Pericardial Fat and the Risk of Heart Failure Kenchaiah, Satish; Ding, Jingzhong; Carr, J. Jeffrey ...
Journal of the American College of Cardiology,
06/2021, Letnik:
77, Številka:
21
Journal Article
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Obesity is a well-established risk factor for heart failure (HF). However, implications of pericardial fat on incident HF is unclear.
This study sought to examine the association between pericardial ...fat volume (PFV) and newly diagnosed HF.
This study ascertained PFV using cardiac computed tomography in 6,785 participants (3,584 women and 3,201 men) without pre-existing cardiovascular disease from the MESA (Multi-Ethnic Study of Atherosclerosis). Cox proportional hazards regression was used to evaluate PFV as continuous and dichotomous variable, maximizing the J-statistic: (Sensitivity + Specificity – 1).
In 90,686 person-years (median: 15.7 years; interquartile range: 11.7 to 16.5 years), 385 participants (5.7%; 164 women and 221 men) developed newly diagnosed HF. PFV was lower in women than in men (69 ± 33 cm3 vs. 92 ± 47 cm3; p < 0.001). In multivariable analyses, every 1-SD (42 cm3) increase in PFV was associated with a higher risk of HF in women (hazard ratio HR: 1.44; 95% confidence interval CI: 1.21 to 1.71; p < 0.001) than in men (HR: 1.13; 95% CI: 1.01 to 1.27; p = 0.03) (interaction p = 0.01). High PFV (≥70 cm3 in women; ≥120 cm3 in men) conferred a 2-fold greater risk of HF in women (HR: 2.06; 95% CI: 1.48 to 2.87; p < 0.001) and a 53% higher risk in men (HR: 1.53; 95% CI: 1.13 to 2.07; p = 0.006). In sex-stratified analyses, greater risk of HF remained robust with additional adjustment for anthropometric indicators of obesity (p ≤ 0.008), abdominal subcutaneous or visceral fat (p ≤ 0.03) or biomarkers of inflammation and hemodynamic stress (p < 0.001) and was similar among Whites, Blacks, Hispanics, and Chinese (interaction p = 0.24). Elevated PFV predominantly augmented the risk of HF with preserved ejection fraction (p < 0.001) rather than reduced ejection fraction (p = 0.31).
In this large, community-based, ethnically diverse, prospective cohort study, pericardial fat was associated with an increased risk of HF, particularly HF with preserved ejection fraction, in women and men.
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We have determined the three-dimensional (3D) architecture of the
Caulobacter crescentus genome by combining genome-wide chromatin interaction detection, live-cell imaging, and computational ...modeling. Using chromosome conformation capture carbon copy (5C), we derive ∼13 kb resolution 3D models of the
Caulobacter genome. The resulting models illustrate that the genome is ellipsoidal with periodically arranged arms. The
parS sites, a pair of short contiguous sequence elements known to be involved in chromosome segregation, are positioned at one pole, where they anchor the chromosome to the cell and contribute to the formation of a compact chromatin conformation. Repositioning these elements resulted in rotations of the chromosome that changed the subcellular positions of most genes. Such rotations did not lead to large-scale changes in gene expression, indicating that genome folding does not strongly affect gene regulation. Collectively, our data suggest that genome folding is globally dictated by the
parS sites and chromosome segregation.
► Chromatin interaction mapping and modeling elucidate
Caulobacter genome structure ► The genome is ellipsoidal with periodically arranged arms ► The
parS region shapes whole genome structure and affects chromatin compaction ► The
parS region is the only genomic region stably attached to the cell envelope
UiO-66 is a Zr-based MOF that is being highly investigated for a wide variety of small molecule gas separations since it possess unprecedented thermal, chemical, and mechanical stability. In this ...work, we have investigated the performance of various functionalized variations of UiO-66 (UiO-66-OH, UiO-66-(OH)2, UiO-66-NO2, UiO-66-NH2, UiO-66-SO3H, and UiO-66-(COOH)2) towards ammonia removal from air. Functionalized UiO-66 analogs have been synthesized solvothermally and characterized using ammonia breakthrough measurements under dry and humid (80% RH) air conditions along with powder X-ray diffraction (PXRD) patterns and results from BET modeling of N2 adsorption isotherms. Counter to chemical intuition, our study demonstrates that the ammonia capacities of UiO-66-SO3H and UiO-66-(COOH)2 are lower than UiO-66-OH and UiO-66-NH2. This is due to significant reduction in the framework porosity (surface area and pore volume) upon functionalization with bulky functional groups such as –COOH and –SO3H. The –OH group is the least bulky functional group considered in the work and interacts favorably with ammonia. UiO-66-OH has a capacity of ~5.7mmol/g for ammonia under dry conditions which is very close to the ammonia removal goal of 0.1g/g MOF (or ~6mmol/g). However, we observed a decrease in the ammonia capacities of functionalized UiO-66 variations under humid conditions due to competition between water and ammonia molecules for adsorption on the active sites. Overall, balancing the water adsorption behavior and high selectivity and high capacity for ammonia is crucial to developing new adsorbents for ammonia removal from air.
