Although the genetic causes of hypertrophic cardiomyopathy (HCM) are widely recognized, considerable lag in the development of targeted therapeutics has limited interventions to symptom palliation. ...This is in part attributable to an incomplete understanding of how point mutations trigger pathogenic remodeling. As a further complication, similar mutations within sarcomeric genes can result in differential disease severity, highlighting the need to understand the mechanism of progression at the molecular level. One pathway commonly linked to HCM progression is calcium homeostasis dysregulation, though how specific mutations disrupt calcium homeostasis remains unclear.
To evaluate the effects of early intervention in calcium homeostasis, we used 2 mouse models of sarcomeric HCM (cardiac troponin T R92L and R92W) with differential myocellular calcium dysregulation and disease presentation. Two modes of intervention were tested: inhibition of the autoactivated calcium-dependent kinase (calmodulin kinase II CaMKII) via the AC3I peptide and diltiazem, an L-type calcium channel antagonist. Two-dimensional echocardiography was used to determine cardiac function and left ventricular remodeling, and atrial remodeling was monitored via atrial mass. Sarcoplasmic reticulum Ca
ATPase activity was measured as an index of myocellular calcium handling and coupled to its regulation via the phosphorylation status of phospholamban.
We measured an increase in phosphorylation of CaMKII in R92W animals by 6 months of age, indicating increased autonomous activity of the kinase in these animals. Inhibition of CaMKII led to recovery of diastolic function and partially blunted atrial remodeling in R92W mice. This improved function was coupled to increased sarcoplasmic reticulum Ca
ATPase activity in the R92W animals despite reduction of CaMKII activation, likely indicating improvement in myocellular calcium handling. In contrast, inhibition of CaMKII in R92L animals led to worsened myocellular calcium handling, remodeling, and function. Diltiazem-HCl arrested diastolic dysfunction progression in R92W animals only, with no improvement in cardiac remodeling in either genotype.
We propose a highly specific, mutation-dependent role of activated CaMKII in HCM progression and a precise therapeutic target for clinical management of HCM in selected cohorts. Moreover, the mutation-specific response elicited with diltiazem highlights the necessity to understand mutation-dependent progression at a molecular level to precisely intervene in disease progression.
Many mechanically ventilated patients with acute respiratory distress syndrome develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a ...number of mechanisms (e.g., damage the alveolar epithelium, biotrauma). The objective of this study was t test the hypothesis that mechanical ventilation plays an important role in the pathogenesis of lung fibrosis.
C57BL/6 mice were randomized into four groups: healthy controls; hydrochloric acid aspiration alone; vehicle control solution followed 24 hrs later by mechanical ventilation (peak inspiratory pressure 22 cm H(2)O and positive end-expiratory pressure 2 cm H(2)O for 2 hrs); and acid aspiration followed 24 hrs later by mechanical ventilation. The animals were monitored for up to 15 days after acid aspiration. To explore the direct effects of mechanical stress on lung fibrotic formation, human lung epithelial cells (BEAS-2B) were exposed to mechanical stretch for up to 48 hrs.
Impaired lung mechanics after mechanical ventilation was associated with increased lung hydroxyproline content, and increased expression of transforming growth factor-β, β-catenin, and mesenchymal markers (α-smooth muscle actin and vimentin) at both the gene and protein levels. Expression of epithelial markers including cytokeratin-8, E-cadherin, and prosurfactant protein B decreased. Lung histology demonstrated fibrosis formation and potential epithelia-mesenchymal transition. In vitro direct mechanical stretch of BEAS-2B cells resulted in similar fibrotic and epithelia-mesenchymal transition formation.
Mechanical stress induces lung fibrosis, and epithelia-mesenchymal transition may play an important role in mediating the ventilator-induced lung fibrosis.
The aim of this study was to couple biochemical and molecular methodologies for evaluating the impact of two recycling technologies (composting and vermicomposting) on a toxic organic waste. To do ...this, six enzyme activities controlling the key metabolic pathways of the breakdown of organic matter, real-time PCR assays targeting 16S rRNA genes, and denaturing gradient gel electrophoresis (DGGE) profiling-sequence analysis of PCR-amplified 16S rRNA fragments have been used to determine the functional diversity, bacterial number, and bacterial community structure, respectively, in a mixture of olive waste and sheep manure, and in the derived compost and vermicompost. Both the recycling technologies were effective in activating the microbial parameters of the toxic waste, the vermicomposting being the best process to produce greater bacterial diversity, greater bacterial numbers and greater functional diversity. Although several identical populations were detected in the processed and non-processed materials, each technology modified the original microbial communities of the waste in a diverse way, indicating the different roles of each one in the bacterial selection.
•The ultrasound pulses reduce the natural microflora, L. delbrueckii and L. monocytogenes of a raw meat emulsion.•Each kind of microorganism has a different answer to ultrasound treatments.•A model ...of desirability contributes to find the best parameters to apply ultrasound waves to inactivate microorganisms.
