Whether early young adulthood dietary patterns predict the risk of metabolic syndrome (MetS) and diabetes-related endpoints prior to middle age remains unknown. We examined the prospective ...associations of dietary patterns in early young adulthood with MetS and diabetes-related endpoints at later young adulthood.
We used data of young adults from a long running birth cohort in Australia. The Western dietary pattern rich in meats, refined grains, processed and fried foods and the prudent dietary pattern rich in fruits and vegetables, whole grains and legumes were derived using principal component analysis at the 21-year follow-up from dietary data obtained by a food frequency questionnaire. Fasting blood samples at 30 years were collected from each participant and their blood biomarkers, anthropometric and blood pressure were measured. MetS, insulin resistance, and prediabetes were based on clinical cut-offs; increased β-cell function and insulin resistance were based on upper quartiles. Log-binomial models were used to estimate diet-related risks of each outcome adjusting for potential confounders.
Greater adherence to the Western pattern predicted higher risks of MetS (RR: 2.32; 95% CI: 1.34, 4.00), increased insulin resistance (1.69; 1.07, 2.65), high β-cell function (1.60; 1.10, 2.31) and less likelihood of increased insulin sensitivity (0.57; 0.39, 0.84) in adjusted models. Conversely, adhering more to the prudent pattern predicted lower risks of MetS (RR: 0.47; 95% CI: 0.29, 0.75), increased insulin resistance (0.57; 0.39, 0.82), high β-cell function (0.69; 0.50, 0.93) and a greater likelihood of increased insulin sensitivity (1.84; 1.30, 2.60).
This prospective study of young adults indicates greater adherence to unhealthy Western diet predicted higher risks of MetS and increased insulin resistance, whereas healthy prudent diet predicted lower risks. Optimizing diets to improve later cardiometabolic health needs to occur in early adulthood.
Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal ...antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).
Low-intensity ultrasound (LIUS) was shown to be beneficial in mitigating inflammation and facilitating tissue repair in various pathologies. Determination of the molecular mechanisms underlying the ...anti-inflammatory effects of LIUS allows to optimize this technique as a therapy for the treatment of malignancies and aseptic inflammatory disorders.
We conducted cutting-edge database mining approaches to determine the anti-inflammatory mechanisms exerted by LIUS.
Our data revealed following interesting findings: (1) LIUS anti-inflammatory effects are mediated by upregulating anti-inflammatory gene expression; (2) LIUS induces the upregulation of the markers and master regulators of immunosuppressor cells including MDSCs (myeloid-derived suppressor cells), MSCs (mesenchymal stem cells), B1-B cells and Treg (regulatory T cells); (3) LIUS not only can be used as a therapeutic approach to deliver drugs packed in various structures such as nanobeads, nanospheres, polymer microspheres, and lipidosomes, but also can make use of natural membrane vesicles as small as exosomes derived from immunosuppressor cells as a novel mechanism to fulfill its anti-inflammatory effects; (4) LIUS upregulates the expression of extracellular vesicle/exosome biogenesis mediators and docking mediators; (5) Exosome-carried anti-inflammatory cytokines and anti-inflammatory microRNAs inhibit inflammation of target cells via multiple shared and specific pathways, suggesting exosome-mediated anti-inflammatory effect of LIUS feasible; and (6) LIUS-mediated physical effects on tissues may activate specific cellular sensors that activate downstream transcription factors and signaling pathways.
Our results have provided novel insights into the mechanisms underlying anti-inflammatory effects of LIUS, and have provided guidance for the development of future novel therapeutic LIUS for cancers, inflammatory disorders, tissue regeneration and tissue repair.
Heart failure (HF) and atrial fibrillation (AF) frequently coexist, and they can beget one another due to similar factors and shared pathophysiology. These pathophysiologic changes promote the ...episodes of AF, while they in turn predispose to the exacerbation of HF. In this review, we will discuss pathophysiological mechanisms shared by AF and HF. Patients with concomitant HF and AF are at a particularly high risk of thromboembolism, which contribute to even worse symptoms and poorer prognosis. Vitamin K antagonists (VKA) (warfarin) were the traditional medication in AF patients for the prevention of stroke, whereas the advance of novel non-VKA oral anticoagulants (NOACs) (dabigatran, apixaban, rivaroxaban, and edoxaban) is challenging these standard prescriptions. NOACs’ potential advantages over warfarin, including fixed dosing regimens, wide therapeutic window, and more sustained anticoagulant response, promote clinicians to consider these novel agents in the first place. However, some data suggested patients with AF and HF may receive different therapeutic response than those with AF alone in anticoagulant treatment. Accordingly, we aim to assess the potential role of oral anticoagulants, especially NOACs, in the management of patients with concomitant AF and HF.
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC ...remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with
loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Caspase-1 is present in the cytosol as an inactive zymogen and requires the protein complexes named "inflammasomes" for proteolytic activation. However, it remains unclear whether the proteolytic ...activity of caspase-1 is confined only to the cytosol where inflammasomes are assembled to convert inactive pro-caspase-1 to active caspase-1.
We conducted meticulous data analysis methods on proteomic, protein interaction, protein intracellular localization, and gene expressions of 114 experimentally identified caspase-1 substrates and 38 caspase-1 interaction proteins in normal physiological conditions and in various pathologies.
