Biology subjects

Mohan, S.

Publications and source records attributed to Mohan, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Circadian clock control of translation fidelity through MetRS-mediated methionine misincorporation

Translation fidelity is generally viewed as a constitutive process that deteriorates under stress and aging. Here we show that the fidelity of amino acid incorporation is instead dynamically regulated by the circadian clock. In Neurospora crassa, methionine (Met) misincorporation into proteins exhibits robust daily rhythms, peaking at night coincident with elevated reactive oxygen species (ROS). Rhythmic Met misincorporation requires the circadian clock, the ERK-family MAPK MAK1, and MAK1-dependent phosphorylation of methionyl-tRNA synthetase (MetRS), linking circadian signaling to regulated mistranslation associated with oxidative stress resistance. Preventing MetRS phosphorylation abolishes rhythmic Met misincorporation, impairs growth, and increases sensitivity to oxidative stress, whereas a phosphomimetic MetRS mutant enhances oxidative stress survival. Proteome-wide analyses identified thousands of Met misincorporation events, including a rhythmic subset that oscillates independently of corresponding protein abundance, suggesting that mistranslation dynamically remodels proteome composition across the day. Together, these findings establish translation fidelity as a regulated circadian output and support a model in which the circadian clock temporally regulates mistranslation to enhance oxidative stress resilience. Significance StatementBiological clocks regulate translation termination fidelity, but whether they also control the accuracy of amino acid incorporation during protein synthesis was unknown. We show that the circadian clock drives rhythmic methionine misincorporation into proteins through ERK-family MAPK signaling and phosphorylation of methionyl-tRNA synthetase. Methionine misincorporation peaks during periods of elevated oxidative stress, and disrupting this regulation compromises oxidative stress survival, whereas constitutive activation enhances resistance. Together with previous work on translation termination fidelity, these findings reveal that biological clocks regulate multiple layers of translation fidelity and identify adaptive mistranslation as a mechanism that promotes cellular resilience.

molecular biology↗

bioRxiv2026

Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model

Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.

neuroscience↗

bioRxiv2026

Transcriptomics and mutational analysis to screen immunogenic neoantigen peptides and Patient stratification based on immune subtypes for TNBC

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype with limited therapeutic options. In this study, we performed an integrative analysis of TNBC genomics data, including gene expression, somatic mutations, copy number alterations, survival outcomes, immune profiling, and clustering, to identify potential neoantigens, patient populations suitable for vaccination, and biomarkers for evaluating vaccine efficacy. This Integrated analysis identified POSTN and CAP1 as tumor-specific antigens. Incorporation of TNBC-specific mutations into the screened wild-type antigens led to the identification of three neoantigenic peptides with high potential for vaccine development. Immune subtyping stratified TNBC patients into four distinct subtypes, among which IS1 and IS3 were characterized by poor immune infiltration, lower mutation burden, and unfavorable prognosis, whereas IS2 and IS4 exhibited enhanced immune activity and better clinical outcomes. A vaccine incorporating the identified neoantigen peptides may potentially remodel the immune landscape of immune-cold subtypes (IS1 and IS3), converting them into immune-enriched phenotypes through vaccine-induced immune stimulation. Furthermore, weighted gene co-expression network analysis identified ten immune-related biomarkers from the blue and gray modules that were significantly associated with improved survival in IS2 and IS4. Functional enrichment and protein-protein interaction analyses revealed that hub genes primarily involved in immunoglobulin kappa chains and cytokine/TNF signaling pathways may serve as valuable immune biomarkers for prognostic assessment and monitoring vaccine efficacy.

cancer biology↗

bioRxiv2025

Emergence of Dual-Risk Klebsiella pneumoniae: Global Hotspots of Convergence Between Resistance and Hypervirulence

