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Sengupta, S.

Publications and source records attributed to Sengupta, S..

At least 37 records · Page 2Linked to original sources

On the Utility of Virtual Staining for Downstream Applications as it relates to Task Network Capacity

Virtual staining, or in-silico-labeling, has been proposed to computationally generate synthetic fluorescence images from label-free images by use of deep learning-based image-to-image translation networks. In most reported studies, virtually stained images have been assessed only using traditional image quality measures such as structural similarity or signal-to-noise ratio. However, in biomedical imaging, images are typically acquired to facilitate an image-based inference, which we refer to as a downstream biological or clinical task. This study systematically investigates the utility of virtual staining for facilitating clinically relevant downstream tasks (like segmentation or classification) with consideration of the capacity of the deep neural networks employed to perform the tasks. Comprehensive empirical evaluations were conducted using biological datasets, assessing task performance by use of label-free, virtually stained, and ground truth fluorescence images. The results demonstrated that the utility of virtual staining is largely dependent on the ability of the segmentation or classification task network to extract meaningful task-relevant information, which is related to the concept of network capacity. Examples are provided in which virtual staining does not improve, or even degrades, segmentation or classification performance when the capacity of the associated task network is sufficiently large. The results demonstrate that task network capacity should be considered when deciding whether to perform virtual staining.

bioinformatics↗

RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis

Adaptive modulation of physiological traits in response to environmental variability, particularly dietary fluctuations, is essential for organismal fitness. Such adaptability is governed by complex gene-diet interactions, yet the molecular circuits integrating microbe-derived metabolites with host metabolic and stress response pathways remain less explored. Here, we identify the conserved mechanistic target of rapamycin complex 2 (mTORC2) component, RICTOR, as a critical regulator of dietary plasticity in Caenorhabditis elegans, specifically in response to bacterially derived vitamin B12 (B12). Loss of rict-1, the C. elegans ortholog of RICTOR, confers enhanced osmotic stress tolerance and longevity on B12-rich bacterial diets. These phenotypic adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the folate-methionine cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism. The latter catalyzes the formation of succinyl-CoA, subsequently converted to succinate via the tricarboxylic acid (TCA) cycle. Elevated succinate levels were found to induce mitochondrial fragmentation, thereby activating mitophagy, an autophagic process indispensable for the increased stress resilience and longevity observed in the rict-1 mutants. Crucially, this Met-C-mitophagy axis is modulated by microbial inputs, with B12 and methionine acting as proximal dietary signals. Our findings delineate a mechanistic framework through which RICTOR restrains host sensitivity to microbial-derived metabolites, thus maintaining mitochondrial homeostasis and regulating lifespan. This work reveals a pivotal role for RICTOR in insulating host physiology from environmental nutrient-driven perturbations by modulating organellar quality control pathways.

cell biology↗

High-Throughput Tracking of Freely Moving Drosophila Reveals Variations in Aggression and Courtship Behaviors

Aggression is a nearly universal behavior used to secure food, territory, and mates across species, including the fruit fly Drosophila melanogaster. In fruit flies, both sexes display aggression through stereotypical motor patterns. This, along with their sophisticated genetic and molecular toolkit, makes Drosophila melanogaster an excellent model for studying aggression. While male- and female-specific aggressive motor programs have been qualitatively described, automated systems for quantifying these behaviors in freely moving flies remain limited in their ability to combine high-resolution analysis with high throughput. Here, we pair a high-resolution, high-throughput imaging system (the Kestrel) with DeepLabCut pose estimation to create a pipeline that tracks multiple freely moving fly pairs and quantifies social dynamics with high fidelity. We validated body-part tracking using published benchmarks. The platform reliably reproduced a known phenotype: heightened female aggression following thermogenetic activation of cholinergic pC1 neurons in female brain. It also detected increased unilateral wing extension, a courtship display inversely related to aggression, between two males upon activating a previously uncharacterized [~]40-neuron group in the male brain. Pose-based analysis revealed locomotive differences between experimental and control groups, and subtle, genotype-specific variations in head butts and UWEs. This workflow enables high-throughput screening and mechanistic dissection of social behaviors.

