👤 Amita Sehgal

Fatty acid desaturase (FADS1) variant-rs174550 strongly regulates polyunsaturated fatty acid (PUFA) biosynthesis. Additionally, the FADS1 is related to mitochondrial function. Thus, we investigated whether changes in mitochondrial function are associated with the genetic variation in FADS1 (rs174550) in human adipocytes isolated from individuals consuming diets enriched with either dietary alpha-linolenic (ALA) or linoleic acid (LA). Two cohorts of men homozygous for the genotype of FADS1 (rs174550) were studied: FADSDIET2 dietary intervention study with ALA- and LA-enriched diets and Kuopio Obesity Surgery study (KOBS), respectively. We could demonstrate that differentiated human adipose-derived stromal cells from subjects with the TT genotype had higher mitochondrial metabolism compared with subjects with the CC genotype of FADS1-rs174550 in the FADSDIET2. Responses to PUFA-enriched diets differed between the genotypes of FADS1-rs174550, showing that ALA, but not LA, -enriched diet stimulated mitochondrial metabolism more in subjects with the CC genotype when compared with subjects with the TT genotype. ALA, but not LA, proportion in plasma phospholipid fraction correlated positively with adipose tissue mitochondrial-DNA amount in subjects with the CC genotype of FADS1-rs174550 in the KOBS. These findings demonstrate that the FADS1-rs174550 is associated with modification in mitochondrial function in human adipocytes. Additionally, subjects with the CC genotype, when compared with the TT genotype, benefit more from the ALA-enriched diet, leading to enhanced energy metabolism in human adipocytes. Altogether, the FADS1-rs174550 could be a genetic marker to identify subjects who are most suitable to receive dietary PUFA supplementation, establishing also a personalized therapeutic strategy to improve mitochondrial function in metabolic diseases. Show less

Alzheimer's disease contributes to 60-70% of all dementia cases in the general population. Belonging to the BIN1/amphiphysin/RVS167 (BAR) superfamily, the bridging integrator (BIN1) has been identified to impact two major pathological hallmarks in Alzheimer's disease (AD), i.e., amyloid beta (Aβ) and tau accumulation. Aβ accumulation is found to increase by BIN1 knockdown in cortical neurons in late-onset AD, due to BACE1 accumulation at enlarged early endosomes. Two BIN1 mutants, KR and PL, were identified to exhibit Aβ accumulation. Furthermore, BIN1 deficiency by BIN1-related polymorphisms impairs the interaction with tau, thus elevating tau phosphorylation, altering synapse structure and tau function. Even though the precise role of BIN1 in the neuronal tissue needs further investigation, the authors aim to throw light on the potential of BIN1 and unfold its implications on tau and Aβ pathology, to aid AD researchers across the globe to examine BIN1, as an appropriate target gene for disease management. Show less

Mantle cell lymphoma (MCL) is a lethal hematological malignancy with a median survival of 4 years. Its lethality is mainly attributed to a limited understanding of clinical tumor progression and resistance to current therapeutic regimes. Intrinsic, prolonged drug treatment and tumor-microenvironment (TME) facilitated factors impart pro-tumorigenic and drug-insensitivity properties to MCL cells. Hence, elucidating neoteric pharmacotherapeutic molecular targets involved in MCL progression utilizing a global "unified" analysis for improved disease prevention is an earnest need. Using integrated transcriptomic analyses in MCL patients, we identified a Fibroblast Growth Factor Receptor-1 (FGFR1), and analyses of MCL patient samples showed that high FGFR1 expression was associated with shorter overall survival in MCL patient cohorts. Functional studies using pharmacological intervention and loss of function identify a novel MYC-EZH2-CDKN1C axis-driven proliferation in MCL. Further, pharmacological targeting with erdafitinib, a selective small molecule targeting FGFRs, induced cell-cycle arrest and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. We performed extensive pre-clinical assessments in multiple in-vivo model systems to confirm the therapeutic potential of erdafitinib in MCL and demonstrated FGFR1 as a viable therapeutic target in MCL. Show less

The diagnostic performance of pleural fluid interleukins as potential biomarkers for tuberculous pleural effusion (TPE) remains unclear. We assessed the diagnostic accuracy of various interleukins in the pleural fluid for TPE and evaluated their ability to differentiate TPE from other effusions. We queried the PubMed and Embase databases for studies indexed till October 2021. We included studies that (a) provided information regarding sensitivity and specificity of pleural fluid interleukins for diagnosing TPE, or (b) compared pleural fluid interleukin levels between TPE and malignant or parapneumonic effusions. We used hierarchical summary receiver operating characteristic plots to model summary sensitivity and specificity. Random effects modeling was employed to pool standardized mean differences (SMD) across descriptive studies comparing TPE and other effusions. We included 80 publications in our review; most were small and of poor quality. All interleukins except interleukin-27 (interleukins 1-beta, 2, 4, 6, 8, 10, 12, 12p40, 13, 18, 33) showed poor diagnostic accuracy and inconsistent discrimination of TPE from other effusions. The summary estimates for sensitivity, specificity, and diagnostic odds ratio were 0.94 (95 % CI 0.85-0.98), 0.97 (95 % CI 0.93-0.99), and 507.13 (95 % CI 130.66-1968.34) respectively for pleural fluid interleukin-27. Mean pleural fluid interleukin-27 levels in TPE were significantly higher than malignant (summary SMD 3.72, 95 % CI 2.81-4.63) or parapneumonic (summary SMD 2.45, 95 % CI -1.80-3.09) effusions. Pleural fluid interleukins are poor diagnostic biomarkers for TPE. Only pleural fluid interleukin-27 exhibited good accuracy in diagnosing TPE and needs further evaluation. Show less

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations. Show less

A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states. Show less