BackgroundKlebsiella pneumoniae is a major pathogen causing both healthcare- and community-associated infections. Traditionally classified as classical (cKp) or hypervirulent (hvKp), recent reports suggest increasing overlap between antimicrobial resistance (AMR) and virulence, leading to "dual-risk" clones that are both invasive and difficult to treat. ObjectivesTo perform a large-scale genomic analysis of K. pneumoniae isolates and systematically characterize the convergence of AMR and hypervirulence, with a focus on global distribution, clonal structure, and accessory genome functions. MethodsWe analyzed 3,443 genomes curated from 25 international studies. Virulence scoring was standardized using a Kleborate-based framework, while AMR genes were identified with ResFinder. Multilocus sequence typing (MLST), plasmid replicon typing, and K/O antigen profiling were conducted. Convergence was defined as hvKp (virulence score [≥]3) carrying high-priority AMR determinants. Pan-genome-wide association (pan-GWAS) was performed with Roary and Scoary, followed by functional enrichment using ShinyGO. ResultsAmong hvKp isolates, 59.4% carried carbapenemases, ESBLs, or 16S rRNA methyltransferases, demonstrating widespread convergence. Convergent lineages were dominated by ST231 and ST23, with India and the Middle East identified as geographic hotspots. HvKp isolates carried a higher plasmid replicon burden and were enriched in KL1/KL2 and O1/O2 serotypes. Pan-GWAS revealed hvKp-associated accessory genes linked to envelope stress response, nucleotide metabolism, and membrane transport, highlighting adaptive traits beyond canonical virulence loci. ConclusionOur findings redefine the hvKp/cKp dichotomy as a continuum shaped by plasmids and selective pressures. The emergence of dual-risk clones has urgent implications for diagnostics, surveillance, and treatment strategies in regions with high AMR prevalence.

genomics↗

bioRxiv2025

Detection of five viruses commonly implicated with Bovine Respiratory Disease using loop-mediated isothermal amplification

Herein, we present novel quantitative loop-mediated isothermal amplification (qLAMP) and reverse-transcription qLAMP (RT-qLAMP) assays for the detection of five viruses commonly implicated with the onset and progression of bovine respiratory disease (BRD): Bovine Alphaherpesvirus Type 1 (BHV-1), Bovine Adenovirus Type 3 (BAV-3), Bovine Respiratory Syncytial Virus (BRSV), Bovine Viral Diarrhea Virus Type 1 (BVDV-1), and Bovine Parainfluenza Virus Type 3 (BPIV-3). Using contrived samples spiked with whole viruses, we found that our extraction-free assays have limits of detection between 30 and 1,057 copies per reaction (1.8% final sample concentration) with minimal sample processing. Using dual-tipped swabs and 1.4 mL resuspension volumes, these limits of detection are on the order of 2 x 105 copies per swab for BAV-3 and BHV-1 and between 6.31 x 106 to 8.22 x 106 copies per swab in the case of BPIV-3, BRSV, and BVDV-1. Analytical sensitivities ranged from 73 - 100% and analytical specificities ranged from 90 - 100%. Additionally, we introduced a streamlined pipeline to minimize the experimental workload to design, screen, select, and characterize LAMP performance for developing assays. The assays targeting these BRD viruses can be utilized to develop colorimetric LAMP assays that enable the sensitive and specific detection of these viruses chute side to aid in diagnosing and treating BRD. The associated development pipeline enables more rapid development of LAMP-based diagnostic tools targeting emerging pathogens.

bioengineering↗

bioRxiv2025

A dual-localized geraniol synthase and a previously unreported cytosolic geranyl pyrophosphatase contribute to geraniol formation in lemongrass

