Biology subjects

Singh, S.

Publications and source records attributed to Singh, S..

At least 217 records · Page 12Linked to original sources

bioRxiv2024

Impact of Species-Specific Plant Growth-Promoting Rhizobacteria (PGPR) on Maize (Zea mays) Phenotypic and Biochemical Diversity

Maize (Zea mays) is a vital cereal crop used as a staple diet in many countries. In contemporary farming practises, inoculation with plant-growth-promoting rhizobacteria (PGPR) can be promoted as a sustainable alternative to chemical fertilizers and pesticides in cereal crops including maize. For experimental verification of the above-mentioned hypothesis, four PGPR inoculants Pseudomonas fluorescens, P. putida, Azospirillum lipoferum and Bacillus subtilis were applied to three maize genotypes (AXE*, PMH1 and PMH10) and their effects were studied by measurement of various morphological and biochemical paramters. Substantial increase in the amount of chlorophyll a (45%), chlorophyll b (100%), total chlorophyll (95%), nitrate reductase (22%), superoxide dismutase (52%), protein content (16%), methionine content (31.8%), grain protein content (69%) were recorded over the control (non-treated or mock) plants. Morphological parameters also exhibited an increase in leaf number (53%), fresh weight (41%) and dry weight (62%) in test plants. Comparable outcome was observed for whole cob weight showing an increase of 42%, cob weight (60%), hundred-grain weight (25.9%), maize grain yield m-2 (18%) and yield ha-1 (18%) over the control. This study highlights the efficacy of the aforementioned four PGPR species as the most effective for maize crops. Bacillus subtilis and Azospirillum lipoferum may be considered species-specific PGPRs due to their superior performance compared to other strains. The considerable growth-promoting advantages observed in maize plants treated with bacterial inoculation indicated that PGPRs have the potential to be employed as sustainable solutions in maize production.

plant biology↗

bioRxiv2024

The Effects of Bipolar Disorder Granule Cell Hyperexcitability and Lithium Therapy on Pattern Separation in a Computational Model of the Dentate Gyrus

Induced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. These abnormalities are normalised after the application of lithium in neurons derived from lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus (DG). We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into DG networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using linear mixed effects modelling. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results agree with a hypothesised relationship between behavioural mnemonic discrimination and DG PS, as previous research has suggested that mnemonic discrimination improves after lithium therapy in lithium responders only. Our work can be expanded on in the future by simulating the effects of lithium-induced neurogenesis on PS.

neuroscience↗

bioRxiv2024

A versatile information retrieval framework for evaluating profile strength and similarity

In profiling assays, thousands of biological properties are measured across many samples, yielding biological discoveries by capturing the state of a cell population, often at the single-cell level. However, for profiling datasets, it has been challenging to evaluate the phenotypic activity of a sample and the phenotypic consistency among samples, due to profiles high dimensionality, heterogeneous nature, and non-linear properties. Existing methods leave researchers uncertain where to draw boundaries between meaningful biological response and technical noise. Here, we developed a statistical framework that uses the well-established mean average precision (mAP) as a single, data-driven metric to bridge this gap. We validated the mAP framework against established metrics through simulations and real-world data applications, revealing its ability to capture subtle and meaningful biological differences in cell state. Specifically, we used mAP to assess both phenotypic activity for a given perturbation (or a sample) as well as consistency within groups of perturbations (or samples) across diverse high-dimensional datasets. We evaluated the framework on different profile types (image, protein, and mRNA profiles), perturbation types (CRISPR gene editing, gene overexpression, and small molecules), and profile resolutions (single-cell and bulk). Our open-source software allows this framework to be applied to identify interesting biological phenomena and promising therapeutics from large-scale profiling data.

bioinformatics↗

bioRxiv2024

A dynamin-like protein in the human malaria parasite plays an essential role in mitochondrial homeostasis and fission during asexual blood stages

Malaria parasite harbors a single mitochondrion and its proper segregation during the parasite multiplication is crucial for propagation of the parasite within the host. Mitochondrial fission machinery consists of a number of proteins that associate with mitochondrial membrane during segregation. Here, we have identified a dynamin-like protein in P. falciparum, PfDyn2, and deciphered its role in mitochondrial division, segregation and homeostasis. GFP targeting approach combined with high resolution microscopy studies showed that the PfDyn2 associates with mitochondrial membrane to form a clip/hairpin loop like structure around it at specific sites during mitochondrial division. The C-terminal degradation tag mediated inducible knock-down (iKD) of PfDyn2 resulted in significant inhibition of parasite growth. PfDyn2-iKD hindered mitochondrial development and functioning, decreased mtDNA replication, and induced mitochondrial oxidative-stress, ultimately causing parasite death. Further, treatment of parasites with dynamin specific inhibitors disrupted the recruitment of PfDyn2 on the mitochondria, blocked mitochondrial development, and induced oxidative stress. Regulated overexpression of a phosphorylation mutant of PfDyn2 (Ser-612-Ala) had no effect on the recruitment of PfDyn2 on the mitochondria; normal mitochondrial division and parasite growth showed that phosphorylation/dephosphorylation of this conserved serine residue (Ser612) may not be responsible for regulating recruitment of PfDyn2 to the mitochondrion. Overall, we show essential role of PfDyn2 in mitochondrial dynamics and fission as well as in maintaining its homeostasis during asexual cycle of the parasite.