neuroscience↗

Multi-agent AI System for High Quality Metadata Curation at Scale

High-quality metadata is essential for downstream AI applications, yet metadata curation remains a persistent bottleneck in biomedical research. The core challenge lies in balancing quality and scalability. Manual curation delivers high quality, reliable annotations but is time-intensive and non-scalable; automated approaches, including those based on natural language processing, can scale but often fall short in accuracy and completeness. This tradeoff is particularly severe in public datasets, where metadata is frequently distributed across multiple sources for a single dataset. A notable example includes multi-omics datasets available on GEO and similar public repositories, which are often accompanied by associated publications. These supplementary sources can be leveraged to substantially enhance metadata quality, thereby supporting downstream applications such as classifier model development or the identification of biologically relevant cohorts, etc. We present a first-in-class multi-agent AI system that bridges the gap, achieving both high quality and scalability in metadata curation. Built on large-language models (LLMs), our system orchestrates a set of specialized agents that collaboratively extract, normalize, and infer critical metadata fields such as tissue, disease, cell line, sampling site, demographics, and experimental context from GEO entries, associated publications. A central orchestrator agent delegates tasks such as data retrieval, document parsing, ontology mapping, and context inference to expert sub-agents, enabling scalable, end-to-end automation. Applied to GEO data sets, a notoriously difficult metadata domain, our system achieves a 93% recall on average across 23 key fields (all original terms, normalized terms, and corresponding ontology ids) that include information about disease, tissue, treatment, donor-related information, outperforming existing automated baselines and approaches expert level quality. We also present a system that can easily scale to curate hundreds of metadata fields of interest with similar precision. This work demonstrates that an LLM-based multi-agent architecture can overcome traditional trade-offs in metadata curation, enabling both precision and scale, and offers a promising path forward for curating large public biomedical repositories for downstream AI applications.

scientific communication and education↗

Integrative plasma lipidomics and proteomics profiling to decipher potential biomarkers of dilated cardiomyopathy

BackgroundDilated cardiomyopathy (DCM), primarily characterised by left ventricular dilatation and systolic dysfunction, is one of the leading causes of heart failure and requires a critical clinical investigative strategy. However, conventional imaging techniques such as echocardiography and MRI, along with some classical CVD markers (NTproBNP, cTnT), fall short in diagnosing DCM-specific phenotypes. Thus, the need for biochemical markers with enhanced accuracy to DCM is of enormous importance. Lipids and proteins play essential roles in maintaining myocardial function. The homeostatic disruption of such biomolecules might contribute to DCM pathogenesis, thus offering to serve as potential biomarkers for DCM. Moreover, the lack of global lipidomics studies and specific protein markers in DCM patients prompted us to explore the disease pathophysiology through an integrative omics-based analysis coupled with an ML-derived approach. ObjectiveTo identify accurate, precise and specific circulatory lipidomic and proteomic biomarkers of DCM using high-resolution mass spectrometry and machine learning (ML)-based approaches. MethodsHigh-resolution-mass-spectrometry-based lipidomics and proteomics were applied to identify lipid and protein biomarkers in a cohort (n=360) of healthy and DCM patients. Top protein classifiers were further evaluated using single-cell transcriptomics on publicly available datasets from DCM myocardium and validated using ELISA. A biomarker panel was built by the integration of lipidomics and validated proteomics data using machine-learning-based approaches. ResultsA total of 125 lipids and 10 proteins have been primarily discovered with significant alterations in DCM (0.8 [&ge;] FC [&ge;] 1.2; padj < 0.05). Using a Boruta-based ML approach, we identified 39 lipids and 10 proteins as primary discriminators between DCM and controls. ELISA validation confirmed the potential of B2M (6.85 {+/-} 2.86 g/ml vs. 4.26 {+/-} 1.25 g/ml; p < 0.0001) and Tetranectin (CLEC3B) (1.99 {+/-} 0.88 g/ml vs. 2.49 {+/-} 0.90 g/ml; p = 0.0006) to emerge as protein biomarkers of DCM. In line with that, the single-cell transcriptomic analysis showed a similar trend of alteration of tetranectin (CLEC3B) in cardiomyocytes and {beta}2microglobulin (B2M) in varied cell types of the myocardium. Further, Integrated ROC analysis combining the top 8 lipid discriminators with B2M and CLEC3B achieved an AUC of 0.995, demonstrating enhanced diagnostic precision compared to the classical CVD marker NTproBNP (0.965). ConclusionThis study offers a system-omics-based perspective on first-global lipidomic and proteomic changes associated with DCM pathophysiology, with a high potential for diagnostic application.