Geraniol, a major constituent of many essential oils and precursor for geraniol-derived aldehydes and acetates, is produced in plants through the action of a terpene synthase encoding geraniol synthase or via terpene synthase-independent non-canonical pathway involving a Nudix hydrolase and a yet to be discovered pyrophosphatase. Here, we identify a geraniol synthase (Cymbopogon flexuosus geraniol synthase; CfGES) that catalyzes the conversion of geranyl pyrophosphate (GPP) (also known as geranly diphosphate) to geraniol, as well as a previously unreported geranyl pyrophosphatase (CfG(P)Pase) that acts on both GPP and geranyl monophosphate (GP), albeit with different efficiencies, to generate geraniol. Virus-induced gene silencing of CfGES or CfG(P)Pase resulted in a substantial reduction in geraniol and its immediate product citral in lemongrass leaves. Conversely, transient overexpression of CfGES or CfG(P)Pase resulted in enhanced production of geraniol and citral in lemon balm (Melissa officinalis) leaves, as well as geraniol, citronellol, and citral in rose (Rosa damascena) flower petals. Subcellular localization studies revealed that while CfGES exhibited dual cytosolic/plastidial localization, CfG(P)Pase was localized to the cytosol. This localization pattern was further supported by the significantly higher geraniol-forming activity observed in the purified cytosolic protein fraction compared to the chloroplast fraction. Our study uncovers the missing step in cytosolic geraniol formation via a TPS-independent non-canonical route and demonstrates that geraniol, required for citral production in lemongrass, is synthesized by cytosolic CfG(P)Pase and cytosol-/plastid-localized CfGES.

plant biology↗

bioRxiv2025

Cardioprotective effects of AMPK activation in H1N1 influenza virus infection

Cardiac complications are among the most common and severe extrapulmonary manifestations of influenza virus infection, yet they are rarely recapitulated in mouse models without immunodeficiency. We found that influenza virus A/California/04/2009 (H1N1) carrying a mouse-adaptive amino acid substitution in the PB2 protein (E158A) disseminates to the heart in WT C57BL/6 mice, where it induces inflammation, electrical dysfunction, and fibrotic remodeling. Influenza virus-infected heart tissue was significantly altered in mitochondrial metabolism, extracellular matrix, circadian rhythm, and immunity pathways. Particularly striking was activation of gene expression downstream of the mitochondrial biogenesis-promoting AMPK/PGC-1 axis, which occurred late in infection but failed to reverse the repression of mitochondria-associated genes, suggesting an insufficient or delayed compensatory response. Accordingly, we administered AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) early in infection and observed restoration of mitochondria-associated gene levels, amelioration of cardiac electrical dysfunction and fibrosis, and improvement in survival without overt effects on lung function. Overall, the advent of an immunocompetent model for severe influenza-associated cardiac dysfunction revealed activation of AMPK signaling as a host-targeted metabolic intervention for mitigating virus-induced heart pathologies

microbiology↗

bioRxiv2025

Gasdermin E is Dispensable for H1N1 Influenza Virus Pathogenesis in Mice

Targeting cell death pathways, including pyroptosis and necroptosis, has been shown to mitigate influenza virus infection severity. Here, we examined whether pyroptosis specifically driven by the pore-forming protein gasdermin E (GSDME) is involved in regulating influenza virus infection outcomes. We found that Gsdme-/- mice showed similar weight loss and survival in severe A/PR/8/34 (H1N1) virus infections compared to WT counterparts. Likewise, lung dysfunction, histopathological damage, viral titers, and inflammatory cytokine levels were similar in the two groups. Global transcriptomic analysis also revealed similar inflammatory and antiviral gene expression programs in WT versus Gsdme-/- mouse lungs at baseline and in response to infection. To confirm the generality of these findings, we infected mice with 2009 pandemic H1N1 virus and again observed similar weight loss, mortality, and lung dysfunction in WT and Gsdme-/- mice. Our results overall demonstrate that GSDME contributes negligibly to the host response against H1N1 influenza virus, refining our understanding of cell death pathways in influenza pathogenesis.

immunology↗

bioRxiv2025

Heterogeneity and variability in short term synaptic plasticity and implications for signal transformation

