Biology subjects

Sen, S.

Publications and source records attributed to Sen, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Oxidized TRX1 and DPP8/9 stabilize the MIA40-AIFM1 complex during intrinsic apoptosis

Mammalian cells execute diverse death programs with distinct immunological consequences. Mitochondrial outer membrane permeabilization (MOMP) drives typically immunologically silent intrinsic apoptosis by releasing cytochrome c and other proapoptotic proteins into the cytosol. Here, we show that MOMP also engages two established repressors of the pyroptosis-inducing NLRP1 inflammasome, oxidized thioredoxin-1 (oxTRX1) and catalytically active DPP8/9, in a coordinated redox and proteostasis program. Immediately after MOMP, oxTRX1 forms a disulfide with MIA40 Cys4 at the MIA40-AIFM1 interface. Subsequently, DPP8/9 cleave AK2, targeting this competing AIFM1 ligand for degradation. Biochemical reconstitution and cryo-EM reveal that oxTRX1 promotes AIFM1 dimerization and preferentially stabilizes MIA40-AIFM1 over AK2-AIFM1. Thus, redox-dependent complex assembly and selective proteolysis converge to favor MIA40-bound AIFM1 after MOMP. These findings suggest how post-MOMP remodeling could reinforce NLRP1 restraint during apoptosis and how disruption of this program could trigger pyroptosis.

cell biology↗

bioRxiv2026

Certified Design Regions under Parametric Plant Uncertainty with Application to Antithetic Integral Feedback

Kinetic parameters in engineered biomolecular circuits are typically known only within intervals and are not precisely tunable; controller synthesis is therefore naturally posed over sets of gains rather than at a single nominal design. We formulate robust controller tuning under parametric plant uncertainty as a universally quantified set-inversion problem: given a plant-parameter box, compute the controller gains that stabilize every plant in the box. Robust stability is decided by Hurwitz sign conditions, which are bounded over the joint gain-parameter domain using validated range enclosures, yielding machine-checkable certificates of local exponential stability of the deterministic equilibrium. Numerical experiments show that the certified region depends strongly on the range enclosure. For an antithetic integral feedback (AIF) controller acting on a two-species gene-expression cascade, a tensor-product Bernstein enclosure certifies 83.2% of the design plane at bisection tolerance epsilon=0.05 with 324 terminal boxes, whereas four baseline enclosures certify between 50.9% and 58.9% on the same paving. For a fifth-order loop, the certified fraction increases from 34.4% to 73.8%, and the certified and excluded terminal boxes confine the robustly stabilizing area to a window of about 2.1 percentage points. Finally, for a refining variant of the algorithm in which the plant box is refined alongside the design box, the undecided area satisfies |U(epsilon)|=O(epsilon) under a non-degeneracy assumption on the stability boundary.

synthetic biology↗

bioRxiv2026

Boron-induced microbial filtering delays early rhizosphere establishment in agricultural soil

Excessive application of boron-based fertilizers in agriculture has led to increased boron accumulation in soil, adversely affecting microbial communities and plant species, ultimately contributing to boron-induced desertification. This study presents the first metagenome-based analysis of boron-contaminated agricultural soil in Northern West Bengal, India, providing a comprehensive profile of the soil microbiome under boron stress. Boron-amended and unamended agricultural soil samples were analyzed using metagenomics sequencing approach over 365 days under natural environmental conditions. The results revealed a significant decline in bacterial diversity in boron-amended soil, with Firmicutes emerging as the dominant phylum. Notably, all boron-tolerant bacterial strains belonged to Firmicutes, suggesting that high boron levels impose selective pressure favouring Gram-positive bacteria. The enrichment of metal-resistant and oligotrophic bacterial taxa in boron-amended soil underscores microbial adaptation to boron stress. In addition to microbial community dynamics, we investigated plant succession in boron-enriched soil, offering novel insights into the interplay between above- and below-ground ecosystems. Our findings highlight two key adaptive traits, high boron tolerance and oligotrophic survival strategies, that enable bacterial communities to persist in boron-rich environments. These results enhance our understanding of microbial resilience in chemically stressed soils and have implications for soil health and sustainable agriculture.

microbiology↗

bioRxiv2026

A Structural Design Principle for Temperature Robustness in Biomolecular Circuits

