The association between intake of fruits, vegetables, and legumes with cardiovascular disease and deaths has been investigated extensively in Europe, the USA, Japan, and China, but little or no data ...are available from the Middle East, South America, Africa, or south Asia.
We did a prospective cohort study (Prospective Urban Rural Epidemiology PURE in 135 335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low-income, middle-income, and high-income countries in seven geographical regions: North America and Europe, South America, the Middle East, south Asia, China, southeast Asia, and Africa. We documented their diet using country-specific food frequency questionnaires at baseline. Standardised questionnaires were used to collect information about demographic factors, socioeconomic status (education, income, and employment), lifestyle (smoking, physical activity, and alcohol intake), health history and medication use, and family history of cardiovascular disease. The follow-up period varied based on the date when recruitment began at each site or country. The main clinical outcomes were major cardiovascular disease (defined as death from cardiovascular causes and non-fatal myocardial infarction, stroke, and heart failure), fatal and non-fatal myocardial infarction, fatal and non-fatal strokes, cardiovascular mortality, non-cardiovascular mortality, and total mortality. Cox frailty models with random effects were used to assess associations between fruit, vegetable, and legume consumption with risk of cardiovascular disease events and mortality.
Participants were enrolled into the study between Jan 1, 2003, and March 31, 2013. For the current analysis, we included all unrefuted outcome events in the PURE study database through March 31, 2017. Overall, combined mean fruit, vegetable and legume intake was 3·91 (SD 2·77) servings per day. During a median 7·4 years (5·5–9·3) of follow-up, 4784 major cardiovascular disease events, 1649 cardiovascular deaths, and 5796 total deaths were documented. Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex, and centre (random effect). The estimates were substantially attenuated in the multivariable adjusted models for major cardiovascular disease (hazard ratio HR 0·90, 95% CI 0·74–1·10, ptrend=0·1301), myocardial infarction (0·99, 0·74–1·31; ptrend=0·2033), stroke (0·92, 0·67–1·25; ptrend=0·7092), cardiovascular mortality (0·73, 0·53–1·02; ptrend=0·0568), non-cardiovascular mortality (0·84, 0·68–1·04; ptrend =0·0038), and total mortality (0·81, 0·68–0·96; ptrend<0·0001). The HR for total mortality was lowest for three to four servings per day (0·78, 95% CI 0·69–0·88) compared with the reference group, with no further apparent decrease in HR with higher consumption. When examined separately, fruit intake was associated with lower risk of cardiovascular, non-cardiovascular, and total mortality, while legume intake was inversely associated with non-cardiovascular death and total mortality (in fully adjusted models). For vegetables, raw vegetable intake was strongly associated with a lower risk of total mortality, whereas cooked vegetable intake showed a modest benefit against mortality.
Higher fruit, vegetable, and legume consumption was associated with a lower risk of non-cardiovascular, and total mortality. Benefits appear to be maximum for both non-cardiovascular mortality and total mortality at three to four servings per day (equivalent to 375–500 g/day).
Full funding sources listed at the end of the paper (see Acknowledgments).
Objectives
The single‐tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV‐1‐infected adults was approved based on bioequivalence. We assessed the ...clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF.
Methods
We conducted two distinct randomized, double‐blind, active‐controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV‐1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV‐1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96.
Results
We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 difference 0.7%; 95% confidence interval (CI) −4.3 to +5.8% and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI −4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment‐emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001).
Conclusions
Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment‐emergent resistance.
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•A comprehensive survey of HCN1 and HCN2 channel phosphorylation.•Very similar phosphosite patterns in HCN1 and HCN2 channels between humans and rats.•Increase in phosphorylation ...level at HCN1-S791 in chronically epileptic rats.•HCN1-S791D causes a hyperpolarizing shift in Ih gating when expressed in oocytes.
