Notes

A new 16S rRNA gene sequencing based review involving oral microbiota throughout migraine individuals inside China.
The hallmark of atherogenesis is characterized as endothelial dysfunction and subsequent macrophage activation. Although our previous study has demonstrated that endothelin-1 (ET-1) plays an important role in atherogenesis, the underlying mechanism remains deeply investigation. Enhanced atherosclerotic plaques were observed in endothelium-specific ET-1 overexpression ApoE-/- mice (eET-1/ApoE-/-) concomitant with increased secretion of pro-inflammatory adhesion molecules and cytokines. The conditional media used for culturing human umbilical vein endothelial cells (HUVECs) with AdET-1 infection and subjected to OX-LDL stimulation, was collected and utilized for bone marrow-derived macrophages (BMDMs) culturing. RT-PCR analysis showed increased genes expression related to classical M1 macrophages but decreased alternative activated M2 macrophages genes expression in macrophage culturing with the conditional media. read more Furthermore, consistent regulations of macrophage polarization were observed using isolated exosomes from the conditional media. More importantly, we noticed that miR-33 was enriched in the exosomes derived by HUVECs with AdET-1 infection, while bioinformatics analysis further indicated that miR-33 directly targeted NR4A and miR-33/NR4A axis was required for the effect of endothelial-specific ET-1 overexpression on pro-inflammatory macrophage activation. By contrast, such effects could be reversed by ET-1 knockdown. Taken together, our study indicated that the exosomes derived by HUVECs with AdET-1 infection can transfer miR-33 to macrophages and subsequently promote pro-inflammatory macrophage activation by directly targeting to NR4A. These evidences clearly revealed that miR-33/NR4A axis was the important mechanism underlying the effect of ET-1 on macrophage activation and indicated that ET-1 may act as a promising target for atherosclerosis management.The eukaryotic plasma membrane's lipid composition is found to be ubiquitously asymmetric comparing inner and outer leaflets. This membrane lipid asymmetry plays a crucial role in diverse cellular processes critical for cell survival. A specialized set of transmembrane proteins called translocases, or flippases, have evolved to maintain this membrane lipid asymmetry in an energy-dependent manner. One potential consequence of local variations in membrane lipid asymmetry is membrane remodeling, which is essential for cellular processes such as intracellular trafficking. Recently, there has been a surge in the identification and characterization of flippases, which has significantly advanced the understanding of their functional mechanisms. Furthermore, there are intriguing possibilities for a coupling between membrane curvature and flippase activity. In this review we highlight studies that link membrane shape and remodeling to differential stresses generated by the activity of lipid flippases with an emphasis on data obtained through model membrane systems. We review the common mechanistic models of flippase-mediated lipid flipping and discuss common techniques used to test lipid flippase activity. We then compare the existing data on lipid translocation rates by flippases and conclude with potential future directions for this field.Structure determination of membrane proteins is critical to the molecular understanding of many life processes, yet it has historically been a technically challenging endeavor. This past decade has given rise to a number of technological advancements, techniques, and reagents, which have facilitated membrane protein structural biology, resulting in an ever-growing number of membrane protein structures determined. To collate these advances, we have mined available literature to analyze the purification and structure determination specifics for all uniquely solved membrane protein structures from 2010 to 2019. Our analyses demonstrate the strong impact of single-particle cryo-electron microscopy on the field and illustrate how this technique has affected detergent and membrane mimetic usage. Furthermore, we detail how different structure determination methods, taxonomic domains and protein classes have unique detergent/membrane mimetic profiles, highlighting the importance of tailoring their selection. Our analyses provide a quantitative overview of where the field of membrane protein structural biology stands and how it has developed over time. We anticipate that these will serve as a useful tool to streamline future membrane protein structure determination by guiding the choice of detergent/membrane mimetic.Mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and proliferation by sensing fluctuations in environmental cues such as nutrients, growth factors, and energy levels. The Rag GTPases (Rags) serve as a critical module that signals amino acid (AA) availability to modulate mTORC1 localization and activity. Recent studies have demonstrated how AAs regulate mTORC1 activity through Rags. Here, we uncover an unconventional pathway that activates mTORC1 in response to variations in threonine (Thr) levels via mitochondrial threonyl-tRNA synthetase TARS2. TARS2 interacts with inactive Rags, particularly GTP-RagC, leading to increased GTP loading of RagA. mTORC1 activity in cells lacking TARS2 is resistant to Thr repletion, showing that TARS2 is necessary for Thr-dependent mTORC1 activation. The requirement of TARS2, but not cytoplasmic threonyl-tRNA synthetase TARS, for this effect demonstrates an additional layer of complexity in the regulation of mTORC1 activity.In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.The APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease and the APOE ε2 allele the strongest genetic protective factor after multiple large scale genome-wide association studies and genome-wide association meta-analyses. However, no therapies directed at APOE are currently available. Although initial studies causally linked APOE with amyloid-β peptide aggregation and clearance, over the past 5 years our understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier disruption. Because all these pathological processes can potentially contribute to cognitive impairment, it is important to use this new knowledge to develop therapies directed at APOE. Several therapeutic approaches have been successful in mouse models expressing human APOE alleles, including increasing or reducing APOE levels, enhancing its lipidation, blocking the interactions between APOE and amyloid-β peptide, and genetically switching APOE4 to APOE3 or APOE2 isoforms, but translation to human clinical trials has proven challenging.
Millions of children globally are at risk of not reaching their developmental potential because of early adversities. We hypothesised that responsive caregiving and learning opportunities, components of nurturing care, at pre-school ages might mitigate the effects of adversities.

