Biology subjects

Choudhury, M.

Publications and source records attributed to Choudhury, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Uncovering a New Role of Dleu2/miR-15a/16-1 Cluster in Insulin Resistance and Obesity

Obesity is a global epidemic characterized by metabolic dysfunction, with white adipose tissue playing a pivotal role in these processes. Noncoding RNAs, such as long non-coding RNAs (lncRNAs) and short non-coding RNAs (e.g., microRNAs), have been identified as an emerging class of regulatory molecules that can influence metabolic function. Here, the Dleu2/miR-15a/16-1 cluster (known as 13q14-Minimal Deleted Region, i.e., MDR), which encodes the lncRNA Dleu2 and miR-15a/16-1, a previously unrecognized player in metabolic function, is shown to contribute to obesity and insulin resistance. Using a combination of phenotypic and molecular approaches, this study establishes that MDR governs metabolic regulation for the first time. In a nutshell, this study identifies a new role of a lncRNA-miRNA cluster, previously implicated exclusively in cancer, in the regulation of obesity, thereby extending its biological significance beyond oncology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/745519v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@424a1borg.highwire.dtl.DTLVardef@f6e3eorg.highwire.dtl.DTLVardef@10ebf0borg.highwire.dtl.DTLVardef@120803c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDeletion of MDR contributes to obesity, insulin resistance, and impaired energy metabolism C_LIO_LILoss of MDR reduces circulating adiponectin levels, indicating metabolic dysfunction C_LIO_LIMDR regulates satiety signaling in visceral adipose tissue and increases serum leptin levels C_LIO_LIMDR modulates several unrecognized new transcriptional regulators in obesity C_LIO_LIFirst evidence to establish the metabolic role of MDR beyond cancer biology C_LI

molecular biology↗

bioRxiv2026

Low-affinity binding motif in microtubule plus-end condensates specializes microtubule function

The microtubule plus-end tracking proteins (+TIPs) CLIP-170/Bik1 and EB/Bim1 form a condensate, the +TIP body, at the plus-end of most microtubules in vivo. Remarkably, however, these +TIP bodies typically impart different dynamics and interaction profiles to distinct microtubules, according to their cellular function. The molecular mechanisms underlying the functional versatility of the +TIP body are unknown. Here, we show that the +TIP Kar9 utilizes repeats of a lysine-aspartate-lysine (KDK)-centered short linear motif (SLiM) to interact with Bik1 on a restricted subset of cytoplasmic microtubules during yeast mitosis. Furthermore, these multivalent Kar9-Bik1 interactions tune the material behavior of the +TIP body to specify proper microtubule function. Indicating that KDK serves as generic Bik1-interaction motif, similar motifs are also present in Kip2, where they mediate Bik1-dependent recruitment of Kip2 to the +TIP body. Together, our study provides insights into how low-affinity Bik1 interactors diversify microtubule function by locally specializing the content and behavior of +TIP bodies.