Because hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels modulate the excitability of cortical and hippocampal principal neurons, these channels play a key role in the hyperexcitability that occurs during the development of epilepsy after a brain insult, or epileptogenesis. In epileptic rats generated by pilocarpine-induced status epilepticus, HCN channel activity is downregulated by two main mechanisms: a hyperpolarizing shift in gating and a decrease in amplitude of the current mediated by HCN channels, Ih. Because these mechanisms are modulated by various phosphorylation signaling pathways, we hypothesized that phosphorylation changes occur at individual HCN channel amino acid residues (phosphosites) during epileptogenesis. We collected CA1 hippocampal tissue from male Sprague Dawley rats made epileptic by pilocarpine-induced status epilepticus, and age-matched naïve controls. We also included resected human brain tissue containing epileptogenic zones (EZs) where seizures arise for comparison to our chronically epileptic rats. After enrichment for HCN1 and HCN2 isoforms by immunoprecipitation and trypsin in-gel digestion, the samples were analyzed by mass spectrometry. We identified numerous phosphosites from HCN1 and HCN2 channels, representing a novel survey of phosphorylation sites within HCN channels. We found high levels of HCN channel phosphosite homology between humans and rats. We also identified a novel HCN1 channel phosphosite S791, which underwent significantly increased phosphorylation during the chronic epilepsy stage. Heterologous expression of a phosphomimetic mutant, S791D, replicated a hyperpolarizing shift in Ih gating seen in neurons from chronically epileptic rats. These results show that HCN1 channel phosphorylation is altered in epilepsy and may be of pathogenic importance.
Understanding individuals' response to dietary bioactives is crucial for personalized nutrition. We report here for the first time in a Caucasian cohort (5-90 years,
n
= 839) that aging is the main ...factor that determines the gut microbiota involved in the ellagic acid-ellagitannin metabolism (urolithin metabotypes), with potential consequences for human health.
Human urolithin gut microbiota metabotypes are mainly determined by aging.
The Afterglow and Kilonova of the Short GRB 160821B Troja, E.; Castro-Tirado, A. J.; Gonzalez, J Becerra ...
Monthly Notices of the Royal Astronomical Society,
08/2019, Letnik:
489, Številka:
2
Journal Article
Recenzirano
Odprti dostop
GRB 160821B is a short duration gamma-ray burst (GRB) detected and localized by the Neil Gehrels Swift Observatory in the outskirts of a spiral galaxy at z = 0.1613, at a projected physical offset of ...16 kpc from the galaxy’s center. We present X-ray, optical/nIR, and radio observations of its counterpart and model them with two distinct components of emission: a standard afterglow, arising from the interaction of the relativistic jet with the surrounding medium, and a kilonova, powered by the radioactive decay of the sub-relativistic ejecta. Broadband modelling of the afterglow data reveals a weak reverse shock propagating backward into the jet, and a likely jet-break at 3.5 d. This is consistent with a structured jet seen slightly off-axis (θview ∼ θcore) while expanding into a low-density medium (n ≈ 10−3 cm−3). Analysis of the kilonova properties suggests a rapid evolution towards red colours, similar toAT2017gfo, and a low-nIR luminosity, possibly due to the presence of a long-lived neutron star. The global properties of the environment, the inferred low mass (Mej <~ 0.006 Msun) and velocities (vej >~ 0.05c) of lanthanide-rich ejecta are consistent with a binary neutron star merger progenitor.
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•The Mexican fermented beverages have microbiological, nutritional and medicinal potential.•The Mexican fermented beverages contain an extensive range of microbial community ...associated.•The bioactive compounds associated are polypheols, flavonoids, between others.•The leading microorganisms present are: yeasts, AAB, LAB, fungi, and others.
In Mexico, close to 200 fermented products have been described, of which, approximately 20 are beverages. They were obtained through rustic and ancestral fermentation methods by different indigenous Mexican communities; most of them were used in ceremonies, agricultural work, and other occasions. For their elaboration, different substrates obtained from plants are used, where uncontrolled and low-scale spontaneous anaerobic fermentation occurs. In Mexico, some of these products are considered as nutritional sources and functional beverages; the study of those products has revealed the presence of multiple compounds of biological importance. Additionally, elder generations attribute healing properties against diverse illnesses to these beverages. The aim of this review is to highlight the available information on twelve traditional Mexican fermented beverages, their traditional uses, and their fermentation processes along with toxicological, chemical, nutritional, and functional studies as seen from different areas of investigation. In the literature, pulque, cocoa, and pozol were the beverages with the greatest amount of described health properties; sendechó and guarapo were less characterized. Polyphenols, gallic and ferulic acid, anthocyanins and saponins were the most abundant molecules in all beverages. Finally, it is important to continue this research in order to determine the microorganisms that are involved in the fermentation process, as well as the organoleptic and beneficial properties they lend to the traditional Mexican fermented beverages.