There are many sources of heterogeneity in the CA1 network, including plasticity, connectivity and cell properties, yet the extent and functional consequences of this diversity remains poorly understood. We used patterned optogenetic stimulation of CA3 pyramidal neurons and whole-cell patch clamp recordings from CA1 pyramidal neurons in acute mouse hippocampal slices, to characterize the contributions of different forms of heterogeneity to information flow. We found pronounced heterogeneity in synaptic responses and short-term plasticity (STP), influenced by the neurotransmitter identity, input pattern, and size of the activated presynaptic ensemble. Inhibitory synapses exhibited greater diversity in both response variability and depression profiles than excitatory synapses. We incorporated these readings in a molecule-to-network multiscale model of the CA3->CA1 circuit. The reference model shows strong decorrelation of autocorrelated input, but removal of STP makes the decorrelation frequency dependent. Removal of stochasticity and heterogeneity in connections makes the output periodic. Thus heterogeneity, short-term plasticity, and stochasticity each have distinct effects on cellular information transmission.

neuroscience↗

bioRxiv2025

Reward impulsivity is linked to addictive-like behaviors towards sweet food and sugary drinks but not fatty food

Overconsumption of hyperpalatable food is a worldwide problem. Although many previous studies have shown the link between monetary delay discounting and propensity to overconsume food, the studies did not focus on the link between delay discounting and various subcategories of palatable food. In the present study, we investigate the link between the individual propensity to choose smaller immediate rather than larger delayed reward and the degree of problematic eating behavior for five types of palatable food (sweets, sugary drinks, fatty food, salty snacks, and starchy food). The delay discounting task was used to measure propensity to choose immediate rather than delayed rewards, while the degree of addictive-like behavior was measured using the modified Yale food addiction scale (mYFAS) for each food category. Both model-free and model-based analysis showed that there is a significant correlation between the addiction score for sweet food and the tendency to choose smaller immediate rather than larger delayed rewards. A model-based analysis showed the same significant correlation for sugary drinks. However, no such correlation was observed for other food categories (fatty, salty, or starchy food), suggesting that reward impulsivity may play different roles in addictive-like behavior towards various food categories.

neuroscience↗

bioRxiv2025

Subtype-specific enhancer RNAs define transcriptional regulators and prognosis in breast cancers

Gene expression is tightly controlled by DNA elements called enhancers by associating with lineage-specific transcription factors. These enhancers transcribe non-coding RNAs (called enhancer RNAs or eRNAs). eRNA expression is an early indicator of transcription factor activity and is associated with treatment response and survival in cancer patients. However, the attempts to identify prognostic eRNAs in breast cancers were inadequate, as these studies ignored the heterogenous nature of breast cancers with distinct molecular subtypes. By analysing [~]300,000 eRNA loci profiled using RNA-sequencing datasets from 1,095 breast cancer patients using machine learning approaches, we categorised eRNAs which are specific to breast cancer molecular subtypes and survival. The classified eRNAs were associated with gene pathways related to relevant subtypes. Interestingly, transcription factor analyses highlighted involvement of nuclear receptors other than the estrogen receptor with luminal-specific eRNAs. Basal eRNAs showed association with the transcriptional corepressor TRIM28 and androgen receptor. Luminal eRNAs were associated with better outcomes and Her2 eRNAs with worse outcome in patients. Overall, we demonstrate that machine learning approaches performed on RNA-seq datasets can classify subtype-specific and prognostic eRNAs which can be used to identify critical gene pathways and transcription factor networks in breast cancer.

cancer biology↗

bioRxiv2024

CrGEF1, CrGAP1, and CrGDI2 function as key regulators of ROP-GTPase mediated modulation of alkaloid biosynthesis in Catharanthus roseus