Cell Biology↗

bioRxiv2026

Targeting the DNA damage repair protein RAD51 alters fibroblast metabolism and enhances apoptosis in pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by aberrantly activated, apoptosis-resistant profibrotic lung (myo)fibroblasts. Prior research has demonstrated that lung fibroblasts from patients with IPF exhibit resistance to DNA damage, suggesting that this behavior contributes to their persistent survival and continuous proliferation. We propose that elevated levels of the DNA damage repair protein RAD51 regulate myofibroblast activation and apoptosis and provide a potential therapeutic target to impede fibrosis progression. MethodsHuman lung fibroblasts were transfected with siRNA against RAD51 or treated with RAD51-specific inhibitor B02 and markers of fibrosis, DNA damage, apoptosis, metabolic reprogramming, and mitochondrial dynamics were assessed. The preclinical efficacy of B02 was evaluated in human precision cut lung slices (PCLS) and in a mouse model of pulmonary fibrosis. FindingsRAD51 expression was significantly upregulated in the lungs and lung fibroblasts of IPF patients. Knockdown or inhibition of RAD51 in fibroblasts reduced profibrotic marker expression, suppressed mTORC1 signaling and mitochondrial function, and increased apoptosis susceptibility. Pharmacological inhibition of RAD51 shifted the profibrotic phenotype towards a fibrosis-resolving state in human and mouse PCLS, and in a bleomycin-induced mouse model of lung fibrosis. InterpretationThe inhibition of RAD51 exerts therapeutic benefits in lung fibrosis by promoting apoptosis. Our findings identify that inhibiting RAD51 with B02 in fibroblasts impairs DNA repair and induces metabolic reprogramming, making it a potential therapeutic target. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPulmonary fibrosis (PF) is characterized by excessive fibroblast activation and subsequent deposition of extracellular matrix (ECM) proteins, which ultimately disrupt normal lung architecture. A significant contributing factor to the pathogenesis of pulmonary fibrosis is the presence of fibroblasts that are resistant to apoptosis, preventing normal wound healing. Recent studies highlight the DNA repair protein RAD51 as effective in protecting fibroblasts from death induced by chemotherapy and ionizing radiation. These finding suggested that RAD51 could have a role in fibroblast activation and apoptosis resistance in pulmonary fibrosis. Added value of this studyWe demonstrated that RAD51 is important for maintaining apoptosis-resistant fibrotic fibroblasts and their metabolic abnormalities. Our findings indicated that TGF{beta}-mediated upregulation of RAD51 reduces DNA damage, activates multiple pathways related to fibroblast activation and proliferation, and induces metabolic reprogramming, ultimately regulating apoptosis. Mechanistically, RAD51 inhibition enhanced p53 acetylation at lysine 120 and upregulated the expression proapoptotic proteins PUMA/BAK in mitochondria, promoting apoptosis. Pharmacological inhibition of RAD51 using the specific inhibitor B02 during the fibrotic phase of experimental lung disease effectively ameliorated pulmonary fibrosis. Implications of all the available evidenceOur findings establish that RAD51 plays an important role in the survival of apoptosis-resistant fibrotic fibroblasts. We propose that reducing RAD51 expression leads to the metabolic reprogramming of activated fibroblasts, resulting in decreased mitochondrial respiration, reduced ATP levels, and diminished glycolysis or glutaminolysis. These observations suggest that targeting energy metabolism through RAD51 inhibition could be a viable strategy to enhance apoptosis, thereby creating a therapeutically targetable pathway in fibrotic cells. These findings highlight the potential of RAD51 as a therapeutic target for the treatment of IPF.

cell biology↗

bioRxiv2025

Lytic anti-Staphylococcus aureus phage M963 resensitizes its host to methicillin by a tarS-dependent mechanism

Bacteriophage M963 targeting a clinical strain of methicillin-resistant Staphylococcus aureus (MRSA) was isolated from wastewater. Purification was optimized and the phage was subsequently characterized as a lytic, dsDNA phage within the family Roundtreeviridae and genus Rosenblumvirus. Host range testing against a small library of S. aureus isolates from patients with bacteremia and periprosthetic joint infections showed lytic activity against >60% of tested strains. Evaluation of phage-resistant mutant derivatives of the cognate host showed disruptive mutations within tarS, a gene responsible for modifying wall teichoic acid. tarS products have been proposed as a target of other members of Roundtreeviridae. Synergy testing in MRSA demonstrated phage-antibiotic synergy between M963 and vancomycin, tetracycline, and methicillin. The M963-methicillin synergy prompted testing of the phage-resistant mutant derivatives, showing that phage resistance led to a transient methicillin-susceptible phenotype at clinically relevant minimum inhibitory concentrations in some mutants. Phage M963 is a candidate for compassionate use therapy in appropriate patients. Author SummaryBacteriophages are viruses that kill bacteria. Because of antibiotic resistance, bacteriophages are being used in the treatment of some infections that are resistant to antibiotics or are not improving despite antibiotics. This manuscript describes the discovery of a bacteriophage, named M963, that kills antibiotic resistant Staphylococcus aureus (MRSA). This bacteriophage can kill MRSA from patients with prosthetic joint infections by binding to structures, called wall teichoic acids, on the outside of MRSA. Although the MRSA can evolve to avoid the bacteriophage, this leaves it vulnerable to new antibiotics. By working together with antibiotics, bacteriophage M963 may be a good option for patients with MRSA infections not responding appropriately to standard treatments.

microbiology↗

bioRxiv2025

Latent transforming growth factor binding protein-2 (LTBP2), an IPF biomarker of clinical decline, promotes TGF-beta signaling and lung fibrosis in mice

