The intestinal microbiome is a unique ecosystem and an essential mediator of metabolism and obesity in mammals. However, studies investigating the impact of the diet on the establishment of the gut microbiome early in life are generally lacking, and most notably so in primate models. Here we report that a high-fat maternal or postnatal diet, but not obesity per se, structures the offspring’s intestinal microbiome in Macaca fuscata (Japanese macaque). The resultant microbial dysbiosis is only partially corrected by a low-fat, control diet after weaning. Unexpectedly, early exposure to a high-fat diet diminished the abundance of non-pathogenic Campylobacter in the juvenile gut, suggesting a potential role for dietary fat in shaping commensal microbial communities in primates. Our data challenge the concept of an obesity-causing gut microbiome, and rather provide evidence for a contribution of the maternal diet in establishing the microbiota, which in turn affects intestinal maintenance of metabolic health.
; for the Canadian Oxygen Trial Investigators IMPORTANCE Extremely preterm infants may experience intermittent hypoxemia or bradycardia for many weeks after birth. The prognosis of these events is uncertain. OBJECTIVE To determine the association between intermittent hypoxemia or bradycardia and late death or disability. DESIGN, SETTING, AND PARTICIPANTS Post hoc analysis of data from the inception cohort assembled for the Canadian Oxygen Trial in 25 hospitals in Canada,
The progression of tau pathology in Alzheimer's disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer's disease.
Specific metabolic underpinnings of androgen receptor (AR)-driven growth
in prostate adenocarcinoma (PCa) are largely undefined, hindering the
development of strategies to leverage the metabolic dependencies of this disease
when hormonal manipulations fail. Here we show that the mitochondrial pyruvate
carrier (MPC), a critical metabolic conduit linking cytosolic and mitochondrial
metabolism, is transcriptionally regulated by AR. Experimental MPC inhibition
restricts proliferation and metabolic outputs of the citric acid cycle (TCA)
including lipogenesis and oxidative phosphorylation in AR-driven PCa models.
Mechanistically, metabolic disruption resulting from MPC inhibition activates
the eIF2α/ATF4 integrated stress response (ISR). ISR signaling prevents
cell cycle progression while coordinating salvage efforts, chiefly enhanced
glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm
that MPC function is operant in PCa tumors
in-vivo
using
isotopomeric metabolic flux analysis. In turn, we apply a clinically viable
small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find
that MPC inhibition suppresses tumor growth in hormone-responsive and
castrate-resistant conditions. Collectively, our findings characterize the MPC
as a tractable therapeutic target in AR-driven prostate tumors.
Our pilot study suggests that HHHFNC maybe as effective as NIPPV in preventing endotracheal ventilation in the primary treatment of RDS in premature infants (<35 weeks GA and BW >1,000 g).
Phylogenies derived from gene order data may prove crucial in answering some fundamental open questions in biomolecular evolution. Yet very few techniques are available for such phylogenetic reconstructions. One method is breakpoint analysis, developed by Blanchette and Sankoff ¾ for solving the "breakpoint phylogeny." Our earlier studies confirmed the usefulness of this approach, but also found that BPAnalysis, the implementation developed by Sankoff and Blanchette, was too slow to use on all but very small datasets. We report here on a reimplementation of BPAnalysis using the principles of algorithmic engineering. Our faster (by 2 to 3 orders of magnitude) and flexible implementation allowed us to conduct studies on the characteristics of breakpoint analysis, in terms of running time, quality, and robustness, as well as to analyze datasets that had so far been considered out of reach. We report on these findings and also discuss future directions for our new implementation.
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