cell biology↗

bioRxiv2024

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

cancer biology↗

bioRxiv2024

Assessment of Antibiotic Resistance Profiles in Cultivable Coliform Organisms Isolated from Ganga River Waters Across the Upper, Middle, and Lower Ganga Stretch

Antibiotic resistance in coliform organisms isolated from the Ganga River waters across its Upper, Middle, and Lower stretches was assessed. The study revealed varying levels of antibiotic resistance among the coliform isolates, with differences observed across the different stretches of the river. In the Upper stretch, sites like Devprayag and Gangotri exhibited high levels of E. coli contamination, with corresponding moderate antibiotic resistance (MAR) values. In the Middle stretch, sites like Farrukhabad and Bithoor showed lower E. coli contamination compared to the Upper stretch but had higher MAR values. The Lower stretch, particularly sites like Revelganj and Bahachoki in Bihar, displayed significantly elevated E. coli contamination levels and MAR values. These findings underscore the presence of antibiotic-resistant coliform organisms in different segments of the Ganga River, emphasizing the need for targeted interventions to mitigate antibiotic resistance spread in this vital water resource. Understanding the antibiotic resistance profiles at specific sites along the Ganga River can inform strategies to preserve water quality and protect public health in regions dependent on this iconic river.

microbiology↗

bioRxiv2024

PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes

Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, in particular gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including Alzheimers disease risk, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.

biochemistry↗

bioRxiv2024

Genome-Wide Identification of G-Quadruplex forming regions in Arabidopsis: Unraveling the Role of Pif like Helicase (AtPLH1) in Gene Regulation and Stress Response

G-quadruplexes (GQSes) are highly stable DNA secondary structures, which exist as knots in the genome during different cellular processes like replication, transcription and translation. Although several studies have shown the role of GQS-helicases regulating several cellular processes in yeast and human, their detailed characterization in plants is still lacking. In this study, we identified GQS-enriched regions by DNA affinity purification followed by sequencing from Arabidopsis Pif-like helicase 1 (Atplh1) mutant. Differentially enriched peaks (DEPs) in the mutant showed preferential distribution in the exonic and promoter regions. The genes involved in various processes like transcriptional regulation, UDP- glucosylation, response to abiotic stress, ethylene biosynthesis and response to carbohydrate stimulus, were found to be differentially regulated between control and mutant plants. The differentially expressed genes (DEGs) showed enrichment of binding sites of ERF, WRKY, BBM and BIM transcription factors. Further, the DEGs harboring DEPs were found associated with response to wounding and salt stress, response to unfolded protein, heat stress response and UDP-glycosyl transferase activity. In addition, the mutants exhibited lesser growth inhibition under cold stress. Overall, our study identified genome-wide GQSes in Arabidopsis and altered gene expression regulated by AtPLH1.

plant biology↗

bioRxiv2024

Overexpression of barley heat stress transcription factor HvHsfA6a provide thermotolerance by thermopriming

Adverse impacts of climate change, including high temperature on cereal crop production, have been evidenced globally. In plants, heat shock factors (HSFs) are crucial components of heat stress associated rescue mechanisms and are also required for normal biological processes. Here, we functionally characterized a highly heat stress responsive HvHSFA6a in barley by developing constitutively overexpressing transgenic lines. These transgenic lines showed heat tolerant phenotype via improved photosynthesis, antioxidants and upregulation of HSPs and metabolites involved in stress amelioration and keeping thermomemory as compared to wild type plants. Global transcriptomics and ChIP sequencing revealed that HvHSFA6a orchestrates the expression of several genes through direct binding with other HSFs containing consensus HSE in their promoter regions. A GC-MS based metabolomics analysis also revealed the alterations in key metabolic processes such as carbohydrate metabolism, citric acid cycle, amino acids and secondary metabolism. Higher accumulation of key metabolites such as sucrose, galactinol, shikimate and ascorbate has been observed under both control and heat stress in transgenic lines as compared to wild type plants. Taken together, the results suggest that overexpression of HvHsfA6a prime the plants for heat stress conditions by alteration in gene expression and metabolic status. HighlightPriming is a mechanism by which plants respond to various abiotic and biotic stresses. Through multi omics approach we found that barley HsfA6a provide thermotolernce in transgenic plants through priming effect on transcriptome and metabolome.