We analysed longitudinal birth cohort data from Brazil (1993 Pelotas Birth Cohort, n=632) and South Africa (Birth to Twenty Plus [Bt20+] Birth Cohort, n=1130) to assess whether responsive caregiving and learning opportunities at pre-school ages (2-4 years) modified associations between cumulative early adversities and adolescent human capital. The cumulative adversities score (range 0-9) included household wealth and crowding; mothers' schooling, height, age, and mental health; and children's birthweight, gestational age, and length at age 12 months. We extracted data on responsive caregiving and learning opportunities from the Early Childhood Home Observation for Measurement of the Environment inventory, assessed at age 4 years Bt20+ cohort (0·86 [-0·12 to 1·83] and 0·65 [-0·32 to 1·61], respectively). Associations between early adversities and IQ were modified by learning opportunities in the 1993 Pelotas cohort (beta coefficient for interaction 1·74, 95% CI 0·43 to 3·04; p=0·0092) and by responsive caregiving in the Bt20+ cohort (2·24, 0·94 to 3·54; p=0·0075). High nurturing environment attenuated the negative effects of early cumulative adversities on IQ.

Early nurturing home environments protect young children against effects of early adversities on adolescent IQ, with long-term positive associations on adolescent cognition in two middle-income countries.

Bill & Melinda Gates Foundation.
Bill & Melinda Gates Foundation.
To translate and cross-culturally adapt the Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) for use in Brazilian Portuguese. The CBBDQ is an 18-item tool covering 10 bladder and 8 bowel symptoms that was developed for use with children of 5 to 12 years of age with bowel and bladder dysfunction (BBD). The instrument has already been validated for use in Dutch and English.

In the process of translation and cultural adaptation from English to Portuguese, the CBBDQ was submitted to undergo the required steps as established by the international methodological criteria forward translation, synthesis, back-translation, expert panel review and pre-testing.

Ninety-three parents of children with lower urinary tract dysfunction answered the questionnaire. The mean age of the children was 7.6±2.1 years and 54 were female. Internal consistency was excellent, with a Cronbach's alpha of 0.91 to 0.96. Additionally, reliability was high, with an intraclass correlation coefficient of 0.94 (95%CI 0.85-0.93; p<0.0001).

The translation and cultural adaptation of the CBBDQ enabled a quantitative evaluation of bladder and bowel symptoms to be performed in Brazilian children. The scores achieved allow the severity of BBD to be evaluated, as well as the patient's progress during treatment. The use of this questionnaire in clinical practice and research will allow more consistent data on BBD to be obtained.
The translation and cultural adaptation of the CBBDQ enabled a quantitative evaluation of bladder and bowel symptoms to be performed in Brazilian children. The scores achieved allow the severity of BBD to be evaluated, as well as the patient's progress during treatment. The use of this questionnaire in clinical practice and research will allow more consistent data on BBD to be obtained.
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