Raw meat emulsions may have natural, spoilage and pathogenic microorganisms due to the origin and characteristics of this food matrix. All of these microorganisms must be minimized during industrial processing to make food consumption safe and meet quality regulations. Therefore, in this research, the effect of probe ultrasound on the inactivation of three kinds of microorganisms in a raw meat emulsion is evaluated. The microorganisms are: natural microflora NAM, Listeria monocytogenes LIS, and Lactobacillus delbrueckii LAC. A high-intensity probe ultrasound system was used, during 1.0, 2.5, 5.0, 7.5 and 10 min, with pulsed waves of 0.0, 10, 20 and 30 seg, and 200, 250, 300, 350 and 400 W of power. The interrelation between time, wave pulse cycle, and power factors was assessed. The results showed a positive linear independence effect in the treatments without wave pulse for each microorganism, and a quadratic interaction with the time and the ultrasound power for the inactivation of the three kinds of microorganisms. Besides, the desirability function for the inactivation reached up to 60% of the microbial population with the probe ultrasound treatment, with 10 min, a 7.56 s wave pulse and 400 W of power. Thus, these results could be useful to decide the incorporation of mild and emerging technologies in a meat industry line process.
To identify quantitative trait loci (QTLs) conditioning salt tolerance in soybean (
Glycine max
(L.) Merr.), two recombinant inbred line (RIL) populations derived from crosses of FT-Abyara × C01 and ...Jin dou No. 6 × 0197 were used in this study. The FT-Abyara × C01 population consisted of 96 F
7
RILs, and the Jin dou No. 6 × 0197 population included 81 F
6
RILs. The salt tolerant parents FT-Abyara and Jin dou No. 6 were originally from Brazil and China, respectively. The QTL analysis identified a major salt-tolerant QTL in molecular linkage group N, which accounted for 44.0 and 47.1% of the total variation for salt tolerance, in the two populations. In the FT-Abyara × C01 population, three RILs were found to be heterozygous around the detected QTL region. By selfing the three residual heterozygous lines, three sets of near isogenic lines (NILs) for salt tolerance were developed. An evaluation of salt tolerance of the NILs revealed that all the lines with FT-Abyara chromosome segment at the QTL region showed significantly higher salt tolerance than the lines without the FT-Abyara chromosome segment. Results of the NILs validated the salt tolerance QTL detected in the RIL populations.
Work has not examined if acculturation or enculturation may predict endorsed benefits, barriers, and intentions to seek mental health services for depression, specifically among Latino students ...enrolled in a rural and majority Latino immigrant institution of higher education. An improved understanding of factors informing mental health help-seeking is needed to identify possible intervention points to address gaps in accessing depression treatment. Participants (N = 406) read a vignette depicting a person with depressive symptoms. Participants were asked if they would seek help for depression if in the situation described in the vignette. Participants provided text responses about their preferences for managing depression symptoms and their mental health help-seeking history. Additionally, participants completed a self-report depression symptom screener, demographic surveys, acculturation assessment, and questionnaires on perceived benefits and barriers to seeking mental health services. Path analysis was used to test the link between acculturation status and intent to seek services for depression, with benefits and barriers as mediators. The results revealed that higher perceived benefits and lower barriers were directly associated with greater intentions to seek help. Furthermore, an indirect effect of acculturation on help-seeking intentions via higher perceived benefits of seeking care was observed. These findings persisted after controlling for age, gender, depression, and history of seeking care for depression. Future work should test the replicability of this finding with diverse college students living in predominantly immigrant communities. Universities might consider tailoring outreach initiatives to provide information on the range and accessibility of mental health services, the location of mental health service centers, and the procedures for accessing such services.Work has not examined if acculturation or enculturation may predict endorsed benefits, barriers, and intentions to seek mental health services for depression, specifically among Latino students enrolled in a rural and majority Latino immigrant institution of higher education. An improved understanding of factors informing mental health help-seeking is needed to identify possible intervention points to address gaps in accessing depression treatment. Participants (N = 406) read a vignette depicting a person with depressive symptoms. Participants were asked if they would seek help for depression if in the situation described in the vignette. Participants provided text responses about their preferences for managing depression symptoms and their mental health help-seeking history. Additionally, participants completed a self-report depression symptom screener, demographic surveys, acculturation assessment, and questionnaires on perceived benefits and barriers to seeking mental health services. Path analysis was used to test the link between acculturation status and intent to seek services for depression, with benefits and barriers as mediators. The results revealed that higher perceived benefits and lower barriers were directly associated with greater intentions to seek help. Furthermore, an indirect effect of acculturation on help-seeking intentions via higher perceived benefits of seeking care was observed. These findings persisted after controlling for age, gender, depression, and history of seeking care for depression. Future work should test the replicability of this finding with diverse college students living in predominantly immigrant communities. Universities might consider tailoring outreach initiatives to provide information on the range and accessibility of mental health services, the location of mental health service centers, and the procedures for accessing such services.