molecular biology↗

bioRxiv2024

Evaluation Of Suitability Analysis of Gangetic Water from Upper, Middle, And Lower Ganga Rivers

This study assesses the suitability of water from distinct segments of the Ganga River in India for drinking, irrigation, and industrial purposes, utilizing various indices. Conducted in MAR-MAY 2023, water samples were collected from multiple sites along the river, and categorized into upper, middle, and lower stretches. The findings revealed differing levels of suitability for various purposes among the sampled sites within each stretch. Parameters for drinking water quality generally adhered to specified limits across all stretches, except for E. coli, emphasizing the importance of disinfection measures. Moreover, the study evaluated irrigation suitability, with most sites falling within the good to excellent range, albeit some exhibiting elevated sodium levels, particularly in the lower stretch. Analysis of major ion abundance revealed an alkaline nature dominated by sodium and potassium ions over calcium and magnesium ions across all stretches. Heavy metal concentrations were either within specified limits or absent, indicating minimal industrial pollution. However, caution is warranted regarding industrial applications due to water aggressiveness, as suggested by indices such as the Langelier saturation index and Ryznar stability index, which hint at potential corrosion issues. Water quality in the Ganga River in India exhibited variability across the upper, middle, and lower stretches, with each segment presenting unique characteristics and suitability levels. Continuous monitoring and control measures, especially concerning the most probable number (MPN) of contaminants, are imperative to ensure the sustainability of water quality and meet the diverse usage needs along the river. The evaluation of Gangetic water from the Upper, Middle, and Lower Ganga Rivers is crucial for understanding water quality in one of Indias vital river basins. This study assesses physical, chemical, and biological parameters to determine suitability for drinking, irrigation, and aquatic life. Factors like pH, dissolved oxygen, turbidity, nutrients, heavy metals, and microbial load are analyzed to reveal water quality and potential risks. Temporal and spatial variations, influenced by natural processes and human activities, are explored. The findings aid in sustainable water management and conservation in the Gangetic basin, addressing the urgent need to safeguard this critical resource.

microbiology↗

bioRxiv2024

Expression of Plasmodium Major Facilitator Superfamily Protein in Transporters-Delta Candida Identifies a Drug Transporter

AimTo assess the functional relevance of a putative Major Facilitator Superfamily (MFS) protein (PF3D7_0210300; "PfMFS_DT") as a drug transporter, using Candida glabrata for orthologous protein expression. MethodsCDS encoding PfMFS_DT was integrated into the genome of genetically engineered C. glabrata strain MSY8 via homologous recombination, followed by assessing its functional relevance as a drug transporter. Results and ConclusionThe modified C. glabrata strain exhibited plasma membrane localization of PfMFS_DT and characteristics of an MFS transporter, conferring resistance to antifungals, ketoconazole and itraconazole. The nanomolar inhibitory effects of the drugs on the intra-erythrocytic growth of P. falciparum highlight their antimalarial properties. This study proposes PfMFS_DT as a drug transporter, expanding the repertoire of the currently known antimalarial "resistome".

cell biology↗

bioRxiv2024

Characterization of a new lacrimal gland cell line in 2D and 3D cell culture models

The lacrimal gland produces the tear films aqueous component, which moistens and nourishes the ocular surface to maintain eye health. Reduced production of this component leads to dry eye disease, which affects over 250 million people worldwide. Despite the impact on patients, the availability of primary human material to study underlying disease mechanisms is severely limited and there is no cell model available for human lacrimal gland epithelial cells. After insertion of an SV40 antigen into primary human lacrimal gland epithelial cells, we selected, expanded, and characterized three epithelial cell clones from a female lacrimal gland donor. We show their epithelial character at genomic (PCR and RNAseq) and protein (immunofluorescence) levels and grow these cells in a 3D cell spheroid model. Here, we report the development of an immortalized human lacrimal gland epithelial cell line that improves accessibility to study the molecular pathogenesis mechanisms of dry eye disease and link them to causal treatments. We show the expression of typical lacrimal gland epithelial cell marker genes (e.g. PAX6, FOXC1, AQP5, CSTB, and CST6) and describe the feasibility of the cells to form 2D cell sheets and 3D cell spheroids. We successfully established immortalized human lacrimal gland cells with epithelial character. In the future, the integration of these cells into larger studies holds great potential for advancing our understanding of dry eye disease and its underlying cellular mechanisms.

cell biology↗

bioRxiv2024

UBA1-CDK16: A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism

RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16, a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.