The identification of clinically predictive serum biomarkers for pulmonary fibrosis is a significant challenge and important goal. Multiple recent proteomic biomarker studies have identified latent transforming growth factor binding protein-2 (LTBP2) as a circulating factor associated with disease progression in fibrotic lung diseases in humans (including IPF), but its role in the development of fibrosis is incompletely defined. LTBP2 competes with the large latent transforming growth factor-beta (TGF{beta}) complex (LLC) for binding to the N-terminus of fibrillin and is thought to promote the release of active TGF{beta}. We hypothesized that LTBP2 deficiency would promote LLC sequestration in matrix and reduce TGF{beta} signaling. We recently reported an LTBP2 knockout (Ltbp2-/-) mouse with no baseline lung abnormalities. Here we show that Ltbp2-/- mice exposed to either bleomycin or silica have a significant reduction in fibrosis compared to wild type controls. Consistent with reduced fibrosis, after bleomycin Ltbp2-/- mouse lungs have reduced TGF{beta} signaling and isolated fibroblasts from Ltbp2-/-mice exhibit impaired migration in an in vitro wound closure assay. Transcriptomic analysis of bleomycin-treated control and Ltbp2-/- mouse lung tissue identified multiple LTBP2-regulated genes, including the lncRNA antisense of IGFR2 non-coding RNA (Airn) which has reported antifibrotic effects. Interestingly, we also observed that Ltbp2-/- mice had impaired epithelial repair after bleomycin treatment, a phenotype that also occurred in a naphthalene model of club cell injury. These findings provide evidence that LTBP2 is profibrotic and facilitates TGF{beta} signaling but is also required for normal airway epithelial repair.

pathology↗

bioRxiv2024

Differing genetics of saline and cocaine self administration in the hybrid mouse diversity panel

To identify genes that regulate the response to the potentially addictive drug cocaine, we performed a control experiment using genome-wide association studies (GWASs) and RNA-Seq of a panel of inbred and recombinant inbred mice undergoing intravenous self-administration of saline. A linear mixed model increased statistical power for analysis of the longitudinal behavioral data, which was acquired over 10 days. A total of 145 loci were identified for saline compared to 17 for the corresponding cocaine GWAS. Only one locus overlapped. Transcriptome-wide association studies (TWASs) using RNA-Seq data from the nucleus accumbens and medial frontal cortex identified 5031434O11Rik and Zfp60 as significant for saline self-administration. Two other genes, Myh4 and Npc1, were nominated based on proximity to loci for multiple endpoints or a cis locus regulating expression. All four genes have previously been implicated in locomotor activity, despite the absence of a strong relationship between saline taking and distance traveled in the open field. Our results indicate a distinct genetic basis for saline and cocaine self-administration, and suggest some common genes for saline self-administration and locomotor activity.

genetics↗

bioRxiv2024

ecPath detects ecDNA in tumors from histopathology images

Circular extrachromosomal DNA (ecDNA) can drive tumor initiation, progression and resistance in some of the most aggressive cancers and is emerging as a promising anti-cancer target. However, detection currently requires costly whole-genome sequencing (WGS) or labor-intensive cytogenetic or FISH imaging, limiting its application in routine clinical diagnosis. To overcome this, we developed ecPath (ecDNA from histopathology), a computational method for predicting ecDNA status from routinely available hematoxylin and eosin (H&E) images. ecPath implements a deep-learning method we call transcriptomics-guided learning, which utilizes both transcriptomics and H&E images during the training phase to enable successful ecDNA prediction from H&E images alone, a task not achievable with models trained on H&E images only. It is trained on more than 6,000 tumor whole-slide images from the TCGA cohort with the best performance in predicting ecDNA status in brain and stomach tumors (average AUC=0.78). ecPath revealed that ecDNA-positive tumors are enriched with pleomorphic, larger and high-density nuclei. Testing in an independent cohort, ecPath predicted ecDNA status of 985 pediatric brain tumor patients with an AUC of 0.72. Finally, we applied ecPath to identify ecDNA-positive tumors in the TCGA cohort for which no WGS data were available. Like WGS-based ecDNA-positive labels, the predicted ecDNA-positive status also identify poor prognoses for low grade glioma patients. These results demonstrate that ecPath enables the detection of ecDNA from routinely available H&E imaging alone and help nominate aggressive tumors with ecDNA to study and target it.

pathology↗

bioRxiv2024

A fluid droplet harvests the force generated by shrinking microtubules in living cells