We made the following important findings: (1) Caspase-1 substrates and interaction proteins are localized in various intracellular organelles including nucleus and secreted extracellularly; (2) Caspase-1 may get activated in situ in the nucleus in response to intra-nuclear danger signals; (3) Caspase-1 cleaves its substrates in exocytotic secretory pathways including exosomes to propagate inflammation to neighboring and remote cells; (4) Most of caspase-1 substrates are upregulated in coronary artery disease regardless of their subcellular localization but the majority of metabolic diseases cause no significant expression changes in caspase-1 nuclear substrates; and (5) In coronary artery disease, majority of upregulated caspase-1 extracellular substrate-related pathways are involved in induction of inflammation; and in contrast, upregulated caspase-1 nuclear substrate-related pathways are more involved in regulating cell death and chromatin regulation.
Our identification of novel caspase-1 trafficking sites, nuclear and extracellular inflammasomes, and extracellular caspase-1-based inflammation propagation model provides a list of targets for the future development of new therapeutics to treat cardiovascular diseases, inflammatory diseases, and inflammatory cancers.
► The age 6 is an important threshold to define bilingual status: early vs. late. ► Hemisphere lateralization of early bilinguals is influenced by composition of words. ► Stroop effect is stronger ...with words presented to the language dominated hemisphere.
It has been generally accepted that the left hemisphere is more functionally specialized for language than the right hemisphere for right-handed monolinguals. But more and more studies have also demonstrated right hemisphere advantage for some language tasks with certain participants. A recent comprehensive survey has shown that hemisphere lateralization of language depends on the bilingual status of the participants, with bilateral hemispheric involvement for both languages of early bilinguals, who acquired both languages by age of 6, left hemisphere dominance for language of monolinguals, and also left hemisphere dominance for both languages of late bilinguals, who acquired the second language after age of 6. We propose a preliminary model which takes into account both composition of stimulus words and bilingual status of participants to resolve the apparent controversies regarding hemisphere lateralization of various reading experiments in the literature with focus on Chinese characters, and to predict lateralization patterns for future experiments in Chinese word reading. The bilingual status includes early bilingual, late bilingual and monolingual. However, we have tested this model only with late Chinese–English bilingual participants by using a Stroop paradigm in this paper, though the aim of our model is to disentangle the controversies in the lateralization effect of Chinese character reading. We show here with stimuli written in Chinese single characters that the Stroop effect was stronger when the stimuli were presented to the right than to the left visual field, implying that the language information and color identification/naming may interact more strongly in the left hemisphere. Therefore, our experimental results indicate left hemisphere dominance for Chinese character processing, providing evidence for one part of our model.
The effect of language on the categorical perception of color is stronger for stimuli in the right visual field (RVF) than in the left visual field, but the neural correlates of the behavioral RVF ...advantage are unknown. Here we present brain activation maps revealing how language is differentially engaged in the discrimination of colored stimuli presented in either visual hemifield. In a rapid, event-related functional MRI study, we measured subjects' brain activity while they performed a visual search task. Compared with colors from the same lexical category, discrimination of colors from different linguistic categories provoked stronger and faster responses in the left hemisphere language regions, particularly when the colors were presented in the RVF. In addition, activation of visual areas 2/3, responsible for color perception, was much stronger for RVF stimuli from different linguistic categories than for stimuli from the same linguistic category. Notably, the enhanced activity of visual areas 2/3 coincided with the enhanced activity of the left posterior temporoparietal language region, suggesting that this language region may serve as a top-down control source that modulates the activation of the visual cortex. These findings shed light on the brain mechanisms that underlie the hemifield- dependent effect of language on visual perception.
The extent to which dietary patterns influence the risk of abnormal blood lipids throughout young adulthood remains unclear. The aim was to investigate whether early young adulthood dietary patterns ...predict the risk of abnormal blood lipids during later young adulthood.
We used data from a long running birth cohort study in Australia. Western dietary pattern rich in meats, processed foods and high-fat dairy products and prudent pattern rich in fruit, vegetables, fish, nuts, whole grains and low-fat dairy products were derived using principal component analysis at the 21-year follow-up from dietary data obtained using a food frequency questionnaire. After 9-years, fasting blood samples of all participants were collected and their total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols and triglyceride (TG) levels were measured. Abnormal blood lipids were based on clinical cut-offs for total, LDL and HDL cholesterols, and TG and relative distributions for total:HDL and TG:HDL cholesterols ratios. Log-binomial models were used to estimate risk of each outcome in relation to dietary patterns. Greater adherence to the Western pattern predicted increased risks of high LDL (RR: 1.47; 95%CI: 1.06, 2.03) and TG (1.90; 1.25, 2.86), and high ratios of total:HDL (1.48; 1.00, 2.19) and TG:HDL (1.78; 1.18, 2.70) cholesterols in fully adjusted models. Conversely, a prudent pattern predicted reduced risks of low HDL (0.58; 0.42, 0.78) and high TG (0.66; 0.47, 0.92) and high total:HDL (0.71; 0.51, 0.98) and TG:HDL (0.61; 0.45, 0.84) cholesterols ratios.
This is the first prospective study to show greater adherence to unhealthy Western diet predicted increased risks of abnormal blood lipids, whereas healthy prudent diet predicted lower such risks in young adults. Addressing diets in early course may improve cardiovascular health of young adults.
•Longitudinal cohort studies examining the associations between dietary patterns and abnormal blood lipids in young adults are lacking.•Western pattern in early young adulthood is associated with higher risk of abnormal blood lipids in later young adulthood.•Prudent pattern in early young adulthood is associated with lower risk of abnormal blood lipids in later young adulthood.•Each dietary pattern is associated with higher risk of high lipoprotein ratios that closely associate with higher risk of CVD than isolated blood lipids.•Addressing diets in the early course of young adulthood may have beneficial effect in reducing the risk of CVD in later life course.
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