ROP-GTPase Regulatory Proteins (RGRPs) have been shown to control plant morphogenesis, development and immunity, however, their role in specialized metabolism is hitherto not known. Here, we demonstrate that specific RGRPs control monoterpene indole alkaloid (MIA) biosynthesis by interacting with distinct Rho of Plants (ROP) in Catharanthus roseus. Among the five Guanine nucleotide Exchange Factors (GEFs), four GTPase-activating proteins (GAPs), and two GDP dissociation inhibitors (GDIs) identified in the C. roseus genome, only CrGEF1, CrGAP1, and CrGDI2 specifically interacted with CrROP3 and CrROP5. These RGRPs displayed distinct cytosolic and/or membrane localization patterns, with their transcripts predominantly expressed in aerial tissues. Functional studies revealed that CrGEF1 acts as a positive regulator of MIA biosynthesis, as its silencing led to a reduction in MIA production, while overexpression enhanced MIA levels. Conversely, CrGAP1 and CrGDI2 function as negative regulators, with their silencing resulting in increased MIA production and their overexpression causing reduced MIA levels. Notably, terminal truncated forms of these RGRPs showed interaction with CrROP3 or CrROP5 but failed to influence MIA biosynthesis, underscoring the importance of these domains in their regulatory functions. Overall, our findings uncover a previously unexplored mechanism by which distinct RGRPs coordinate with specific ROPs to regulate transcription factors and fine-tune MIA biosynthesis in C. roseus. SignificancePlants fine-tune their metabolic pathways to adapt to environmental and physiological cues, balancing primary and specialized metabolism. Here, we uncover a feedback regulatory mechanism by which ROP-GTPase regulatory proteins (RGRPs) control alkaloid biosynthesis in Catharanthus roseus. We found that CrGEF1, CrGAP1, and CrGDI2 specifically interact with ROP-GTPases CrROP3 and CrROP5, modulating the monoterpene indole alkaloid (MIA) pathway. This RGRP-ROP module plays a crucial role in dynamically regulating MIA levels, where CrGEF1 promotes MIA production while CrGAP1 and CrGDI2 act as negative regulators. These findings highlight the importance of RGRP-ROP circuitry in control of alkaloid biosynthesis in C. roseus, and specialized metabolism in plants.

plant biology↗

bioRxiv2024

Empirically establishing drug exposure records directly from untargeted metabolomics data

Despite extensive efforts, extracting information on medication exposure from clinical records remains challenging. To complement this approach, we developed the tandem mass spectrometry (MS/MS) based GNPS Drug Library. This resource integrates MS/MS data for drugs and their metabolites/analogs with controlled vocabularies on exposure sources, pharmacologic classes, therapeutic indications, and mechanisms of action. It enables direct analysis of drug exposure and metabolism from untargeted metabolomics data independent of clinical records. Our library facilitates stratification of individuals in clinical studies based on the empirically detected medications, exemplified by drug-dependent microbiota-derived N-acyl lipid changes in a cohort with human immunodeficiency virus. The GNPS Drug Library holds potential for broader applications in drug discovery and precision medicine.

bioinformatics↗

bioRxiv2024

Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy

IntroductionLimb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. MethodsThe ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. ResultsThe GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as Definitive, 4 (11%) as Moderate and 1 (3%) as Limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. ConclusionsThe expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

genetics↗

bioRxiv2022

The Radiogenomic and Spatiogenomic Landscapes of Glioblastoma, and Their Relationship to Oncogenic Drivers

Glioblastoma (GBM) is well-known for its molecular and spatial heterogeneity, which poses a challenge for precision therapies and clinical trial stratification. Here, in a comprehensive radiogenomics study of 358 GBMs, we investigated the associations between the imaging and spatial characteristics of the tumors with their cancer gene mutation status, as well as with the cross-sectionally inferred likely order of mutational events. We show that cross-validated machine learning analysis of multi-parametric MRI scans results in distinctive in vivo imaging signatures of several mutations, which are relatively more distinctive in homogeneous tumors which harbor only one of these mutations. These imaging signatures offer mechanistic insights into how various mutations influence the phenotype of the tumor and its surrounding infiltrated brain tissue via neovascularization and vascular leakage, increased cell density, invasion and migration, and other characteristics captured by respective imaging features. Furthermore, we found that spatial location and tumor distribution vary, depending on the GBMs molecular characteristics. Finally, distinct imaging and spatial characteristics were associated with cross-sectionally estimated evolutionary trajectories of the tumors. Collectively, our study establishes a panel of in vivo and clinically accessible imaging-AI biomarkers of GBM that reflect their molecular composition and oncogenic drivers.

bioengineering↗

bioRxiv2022

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (Ksr2) locus develop severe early-onset obesity and type 2 diabetes (T2D). Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with Ksr2s known role as a regulator of feeding by its function in the hypothalamus, pair feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in absence of Ksr2, bone strength, as well as fracture healing response remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how Ksr2, an adiposity and diabetic gene, regulates bone metabolism.

genetics↗

bioRxiv2022

In vitro and in silico analysis proving DPP4 inhibition and diabetes associated gene network modulation by a polyherbal formulation - Nisakathakadi Kashaya.