The energy-consuming dynamic instability of microtubules generates significant forces which are thought to be harnessed to move large cargos in cells. However, identification of mechanisms which can capture the force released during microtubule depolymerization to move large loads has been elusive. In this work we show that a biomolecular condensate provides an elegant solution to this problem. Using live cell super-resolution microscopy, we directly observe that budding yeast +TIP bodies are nanoscale droplets with classic fluid-like behaviors which accumulate type V myosin (Myo2) at their surfaces. We find that conserved self-oligomerization interfaces in the protein Kar9 tune the biophysical properties of the viscoelastic +TIP body and its ability to e]iciently move the mitotic spindle. Our findings introduce a paradigm for how forces generated by microtubule dynamics are harnessed in cells and open a frontier of research on nanoscale biomolecular condensates in their native environment.

biophysics↗

bioRxiv2024

Multi-SpinX: An Advanced Framework for Automated Tracking of Mitotic Spindles and Kinetochores in Multicellular Environments

SpinX, an AI-guided spindle tracking software, allows the 3-dimensional (3D) tracking of metaphase spindle movements in mammalian cells. Using over 900 images of dividing cells, we create the Multi-SpinX framework to significantly expand SpinXs applications: a) to track spindles and cell cortex in multicellular environments, b) to combine two object tracking (spindle with kinetochores marked by centromeric probes) and c) to extend spindle tracking beyond metaphase to prometaphase and anaphase stages where spindle morphology is different. We have used a human-in-the-loop approach to assess our optimisation steps, to manually identify challenges and to build a robust computational pipeline for segmenting kinetochore pairs and spindles. Spindles of both H1299 and RPE1 cells have been assessed and validated for use through Multi-SpinX, and we expect the tool to be versatile in enabling quantitative studies of mitotic subcellular dynamics.

cell biology↗

bioRxiv2023

Incidences of Helicobacter infection in pigs and tracing occupational hazard in pig farmers

Helicobacter species (H. sp.) is a gram-negative spiral-shaped motile bacteria that causes gastritis in pigs and also colonizes the human stomach. The current study seeks to assess the prevalence of various H. sp. in the gastric mucosa of slaughtered and dead pigs, as well as the prevalence of Helicobacter infection among pig farmers. A total of 403 stomach samples from various pig slaughter points, 74 necropsy samples from various pig farms and 97 stool samples from pig farmers were collected from Assam, India. Among 477 pig stomach samples tested, 214 samples with gastritis (20.09%) showed Gram negative, spiral-shaped organisms in brush cytology from the mucosal surface, and the rest of the 263 stomach samples without any gastric lesion showed only 3.04% Gram negative, spiral-shaped organisms. In ultrastructure investigation, Scanning Electron Microscopy (SEM) of the four urease positive stomach samples revealed a tightly coiled Helicobacter bacterium (spiral-shaped) found in the mucous lining of the stomach. In histopathological examination of pars esophagia, cardiac and fundic mucosa showed chronic gastritis associated with hemorrhagic necrosis, leucocytic infiltration with neutrophils and macrophages, and lymphoid aggregates (lymphoid follicles) etc. PCR confirmed 16S rRNA genes of Helicobacter suis (H. suis) where a total of 42 (19.63%) out of 214 pig stomach samples and 2 (2.08%) out of 96 stool samples of pig farmers were found positive for H. suis. of these 96 stool samples of pig farmers 3 (3.12%) were confirmed positive for Helicobacter pylori (H. pylori) Phosphoglucosamine mutase gene in PCR. Phylogenic analysis of the 16S rRNA gene of H. suis showed distinct clusters with other H. sp. In conclusion, this study provides evidence for the prevalence of Helicobacter both in pig gastric mucosa and human stool. The findings highlight the need for improved sanitation and hygiene practices among pig farmers to minimize the risk of Helicobacter infection in humans.

microbiology↗

bioRxiv2023

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

genomics↗

bioRxiv2023

Metagenomic analysis of Pigs' faecal microbiome and its functional response associated with dietary fibre