The dominant paradigm for temperature robustness in biomolecular circuits is for the parameters to be tuned to have matching temperature dependencies so that their overall effect cancels out. This contrasts with the robustness due to circuit structure, typically operative in circuits where robustness to a single input parameter is desired. The importance of the circuit structure in temperature robustness is generally unclear. We addressed this issue in a benchmark negative feedback circuit using a combination of theoretical modelling and experimental measurements. We found that the response to a temperature perturbation in a model of negative feedback was qualitatively different from the response in a model without feedback. We experimentally measured the response of the negative feedback circuit to a temperature perturbation and found that it was smaller than that of the circuit without feedback, in line with the theoretical finding. We confirmed this theoretical prediction experimentally. The initial response of the negative feedback circuit, paradoxically, was larger than the circuit without feedback. The resolution of this paradox was in accounting for the faster dynamics in the negative feedback circuit. These results show a simple design principle of temperature robustness that can operate in a widespread circuit motif and may also apply to other perturbations which, like temperature, affect multiple parameters simultaneously.

systems biology↗

bioRxiv2026

Using Shared Features Improves Metabolite Effect Estimation

External biological knowledge provides valuable information about relationships among metabolites, yet this information is usually not incorporated directly into statistical estimation procedures. Most existing approaches estimate metabolite effects independently, ignoring known biochemical structure such as shared subclasses and pathway membership. We propose a Bayesian hierarchical framework that improves metabolite effect estimates by incorporating external biological information describing relationships among metabolites. The proposed method improves metabolite-specific estimates by allowing related metabolites to borrow information from one another while preserving metabolite-level inference. We evaluate the methodology using simulation studies across a range of sample sizes and heterogeneity regimes together with three metabolomics applications involving distinct biological annotation structures. Across both simulated and real datasets, incorporating external biological information consistently improves metabolite effect estimation. Gains are most pronounced when sample sizes are small and metabolite classes are informative, i.e. more homogenous within classes.

bioinformatics↗

bioRxiv2026

Convergent genomic variation and wild-type composite RNA-seq profiling identify candidate modules associated with 3-nitropropionic acid utilization in Leclercia barmai

3-Nitropropionic acid (3-NPA) is a toxic nitroaliphatic compound, but the genomic basis of bacterial adaptation to 3-NPA remains incompletely resolved, especially in organisms lacking a canonical nitronate monooxygenase. Here, we used phenotype screening, whole-genome resequencing, targeted UHPLC-MS/MRM, and composite RNA-seq profiling to investigate 3-NPA utilization in Leclercia barmai EMC7. Following attempted Tn5-Mob mutagenesis and kanamycin-based recovery, two independently derived mutants, LTM01 and LTM14, showed impaired growth under 3-NPA-dependent minimal conditions. No stable transposon insertion was detected in either mutant. Comparative genome analysis instead revealed convergent loss-of-function (LOF) mutations affecting amino acid metabolism, nitrogen allocation, central carbon metabolism, cofactor-linked functions, transport, and metal-redox homeostasis, while the predicted flavin-dependent nitro-redox candidate and canonical nitrate/nitrite reduction loci were not disrupted. Targeted UHPLC-MS/MRM analysis showed that wild-type EMC7 depleted approximately 50% of 3-NPA within 36 h, whereas the mutants displayed poor 3- NPA-utilization phenotypes under the same growth framework. Wild-type RNA-seq under glucose-3NPA relative to glucose-KNO3 identified a broad expression profile involving flavin-redox functions, nitrogen assimilation, oxidative-stress response, envelope stress, efflux, cofactor metabolism, and iron homeostasis. Integration of mutant LOF profiles with wild-type gene expression data showed that several disrupted genes or functional counterparts belonged to modules showing expression changes during the wild-type glucose-3NPA response. These findings identify candidate adaptive modules associated with 3-NPA utilization in EMC7, including nitrogen redistribution, carbon entry, sulfur-redox support, cofactor supply, transport, envelope remodeling, and metal-redox control. These results extend the landscape of metabolic adaptation beyond canonical pathways in environmental bacteria.

microbiology↗

bioRxiv2026

Glycocalyx-Directed Enzymatic Hydrogels Unlocks Fibroblast Regeneration to Promote Diabetic Wound Healing