Frontiers of disease biology started recognizing the importance of systems and network medicine approach for managing chronic disease like diabetes. Dipeptidyl-peptidase IV (DPP4) inhibitors are one such class of anti-diabetic drugs recognized for their systemic biological actions. Polyherbal preparations like Ayurveda formulations are ideal for identifying novel DPP4 inhibitors having greater efficacy and safety profile. Additionally, expanding the research on the multitargeted mode of action of these polyherbal formulations can render novel insights into the complex biology of disease manifestations. The current study aims at identifying DPP4 inhibitory potential of a clinically established Ayurveda anti-diabetic formulation Nisakathakadi Kashaya (NK) using in vitro and in silico methods as well as the modulation of diabetes associated gene network by NK. a. Standard enzyme inhibition assay was used to study the DPP4 inhibitory potential of NK, followed by bioinformatics and computational biology tools for identifying the potential bioactives and their molecular interactions involved in DPP4 inhibition. STITCH, CHEMBL and BindingDB databases were used for target mapping and depicting the multi-targeted network pharmacology interaction of NK and the formulation. EnrichR was used to depict a sub-network of diabetes proteins and their relationship with diabetes associated comorbidities. NK demonstrated a dose dependent DPP4 inhibition with an IC50 of 2.06 g GAE/mL. Molecular docking identified three compounds namely Terchebin, Locaracemoside B and 1,2,4,6 Tetra o Galloyl Beta D Glucose showing stable interactions with DPP4 similar to the standard drug Vildagliptin. The network pharmacology analysis of NK identified a number of targets like TNF, TGF{beta}1, SOD1, SOD2, AKT1, DPP4 and GLP1R in its protein-protein interaction network which are vital to diabetic progression and complications. The present work demonstrated that the polyherbal formulation NK has DPP4 inhibition potential and modulates a large number of diabetes related proteins and pathways. The approach adopted in the current study by combining in vitro and in silico methods allowed us to understand the mechanism of DPP4 inhibition by the formulation and also the possible pharmacological networking through which the formulation exert its systemic effect in diabetes management.

systems biology↗

bioRxiv2022

Differences in pathways contributing to thyroid hormone effects on postnatal cartilage calcification versus secondary ossification center development

The proximal and distal femur epiphysis of mice are both weight bearing structures derived from chondrocytes but differ in development. Mineralization at the distal epiphysis occurs in an osteoblast rich secondary ossification center (SOC), while the chondrocytes of the proximal femur head (FH) in particular, are directly mineralized. Thyroid hormone (TH) plays important roles in distal knee SOC formation, but whether TH also affects proximal FH development remains unexplored. Here, we found that TH controls chondrocyte maturation and mineralization at the FH in vivo through studies in Thyroid stimulating hormone receptor (Tshr-/-) hypothyroid mice by X-ray, histology, transcriptional profiling, and immunofluorescence staining. Both in vivo, and in vitro studies conducted in ATDC5 chondrocyte progenitors concur that TH regulates expression of genes that modulate mineralization (Bsp, Ocn, Dmp1, Opn, and Alp). Our work also delineates differences in prominent transcription factor regulation of genes involved in the different mechanisms leading to proximal FH cartilage calcification and endochondral ossification at the distal femur. The information on the molecular pathways contributing to postnatal cartilage calcification can provide insights on therapeutic strategies to treat pathological calcification that occurs in soft tissues such as aorta, kidney, and articular cartilage.

physiology↗