Image-domain motion correction of black-blood contrast T2-weighted fetal cardiovascular magnetic resonance imaging (CMR) using slice-to-volume registration (SVR) provides high-resolution ...three-dimensional (3D) images of the fetal heart providing excellent 3D visualisation of vascular anomalies 1. However, 3D segmentation of these datasets, important for both clinical reporting and the application of advanced analysis techniques is currently a time-consuming process requiring manual input with potential for inter-user variability.
In this work, we present novel 3D fetal CMR population-averaged atlases of normal and abnormal fetal cardiovascular anatomy. The atlases are created using motion-corrected 3D reconstructed volumes of 86 third trimester fetuses (gestational age range 29-34 weeks) including: 28 healthy controls, 20 cases with postnatally confirmed neonatal coarctation of the aorta (CoA) and 38 vascular rings (21 right aortic arch (RAA), 17 double aortic arch (DAA)). We used only high image quality datasets with isolated anomalies and without any other deviations in the cardiovascular anatomy.In addition, we implemented and evaluated atlas-guided registration and deep learning (UNETR) methods for automated 3D multi-label segmentation of fetal cardiac vessels. We used images from CoA, RAA and DAA cohorts including: 42 cases for training (14 from each cohort), 3 for validation and 6 for testing. In addition, the potential limitations of the network were investigated on unseen datasets including 3 early gestational age (22 weeks) and 3 low SNR cases.
We created four atlases representing the average anatomy of the normal fetal heart, postnatally confirmed neonatal CoA, RAA and DAA. Visual inspection was undertaken to verify expected anatomy per subgroup. The results of the multi-label cardiac vessel UNETR segmentation showed 100Formula: see text per-vessel detection rate for both normal and abnormal aortic arch anatomy.
This work introduces the first set of 3D black-blood T2-weighted CMR atlases of normal and abnormal fetal cardiovascular anatomy including detailed segmentation of the major cardiovascular structures. Additionally, we demonstrated the general feasibility of using deep learning for multi-label vessel segmentation of 3D fetal CMR images.
Two key proteins for cellular communication between astrocytes and neurons are αvβ3 integrin and the receptor Thy-1. Binding of these molecules in the same (cis) or on adjacent (trans) cellular ...membranes induces Thy-1 clustering, triggering actin cytoskeleton remodeling. Molecular events that could explain how the Thy-1-αvβ3 integrin interaction signals have only been studied separately in different cell types, and the detailed transcellular communication and signal transduction pathways involved in neuronal cytoskeleton remodeling remain unresolved. Using biochemical and genetic approaches, single-molecule tracking, and high-resolution nanoscopy, we provide evidence that upon binding to αvβ3 integrin, Thy-1 mobility decreased while Thy-1 nanocluster size increased. This occurred concomitantly with inactivation and exclusion of the non-receptor tyrosine kinase Src from the Thy-1/C-terminal Src kinase (Csk)-binding protein (CBP)/Csk complex. The Src inactivation decreased the p190Rho GTPase activating protein phosphorylation, promoting RhoA activation, cofilin, and myosin light chain II phosphorylation and, consequently, neurite shortening. Finally, silencing the adaptor CBP demonstrated that this protein was a key transducer in the Thy-1 signaling cascade. In conclusion, these data support the hypothesis that the Thy-1-CBP-Csk-Src-RhoA-ROCK axis transmitted signals from astrocytic integrin-engaged Thy-1 (trans) to the neuronal actin cytoskeleton. Importantly, the β3 integrin in neurons (cis) was not found to be crucial for neurite shortening. This is the first study to detail the signaling pathway triggered by αvβ3, the endogenous Thy-1 ligand, highlighting the role of membrane-bound integrins as trans acting ligands in astrocyte-neuron communication.
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•Astrocyte αvβ3 integrin engages neuronal Thy-1 in trans to induce neurite shortening.•Neuronal β3 integrin Thy-1 cis interaction appears dispensable for neurite retraction.•αvβ3 stimulation of Thy-1 in trans clusters Thy-1/CBP/Csk in a multi-protein complex•CBP is a transmembrane transducer for Thy-1 signaling in neurons.•Integrin-Thy-1 binding induces neurite retraction by inhibiting Src and activating RhoA.
Liver cancer is the fourth most common cause of cancer‐related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are ...still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co‐inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well‐tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.
We show that, upon mTOR inhibition with AZD8055, there is upregulation of several receptor tyrosine kinases. As consequence, SHP2 signals through the mTOR pathway. Hence, dual blockade of SHP2 and mTOR can effectively suppress the mTOR pathway and drive anti‐cancer response, both in vitro and in vivo, in several hepatocellular carcinoma models.
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