systems biology↗

STUDIES ON INTERACTION OF MORIN WITH CURLI TO IDENTIFY AGGREGATION NATURE

Morin (3,5,7,2',4'-pentahydroxyflavone) is a flavonoid compound exhibited a range of biological functions, including anti-inflammatory, antioxidant, antiviral, and anti-allergic activities. It has the ability to disaggregate amyloid fibrils, making it a potential inhibitor of diseases caused by amyloid protein fibrillation. This study focuses on the interaction between Morin and Curli amyloid fibrils, which are produced by some Enterobacteriaceae, including Salmonella sp. And E. coli, as a major component of their biofilms. The Curli amyloid fibrils can lead to neurodegenerative diseases through a signalling cascade causing various human diseases, such as Alzheimers and Huntingtons diseases. Thioflavin T (ThT) fluorescence assays to purified Curli, and molecular docking between Morin and Curli indicates nature of binding at molecular level. The results showed that Morin quenched Curli fluorescence in a concentration-dependent manner, indicating dynamic quenching. Stern-Volmer analysis revealed that Morin binds to Curli with a binding constant of approximately 102 L/mol. This binding was found to be spontaneous, with hydrophobic interactions playing a significant role. ThT fluorescence assays confirmed that Morin inhibited Curli fibrillation, suggesting a potential therapeutic application. Molecular docking analysis revealed specific interactions between Morin and Curli, providing insights into their binding at the molecular level. In conclusion, this study demonstrates the dynamic quenching of Curli fluorescence by Morin and suggested that Morin may inhibit Curli fibrillation, making it a valuable candidate for the development of therapeutic drugs.

biochemistry↗

A Software for Identification and Characterization of Theta Rhythms in the Hippocampus

Characterizing theta rhythms in the hippocampus provides a window into understanding memory processing. An inquiry that arises when an animal sustains a pathological state is how theta rhythms are affected. In pathological states like epilepsy or Alzheimers, these rhythms change in specific ways. Statistically robust changes in these rhythms could serve as potential biomarkers, indicating the severity of the animals condition and the effectiveness of a drug. However, this understanding depends on how the data is analyzed. There are currently no standard criteria for recognizing theta dominance in experimental recordings. To address this, we have developed novel MATLAB-based software with an easy-to-use graphical user interface which enables identifying and analyzing theta rhythms in a standard way. We discuss the softwares functionality and its underlying algorithms. The algorithms were developed using previously acquired EEG/LFP data recorded from the hippocampus of a mouse kindling model of epilepsy. Two primary analyses were conducted to test the softwares functionality: first, comparing theta rhythms during the baseline period versus during spontaneous recurrent seizures; second, analyzing the timing of theta rhythms relative to the seizure event. Our illustrative results indicate that our developed software can robustly identify theta events with statistically significant feature differences. Further, the examination presented here with two mice shows that while theta events can occur just before seizures, it takes tens of minutes post-seizure before theta rhythms occur again. Our software thus provides the user with the ability to robustly identify and characterize theta rhythms and their feature changes. Significance StatementTheta rhythms in the hippocampus are fundamental for spatial navigation and memory formation. Their observed changes during several pathological states such as epilepsy and Alzheimers make them highly interesting to be able to serve as biomarkers. However, their variability (in terms of the time of occurrence, duration, and frequency range) makes them challenging to quantify. The absence of available tools for the automatic extraction of these rhythms from extended datasets significantly hampers processing efficiency and reduces accuracy and consistency. Clinicians and researchers often manually inspect their data to identify these rhythms, a process that is not only time-consuming but also inherently subjective. We have thus developed a MATLAB software for precise, automatic analysis of theta rhythms in EEG/LFP recordings.

neuroscience↗

Effect of external cues on clock-driven protection from Influenza A infection

Influenza and other respiratory viral pathogens are leading causes of mortality and morbidity. We previously demonstrated that circadian rhythms confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We demonstrate that disrupting environmental lighting cues within a critical window of vulnerability abrogates time-of-day specific protection. This poor outcome is mediated by a dysregulated immune response, evidenced by the accumulation of inflammatory monocytes and CD8+ cells in the lungs and a transcriptomic profile indicative of an exaggerated immune response. Disruption of the light cycle does not affect outcomes in a clock mutant, indicating that it acts by compromising endogenous timekeeping. Importantly, rhythmic meal timing mitigates the adverse effects of disrupted light cycles, suggesting that external cycling cues, which act through different body clocks, can substitute for each other. Our findings highlight the crucial interplay between environmental factors and endogenous clocks in shaping influenza outcomes, offering significant translational potential for improving the care of critically ill patients with respiratory viral infections.