genomics↗

bioRxiv2024

The ELF3-BBX24/BBX25-PIF4 module controls thermosensory growth in Arabidopsis

Temperature serves as a crucial environmental cue governing the growth and adaptation of plants in their natural habitat. PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is a central regulator that promotes thermomorphogenesis in Arabidopsis. Understanding its precise regulation is critical for optimal thermomorphogenic growth. Here, we identified two BBX proteins, BBX24 and BBX25, as novel components of the PIF4-mediated thermosensory pathway and act to promote warm temperature-mediated growth. The bbx24 and bbx25 single and double mutants showed moderate to strong temperature-insensitive hypocotyl and cotyledon growth. Warm temperature induces BBX24 and BBX25 mRNA expression and protein accumulation. Genetic and biochemical analysis revealed that BBX24/BBX25 promotes PIF4-mediated thermosensory growth by counteracting a key component of the evening complex, ELF3. While ELF3 inhibits BBX24/BBX25 gene expression at low ambient temperatures in the evening, warm temperature-mediated inhibition of ELF3 activity results in enhanced BBX24/BBX25 activity. Moreover, BBX24/25 inhibit ELF3 function through direct physical interaction and likely relieves repression on PIF4, enhancing its activity and thermomorphogenesis. Together, this study unravels ELF3-BBX24/BBX25-PIF4 as a key regulatory module that controls growth and development under varying temperature cues.

plant biology↗

bioRxiv2024

NEKL-4 regulates microtubule stability and mitochondrial health in C. elegans ciliated neurons

Ciliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant in cilia, and its dysregulation may contribute to ciliopathies and neurodegeneration. Mutation of the deglutamylase CCP1 causes infantile-onset neurodegeneration. In C. elegans, ccpp-1 loss causes age-related ciliary degradation that is suppressed by mutation in the conserved NEK10 homolog nekl-4. NEKL-4 is absent from cilia, yet negatively regulates ciliary stability via an unknown, glutamylation-independent mechanism. We show that NEKL-4 was mitochondria-associated. nekl-4 mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressed ccpp-1 mutant lifespan extension in response to oxidative stress. A kinase-dead nekl-4(KD) mutant ectopically localized to ccpp-1 cilia and rescued degenerating microtubule doublet B-tubules. A nondegradable nekl-4(PEST{Delta}) mutant resembled the ccpp-1 mutant with dye filling defects and B-tubule breaks. The nekl-4(PEST{Delta}) Dyf phenotype was suppressed by mutation in the depolymerizing kinesin-8 KLP-13/KIF19A. We conclude that NEKL-4 influences ciliary stability by activating ciliary kinesins and promoting mitochondrial homeostasis. SummaryNeurodegeneration and ciliary degeneration are caused by mutation of the deglutamylase CCP1/CCPP-1 in humans and C. elegans. The conserved NIMA-related kinase NEKL-4/NEK10 can suppress or promote degeneration in an activity-dependent manner that involves cilia-mitochondria communication and that is independent of glutamylation.

cell biology↗

bioRxiv2024

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF- {kappa}B signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the E{micro}-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-{kappa}B signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated E{micro}-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-{kappa}B signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli. STATEMENT OF SIGNIFICANCESpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NF-{kappa}B signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NF-{kappa}B pathway and UPR) highlighting its use in drug-resistant CLL. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/578283v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1dd7a38org.highwire.dtl.DTLVardef@1831c85org.highwire.dtl.DTLVardef@c571f9org.highwire.dtl.DTLVardef@bdce53_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

PPARγ mediated enhanced lipid biogenesis fuels Mycobacterium tuberculosis growth in hepatocytes.

Mycobacterium tuberculosis (Mtb) infection of the lungs, besides producing prolonged cough with mucus, also causes progressive fatigue and cachexia with debilitating loss of muscle mass. While anti-tuberculosis (TB) drug therapy is directed toward eliminating bacilli, the treatment regimen ignores the systemic pathogenic derailments that probably dictate TB-associated mortality and morbidity. Presently, it is not understood whether Mtb spreads to metabolic organs and brings about these impairments. Here we show that Mtb creates a replication-conducive milieu of lipid droplets in hepatocytes by upregulating transcription factor PPAR{gamma} and scavenging lipids from the host cells. In hepatocytes, Mtb shields itself against the common anti-TB drugs by inducing drug-metabolizing enzymes. Infection of the hepatocytes in the in vivo aerosol mice model can be consistently observed post-week 4 along with enhanced expression of PPAR{gamma} and drug-metabolizing enzymes. Moreover, histopathological analysis indeed shows the presence of Mtb in hepatocytes along with granuloma-like structures in human biopsied liver sections. Hepatotropism of Mtb during the chronic infectious cycle results in immuno-metabolic dysregulation that could magnify local and systemic pathogenicity, altering clinical presentations.

microbiology↗

bioRxiv2024

Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, [~]12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo. Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.

cancer biology↗