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•UiO-66 and 6 variants were synthesized and studied for adsorption of ammonia from air.•Functional groups were chosen for high interaction with ammonia.•Hydroxyl groups interact the most effectively with ammonia at low concentration.•Breakthrough curves were measured on all materials using a microbreakthrough system.•Large-pore MOFs (>10Å) are necessary for efficient use of complex functionalization.
Use of empirical broad-spectrum antibiotics for pneumonia has increased owing to concern for resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA). The association of ...empirical anti-MRSA therapy with outcomes among patients with pneumonia is unknown, even for high-risk patients.
To compare 30-day mortality among patients hospitalized for pneumonia receiving empirical anti-MRSA therapy vs standard empirical antibiotic regimens.
Retrospective multicenter cohort study was conducted of all hospitalizations in which patients received either anti-MRSA or standard therapy for community-onset pneumonia in the Veterans Health Administration health care system from January 1, 2008, to December 31, 2013. Subgroups of patients analyzed were those with initial intensive care unit admission, MRSA risk factors, positive results of a MRSA surveillance test, and positive results of a MRSA admission culture. Primary analysis was an inverse probability of treatment-weighted propensity score analysis using generalized estimating equation regression; secondary analyses included an instrumental variable analysis. Statistical analysis was conducted from June 14 to November 20, 2019.
Empirical anti-MRSA therapy plus standard pneumonia therapy vs standard therapy alone within the first day of hospitalization.
Risk of 30-day all-cause mortality after adjustment for patient comorbidities, vital signs, and laboratory results. Secondary outcomes included the development of kidney injury and secondary infections with Clostridioides difficile, vancomycin-resistant Enterococcus species, or gram-negative bacilli.
Among 88 605 hospitalized patients (86 851 men; median age, 70 years interquartile range, 62-81 years), empirical anti-MRSA therapy was administered to 33 632 (38%); 8929 patients (10%) died within 30 days. Compared with standard therapy alone, in weighted propensity score analysis, empirical anti-MRSA therapy plus standard therapy was significantly associated with an increased adjusted risk of death (adjusted risk ratio aRR, 1.4 95% CI, 1.3-1.5), kidney injury (aRR, 1.4 95% CI, 1.3-1.5), and secondary C difficile infections (aRR, 1.6 95% CI, 1.3-1.9), vancomycin-resistant Enterococcus spp infections (aRR, 1.6 95% CI, 1.0-2.3), and secondary gram-negative rod infections (aRR, 1.5 95% CI, 1.2-1.8). Similar associations between anti-MRSA therapy use and 30-day mortality were found by instrumental variable analysis (aRR, 1.6 95% CI, 1.4-1.9) and among patients admitted to the intensive care unit (aRR, 1.3 95% CI, 1.2-1.5), those with a high risk for MRSA (aRR, 1.2 95% CI, 1.1-1.4), and those with MRSA detected on surveillance testing (aRR, 1.6 95% CI, 1.3-1.9). No significant favorable association was found between empirical anti-MRSA therapy and death among patients with MRSA detected on culture (aRR, 1.1 95% CI, 0.8-1.4).
This study suggests that empirical anti-MRSA therapy was not associated with reduced mortality for any group of patients hospitalized for pneumonia. These results contribute to a growing body of evidence that questions the value of empirical use of anti-MRSA therapy using existing risk approaches.
Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance ...editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification.
Smartphones are increasingly integrated into everyday life, but frequency of use has not yet been objectively measured and compared to demographics, health information, and in particular, sleep ...quality.
The aim of this study was to characterize smartphone use by measuring screen-time directly, determine factors that are associated with increased screen-time, and to test the hypothesis that increased screen-time is associated with poor sleep.
