p21-activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils

Neutrophils serve as a first line of defense in innate immunity owing in part to their ability to rapidly migrate towards chemotactic factors derived from invading pathogens. As a migratory function, neutrophil chemotaxis is regulated by the Rho family of small GTPases. However, the mechanisms by which Rho GTPases orchestrate cytoskeletal dynamics in migrating neutrophils remain ill-defined. In this study, we characterized the role of p21-activated kinase (PAK) downstream of Rho GTPases in cytoskeletal remodeling and chemotactic processes of human neutrophils. We found that PAK activation occurred upon stimulation of neutrophils with f-Met-Leu-Phe (fMLP), and PAK accumulated at the actin-rich leading edge of stimulated neutrophils, suggesting a role for PAK in Rac-dependent actin remodeling. Treatment with the pharmacological PAK inhibitor, PF3758309, abrogated the integrity of RhoA-mediated actomyosin contractility and surface adhesion. Moreover, inhibition of PAK activity impaired neutrophil morphological polarization and directional migration under a gradient of fMLP, and was associated with dysregulated Ca2+ signaling. These results suggest that PAK serves as an important effector of Rho-family GTPases in neutrophil cytoskeletal reorganization, and plays a key role in driving efficient directional migration of human neutrophils

On-farm net benefit of genotyping candidate female replacement cattle and sheep

peer-reviewedThe net benefit from investing in any technology is a function of the cost of implementation and the expected return in revenue. The objective of the present study was to quantify, using deterministic equations, the net monetary benefit from investing in genotyping of commercial females. Three case studies were presented reflecting dairy cows, beef cows and ewes based on Irish population parameters; sensitivity analyses were also performed. Parameters considered in the sensitivity analyses included the accuracy of genomic evaluations, replacement rate, proportion of female selection candidates retained as replacements, the cost of genotyping, the sire parentage error rate and the age of the female when it first gave birth. Results were presented as an annualised monetary net benefit over the lifetime of an individual, after discounting for the timing of expressions. In the base scenarios, the net benefit was greatest for dairy, followed by beef and then sheep. The net benefit improved as the reliability of the genomic evaluations improved and, in fact, a negative net benefit of genotyping was less frequent when the reliability of the genomic evaluations was high. The impact of a 10% point increase in genomic reliability was, however, greatest in sheep, followed by beef and then dairy. The net benefit of genotyping female selection candidates reduced as replacement rate increased. As genotyping costs increased, the net benefit reduced irrespective of the percentage of selection candidates kept, the replacement rate or even the population considered. Nonetheless, the association between the genotyping cost and the net benefit of genotyping differed by the percentage of selection candidates kept. Across all replacement rates evaluated, retaining 25% of the selection candidates resulted in the greatest net benefit when genotyping cost was low but the lowest net benefit when genotyping cost was high. Genotyping breakeven cost was non-linearly associated with the percentage of selection candidates retained, reaching a maximum when 50% of selection candidates were retained, irrespective of replacement rate, genomic reliability or the population. The genotyping breakeven cost was also non-linearly associated with replacement rate. The approaches outlined within provide the back-end framework for a decision support tool to quantify the net benefit of genotyping, once parameterised by the relevant population metrics

Quantum wave equation of photon

In this paper, we give the quantum wave equations of single photon when it is in the free or medium space. With these equations, we can study light interference and diffraction with quantum approach. Otherwise, they can be applied in quantum optics and photonic crystal.Comment: 8 pages, 0 figure

Thresholds of biodiversity and ecosystem function in a forest ecosystem undergoing dieback

Ecological thresholds, which represent points of rapid change in ecological properties, are of major scientific and societal concern. However, very little research has focused on empirically testing the occurrence of thresholds in temperate terrestrial ecosystems. To address this knowledge gap, we tested whether a number of biodiversity, ecosystem functions and ecosystem condition metrics exhibited thresholds in response to a gradient of forest dieback, measured as changes in basal area of living trees relative to areas that lacked recent dieback. The gradient of dieback was sampled using 12 replicate study areas in a temperate forest ecosystem. Our results provide novel evidence of several thresholds in biodiversity (namely species richness of ectomycorrhizal fungi, epiphytic lichen and ground flora); for ecological condition (e.g. sward height, palatable seedling abundance) and a single threshold for ecosystem function (i.e. soil respiration rate). Mechanisms for these thresholds are explored. As climate-induced forest dieback is increasing worldwide, both in scale and speed, these results imply that threshold responses may become increasingly widespread