Chronic diabetic wounds remain a major clinical challenge because current therapies address infection or supplement growth factors without correcting the cellular dysfunction that prevents regeneration. We identify pathological glycocalyx thickening in diabetic dermal fibroblasts (DDFs) as a driver of elevated caspase 3, 8, and 9 expression and heightened apoptosis -- deficits that stall wound repair. Cleavage of sialic acid residues by neuraminidase (NMase) reverses this dysfunction, restoring fibroblast migration, proliferation, and contractility. We engineer a photo-crosslinked hybrid hydrogel combining methacrylated gelatin (GelMA) with high-molecular-weight methacrylated chitosan (HMW ChMA). ChMA increases storage modulus 8-12-fold, reduces pore size, and confers antibacterial activity against gram-positive and gram-negative bacteria, addressing infection susceptibility. The fortified HMW hybrid (HMWH) network enables sustained, localized NMase delivery that outperforms GelMA alone in resisting degradation and controlling release kinetics. NMase-loaded HMWH (N-HMWH) gels enhance DDF proliferation and migration in vitro, correlating with reduced focal adhesion size and increased turnover. In a diabetic rat model, N-HMWH patches achieve superior wound closure, outperforming EGF therapy, with robust epidermal regeneration, neovascularization, and collagen deposition. This work establishes glycocalyx-targeting hydrogels as a new class of wound therapeutics addressing the root cause of diabetic fibroblast failure, not just compensating with growth factors.

bioengineering↗

bioRxiv2026

Lipid Droplets Direct Amyloid Assembly and β-Cell Stress through Interfacial Control of Amylin Aggregation

Islet amyloid polypeptide (IAPP, amylin) aggregation is a central pathological feature of type 2 diabetes, yet the cellular factors governing its conformational conversion remain incompletely understood. Here, we identify lipid droplets (LDs) as active modulators of amylin structure, aggregation, and {beta}-cell stress. Using artificial and native LDs, we show that amylin binds LD surfaces with high affinity and undergoes accelerated conversion into {beta}-sheet-rich conformations. LDs promote rapid nucleation while constraining fibril elongation, yielding shorter and morphologically distinct amyloid assemblies. Residue-resolved NMR mapping reveals a conserved N-terminal interaction interface, which is amplified upon removal of LD surface proteins, indicating that the LD proteome modulates peptide engagement and aggregation pathways. In {beta}-cells, lipid loading drives intracellular colocalization of amylin with LDs and reshapes transcriptional stress responses, attenuating ER stress and apoptosis while altering markers of {beta}-cell identity. Finally, systemic lipidomic profiling reveals coordinated remodeling of neutral lipid species across dysglycaemic states, linking intracellular LD dynamics with whole-body lipid metabolism. Together, our findings establish lipid droplets as dynamic scaffolds that reshape amylin aggregation pathways and associated {beta}-cell stress responses, providing a mechanistic bridge between lipid dysregulation and islet amyloidosis in diabetes. Significance StatementLipid droplets accumulate in pancreatic {beta}-cells during metabolic stress, yet their role in amylin aggregation remains unclear. Using structural, biophysical, and cellular approaches, we show that lipid droplet interfaces directly bind human amylin, reshape its aggregation pathway, and alter fibril morphology. Native lipid droplets and their associated surface proteins further modulate aggregation kinetics and peptide conformations. In {beta}-cells, lipid loading enhances amylin colocalization with lipid droplets and modifies stress and survival responses. Complementary lipidomic profiling reveals systemic remodeling of neutral lipid species across dysglycaemic states. These findings identify lipid droplets as active regulators of amyloid-associated proteostasis, linking lipid dysregulation to {beta}-cell dysfunction in type 2 diabetes.

Cell Biology↗

bioRxiv2026

Certified Steady-State Parameter-Interval Design for Uncertain Biomolecular Models using a Global Shaving Contractor

The design of parameter intervals that provably enforce steady-state specifications in biomolecular circuits is challenging due to nonlinear reaction kinetics, parametric uncertainty, and the under-determined nature of steady-state constraints. Most validated approaches either rely on recursive subdivision (set inversion) or may stall due to dependency effects when applied directly in parameter space, limiting scalability in moderate to high dimensions. This paper introduces a global shaving contractor that contracts an initial parameter box by repeatedly applying certified interval-exclusion tests against a prescribed steady-state set. The proposed procedure returns a guaranteed outer enclosure of the feasible parameter set and provides finite-termination guarantees, along with worst-case bounds on the number of inclusion-function evaluations. Case studies spanning low-dimensional motifs and a sixteen-parameter integral-feedback model, including bistability specifications for a CRISPRi toggle switch, demonstrate substantial contraction of design domains without subdivision. The resulting certificates support uncertainty-aware circuit tuning, rigorous parameter screening, and robust design workflows in systems & synthetic biology and related nonlinear dynamical-system design problems.

