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Purpose: Testicular cancer (TC) treatment is clearly associated with cardiovascular morbidity and mortality. To enable development of preventive strategies for cardiovascular disease (CVD), we assessed cardiometabolic risk factors and quality of life (QoL) in TC survivors., Methods: Incidence of coronary artery disease, myocardial infarction, and heart failure after TC treatment was assessed in a multicenter cohort comprising 4,748 patients treated at the age of 12-50 years between 1976 and 2007. Patients who had developed CVD and a random sample from the cohort (subcohort) received a questionnaire on cardiometabolic risk factors and QoL. A subgroup of responders in the subcohort additionally underwent clinical evaluation of cardiovascular risk factors., Results: After a median follow-up of 16 years, 272 patients had developed CVD. Compared with orchidectomy only, cisplatin combination chemotherapy was associated with an increased CVD risk (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.1). Patients who were obese or a smoker at diagnosis (HR, 4.6; 95% CI, 2.0 to 10.0 and HR, 1.7; 95% CI, 1.1 to 2.4, respectively), developed Raynaud's phenomenon (HR, 1.9; 95% CI, 1.1 to 3.6) or dyslipidemia (HR, 2.8; 95% CI, 1.6 to 4.7) or had a positive family history for CVD (HR, 2.9; 95% CI, 1.7 to 4.9) had higher CVD risk. More TC survivors with CVD reported inferior QoL on physical domains than survivors who did not develop CVD. Of 304 TC survivors who underwent clinical evaluation for cardiovascular risk factors (median age at assessment: 51 years), 86% had dyslipidemia, 50% had hypertension, and 35% had metabolic syndrome, irrespective of treatment., Conclusion: Cardiovascular events in TC survivors impair QoL. Many TC survivors have undetected cardiovascular risk factors. We advocate early lifestyle adjustments and lifelong follow-up with low-threshold treatment of cardiovascular risk factors, especially in obese and smoking patients treated with platinum-based chemotherapy.

New Findings: What is the central question of this study? Use of the passive leg movement (PLM) test, a non-invasive assessment of microvascular function, is on the rise. However, PLM reliability in men has not been adequately investigated, nor has such reliability data, in men, been compared to the most commonly employed vascular function assessment, flow-mediated vasodilation (FMD). What is the main finding and its importance? PLM is a reliable method to assess vascular function in men, and is comparable to values previously reported for PLM in women, and for FMD. Given the importance of vascular function as a predictor of cardiovascular disease risk, these data support the utility of PLM as a clinically relevant measurement., Abstract: Although vascular function is an independent predictor of cardiovascular disease risk, and therefore has significant prognostic value, there is currently not a single clinically accepted method of assessment. The passive leg movement (PLM) assessment predominantly reflects microvascular endothelium-dependent vasodilation and can identify decrements in vascular function with advancing age and pathology. Reliability of the PLM model was only recently determined in women, and has not been adequately investigated in men. Twenty healthy men (age: 27 ± 2 year) were studied on three separate experimental days, resulting in three within-day and three between-day trials. The hyperemic response to PLM was assessed with Doppler ultrasound, and expressed as the absolute peak in leg blood flow (LBF peak ), change from baseline to peak (ΔLBF peak ), absolute area under the curve (LBF AUC ), and change in AUC from baseline (ΔLBF AUC ). PLM-induced hyperemia yielded within-day coefficients of variation (CV) from 10.9 to 22.9%, intraclass correlation coefficients (ICC) from 0.82 to 0.90, standard error of the measurement (SEM) from 8.3 to 17.2%, and Pearson's correlation coefficients (r) from 0.56 to 0.81. Between-day assessments of PLM hyperemia resulted in CV from 14.4 to 25%, ICC from 0.75 to 0.87, SEM from 9.8 to 19.8%, and r from 0.46 to 0.75. Similar to previous reports in women, the hyperemic responses to PLM in men display moderate-to-high reliability, and are comparable to reliability data for brachial artery flow mediated vasodilation. These positive reliability findings further support the utility of PLM as a clinical measurement of vascular function and cardiovascular disease risk., (© 2022 The Authors. Experimental Physiology © 2022 The Physiological Society.)

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Purpose: Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a contralateral TGCT (CTGCT). Although some studies suggest that prior treatment with platinum-based chemotherapy affects CTGCT risk, a relationship between CTGCT risk and platinum dose has not previously been assessed. We analyzed the association between the number of platinum-based chemotherapy cycles and CTGCT risk., Patients and Methods: The risk of developing a metachronous CTGCT was evaluated in a nationwide cohort of 4,755 patients diagnosed with primary TGCT in the Netherlands between 1989 and 2007. Standardized incidence ratios were computed to compare CTGCT incidence with expected TGCT on the basis of TGCT incidence in the general population. The cumulative incidence of CTGCT was estimated in the presence of death as competing risk. The effect of treatment with platinum-based chemotherapy on CTGCT risk was assessed using multivariable Cox proportional hazards regression models., Results: CTGCT was diagnosed in 136 patients (standardized incidence ratio, 14.6; 95% CI, 12.2 to 17.2). The cumulative incidence increased up to 20 years after primary diagnosis, reaching 3.4% (95% CI, 2.8% to 4.0%) after 20 years of follow up. The risk of developing a CTGCT decreased with age (hazard ratio [HR], 0.93; 95% CI, 0.90 to 0.96), was lower after nonseminomatous germ cell tumor (HR, 0.58; 95% CI, 0.35 to 0.96) and decreased with every additional cycle of chemotherapy (HR per cycle , 0.74; 95% CI, 0.64 to 0.85)., Conclusion: Approximately one in every 30 survivors of TGCT will develop a CTGCT, with CTGCT incidence increasing up to 20 years after a primary TGCT. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with CTGCT risk.

