👤 Geeti P Arora

Dietary fibre is an important regulator of the gut microbiome and is associated with many health benefits. However, high levels of fibre intake have also been reported to exacerbate some diseases. Here, we show that mice fed semi-synthetic diets supplemented with purified inulin fibre develop chronic infections with the parasitic whipworm Trichuris muris, concomitant with dysregulated innate antimicrobial defences, exacerbated mucosal inflammation, and altered tryptophan metabolism. Inhibition of tryptophan catabolism or neutralizing either IL-27 or IL-18 restored infection resistance. Inulin-fed mice developed gut microbiota dysbiosis during parasite infection, with Proteobacteria becoming dominant. However, despite drastic differences in gut microbiota compositions in control- and inulin-fed mice, microbiota transfer and depletion experiments demonstrated that dietary inulin triggered chronic T. muris infection in a microbiota-independent manner. Importantly, removing inulin from the diet within a critical immune development window rapidly restored anti-parasite immunity, indicating direct, time-dependent modulation of mucosal immune responses. These data reveal T. muris-induced dysbiosis as a consequence rather than a causative factor of diet-driven changes in host susceptibility, and establish a direct link between dietary fibre and host defence at mucosal surfaces. Video Abstract. Show less

The assessment of serious illness communication (SIC) competence has, to date, primarily utilized tools that are profession-specific and not explicitly designed using competency-based or person-centered frameworks. To address these gaps, we developed and validated a new tool, the Assessment of Clinical Encounters - Communication Tool (ACE-CT). We convened a national panel of interprofessional SIC experts to develop and validate the ACE-CT using a three-phase multi-method approach. Phase 1 focused on item development through review of existing validated tools, and a Bayesian process in which panel members assessed item quality and item-domain correlation. Phase 2 involved item refinement and preliminary validation through stimulated recall interviews using a think-aloud technique. Phase 3 consisted of psychometric analyses for which panel members used the tool to assess video-recorded standardized patient encounters from interprofessional clinicians completing a SIC professional development intervention. In Phase 1, 37 relevant items from previously validated tools were identified, of which 11 items were removed due to redundance. Through the Bayesian process, 14 items were removed and 1 item was generated. Through Phase 2, 2 items were generated, 2 items were combined into 1, and remaining items were refined to optimize measurability and understandability. In Phase 3, reliability was demonstrated through evidence of high internal consistency and moderate reproducibility, both over time and across raters. The tool was found to be responsive and have sound construct validity through evidence of congruence, convergence and credibility. Raters found the tool to be intuitive, easy to complete, and that it accurately captured their perception of the quality of communication observed. The ACE-CT provides a reliable and valid approach to assessing SIC competence among interprofessional clinicians. Through its person-centered orientation, the ACE-CT provides an opportunity to objectively assess elements of SIC that patients and families value. Show less

Physical activity (PA) and sedentary behavior (SB) are associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. This study aims to address this gap, with a specific focus on all-cause dementia. We first assessed the conventional observational associations of three self-reported and three device-based PA/SB measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n max =39,160) and assessed functional enrichment of identified proteins. We then used bi-directional Mendelian randomization (MR) to further evaluate the evidence for causal relationships of PA/SB with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. Our findings revealed 41 proteins consistently associated with all PA measures and 1,027 proteins associated with at least one PA measure. Both conventional observational and MR study designs converged on proteins that appear to increase as a result of PA, including integrins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, LPL, and ADGRG2; on proteins that appear to decrease as a result of PA such as LEP, INHBC, CLMP, PTGDS, ADM, OGN, and PI3; and on proteins that are more responsive to high-intensity PA, such as CA14, CA6, CA4, KIT, and ANGPT2. Functional enrichment analyses revealed processes such as cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, GDF15, ITGAV, ITGAM, ITGA11, HPGDS, GFAP, ADM, AHNAK, and DPP4 were among 21 unique proteins found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis, and inflammation. Our results provide insights into how PA affects biological processes and protects against dementia, and provide avenues for future research into the health-promoting effects of PA. Show less