In recent years, the adoption of statistical process monitoring (SPM) techniques in healthcare has been successful. For instance, biosurveillance and biosignal monitoring have demonstrated direct ...benefits. As the latest reviews of the literature show, parametric SPM techniques have been implemented to evaluate the quality-of-service hospitals provide, track medical equipment, monitor safety markers, or assess the improvements made by quality projects. However, as shown in this research, world-trending topics in data science that include data-driven approaches integrated with SPM have not been reviewed. To bridge this gap and shed light on new research, a systematic review of scientific databases and a taxonomic literature analysis were performed. For the scientometric analysis, a set of bibliometric indicators were obtained to portray the performance of each subtopic, such as examining growth kinetics, identifying top authors, journals, countries and affiliations, as well as creating network maps of co-authorship and keyword co-occurrence. Additionally, the taxonomic analysis involved grouping proposals by methodological approach. Each approach was explained and discussed to identify the advantages, limitations, and challenges that researchers and practitioners may encounter. SPM researchers and practitioners require more flexibility in data-driven approaches to account for frequency unbalance, complexity, dimensionality problems, and speed. Those working in data-driven and computer-oriented areas can expand their toolbox by incorporating sequential approaches to enhance the power of their classifiers, assess risk, reduce misspecification, and adopt model-oriented mindsets.
Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging ...are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 95% CI, 1.0-1.9;
=0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 95% CI, 1.0-1.3;
=0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 95% CI, 1.1-2.7;
=0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.
Background and aims Despite the high interest in biochar as soil amendment, the number of field studies is still limited, being experiments with perennial crops in arid lands particularly lacking. ...This study evaluated the application of compost and biochar in a drip-irrigated organic olive crop in a calcareous soil in South-East Spain. Methods During two consecutive years, changes in soil total organic C (TOC), dissolved organic C (DOC) and water soluble N (WSN), mineral N (NH₄⁺ and NO₃⁻), N₂O emissions, denitrifying enzyme activity (DEA) and number of amoA gen copies were monitored. Results Biochar increased TOC compared to the rest of treatments, whereas DOC and WSN significantly increased in plots amended with compost and the compost-biochar mixture. DEA, amoA-encoding genes and N₂O emissions were highest with the compost-biochar mixture, but results were not always significant. Conclusions Our results show that, in these N-limited and deficit irrigated semi-arid agro-ecosystems, compost amendment has an impact on soil microbiological activity with a link to N availability. Biochar applied alone does not alter the N dynamics, but markedly builds-up soil C. In both cases only during the first year these effects were statistically significant. When applied in combination a synergistic effect was observed and the highest values of DEA, amoA gene copies and N₂O emissions were detected.
Context. The BL Lac object 3C 371 was observed by the Transiting Exoplanet Survey Satellite (TESS) for approximately a year, between July 2019 and July 2020, with an unmatched two-minute imaging ...cadence. In parallel, the Whole Earth Blazar Telescope (WEBT) Collaboration organized an extensive observing campaign, providing three years of continuous optical monitoring between 2018 and 2020. These datasets allow for a thorough investigation of the variability of the source. Aims. The goal of this study is to evaluate the optical variability of 3C 371. Taking advantage of the remarkable cadence of TESS data, we aim to characterize the intra-day variability (IDV) displayed by the source and identify its shortest variability timescale. With this estimate, constraints on the size of the emitting region and black hole mass can be calculated. Moreover, WEBT data are used to investigate long-term variability (LTV), including in terms of the spectral behavior of the source and the polarization variability. Based on the derived characteristics, we aim to extract information on the origin of the variability on different timescales. Methods. We evaluated the variability of 3C 371 by applying the variability amplitude tool, which quantifies variability of the emission. Moreover, we employed common tools, such as ANOVA (ANalysis Of VAariance) tests, wavelet and power spectral density (PSD) analyses to characterize the shortest variability timescales present in the emission and the underlying noise affecting the data. We evaluated the short- and long-term color behavior to understand its spectral behavior. The polarized emission was analyzed, studying its variability and possible rotation patterns of the electric vector position angle (EVPA). Flux distributions of the IDV and LTV were also studied with the aim being to link the flux variations to turbulent and/or accretion-disk-related processes. Results. Our ANOVA and wavelet analyses reveal several entangled variability timescales. We observe a clear increase in the variability amplitude with increasing width of the time intervals evaluated. We are also able to resolve significant variations on timescales of as little as ∼0.5 h. The PSD analysis reveals a red-noise spectrum with a break at IDV timescales. The spectral analysis shows a mild bluer-when-brighter (BWB) trend on long timescales. On short timescales, mixed BWB, achromatic and redder-when-brighter signatures can be observed. The polarized emission shows an interesting slow EVPA rotation during the flaring period, where a simple stochastic model can be excluded as the origin with a 3 σ significance. The flux distributions show a preference for a Gaussian model for the IDV, and suggest it may be linked to turbulent processes, while the LTV is better represented by a log-normal distribution and may have a disk-related origin.
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