Notes

Accuracy regarding gradient diffusion method for vulnerability testing involving dalbavancin along with comparators.
SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown.

Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts.

SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine.

Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age50.

We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratios (ORs) and 95% CIs for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model.

We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend= .01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n= 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n= 1,878).

In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.
In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.
The gut virome includes eukaryotic viruses and bacteriophages that can shape the gut bacterial community and elicit host responses. The virome can be implicated in diseases, such as irritable bowel syndrome (IBS), where gut bacteria play an important role in pathogenesis. We provide a comprehensive and longitudinal characterization of the virome, including DNA and RNA viruses and paired multi-omics data in a cohort of healthy subjects and patients with IBS.

We selected 2 consecutive stool samples per subject from a longitudinal study cohort and performed metagenomic sequencing on DNA and RNA viruses after enriching for viral-like particles. Viral sequence abundance was evaluated over time, as well as in the context of diet, bacterial composition and function, metabolite levels, colonic gene expression, host genetics, and IBS subsets.

We found that the gut virome was temporally stable and correlated with the colonic transcriptome. We identified IBS-subset-specific changes in phage populations; Microviridae, Myoviridae, and Podoviridae species were elevated in diarrhea-predominant IBS, and other Microviridae and Myoviridae species were elevated in constipation-predominant IBS compared to healthy controls. ABBV-744 We identified correlations between subsets of the virome and bacterial composition (unclassifiable "dark matter" and phages) and diet (eukaryotic viruses).

We found that the gut virome is stable over time but varies among subsets of patients with IBS. It can be affected by diet and potentially influences host function via interactions with gut bacteria and/or altering host gene expression.
We found that the gut virome is stable over time but varies among subsets of patients with IBS. It can be affected by diet and potentially influences host function via interactions with gut bacteria and/or altering host gene expression.Regular exercise has been identified to facilitate neuroplasticity that maximize functional outcome after brain injuries. Brain-derived neurotrophic factor (BDNF) has emerged as a key facilitator of neuroplasticity after exercise. The activity-regulated cytoskeleton associated protein (Arc) is induced by BDNF and N-methyl-d-aspartic acid receptor (NMDAR), contributing to functional modification of neuroplasticity in the hippocampus. Meanwhile, early-life exposure to neuroendocrine disruptor di-(2-ethylhexyl)-phthalate (DEHP) is a risk factor for behavioral deficits, but the mechanisms responsible for DEHP-induced neurotoxicity are not well understood. The purpose of this study is to investigate whether hippocampal Arc expression is impaired by DEHP exposure and to examine the protective role of exercise in the prenatally DEHP-exposed male rats. Sprague Dawley dams were fed with vehicle or DEHP during gestation. The male offspring were trained to treadmill running for 5 weeks followed by examination of behavioral and biochemical outcomes. The results showed that DEHP-exposed rats exhibited impairment of spatial learning and memory as well as down-regulations of BDNF, NMDAR, Arc, and synaptophysin. Importantly, aerobic exercise during childhood-adolescence prevented the impairment of learning and memory by recovering the expressions of BDNF, NMDAR, Arc, and synaptophysin. These findings suggest that exercise may provide beneficial effects on ameliorating the impairment of neuroplasticity in the prenatally DEHP-exposed male rats at late adolescence.Aging is associated with cognitive decline. Importantly cognition and cerebral health is enhanced with interventions like cognitive (CT) and exercise training (ET). However, effects of CT and ET interventions on brain magnetic resonance imaging outcomes have never been compared systematically. Here, the primary objective was to critically and systematically compare CT to ET in healthy older adults on brain MRI outcomes. A total of 38 studies were included in the final review. Although results were mixed, patterns were identified CT showed improvements in white matter microstructure, while ET demonstrated macrostructural enhancements, and both demonstrated changes to task-based BOLD signal changes. Importantly, beneficial effects for cognitive and cerebral outcomes were observed by almost all, regardless of intervention type. Overall, it is suggested that future work include more than one MRI outcome, and report all results including null. To better understand the MRI changes associated with CT or ET, more studies explicitly comparing interventions within the same domain (i.e. resistance vs. aerobic) and between domains (i.e. CT vs. ET) are needed.The development of blood-based biomarkers of Alzheimer's disease (AD) pathology as tools for screening the general population is essential, but persists controversies. We aimed to evaluate the effects of AD core pathological biomarkers on blood, and systematical searched Embase, PubMed and Cochrane for eligible studies. Biomarker performance was rated by random-effects meta-analysis based on the ratio of means method and multivariable-adjusted effect estimates. Finally, 150 articles were included, which demonstrated T-tau (average ratio 1.25-1.62), P-tau 181 (1.36-2.16) and NfL (1.24-1.86) were increased, and AβPPr (0.65-0.88) were decreased from controls to amnestic mild cognitive impairment (aMCI) to AD. Furthermore, Aβ42, Aβ42/Aβ40 ratio and P-tau 217 using ultrasensitive platforms also had great diagnostic accuracy from controls to aMCI to AD. Consequently, significantly changes of blood AD core biomarkers were verified in comparison between AD, aMCI and control, supporting biomarkers were strongly valid in identifying AD and aMCI, which provides a new prospect of AD early diagnosis and progressive monitoring. This study is registered with PROSPERO, number CRD42020191927.Laboratory animal research has provided significant knowledge into the function of cortical circuits at the laminar level, which has yet to be fully leveraged towards insights about human brain function on a similar spatiotemporal scale. The use of functional magnetic resonance imaging (fMRI) in conjunction with neural models provides new opportunities to gain important insights from current knowledge. During the last five years, human studies have demonstrated the value of high-resolution fMRI to study laminar-specific activity in the human brain. This is mostly performed at ultra-high-field strengths (≥ 7 T) and is known as laminar fMRI. Advancements in laminar fMRI are beginning to open new possibilities for studying questions in basic cognitive neuroscience. In this paper, we first review recent methodological advances in laminar fMRI and describe recent human laminar fMRI studies. Then, we discuss how the use of laminar fMRI can help bridge the gap between cortical circuit models and human cognition.Neurodegenerative disorders, particularly in the elderly population, represent one of the most pressing social and health-care problems in the world. Besides the well-established role of both oxidative stress and inflammation, alterations of the immune response have been found to be closely linked to the development of neurodegenerative diseases. Interestingly, various scientific evidence reported that an altered gut microbiota composition may contribute to the development of neuroinflammatory disorders. This leads to the proposal of the concept of the gut-brain-immune axis. In this scenario, polyphenols play a pivotal role due to their ability to exert neuroprotective, immunomodulatory and microbiota-remodeling activities. In the present review, we summarized the available literature to provide a scientific evidence regarding this neuroprotective and immunomodulatory effects and the interaction with gut microbiota of polyphenols and, the main signaling pathways involved that can explain their potential therapeutic application in neurodegenerative diseases.
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