Pig husbandry is the most valued and economically sustainable husbandry in the livestock farming system. The performance and productivity of the pig are chiefly dependent on the nutritional factor steered by gut beneficial bacteria. The swine gut microbiome has a direct relationship with feed efficiency. As a consequence, identifying microbial taxonomy and functional capacity is critical for proper nutrient digestion. In the present investigation, eighteen grower pigs aged 3 months and weighing 30{+/-}0.55 kg were allocated into three different groups using a randomized block layout and supplemented with QPM maize fodder of 0, 5, and 10% to the basal diet by substituting (wt/wt on DM) the maize grains, and named as T0, T1, and T2 to probe the increase in gut beneficial bacteria found in the faecal contents. For comparison with T0, T1, and T2, a random faecal sample designated R was collected from six grower pigs of the same age group and bodyweight fed a maize-soya bean-based diet. The experiment is being carried out to investigate the effect of various maize fodder levels on the metagenomic profiles of pig gut microbiota using the 16S rRNA gene. All of the experimental diets were iso-nitrogenous, with protein content ranging from 18.37 to 18.63 per cent. The data generated by 16S rRNA amplicon analysis was 68, 56, 61, and 39 Mb in R, T0, T1, and T2 samples, respectively. From taxonomic distribution, bacterial phyla namely Firmicutes, Bacteroidetes, Proteobacteria, and Spirochetes are found in descending order of relative abundance in the R, T0, and T1 groups, respectively, while Spirochaetes, Proteobacteria, Fibrobacteres, Bacteroidetes, and Firmicutesare found in descending order of relative abundance in the T2 group. The relative profusion of Fibrobacter succinogenes is 0.89% and 16.84% in the T1 and T2 groups. According to the findings, a higher level of maize fodder in the diet of grower pigs promotes the growth of fibre-degrading bacteria in the gut microbiota, particularly Fibrobacter succinogenes. Moreover, feeding green maize has decreased the population of methanobacteria in the gut of pigs, which in turn has limited the production of methane.

genomics↗

bioRxiv2022

Genetic pathways regulating the longitudinal acquisition of cocaine self administration in mice

To identify genetic pathways for addiction, we analyzed intravenous self-administration of cocaine or saline in a panel of 84 inbred and recombinant inbred mouse strains over 10 days. We integrated the behavior data with RNA-Seq data from the medial frontal cortex and nucleus accumbens from 41 strains. The self-administration of cocaine and saline showed distinct genetic bases. We maximized power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci were identified in the genome-wide association study (GWAS). A transcriptome-wide association study (TWAS) highlighted the Trpv2 ion channel as a key locus for cocaine self-administration from the GWAS. In addition, 17 genes supplementary to the GWAS were identified including Arhgef26, Slc18b1 and Slco5a1. We found numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance of Trpv2, a known cannabinoid receptor, for the response to cocaine as well as identifying further relevant loci.

genetics↗

bioRxiv2022

Detection and Whole Genome of Japanese Encephalitis Virus Genotype III strains isolated from Indian Pig and Mosquito vector

Japanese encephalitis virus(JEV) are globally prevalent as deadly pathogens in human and animals including pig, horse and cattle. Japanese encephalitis (JE) still remains as an important cause of epidemic encephalitis worldwide and exists in a zoonotic transmission cycle. Assam is one of the highly endemic state for JE in India. In the present study, to understand the epidemiological status of JE circulating in pigs and mosquito particularly in Assam, India, molecular detection of JEV and the complete genome sequencing of the JEV isolates from pig and mosquito were done. The complete genome analysis of two JEV isolates from pig and mosquito were revealed7 and 21 numbers of unique points polymorphism of nucleotide during alignment of the sequences with other available sequences, respectively. Phylogenetic analysis revealed that the isolates of present investigation were belongs to genotype III and closely related with the strains of neighbouring country China. This study represents the transboundary nature of the JEV genotype III circulation and maintained the same genotype through mosquito-swine transmission cycles.

genomics↗

bioRxiv2022

Targeting Pulmonary Fibrosis by SLC1A5 dependent Glutamine Transport Blockade

The neutral amino acid glutamine plays a central role in TGF-{beta}-induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5. In this current work, we demonstrated that profibrotic actions of TGF-{beta} are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and targeting SLC1A5 abrogates multiple facets of fibroblast activation. This approach could thus represent a novel therapeutic strategy to treat fibroproliferative diseases. We found that SLC1A5 was highly expressed in fibrotic lung fibroblasts and fibroblasts isolated from IPF lungs. The expression of profibrotic targets, cell migration, and anchorage independent growth by TGF-{beta} required the activity of SLC1A5. Loss or inhibition of SLC1A5 function enhanced fibroblast susceptibility to autophagy, suppressed mTOR, HIF, Myc signaling, and impaired mitochondrial function, ATP production and glycolysis. Pharmacological inhibition of SLC1A5 by small molecule inhibitor V-9302 shifted fibroblast transcriptional profiles from profibrotic to fibrosis resolving, and attenuated fibrosis in a bleomycin treated mouse model of lung fibrosis. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in fibrosis, laying a framework for new paradigm-shifting therapies targeting cellular metabolism for this devastating disease.