Pancreatic cancer (PC) is among the deadliest malignancies, characterized by poor treatment response. Natural bioactive compounds, such as Morin, a flavonoid, have gained interest as potential therapeutic agents due to their anticancer properties but remain unexplored in PC. This study investigates the anticancer effects of Morin on PC cells, particularly its ability to induce mitophagy via the PINK1/Parkin pathway and modulate mitochondrial function and cancer stemness. PANC-1 cells were treated with Morin, and its impact on tumorigenic potential was evaluated using in vitro assays, including cell viability, colony formation, migration, invasion, and spheroid formation, as well as in vivo studies in a nude mice model. Mitochondrial function and apoptosis were assessed through flow cytometry, gene expression analysis, PCR microarrays, transmission electron microscopy (TEM), immunofluorescence, ELISA, western blotting, and molecular docking. Morin exhibited dose-dependent cytotoxicity, significantly reducing viability, colony formation, migration, and invasion in PC. It downregulated mesenchymal and stemness markers (N-cadherin, SNAI1, ZEB1, SOX2, NANOG, OCT4) while upregulating E-cadherin. Morin disrupted spheroid morphology and decreased ALDH activity, indicating reduced cancer stemness. Additionally, Morin-induced mitochondrial dysfunction, as evidenced by decreased membrane potential, ATP synthase activity, and mitochondrial mass, along with increased mitochondrial superoxide production. Upregulation of mitophagy markers (PINK1, Parkin, pAMPK, LC3A/B) and downregulation of fusion (MFN2) confirmed PINK1-mediated mitophagy. Apoptosis induction was supported by Annexin V/PI staining, TEM, elevated caspase-3/-9 levels, and cytochrome c release. Molecular docking confirmed strong Morin-PINK1 interaction. Morin induces mitophagy, promotes apoptosis, and suppresses cancer invasiveness in PC cells, highlighting its potential as an adjuvant therapeutic agent. Future clinical studies are warranted to evaluate its relevance. Show less

Venetoclax showed promising activity in a small phase II trial in relapsed/refractory Waldenström macroglobulinemia (WM). To report the clinical activity of venetoclax and prognostic factors associated with outcomes in a larger cohort, we retrospectively identified 76 patients with relapsed/refractory lymphoplasmacytic lymphoma (LPL)/WM treated with venetoclax monotherapy at nine US medical centers. The median age at venetoclax treatment initiation was 66 years. MYD88, CXCR4, and TP53 mutations were detected in 65 (94%), 23 (40%), and 10 (22%) patients, respectively. The median number of prior lines of treatment was 3, including covalent BTK inhibitor in 82% and alkylating agent in 71% of patients. The overall and major response rates to venetoclax were 70% and 63%, respectively. The median and 2-year progression-free survival (PFS) were 28.5 months and 57%, respectively. The median and 2-year overall survival were not reached and 82%, respectively. Prior treatment with BTK inhibitor was the only factor associated with PFS in multivariate analysis (hazard ratio 2.97, p = 0.012). Venetoclax dose interruptions and/or reductions occurred in 27 patients (41%). Five patients (7%) developed laboratory tumor lysis syndrome (TLS), including 3 (4%) with clinical TLS. Venetoclax resulted in a high response rate and a prolonged PFS in patients with heavily pretreated LPL/WM. Show less

Physical activity (PA), including sedentary behavior, is associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. To address this knowledge gap, we first assessed the conventional observational associations of three self-reported and three device-based PA measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n Show less