Percolation model for structural phase transitions in Li1−x_{1-x}Hx_xIO3_3 mixed crystals

A percolation model is proposed to explain the structural phase transitions found in Li$_{1-x}$H$_x$IO$_3$ mixed crystals as a function of the concentration parameter $x$. The percolation thresholds are obtained from Monte Carlo simulations on the specific lattices occupied by lithium atoms and hydrogen bonds. The theoretical results strongly suggest that percolating lithium vacancies and hydrogen bonds are indeed responsible for the solid solution observed in the experimental range $0.22 < x < 0.36$.Comment: 4 pages, 2 figure

Disparities by sex in P2Y 12 inhibitor therapy duration, or differences in the balance of ischaemic-benefit and bleeding-risk clinical outcomes in older women versus comparable men following acute myocardial infarction? A P2Y 12 inhibitor new user retrospective cohort analysis of US Medicare claims data

Objectives To determine if comparable older women and men received different durations of P2Y 12 inhibitor therapy following acute myocardial infarction (AMI) and if therapy duration differences were justified by differences in ischaemic benefits and/or bleeding risks. Design Retrospective cohort. Setting 20% sample of 2007-2015 US Medicare fee-for-service administrative claims data. Participants ≥66-year-old P2Y 12 inhibitor new users following 2008-2013 AMI hospitalisation (N=30 613). Older women compared to older men with similar predicted risks of study outcomes. Primary and secondary outcome measures Primary outcome: P2Y 12 inhibitor duration (modelled as risk of therapy discontinuation). Secondary outcomes: clinical events while on P2Y 12 inhibitor therapy, including (1) death/hospice admission, (2) composite of ischaemic events (AMI/stroke/revascularisation) and (3) hospitalised bleeds. Cause-specific risks and relative risks (RRs) estimated using Aalen-Johansen cumulative incidence curves and bootstrapped 95% CIs. Results 10 486 women matched to 10 486 men with comparable predicted risks of all 4 study outcomes. No difference in treatment discontinuation was observed at 12 months (women 31.2% risk; men 30.9% risk; RR 1.01; 95% CI 0.97 to 1.05), but women were more likely than men to discontinue therapy at 24 months (54.4% and 52.9% risk, respectively; RR 1.03; 95% CI 1.00 to 1.05). Among patients who did not discontinue P2Y 12 inhibitor therapy, women had lower 24-month risks of ischaemic outcomes than men (13.1% and 14.7%, respectively; RR 0.90; 95% CI 0.84 to 0.96), potentially lower 24-month risks of death/hospice admission (5.0% and 5.5%, respectively; RR 0.91; 95% CI 0.82 to 1.02), but women and men both had 2.5% 24-month bleeding risks (RR 0.98; 95% CI 0.82 to 1.14). Conclusions Risks for death/hospice and ischaemic events were lower among women still taking a P2Y 12 inhibitor than comparable men, with no difference in bleeding risks. Shorter P2Y 12 inhibitor durations in older women than comparable men observed between 12 and 24 months post-AMI may reflect a disparity that is not justified by differences in clinical need

Depressive symptoms, cardiac structure and function, and risk of incident heart failure with preserved ejection fraction and heart failure with reduced ejection fraction in late life