We performed a cross-sectional analysis in a subset of 653 participants enrolled in the Health eHeart Study, an internet-based longitudinal cohort study open to any interested adult (≥ 18 years). Smartphone screen-time (the number of minutes in each hour the screen was on) was measured continuously via smartphone application. For each participant, total and average screen-time were computed over 30-day windows. Average screen-time specifically during self-reported bedtime hours and sleeping period was also computed. Demographics, medical information, and sleep habits (Pittsburgh Sleep Quality Index-PSQI) were obtained by survey. Linear regression was used to obtain effect estimates.
Total screen-time over 30 days was a median 38.4 hours (IQR 21.4 to 61.3) and average screen-time over 30 days was a median 3.7 minutes per hour (IQR 2.2 to 5.5). Younger age, self-reported race/ethnicity of Black and "Other" were associated with longer average screen-time after adjustment for potential confounders. Longer average screen-time was associated with shorter sleep duration and worse sleep-efficiency. Longer average screen-times during bedtime and the sleeping period were associated with poor sleep quality, decreased sleep efficiency, and longer sleep onset latency.
These findings on actual smartphone screen-time build upon prior work based on self-report and confirm that adults spend a substantial amount of time using their smartphones. Screen-time differs across age and race, but is similar across socio-economic strata suggesting that cultural factors may drive smartphone use. Screen-time is associated with poor sleep. These findings cannot support conclusions on causation. Effect-cause remains a possibility: poor sleep may lead to increased screen-time. However, exposure to smartphone screens, particularly around bedtime, may negatively impact sleep.
Most seizures stop spontaneously; however, the molecular mechanisms that terminate seizures remain unknown. Observations that seizures reduced brain pH and that acidosis inhibited seizures indicate ...that acidosis halts epileptic activity. Because acid-sensing ion channel 1a (ASIC1a) is exquisitely sensitive to extracellular pH and regulates neuron excitability, we hypothesized that acidosis might activate ASIC1a, which would terminate seizures. Disrupting mouse ASIC1a increased the severity of chemoconvulsant-induced seizures, whereas overexpressing ASIC1a had the opposite effect. ASIC1a did not affect seizure threshold or onset, but shortened seizure duration and prevented seizure progression. CO2 inhalation, long known to lower brain pH and inhibit seizures, required ASIC1a to interrupt tonic-clonic seizures. Acidosis activated inhibitory interneurons through ASIC1a, suggesting that ASIC1a might limit seizures by increasing inhibitory tone. Our results identify ASIC1a as an important element in seizure termination when brain pH falls and suggest both a molecular mechanism for how the brain stops seizures and new therapeutic strategies.
XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using ...novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry Annexin V/propidium iodide (PI), respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.
The microRNAs of the miR‐200 family maintain the central characteristics of epithelia and inhibit tumor cell motility and invasiveness. Using the Ago‐HITS‐CLIP technology for transcriptome‐wide ...identification of direct microRNA targets in living cells, along with extensive validation to verify the reliability of the approach, we have identified hundreds of miR‐200a and miR‐200b targets, providing insights into general features of miRNA target site selection. Gene ontology analysis revealed a predominant effect of miR‐200 targets in widespread coordinate control of actin cytoskeleton dynamics. Functional characterization of the miR‐200 targets indicates that they constitute subnetworks that underlie the ability of cancer cells to migrate and invade, including coordinate effects on Rho‐ROCK signaling, invadopodia formation, MMP activity, and focal adhesions. Thus, the miR‐200 family maintains the central characteristics of the epithelial phenotype by acting on numerous targets at multiple levels, encompassing both cytoskeletal effectors that control actin filament organization and dynamics, and upstream signals that locally regulate the cytoskeleton to maintain cell morphology and prevent cell migration.
Synopsis
miR‐200 microRNAs are involved in the maintenance of epithelial integrity. Direct, transcriptome‐wide target detection and validation identifies genes functionally grouped as regulators of Rho GTPase signaling, invadopodia formation, metalloprotease activity and cell adhesion, which together regulate cell motility, migration and cancer metastasis.
The global profile of miR‐200 targets in breast cancer cells reveals a network of cytoskeletal regulators
miR‐200 is found to control invadopodia, focal adhesions and Rho GTPase signaling.
Canonical seed‐3′UTR target site interactions are dominant, but target sites in coding regions and non‐canonical interactions are also detected.
Target genes identified in cell lines negatively correlate with miR‐200 across human breast cancer samples as well.
miR‐200 microRNAs are involved in the maintenance of epithelial integrity. Direct, transcriptome‐wide target detection and validation identifies genes functionally grouped as regulators of Rho GTPase signaling, invadopodia formation, metalloprotease activity and cell adhesion, which together regulate cell motility, migration and cancer metastasis.
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