Recent reports suggest that next-generation hair dyes might take inspiration from the natural pigment melanin. In humans, melanin imparts color to hair and skin and acts as a natural sunscreen and ...radical scavenger, thereby protecting lipids and proteins from damage. The most commonly employed synthetic mimic of melanin is polydopamine, and its successful deposition on human hair was recently reported. Herein, we describe an enzymatic approach to synthetic melanin for dyeing human hair in a process that closely mimics part of natural melanogenesis. This chemoenzymatic method avoids the addition of a base and enables the implementation of several monomers beyond dopamine, including tyrosine, tyramine, and their derivatives. Critically, the enzyme provides a milder process for producing coated hair fibers than conventional chemical hair dyeing methods. In addition to providing natural coloration, these coatings have the potential to act as protective sunscreens that prevent photodamage of the inner hair fibers during exposure to sunlight. The protocols developed herein represent a mild and efficient route to nature-inspired multifunctional coatings. Such materials are promising candidates for artificial hair pigmentation and, more generally, could find extensive application as functional fiber coatings.
We report the X-ray crystal structure of a phosphodiesterase (PDE) that includes both catalytic and regulatory domains. PDE2A (215-900) crystallized as a dimer in which each subunit had an extended ...organization of regulatory GAF-A and GAF-B and catalytic domains connected by long α-helices. The subunits cross at the GAF-B/catalytic domain linker, and each side of the dimer contains in series the GAF-A and GAF-B of one subunit and the catalytic domain of the other subunit. A dimer interface extends over the entire length of the molecule. The substrate binding pocket of each catalytic domain is occluded by the H-loop. We deduced from comparisons with structures of isolated, ligand-bound catalytic subunits that the H-loop swings out to allow substrate access. However, in dimeric PDE2A (215-900), the H-loops of the two catalytic subunits pack against each other at the dimer interface, necessitating movement of the catalytic subunits to allow for H-loop movement. Comparison of the unliganded GAF-B of PDE2A (215-900) with previous structures of isolated, cGMP-bound GAF domains indicates that cGMP binding induces a significant shift in the GAF-B/catalytic domain linker. We propose that cGMP binding to GAF-B causes movement, through this linker region, of the catalytic domains, such that the H-loops no longer pack at the dimer interface and are, instead, free to swing out to allow substrate access. This increase in substrate access is proposed as the basis for PDE2A activation by cGMP and may be a general mechanism for regulation of all PDEs.
Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 ...lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55-0.88) and 0.51(0.39-0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (p(trend) = 0.002) and current (p(trend)<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to ...identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.
To determine whether patient and graft survival following transplantation with non-heart-beating donor (NHBD) hepatic allografts is equivalent to heart-beating-donor (HBD) allografts.
With the ...growing disparity between the number of patients awaiting liver transplantation and a limited supply of cadaveric organs, there is renewed interest in the use of hepatic allografts from NHBDs. Limited outcome data addressing this issue exist.
Retrospective evaluation of graft and patient survival among adult recipients of NHBD hepatic allografts compared with recipients of HBD livers between 1993 and 2001 using the United Network of Organ Sharing database.
NHBD (N = 144) graft survival was significantly shorter than HBD grafts (N = 26856). One- and 3-year graft survival was 70.2% and 63.3% for NHBD recipients versus 80.4% and 72.1% (P = 0.003 and P = 0.012) for HBD recipients. Recipients of an NHBD graft had a greater incidence of primary nonfunction (11.8 vs. 6.4%, P = 0.008) and retransplantation (13.9% vs. 8.3%, P = 0.04) compared with HBD recipients. Prolonged cold ischemic time and recipient life support were predictors of early graft failure among recipients of NHBD livers. Although differences in patient survival following NHBD versus HBD transplant did not meet statistical significance, a strong trend was evident that likely has relevant clinical implications.
Graft and patient survival is inferior among recipients of NHBD livers. NHBD donors remain an important source of hepatic grafts; however, judicious use is warranted, including minimization of cold ischemia and use in stable recipients.
Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), ...folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions.
We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status.
Rs6893114 in MTRR (odds ratio OR = 2.10; 95% credible interval CI: 1.20-3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26-0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10-2.87) and two SNP*nutrient interactions betaine*rs2658161 (OR = 0.42; 95% CI: 0.19-0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30-0.91) were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11-0.58; rs10512948; OR = 0.61; 95% CI: 0.41-0.90; rs2924471; OR = 3.31; 95% CI: 1.66-6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43-0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11-2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27-0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15-0.95) were associated with lung cancer risk in never smokers.
