to identifying carcinogenic gene combinations from mutation data

Genome data from cancer patients represents relationships between the presence of a gene mutation and cancer occurrence in a patient. Different types of cancer in human are thought to be caused by combinations of two to nine gene mutations. Identifying these combinations through traditional exhaustive search requires the amount of computation that scales exponentially with the combination size and in most cases is intractable even for cutting-edge supercomputers. We propose a parameter-free heuristic approach that leverages the intrinsic topology of gene-patient mutations to identify carcinogenic combinations. The biological relevance of the identified combinations is measured by using them to predict the presence of tumor in previously unseen samples. The resulting classifiers for 16 cancer types perform on par with exhaustive search results, and score the average of 80.1% sensitivity and 91.6% specificity for the best choice of hit range per cancer type. Our approach is able to find higher-hit carcinogenic combinations targeting which would take years of computations using exhaustive search.

bioinformatics↗