synthetic biology↗

bioRxiv2026

Structure-Property-Performance Engineering of Hydrogel Depots for Long-Acting Peptide Delivery

Controlled release systems for subcutaneous peptide delivery often exhibit a pronounced initial burst release followed by inadequate maintenance of therapeutic exposure, limiting depot lifetime and increasing pharmacokinetic variability. Here, we engineer a dynamic, injectable hydrogel depot technology for months-long delivery of lipidated peptides. Using semaglutide as a model, we establish a modular formulation framework integrating: (i) formulation-driven tuning of depot mechanics to control release kinetics, (ii) cargo complexation strategies leveraging hydrophobic and multivalent ion-mediated interactions, and (iii) oxidative stabilization through sacrificial antioxidant excipients. We evaluated depot performance by rheology, in vitro cargo release, and in vivo pharmacokinetic and pharmacodynamic studies in rodents. Optimized formulations sustained semaglutide exposure for over six weeks from a single administration with two-fold reduction in peak-to-trough exposure and comparable total bioavailability relative to daily dosing, resulting in improved glucose control, weight regulation, and preservation of pancreatic islet content. These results suggest potential for quarterly dosing in humans. Together, this work establishes integrated and generalizable structure-property-performance relationships that account for cargo-matrix and cargo-excipient interactions across burst, diffusion, and erosion regimes to inform a practical formulation framework for engineering long-acting depots for sustained peptide delivery.

bioengineering↗

bioRxiv2026

Altered chromatin accessibility and nucleosome positioning landscape upon HDAC and LSD1 inhibition in cancer cell

Epigenetic enzymes, writers, readers and erasers regulate chromatin landscapes and participate in tumor heterogeneity. While therapeutic targeting of these enzymes has shown clinical promise, the comparative efficacy of mono-versus dual-inhibitor strategies remain unclear. Here, we introduce a multi-modal platform that uses NicE-viewSeq and integrates automated deep learning based spatially resolved chromatin accessibility profiling with high-throughput sequencing following epigenetic inhibitor application. Accessible chromatin landscapes were altered along with nucleosome positioning following inhibition of either LSD1 or HDACs alone, or both together. Coordinated modulation of histone marks and the CoREST complex on chromatin was observed across inhibitory conditions. Transcription factor binding analysis identified three predominant families, ETS, RUNT, and bZIP with enhanced chromatin association upon treatments. Mechanistically, a CoREST-RUNX regulatory axis was uncovered wherein JunB, a member of bZIP family displaces CoREST-RUNX at differentially accessible regions, triggering apoptotic pathways. Therefore, JunB-mediated mechanism reveals a convergent therapeutic vulnerability, offering new avenues for optimizing different combinatorial epigenetic therapy in cancer.

genetics↗

bioRxiv2026

Existence and Localization of a Limit Cycle in a Class of Benchmark Biomolecular Oscillators

Oscillatory behaviour is important in multiple biological contexts. However, the inherent nonlinearity and high dimensionality of mathematical models in biology makes proving the existence and the localization of limit cycle oscillations challenging. Here, we provided an elementary proof for the existence and a method for rigorously localizing the oscillatory solutions in a class of benchmark biomolecular oscillators. To construct the proof, we used a geometric approach based on Brouwers Fixed Point theorem. We constructed a toroidal-like manifold within a positively invariant set by removing the hypervolume containing the fixed point and the trajectories converging to it along its stable manifold. We showed that the vector field describing the system dynamics maps a cross section of the toroidal-like manifold onto itself. The existence of a limit cycle solution in this manifold was guaranteed by Brouwers Fixed Point theorem. For different sets of initial conditions in these cross-sections, we used an interval-based Reachability Analysis to localize the oscillatory behaviour that complements the Brouwers Fixed Point theorem approach. These results add a simple and elegant approach to demonstrating the existence of limit cycles in biomolecular systems as well as a method for rigorous localization of the region of existence.

synthetic biology↗

bioRxiv2026

Identification of small-molecule adjuvants that enhance the sensitivity of Escherichia coli to nitrofurantoin: Roles of Lon and MarA