This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Out-of-hospital cardiac arrest (OHCA) affects over 300,000 individuals per year in the United States with poor survival rates overall. A remarkable 5-fold difference in survival-to-hospital discharge ...rates exist across United States communities.
We conducted a study using qualitative research methods comparing the system of care across sites in Michigan communities with varying OHCA survival outcomes, as measured by return to spontaneous circulation with pulse upon emergency department arrival.
Major themes distinguishing higher performing sites were (1) working as a team, (2) devoting resources to coordination across agencies, and (3) developing a continuous quality improvement culture. These themes spanned the chain of survival framework for OHCA. By examining the unique processes, procedures, and characteristics of higher- relative to lower-performing sites, we gleaned lessons learned that appear to distinguish higher performers. The higher performing sites reported being the most collaborative, due in part to facilitation of system integration by progressive leadership that is willing to build bridges among stakeholders.
Based on the distinguishing features of higher performing sites, we provide recommendations for toolkit development to improve survival in prehospital systems of care for OHCA.
IntroductionOut-of-hospital cardiac arrest (OHCA) is a common, life-threatening event encountered routinely by first responders, including police, fire and emergency medical services (EMS). Current ...literature suggests that there is significant regional variation in outcomes, some of which may be related to modifiable factors. Yet, there is a persistent knowledge gap regarding strategies to guide quality improvement efforts in OHCA care and, by extension, survival. The Enhancing Prehospital Outcomes for Cardiac Arrest (EPOC) study aims to fill these gaps and to improve outcomes.Methods and analysisThis mixed-methods study includes three aims. In aim I, we will define variation in OHCA survival to the emergency department (ED) among EMS agencies that participate in the Michigan Cardiac Arrest Registry to Enhance Survival (CARES) in order to sample EMS agencies with high-survival and low-survival outcomes. In aim II, we will conduct site visits to emergency medical systems—including 911/dispatch, police, non-transport fire, and EMS agencies—in approximately eight high-survival and low-survival communities identified in aim I. At each site, key informant interviews and a multidisciplinary focus group will identify themes associated with high OHCA survival. Transcripts will be coded using a structured codebook and analysed through thematic analysis. Results from aims I and II will inform the development of a survey instrument in aim III that will be administered to all EMS agencies in Michigan. This survey will test the generalisability of factors associated with increased OHCA survival in the qualitative work to ultimately build an EPOC Toolkit which will be distributed to a broad range of stakeholders as a practical ‘how-to’ guide to improve outcomes.Ethics and disseminationThe EPOC study was deemed exempt by the University of Michigan Institutional Review Board. Findings will be compiled in an ‘EPOC Toolkit’ and disseminated in the USA through partnerships including, but not limited to, policymakers, EMS leadership and health departments.
Due to the aging and increasingly complex nature of our patients, frailty has become a high-priority theme in cardiovascular medicine. Despite the recognition of frailty as a pivotal element in the ...evaluation of older adults with cardiovascular disease (CVD), there has yet to be a road map to facilitate its adoption in routine clinical practice. Thus, we sought to synthesize the existing body of evidence and offer a perspective on how to integrate frailty into clinical practice. Frailty is a biological syndrome that reflects a state of decreased physiological reserve and vulnerability to stressors. Upward of 20 frailty assessment tools have been developed, with most tools revolving around the core phenotypic domains of frailty—slow walking speed, weakness, inactivity, exhaustion, and shrinking—as measured by physical performance tests and questionnaires. The prevalence of frailty ranges from 10% to 60%, depending on the CVD burden, as well as the tool and cutoff chosen to define frailty. Epidemiological studies have consistently demonstrated that frailty carries a relative risk of >2 for mortality and morbidity across a spectrum of stable CVD, acute coronary syndromes, heart failure, and surgical and transcatheter interventions. Frailty contributes valuable prognostic insights incremental to existing risk models and assists clinicians in defining optimal care pathways for their patients. Interventions designed to improve outcomes in frail elders with CVD such as multidisciplinary cardiac rehabilitation are being actively tested. Ultimately, frailty should not be viewed as a reason to withhold care but rather as a means of delivering it in a more patient-centered fashion.
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