BACKGROUND: Depressive symptoms are associated with heightened risk of heart failure (HF), but their association with cardiac function and with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) in late life is un-clear. We aimed to determine the prevalence of depression in HFpEF and in HFrEF in late life, and the association of depressive symptoms with cardiac function and incident HFpEF and HFrEF. METHODS AND RESULTS: We studied 6025 participants (age, 75.3±5.1 years; 59% women; 20% Black race) in the ARIC (Atherosclerosis Risk in Communities) study at visit 5 who underwent echocardiography and completed the Center for Epidemiologic Studies Depression Scale questionnaire. Among HF-free participants (n=5086), associations of Center for Epidemiologic Studies Depression Scale score with echocardiography and incident adjudicated HFpEF and HFrEF were assessed using multivariable linear and Cox proportional hazards regression. Prevalent HFpEF, but not HFrEF, was associated with a higher prevalence of depression compared with HF-free participants (P0.05). Over 5.5-year follow-up, higher Center for Epidemiologic Studies Depression Scale score was associated with heightened risk of incident HFpEF (hazard ratio [HR] [95% CI], 1.06 [1.04–1.12]; P=0.02), but not HFrEF (HR [95% CI], 1.02 [0.96–1.08]; P=0.54), independent of echocardiographic measures, NT-proBNP (N-terminal pro-B-type natriuretic peptide), troponin, and hs-CRP (high-sensitivity C-reactive protein) (HR [95% CI], 1.06 [1.00–1.12]; P=0.04). CONCLUSIONS: Worse depressive symptoms predict incident HFpEF in late life, independent of common comorbidities, cardiac structure and function, and prognostic biomarkers. Further studies are necessary to understand the mechanisms linking depression to risk of HFpEF

Contribution of medications and risk factors to QTc interval lengthening in the atherosclerosis risk in communities (ARIC) study

Rationale, aims, and objectives: Prolongation of the corrected QT (QTc) interval is associated with increased morbidity and mortality. The association between QTc interval–prolonging medications (QTPMs) and risk factors with magnitude of QTc interval lengthening is unknown. We examined the contribution of risk factors alone and in combination with QTPMs to QTc interval lengthening. Method: The Atherosclerosis Risk in Communities study assessed 15 792 participants with a resting, standard 12-lead electrocardiogram and ≥1 measure of QTc interval over 4 examinations at 3-year intervals (1987-1998). From 54 638 person-visits, we excluded participants with QRS ≥ 120 milliseconds (n = 2333 person-visits). We corrected the QT interval using the Bazett and Framingham formulas. We examined QTc lengthening using linear regression for 36 602 person-visit observations for 14 160 cohort members controlling for age ≥ 65 years, female sex, left ventricular hypertrophy, QTc > 500 milliseconds at the prior visit, and CredibleMeds categorized QTPMs (Known, Possible, or Conditional risk). We corrected standard errors for repeat observations per person. Results: Eighty percent of person-visits had at least one risk factor for QTc lengthening. Use of QTPMs increased over the 4 visits from 8% to 17%. Among persons not using QTPMs, history of prolonged QTc interval and female sex were associated with the greatest QTc lengthening, 39 and 12 milliseconds, respectively. In the absence of risk factors, Known QTPMs and ≥2 QTPMs were associated with modest but greater QTc lengthening than Possible or Conditional QTPMs. In the presence of risk factors, ≥2 QTPM further increased QTc lengthening. In combination with risk factors, the association of all QTPM categories with QTc lengthening was greater than QTPMs alone. Conclusion: Risk factors, particularly female sex and history of prolonged QTc interval, have stronger associations with QTc interval lengthening than any QTPM category alone. All QTPM categories augmented QTc interval lengthening associated with risk factors

Predictors of Medication Adherence in the Elderly: The Role of Mental Health

The aging population routinely has comorbid conditions requiring complicated medication regimens, yet nonadherence can preclude optimal outcomes. This study explored the association of adherence in the elderly with demographic, socioeconomic, and disease burden measures. Data were from the fifth visit (2011-2013) for 6,538 participants in the Atherosclerosis Risk in Communities Study, conducted in four communities. The Morisky–Green–Levine Scale measured self-reported adherence. Forty percent of respondents indicated some nonadherence, primarily due to poor memory. Logit regression showed, surprisingly, that persons with low reading ability were more likely to report being adherent. Better self-reported physical or mental health both predicted better adherence, but the magnitude of the association was greater for mental than for physical health. Compared with persons with normal or severely impaired cognition, mild cognitive impairment was associated with lower adherence. Attention to mental health measures in clinical settings could provide opportunities for improving medication adherence