Gut microbes play prime role in human health and have shown to exert their influence on various physiological responses including neurological functions. Growing evidences in recent years have ...indicated a key role of gut microbiota in contributing to mental health. The connection between gut and brain is modulated by microbes via neural, neuroendocrinal and metabolic pathways that are mediated through various neurotransmitters and their precursors, hormones, cytokines and bioactive metabolites. Impaired functioning of this connection can lead to manifestation of mental disorders. Around 1 billion of the world population is reported to suffer from emotional, psychological and neurological imbalances, substance use disorders and cognitive, psychosocial and intellectual disabilities. Thus, it becomes imperative to understand the role of gut microbes in mental disorders. Since variations occur in the conditions associated with different mental disorders and some of them have overlapping symptoms, it becomes important to have a holistic understanding of gut dysbiosis in these disorders. In this review, we consolidate the recent data on alterations in the gut microbes and its consequences in various neurological, psychological and neurodegenerative disorders. Further, considering these evidences, several studies have been undertaken to specifically target the gut microbiota through different therapeutic interventions including administration of live microbes (psychobiotics) to treat mental health disorders and/or their symptoms. We review these studies and propose that an integrative and personalized approach, where combinations of microbe-based therapeutic interventions to modulate gut microbes and in-use psychological treatment practices can be integrated and based on patient’s gut microbiome can be potentially adopted for effective treatment of the mental disorders.
Host genetic variants can determine their susceptibility to COVID-19 infection and severity as noted in a recent Genome-wide Association Study (GWAS). Given the prominent genetic differences in ...Indian sub-populations as well as differential prevalence of COVID-19, here, we compute genetic risk scores in diverse Indian sub-populations that may predict differences in the severity of COVID-19 outcomes. We utilized the top 100 most significantly associated single-nucleotide polymorphisms (SNPs) from a GWAS by Pairo-Castineira et al
.
determining the genetic susceptibility to severe COVID-19 infection, to compute population-wise polygenic risk scores (PRS) for populations represented in the Indian Genome Variation Consortium (IGVC) database. Using a generalized linear model accounting for confounding variables, we found that median PRS was significantly associated (
p
< 2 x 10
−16
) with COVID-19 mortality in each district corresponding to the population studied and had the largest effect on mortality (regression coefficient = 10.25). As a control we repeated our analysis on randomly selected 100 non-associated SNPs several times and did not find significant association. Therefore, we conclude that genetic susceptibility may play a major role in determining the differences in COVID-19 outcomes and mortality across the Indian sub-continent. We suggest that combining PRS with other observed risk-factors in a Bayesian framework may provide a better prediction model for ascertaining high COVID-19 risk groups and to design more effective public health resource allocation and vaccine distribution schemes.
Deteriorating weight loss in patients with Huntington's disease (HD) is a complicated peripheral manifestation and the cause remains poorly understood. Studies suggest that body weight strongly ...influences the clinical progression rate of HD and thereby offers a valuable target for therapeutic interventions. Mutant huntingtin (mHTT) is ubiquitously expressed and could induce toxicity by directly acting in the peripheral tissues. We investigated the effects of selective expression of mHTT exon1 in fat body (FB; functionally equivalent to human adipose tissue and liver) using transgenic Drosophila. We find that FB-autonomous expression of mHTT exon1 is intrinsically toxic and causes chronic weight loss in the flies despite progressive hyperphagia, and early adult death. Moreover, flies exhibit loss of intracellular lipid stores, and decline in the systemic levels of lipids and carbohydrates which aggravates over time, representing metabolic defects. At the cellular level, besides impairment, cell death also occurs with the formation of mHTT aggregates in the FB. These findings indicate that FB-autonomous expression of mHTT alone is sufficient to cause metabolic abnormalities and emaciation in vivo without any neurodegenerative cues.
Deinococcus
species are widely studied due to their utility in bioremediation of sites contaminated with radioactive elements. In the present study, we re-evaluated the taxonomic placement of two ...species of the genus
Deinococcus
namely
D. swuensis
DY59
T
and
D. radiopugnans
ATCC 19172
T
based on whole genome analyses. The 16S rRNA gene analysis revealed a 99.58% sequence similarity between this species pair that is above the recommended threshold value for species delineation. These two species also clustered together in both the 16S rRNA gene and core genome based phylogenies depicting their close relatedness. Furthermore, more than 98% of genes were shared between
D. swuensi
s DY59
T
and
D. radiopugnans
ATCC 19172
T
. Interestingly,
D. swuensis
DY59
T
and
D. radiopugnans
ATCC 19172
T
shared high genome similarity in different genomic indices. They displayed an average nucleotide identity value of 97.63%, an average amino acid identity value of 97% and a digital DNA–DNA hybridization value equal to 79.50%, all of which are well above the cut-off for species delineation. Altogether, based on these evidences,
D. swuensis
DY59
T
and
D. radiopugnans
ATCC 19172
T
constitute a single species. Hence, as per the priority of publication, we propose that
Deinococcus swuensis
Lee
et al.
2015 should be reclassified as a later heterotypic synonym of
Deinococcus radiopugnans
.
ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, ...facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80−PD-L2− memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
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•ARID1A enables stepwise and cooperative chromatin binding for PU.1 and NF-kB factors•Multiome analysis shows ARID1A loss drives cell fate toward memory B cell program•ARID1A loss links memory-like FLs to higher DLBCL transformation risk in patients•ARID1A-mutant lymphoma cells show enhanced vulnerability to BAF complex inhibition
Barisic et al. show a chromatin remodeling mechanism by which the BAF complex enables stepwise binding of PU.1 and NF-kB factors, thus restricting the memory B cell program and transformation to an aggressive form of lymphoma.
SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and ...transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.
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•Smarca4 is a haploinsufficient tumor suppressor in B cells•Partial, but not complete, loss of Smarca4 drives germinal center hyperplasia•Smarca4 loss biases centrocyte cell fate toward dark zone recycling•BCL6-antagonistic TFs SPI1, IRF4, and NF-κB have reduced activity following Smarca4 loss
Deng et al. identify a germinal center-specific role for SMARCA4 (BRG1) in regulating centrocyte cell fate decisions by facilitating chromatin accessibility in association with SPI1 (PU.1) and IRF transcription factors. Loss of Smarca4 partially phenocopies BCL6 activation and cooperates with MYC over-expression to drive lymphomagenesis.
Parasitic twins are an extremely rare form of asymmetrical conjoined monochorial monoamniotic twins where one of them has a mostly intact body that is able to survive and which is referred to as ...‘autosite’, while the counterpart, referred to as ‘parasite’, is only rudimentarily developed being physically attached to and nourished by the other twin. Our case is a baby boy with Single Ventricle Heart defect with a thoraco-abdominal mass (epigastric heteropagus twin) attached to the anterior abdominal wall near the umbilicus with minimal visceral sharing. The twins had two external genitalia both in host and parasite micturating separately. After high risk surgery the parasite could be separated completely from the host and postoperative recovery was uneventful.
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