The increasing cases of resistance among UTI pathogens pose a significant threat to the continued clinical use of nitrofurantoin. In this study, we explored the molecular mechanisms underlying nitrofurantoin resistance and investigated the potential of synergistic activity of salicylates in enhancing the antibacterial activity of nitrofurantoin. In our initial observation, deletion of lon ({Delta}lon) conferred enhanced susceptibility to nitrofurantoin. We identified the critical role of Lon protease in regulating the sensitivity to nitrofurantoin. Investigation into the mechanisms revealed that the lon deletion strains show a higher level of marA and nfsA, which is likely to facilitate the conversion of nitrofurantoin from its pro form to its active form. The {Delta}lon strains displayed an elevated level of ROS, membrane alteration and filamentation upon treatment with nitrofurantoin. Higher ROS levels and membrane alteration were reversed upon treatment with glutathione, further confirming the role of oxidative stress in mediating the sensitivity to nitrofurantoin. Building on these mechanistic insights, we tested salicylates to synergistically enhance the efficacy of nitrofurantoin by indirectly inducing marA through the repression of the mar operon, thereby enhancing nfsA transcription. Both sodium salicylate and acetyl salicylate enhanced the efficacy of nitrofurantoin and lowered the dose of nitrofurantoin required to inhibit the growth of the WT strain. Importantly, this synergistic effect with acetyl salicylate was also observed in nitrofurantoin-resistant clinical isolates, where the combination reduced the effective nitrofurantoin concentration required for growth inhibition. This work provides novel insights into the roles of transcriptional regulators and proteolysis in antibiotic susceptibility, advancing the notion that antibiotic adjuvants are a reliable means of reviving the efficacy of antibiotics. ImportanceThis study unravels the uncharacterised role of Lon protease in nitrofurantoin susceptibility and illustrates the enhanced efficacy of nitrofurantoin-salicylate combinations as a promising therapeutic strategy to overcome emerging resistance in UTI pathogens. This study highlights the importance of investigating the repurposing of other FDA-approved molecules to combat resistance.

microbiology↗

bioRxiv2026

A PIWI protein-dependent DNA N6-adenine methylation pathway in Oxytricha protects genomic sequences from deletion

The ciliate Oxytricha undergoes massive genome rearrangements during development to produce a functional nucleus from an encrypted zygotic genome. PIWI-interacting small RNAs protect DNA regions against deletion, but how that protective mark is established has been a mystery. Recently our lab discovered MTA1, a methyltransferase that catalyzes DNA N6-adenine (6mA) methylation. Both MTA1 and the Oxytricha Piwi protein, Otiwi1, are required for development, and Otiwi1 mutation eliminates 6mA signal. To examine the role of 6mA, we analyzed its genome-wide distribution across development in wild-type and MTA1 mutant backcrossed cells. We find specific and abundant enrichment on retained sequences, suggesting a protective role for this epigenetic mark. Furthermore, programmed retention of a DNA region that is normally deleted leads to accumulation of new 6mA marks on the ectopically retained DNA sequence. Together, these results suggest that piRNA-guided 6mA DNA methylation leads to protection of DNA sequences against deletion during nuclear differentiation. HighlightsO_LIDNA N6-methyladenine accumulates on retained DNA regions during Oxytricha development. C_LIO_LImta1 mutant backcrosses have disrupted DNA methylation and a developmental delay. C_LIO_LIDNA N6-adenine methylation during genome rearrangement requires the presence of Otiwi1. C_LIO_LIProgrammed retention of a germline-limited region leads to developmental methylation. C_LI

molecular biology↗

bioRxiv2025

Developing Anti-EGFR/Anti-HER2 Bifunctional Antibody for Solid Tumors by Protein Engineering

Overexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) is common in solid tumors like breast, colorectal, and head and neck cancers, driving oncogenic signaling, therapy resistance, and poor prognosis. Monotherapies often fall short in fully suppressing tumor progression, particularly in cases with EGFR/HER2 co-amplification. Dual-targeting strategies offer enhanced efficacy by mitigating resistance and amplifying antitumor responses. Our study focused on developing and characterizing a bispecific anti-EGFR/HER2 antibody designed to simultaneously block ligand binding and receptor activation while harnessing Fc-mediated immune effector functions. Utilizing knob-into-hole and CrossMab technologies, we engineered a bispecific antibody capable of binding the extracellular domains of both EGFR and HER2. In vitro analyses confirmed its dual-binding capacity. Comparative studies revealed that this bispecific construct outperformed its monospecific counterparts in suppressing proliferation and, notably, in increasing the expression of apoptotic markers in EGFR/HER2-expressing tumor cells. Together, these findings highlight the synergistic therapeutic potential of bispecific antibodies as a promising modality for overcoming the limitations of current monotherapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/696462v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@192972corg.highwire.dtl.DTLVardef@102f9b2org.highwire.dtl.DTLVardef@57377corg.highwire.dtl.DTLVardef@1fbeb9d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Rigorous Quantitative Analysis of Nonlinear Uncertain Biomolecular Systems using Validated Methods