immunology↗

Role of IL10 signaling in the circadian control of host response to Influenza infection

We have previously demonstrated that the circadian clock regulates the host response to influenza A virus (IAV) infection, conferring a time-of-day-specific protection -infection at dawn resulted in a threefold increase in survival and reduced immunopathology compared to infection at dusk. While IL10 is well-known for its immunoregulatory function, its role in IAV remains unclear, with studies reporting both protective and detrimental effects. Given the diurnal rhythmicity of IL-10 receptor (Il10ra) expression in the lung, we investigated the contribution of IL-10 signaling to time-of-day-specific IAV protection. We found that blocking IL10 signaling abrogated the time of day protection, leading to increased immunopathology characterized by enhanced lymphocyte infiltration and global immune activation (transcriptomic analysis). Interestingly, while later, IL-10R blockade also eliminated the time-of-day difference in IAV outcomes, it improved the outcome of dusk-infected mice. Furthermore, natural killer (NK) cell depletion suppressed IL-10 levels in bronchoalveolar lavage, suggesting a role for NK cells in regulating IL-10 signaling. In conclusion, incorporating the circadian context has not only clarified the IL-10 role in IAV infection but also underscored the pivotal influence of circadian regulation on immune responses.

immunology↗

Sources of non-uniform coverage in short-read RNA-Seq data

The origin of several normal cellular functions and related abnormalities can be traced back to RNA splicing. As such, RNA splicing is currently the focus of a vast array of studies. To quantify the transcriptome, short-read RNA-Seq remains the standard assay. The primary technical artifact of RNA-Seq library prep, which severely interferes with analysis, is extreme non-uniformity in coverage across transcripts. This non-uniformity is present in both bulk and single-cell RNA-Seq and is observed even when the sample contains only full-length transcripts. This issue dramatically affects the accuracy of isoform-level quantification of multi-isoform genes. Understanding the sources of this non-uniformity is critical to developing improved protocols and analysis methods. Here, we explore eight potential sources of non-uniformity. We demonstrate that it cannot be explained by one factor alone. We performed targeted experiments to investigate the effect of fragment length, PCR ramp rate, and ribosomal depletion. We assessed existing data sets with varying sample quality, PCR cycle number, reverse transcriptase, and technical or biological replicates. We found evidence that interference of reverse transcription by secondary structure is unlikely to be the major contributing factor, that rRNA pull-down methods do not cause non-uniformity, that PCR ramp rate does not substantially impact non-uniformity, and that shorter fragments do not reduce non-uniformity. All these findings contradict prior publications or recommendations.

bioinformatics↗

Cholesterol deficiency directs autophagy-dependent secretion of extracellular vesicles

Extracellular vesicle (EV) secretion is an important, though not fully understood, intercellular communication process. Lipid metabolism has been shown to regulate EV activity, though the impact of specific lipid classes is unclear. Through analysis of small EVs (sEVs), we observe aberrant increases in sEV release within genetic models of cholesterol biosynthesis disorders, where cellular cholesterol is diminished. Inhibition of cholesterol synthesis at multiple synthetic steps mimics genetic models in terms of cholesterol reduction and sEVs secreted. Further analyses of sEVs from cholesterol-depleted cells revealed structural deficits and altered surface marker expression, though these sEVs were also more easily internalized by recipient cells. Transmission electron microscopy of cells with impaired cholesterol biosynthesis demonstrated multivesicular and multilamellar structures potentially associated with autophagic defects. We further found autophagic vesicles being redirected toward late endosomes at the expense of autophagolysosomes. Through CRISPR-mediated inhibition of autophagosome formation, we mechanistically determined that release of sEVs after cholesterol depletion is autophagy dependent. We conclude that cholesterol imbalance initiates autophagosome-dependent secretion of sEVs, which may have pathological relevance in diseases of cholesterol disequilibrium.

cell biology↗

Breaking Boundaries: New locality records and a reassessment of the conservation status of the Khasi Hill Toad (Bufoides meghalayanus) endemic to Meghalaya, Northeast India

Bufoides meghalayanus is a Critically Endangered toad, endemic to East Khasi Hills, Meghalaya, Northeast India. This endemic toad was presumed to be restricted to just three locations, all within 1-2 km from one another around the type locality in Meghalaya. This article gives the first account of three previously unknown populations, extending the known geographic range of the species significantly. Additionally, we include the newly obtained molecular sequences of B. meghalayanus in a comprehensive molecular phylogeny with a note on its genetic and morphometric variations within these new populations and its congeneric members.