molecular biology↗

bioRxiv2022

L-GIREMI uncovers RNA editing sites in long-read RNA-seq

Using third-generation sequencers, long-read RNA-seq is increasingly applied in transcriptomic studies given its major advantage in characterizing full-length transcripts. A number of methods have been developed to analyze this new type of data for transcript isoforms and their abundance. Another application, which is significantly under-explored, is to identify and analyze single nucleotide variants (SNVs) in the RNA. Identification of SNVs, such as genetic mutations or RNA editing sites, is fundamental to many biomedical questions. In long-read RNA-seq, SNV analysis presents significant challenges, due to the well-known relatively high error rates of the third-generation sequencers. Here, we present the first study to detect and analyze RNA editing sites in long-read RNA-seq. Our new method, L-GIREMI, effectively handles sequencing errors and biases in the reads, and uses a model-based approach to score RNA editing sites. Applied to PacBio long-read RNA-seq data, L-GIREMI affords a high accuracy in RNA editing identification. In addition, the unique advantage of long reads allowed us to uncover novel insights about RNA editing occurrences in single molecules and double-stranded RNA (dsRNA) structures. L-GIREMI provides a valuable means to study RNA nucleotide variants in long-read RNA-seq.

bioinformatics↗

bioRxiv2021

LncRNA DLEU2 regulates Sirtuins and mitochondrial respiratory chain complex IV: a novel pathway in obesity and DOHaD

Long noncoding RNAs (lncRNAs) are commonly dysregulated in cancer but are mostly unknown for roles in metabolic regulation. Sirtuins, an epigenetic modulator class, regulate metabolic pathways. However, how sirtuins are regulated via lncRNA is unknown. In our findings, DLEU2, a lncRNA involved in primarily blood cancers, and sirtuins were both significantly decreased in the livers of high-fat high-fructose diet (HFD-HF) fed male mouse offspring (F1) whose mothers (F0) were either fed chow diet or HFD-HF during reproductive and pregnancy windows. Confirming this connection, upon silencing DLEU2, transcription levels of SIRT1 through 6 and translational levels of SIRT1, 3, 5, and 6 were significantly downregulated. Knockdown of DLEU2 also significantly decreased the protein level of cytochrome-c oxidase (complex IV, MTCO1) without altering other mitochondrial complexes, leading to increased reactive oxygen species production. Interestingly, in F1 livers, the protein level of MTCO1 was also significantly decreased under an HFD-HF diet or even under chow diet if the mother was exposed to HFD-HF. Our findings therefore reveal for the first time that a lncRNA can regulate sirtuins and a specific mitochondrial complex, furthermore suggesting a potential role of DLEU2 in metabolic disorders over one or more generations. HIGHLIGHTSMaternal diet can modulate hepatic lncRNA DLEU2 and its downstream regulators in offspring DLEU2 is required for specific sirtuin regulation and mitochondrial respiration chain complex IV expression Offspring liver depleted of DLEU2 show decreased mitochondrial respiration chain complex IV and specific sirtuins at transcriptional and translational levels

genetics↗

bioRxiv2020

Optimal Adaptive Electrode Selection to Maximize Simultaneously Recorded Neuron Yield

Neural-Matrix style, high-density electrode arrays for brain-machine interfaces (BMIs) and neuroscientific research require the use of multiplexing: Each recording channel can be routed to one of several electrode sites on the array. This capability allows the user to flexibly distribute recording channels to the locations where the most desirable neural signals can be resolved. For example, in the Neuropixel probe, 960 electrodes can be addressed by 384 recording channels. However, currently no adaptive methods exist to use recorded neural data to optimize/customize the electrode selections per recording context. Here, we present an algorithm called classification-based selection (CBS) that optimizes the joint electrode selections for all recording channels so as to maximize isolation quality of detected neurons. We show, in experiments using Neuropixels in non-human primates, that this algorithm yields a similar number of isolated neurons as would be obtained if all electrodes were recorded simultaneously. Neuron counts were 41-85% improved over previously published electrode selection strategies. The neurons isolated from electrodes selected by CBS were a 73% match, by spike timing, to the complete set of recordable neurons around the probe. The electrodes selected by CBS exhibited higher average per-recording-channel signal-to-noise ratio. CBS, and selection optimization in general, could play an important role in development of neurotechnologies for BMI, as signal bandwidth becomes an increasingly limiting factor. Code and experimental data have been made available1.

neuroscience↗