The paper addresses the critical challenge of accurately characterising steady states in biomolecular systems, which are often complex, nonlinear, multistable and subject to significant uncertainties. Traditional numerical methods often fail to provide complete or guaranteed solutions under these conditions. To overcome these limitations, the research proposes and evaluates the application of interval analysis methodologies. We provided algorithms for interval Newton and interval Krawczyk methods for rigorously bounding all possible steady states (both stable and unstable) in multistable, multidimensional nonlinear systems. This study involves a comparative analysis of these two methods in conjunction with interval bisection and interval constraint propagation. We addressed numerical examples for an array of biologically plausible models, involving both feedback and feedforward gene networks. The work recommends the choice of the most suitable method for various types of biomolecular systems, ultimately offering a robust computational framework to understand cellular functions and design synthetic biological circuits.

synthetic biology↗

bioRxiv2025

CB2 cannabinoid receptor-specific therapeutic antibody agonists for treatment of chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication of cancer treatment. CB2 cannabinoid receptor activation reduces inflammation and is an attractive therapeutic target. Antibodies targeting G protein-coupled receptors (GPCRs), like CB2, offer high specificity and peripheral-restriction, thereby minimizing off-target activity. Here, we investigated the efficacy of first-in-class CB2-specific antibody agonists (AB110 and AB120) and an isotype control (AB100) on mechanical and cold hypersensitivity induced by paclitaxel in both tumor-free and mammary (4T1) tumor-bearing female mice. These CB2 antibody agonists exhibit biased G- signaling and also reduce macrophage markers and pro-inflammatory cytokines in vitro. Paclitaxel produced behavioral hypersensitivities to mechanical and cold stimulation, which were reduced by AB110 and AB120 for approximately 48 hours post-injection in female mice. Repeated daily dosing did not lead to tolerance to the anti-allodynic effects. Prophylactic treatment with AB110 and AB120 during paclitaxel treatment delayed, but did not prevent, the development of paclitaxel-induced behavioral hypersensitivities after termination of dosing with antibody agonists. AB100 had no effect under any conditions. The anti-allodynic effects of AB120 were absent in CB2 knockout mice, confirming pharmacological specificity via CB2 receptors. Furthermore, AB120 remained effective in paclitaxel-treated tumor-bearing mice. Neither AB110 nor AB120 affected locomotor activity in otherwise naive mice. The cytotoxic activity of paclitaxel on 4T1 tumor cell line was maintained in the presence of CB2 antibody agonists in vitro. Overall, our results suggest that CB2-specific antibody agonists are promising candidates for treating CIPN, providing lasting pain relief without tolerance, off target effects or unwanted CB1-mediated motor side effects.

neuroscience↗

bioRxiv2025

SignifiKANTE: Efficient P-value computation for gene regulatory networks

Gene regulatory networks (GRNs) are graph-based representations of regulatory relationships between transcription factors and target genes. Various tools exist to infer GRNs from gene expression data, but since this task is computationally intensive, statistical significance estimates are often omitted. While permutation-based empirical P-value computation methods are relatively straightforward to implement, they are prohibitively expensive when applied to popular regression-based GRN inference methods and realistically sized datasets. To address this bottleneck, we developed SignifiKANTE. SignifiKANTE is based on the key insight that the background count distributions of groups of target genes may be highly similar, even if their expression vectors show distinct behavior. Relying on this insight, SignifiKANTE employs gene clustering based on the 1-Wasserstein distance to create a small, constant number of background distributions which enables the simultaneous computation of approximate empirical P-values for multiple target genes. This reduces runtime by orders of magnitudes (for some datasets, from several weeks to few hours), without compromising faithfulness of the obtained P-values. SignifiKANTE extends the popular GRN inference package Arboreto and is available as a Python package on GitHub (https://github.com/bionetslab/SignifiKANTE) and PyPI (https://pypi.org/project/signifikante/).

bioinformatics↗