ecology↗

Metabolomic profiling reveals grade-specific niacinamide accumulation and its therapeutic Potential via SIRT1-CD38-EMT axis modulation in cervical cancer progression

Despite the availability of new therapies for cervical cancer, innovative strategies are essential to address challenges related to drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 100 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. The major metabolic alterations included changes in glycolysis, the citric acid cycle, amino acid metabolism, nucleotide metabolism, and nicotinamide metabolism in a grade-dependent manner. Interestingly, metabolic differences between HPV-positive and HPV-negative tumors included elevated arginine and proline metabolism, nicotinamide metabolism, and phosphatidylcholine biosynthesis. We further validated our findings by analyzing transcriptomics datasets from the Gene Expression Omnibus database to understand the expression patterns of the underlying genes involved in the dysregulated pathways. We observed that nicotinamide metabolism exhibits significant effects in lower-grade cervical cancers and specific HPV genotypes. We treated cervical cancer cell lines with niacinamide (NAM), an amide form of niacin, to evaluate its potential therapeutic efficacy. NAM treatment modulated NAD+ metabolism with key players such as CD38, PARP, NAMPT, and SIRT1, promoting apoptosis and inhibiting cell proliferation in cervical cancer cells. Importantly, the metabolic responses differed between the HPV-positive SiHa cells and HPV-negative C33A cells, reflecting distinct NAD+ metabolic adaptations. The study highlights the metabolic adaptation or shifts in cancer progression and provides insights into NAMs molecular mechanisms and therapeutic potential for precision medicine in cervical cancer.

cancer biology↗

Multidimensional variable dose analysis (mVDA) is a novel method for high-throughput mapping of genetic interactions

The mapping of genetic interactions is a powerful tool to determine gene functions, assemble the structures of biological pathways and to identify therapeutic targets for disease. However, while there have been significant advances in the screening techniques used to identify genetic interactions over the past decade, methods that are sufficiently scalable to test genetic interactions on a genome level are still far from our current capabilities. Here, we describe an approach to genetic interaction screening in Drosophila cells that overcomes the scaling issues associated with most other methods. This method, called multidimensional Variable Dose Analysis (mVDA), allows multiple, random genes to be inhibited within each cell of a mixed population and the relative phenotypes caused by each gene or pair of genes to be deconvoluted. This means that reagent library size and cell population size do not scale exponentially with the number of genes to be tested, unlike previous methods. This method therefore has the potential to allow genome wide mapping of genetic interactions in Drosophila cells for the first time.

genetics↗

The effect of surfactants and film-forming polymers on pulmonary surfactant function measured in vitro is dose-rate dependent

Surfactants and film-forming polymers are common ingredients in consumer spray products such as cleaning products, hair care products, and anti-perspirants. Spraying eases application by creating aerosolised droplets of the product that can distribute evenly over the treated surface. However, these aerosols can potentially be inhaled during their normal application. Droplets that reach the alveoli can interact with the pulmonary surfactant; a complex mixture of phospholipids and proteins that regulates the surface tension at the air-liquid interface. This interaction could elevate the minimum surface tension at maximum compression and change the surface rheology of the pulmonary surfactant at the interface. We tested four surfactants and seven polymers for their ability to inhibit pulmonary surfactant function in vitro and investigated if the inhibition is dose-rate dependent i.e., the product of the concentration (mg/mL) and aerosolisation rate (mL/min). We found that independent of chemical class (surfactant or polymer) there was a clear dose-rate dependent inhibition of pulmonary surfactant function and that different chemicals inhibited function at different dose-rates. We compared the points of departure of inhibitory chemicals to a polymer with known dose-rate dependent lung toxicity. When assessing the risk of chemicals that might be inhaled, it is essential to ensure normal use would not inhibit pulmonary surfactant function leading to immediate effects on the lungs. Lay summarySpray products create a cloud of tiny droplets in the air when they are used. This cloud can be inhaled, and if it reaches the deepest parts of the lungs, it can interact with the thin layer of liquid, called pulmonary surfactant, that covers the cells. It protects the lung tissue during the constant movement of breathing. Droplets can sometimes disrupt the pulmonary surfactant function, making breathing difficult. Chemicals that are used in spray products must be tested to assess if they are harmful if inhaled. In this project we studied the effect of chemicals that are commonly found in spray products on the functioning of the pulmonary surfactant in vitro. The results can be combined with other in vitro methods to test if chemicals are harmful to inhale without testing on animals.