The majority of available transcriptomics-related cancer prognosis studies strive to define one collection of biomarkers that can be used to predict high-risk patients. However, using a single biomarker profile could restrict its strength and applicability to diverse groups of patients. In order to fill this gap, we discuss the prospect of determining several, discrete sets of prognostic biomarkers in Skin Cutaneous Melanoma (SKCM). Our search identifies various genes including CREG1, PCGF5 and VPS13C whose expression pattern depicts significant correlations with overall survival (OS) in SKCM patients. We developed machine learning-based prognostic models using SKCM gene expression data to predict 1-, 3-, and 5-year overall survival. Advanced feature selection approaches were applied to identify prognostic biomarkers. The primary biomarker set consisted of 20 genes selected using state-of-the-art feature selection techniques. Machine learning classifiers were trained to distinguish high-risk from low-risk patients using these biomarkers. The process was systematically repeated to identify seven independent biomarker sets, each containing 20 unique genes without overlap. Model performance was evaluated using AUC and Cohen's Kappa metrics on an independent test dataset. Validation was further performed using the GEO dataset GSE65904, employing subsets of biomarkers from the primary and third sets. The primary biomarker-based prognostic model demonstrated strong predictive ability, achieving an AUC of 0.90 and a Kappa of 0.58 in identifying high-risk SKCM patients. A second independent 20-gene set, with no overlap with the first, produced an AUC of 0.89 and Kappa of 0.56. Across all seven biomarker sets, performance ranged from 0.84 to 0.91 (AUC) and 0.48 to 0.64 (Kappa). Notably, the fifth biomarker set yielded the highest performance with an AUC of 0.91 and Kappa of 0.64. External validation confirmed the predictive utility of selected biomarkers where genes from the primary set achieved an AUC of 0.83 on GSE65904. While genes from the third set achieved an AUC of 0.86 on the same dataset. Our results show that only one gene-expression signature is not sufficient to predict SKCM prognosis. Alternatively, high-risk patients can be accurately predicted using multiple independent biomarker sets providing flexibility in both clinical and computational practices. The high similarity in the results of all seven sets (AUC 0.84-0.91; Kappa 0.48-0.64) signifies the stability and strength of the method. The external validation of these biomarkers with GEO data also helps to confirm the reliability of these biomarkers and hints at their potential wider applicability. This work facilitates transparency by ensuring that all the data and code is publicly accessible (https://github.com/raghavagps/skcm_prognostic_biomarker), which also promotes future developments in creating multi-signature prognostic tools in melanoma. Show less

Considering global climate change concerns, issues related to the energy crisis and technologies reliant on non-fossil renewable energy sources are in high demand. Solar energy emerges as one of the alternatives among all renewable energy resources due to its economic viability and environmental sustainability. There are various types of solar photovoltaic (PV) technologies available for commercial applications, such as organic solar cells, silicon-based solar cells, dye-sensitized solar cells, and perovskite solar cells. Notably, one of the drawbacks of PV devices is their inability to generate power at night or during cloudy days (i.e., low-light conditions). One solution to this problem is to provide backup to the PV devices, such as batteries or energy storage packs. Another less explored alternative backup is the application of long persistent luminescence (LPL) materials as a secondary light source or down shifter. LPL materials can provide an afterglow that can last for hours which can be harvested by PV devices for power generation under low-light conditions. This short overview article discusses the fundamental mechanisms of LPL materials and the feasibility and challenges of integrating LPL materials into PV, which is hoped can provide useful insights for future research directions. Show less

In this study, comparative analysis of skeletal muscle transcriptome was carried out for four biological replicates of Aseel, a fighter type breed and Punjab Brown, a meat type breed of India. The profusely expressed genes in both breeds were related to muscle contraction and motor activity. Differential expression analysis identified 961 up-regulated and 979 down-regulated genes in Aseel at a threshold of log Show less

Mutations in cardiac myosin binding protein C (MyBP-C, encoded by MYBPC3) are the most common cause of hypertrophic cardiomyopathy (HCM). Most MYBPC3 mutations result in premature termination codons (PTCs) that cause RNA degradation and a reduction of MyBP-C in HCM patient hearts. However, a reduction in MyBP-C has not been consistently observed in MYBPC3-mutant induced pluripotent stem cell cardiomyocytes (iPSCMs). To determine early MYBPC3 mutation effects, we used patient and genome-engineered iPSCMs. iPSCMs with frameshift mutations were compared with iPSCMs with MYBPC3 promoter and translational start site deletions, revealing that allelic loss of function is the primary inciting consequence of mutations causing PTCs. Despite a reduction in wild-type mRNA in all heterozygous iPSCMs, no reduction in MyBP-C protein was observed, indicating protein-level compensation through what we believe is a previously uncharacterized mechanism. Although homozygous mutant iPSCMs exhibited contractile dysregulation, heterozygous mutant iPSCMs had normal contractile function in the context of compensated MyBP-C levels. Agnostic RNA-Seq analysis revealed differential expression in genes involved in protein folding as the only dysregulated gene set. To determine how MYBPC3-mutant iPSCMs achieve compensated MyBP-C levels, sarcomeric protein synthesis and degradation were measured with stable isotope labeling. Heterozygous mutant iPSCMs showed reduced MyBP-C synthesis rates but a slower rate of MyBP-C degradation. These findings indicate that cardiomyocytes have an innate capacity to attain normal MyBP-C stoichiometry despite MYBPC3 allelic loss of function due to truncating mutations. Modulating MyBP-C degradation to maintain MyBP-C protein levels may be a novel treatment approach upstream of contractile dysfunction for HCM. Show less

Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy. Show less

Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Five thousand one hundred pregnant women of gestational age 24-28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women. Show less

Histone modifications play an important role in chromatin organization and gene regulation, and their interpretation is referred to as epigenetic control. The methylation levels of several lysine residues in histone tails are tightly controlled, and JmjC domain-containing proteins are one class of broadly expressed enzymes catalyzing methyl group removal. However, several JmjC proteins remain uncharacterized, gaps persist in understanding substrate recognition, and the integration of JmjC proteins into signaling pathways is just emerging. The KDM3 subfamily is an evolutionarily conserved group of histone demethylase proteins, thought to share lysine substrate specificity. Here we use a systematic approach to compare KDM3 subfamily members. We show that full-length KDM3A and KDM3B are H3K9me1/2 histone demethylases whereas we fail to observe histone demethylase activity for JMJD1C using immunocytochemical and biochemical approaches. Structure-function analyses revealed the importance of a single amino acid in KDM3A implicated in the catalytic activity towards H3K9me1/2 that is not conserved in JMJD1C. Moreover, we use quantitative proteomic analyses to identify subsets of the interactomes of the 3 proteins. Specific interactor candidates were identified for each of the three KDM3 subfamily members. Importantly, we find that SCAI, a known transcriptional repressor, interacts specifically with KDM3B. Taken together, we identify substantial differences in the biology of KDM3 histone demethylases, namely enzymatic activity and protein-protein interactions. Such comparative approaches pave the way to a better understanding of histone demethylase specificity and protein function at a systems level and are instrumental in identifying the more subtle differences between closely related proteins. Show less

Protein-tyrosine phosphatases (PTPs) are important regulators of cellular signaling and changes in PTP activity can contribute to cell transformation. Little is known about the role of PTPs in Acute Myeloid Leukemia (AML). The aim of this study was therefore to establish a PTP expression profile in AML cells and to explore the possible role of FLT3 ITD (Fms-like tyrosine kinase 3 with internal tandem duplication), an important oncoprotein in AML for PTP gene expression. PTP mRNA expression was analyzed in AML cells from patients and in cell lines using a RT-qPCR platform for detection of transcripts of 92 PTP genes. PTP mRNA expression was also analyzed based on a public microarray data set for AML patients. Highly expressed PTPs in AML belong to all PTP subfamilies. Very abundantly expressed PTP genes include PTPRC, PTPN2, PTPN6, PTPN22, DUSP1, DUSP6, DUSP10, PTP4A1, PTP4A2, PTEN, and ACP1. PTP expression was further correlated with the presence of FLT3 ITD, focusing on a set of highly expressed dual-specificity phosphatases (DUSPs). Elevated expression of DUSP6 in patients harboring FLT3 ITD was detected in this analysis. The mechanism and functional role of FLT3 ITD-mediated upregulation of DUSP6 was then explored using pharmacological inhibitors of FLT3 ITD signal transduction and si/shRNA technology in human and murine cell lines. High DUSP6 expression was causally associated with the presence of FLT3 ITD and dependent on FLT3 ITD kinase activity and ERK signaling. DUSP6 depletion moderately increased ERK1/2 activity but attenuated FLT3 ITD-dependent cell proliferation of 32D cells. In conclusion, DUSP6 may play a contributing role to FLT3 ITD-mediated cell transformation. Show less