biophysics↗

TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transitions in breast tumor cells

Neutrophils have tumor-promoting roles in breast cancer and are detected in higher numbers in aggressive breast tumors. How aggressive breast tumors recruit neutrophils remains undefined. Here, we investigated the roles of TGF-{beta}1 and TNF- in the regulation of neutrophil recruitment by breast cancer cells. TGF-{beta}1 and TNF- are pro-inflammatory factors upregulated in breast tumors and induce epithelial to mesenchymal transitions (EMT), a process linked to cancer cell aggressiveness. We report that, as expected, dual treatment with TGF-{beta}1 and TNF- induces EMT signatures in premalignant M2 cells, which are part of the MCF10A breast cancer progression model. Conditioned media (CM) harvested from M2 cells treated with TGF-{beta}1/TNF- gives rise to amplified neutrophil chemotaxis compared to CM from control M2 cells. This response correlates with higher levels of the neutrophil chemokines CXCL1, CXCL2, and CXCL8 and is significantly attenuated in the presence of a CXCL8-neutralizing antibody. Furthermore, we found that secretion of CXCL1 and CXCL8 from treated M2 cells depends on p38MAPK activity. By combining gene editing, immunological and biochemical approaches, we show that the regulation of neutrophil recruitment and EMT signatures are not mechanistically linked in treated M2 cells. Finally, analysis of publicly available cancer cell line transcriptomic databases revealed a significant correlation between CXCL8 and TGF-{beta}1/TNF--regulated or effector genes in breast cancer. Together, our findings establish a novel role for the TGF-{beta}1/TNF-/p38 MAPK signaling axis in regulating neutrophil recruitment in breast cancer, independent of TGF-{beta}1/TNF- regulated EMT.

cancer biology↗

Evolution of cooperation in multichannel games on multiplex networks

Humans navigate diverse social relationships and concurrently interact across multiple social contexts. An individuals behavior in one context can influence behavior in other contexts. Different payoffs associated with interactions in the different domains have motivated recent studies of the evolution of cooperation through the analysis of multichannel games where each individual is simultaneously engaged in multiple repeated games. However, previous investigations have ignored the potential role of network structure in each domain and the effect of playing against distinct interacting partners in different domains. Multiplex networks provide a useful framework to represent social interactions between the same set of agents across different social contexts. We investigate the role of multiplex network structure and strategy linking in multichannel games on the spread of cooperative behavior in all layers of the multiplex. We find that multiplex structure along with strategy linking enhances the cooperation rate in all layers of the multiplex compared to a well-mixed population, provided the network structure is identical across layers. The effectiveness of strategy linking in enhancing cooperation depends on the degree of similarity of the network structure across the layers and perception errors due to imperfect memory. Higher cooperation rates are achieved when the degree of structural overlap of the different layers is sufficiently large, and the probability of perception error is relatively low. Our work reveals how the social network structure in different layers of a multiplex can affect the spread of cooperation by limiting the ability of individuals to link strategies across different social domains.

animal behavior and cognition↗

Novel miRNA-inducing drugs enable differentiation of retinoic acid-resistant neuroblastoma cells

Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest-derived progenitor cells, poses a significant clinical challenge. In particular, unlike adrenergic (ADRN) neuroblastoma cells, mesenchymal (MES) cells are resistant to chemotherapy and retinoid therapy and thereby significantly contribute to relapses and treatment failures. Previous research suggested that overexpression or activation of miR-124, a neurogenic microRNA with tumor suppressor activity, can induce the differentiation of retinoic acid-resistant neuroblastoma cells. Leveraging our established screen for miRNA-modulatory small molecules, we validated PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, as a robust inducer of miR-124. A combination of PP121 and BDNF-activating bufalin synergistically arrests proliferation, induces differentiation, and maintains the differentiated state of MES SK-N-AS cells for 8 weeks. RNA-seq and deconvolution analyses revealed a collapse of the ADRN core regulatory circuitry (CRC) and the emergence of novel CRCs associated with chromaffin cells and Schwann cell precursors. Using a similar protocol, we differentiated and maintained MES neuroblastoma GI-ME-N and SH-EP cell lines, as well as glioblastoma LN-229 and U-251 cell lines, for over 16 weeks. In conclusion, our novel protocol suggests a promising treatment for therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells provide valuable models for studying mechanisms underlying differentiation, maturation, and senescence.

cancer biology↗