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era., Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis., Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m 2 platinum dose administered (P trend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure., Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 μg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

Patients suffering from heart failure with reduced ejection fraction (HFrEF) experience impaired limb blood flow during exercise, which may be due to a disease-related increase in α-adrenergic receptor vasoconstriction. Thus, in eight patients with HFrEF (63 ± 4 yr) and eight well-matched controls (63 ± 2 yr), we examined changes in leg blood flow (Doppler ultrasound) during intra-arterial infusion of phenylephrine (PE; an α 1 -adrenergic receptor agonist) and phentolamine (Phen; a nonspecific α-adrenergic receptor antagonist) at rest and during dynamic single-leg knee-extensor exercise (0, 5, and 10 W). At rest, the PE-induced reduction in blood flow was significantly attenuated in patients with HFrEF (-15 ± 7%) compared with controls (-36 ± 5%). During exercise, the controls exhibited a blunted reduction in blood flow induced by PE (-12 ± 4, -10 ± 4, and -9 ± 2% at 0, 5, and 10 W, respectively) compared with rest, while the PE-induced change in blood flow was unchanged compared with rest in the HFrEF group (-8 ± 5, -10 ± 3, and -14 ± 3%, respectively). Phen administration increased leg blood flow to a greater extent in the HFrEF group at rest (+178 ± 34% vs. +114 ± 28%, HFrEF vs. control) and during exercise (36 ± 6, 37 ± 7, and 39 ± 6% vs. 13 ± 3, 14 ± 1, and 8 ± 3% at 0, 5, and 10 W, respectively, in HFrEF vs. control). Together, these findings imply that a HFrEF-related increase in α-adrenergic vasoconstriction restrains exercising skeletal muscle blood flow, potentially contributing to diminished exercise capacity in this population.

Mechanobullous epidermolysis bullosa acquisita (mEBA) can have a clinical presentation that is very similar to other blistering diseases, such as porphyria cutanea tarda (PCT) and pseudoporphyria. Direct immunofluorescence is an important feature in the diagnosis of mEBA, although features that overlap with PCT and pseudoporphyria have been reported. This retrospective observational study investigated whether direct immunofluorescence can discriminate mEBA from PCT and pseudoporphyria. Biopsies of 13 patients with mEBA, 10 with PCT and 10 with pseudoporphyria were included. In 7 cases of PCT and 4 of pseudoporphyria, direct immunofluorescence showed a pattern at the dermal-epidermal junction that appeared similar to the u-serrated pattern in mEBA. Vessel wall depositions were observed in all 3 diseases, but were more frequent and more intense in PCT and pseudoporphyria than in mEBA. Careful examination of direct immunofluorescence of mEBA vs. PCT and pseudoporphyria revealed different staining patterns, although overlapping features were present. Therefore, integrating all clinical and laboratory data is essential to differentiate between mEBA, PCT and pseudoporphyria.

New Findings: What is the central question of this study? Do systemic sclerosis patients exhibit impaired nitric oxide-mediated vascular function of the lower limb and are these decrements correlated with plasma biomarkers for inflammation and oxidative stress? What is the main finding and its importance? Findings indicate impaired nitric oxide-mediated vascular function, linked to the incidence of digital ulcers and a milieu of inflammation and oxidative stress. However, the absence of significant correlations between individual biomarkers and blood flow responses suggests that the vasculopathy observed in systemic sclerosis may not be solely the result of derangements in the redox balance or inflammatory signalling., Abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, which may be the consequence of inflammation and oxidative stress that ultimately leads to a reduced nitric oxide (NO) bioavailability. Passive leg movement (PLM) is a novel methodology for assessing lower limb vascular function that is predominantly NO dependent. We combined this vascular assessment with a comprehensive panel of plasma biomarkers to assess the axis of inflammation, oxidative stress and NO in SSc patients (n = 12; 62 ± 11 years of age) compared with healthy control subjects (n = 17; 60 ± 16 years of age). The PLM-induced changes in leg blood flow (LBF; 191 ± 104 versus 327 ± 217 ml min -1 ) and LBF area under the curve (39 ± 104 versus 125 ± 131 ml) were reduced in SSc compared with control subjects. Stratification of patients according to history of digital ulcer (DU) formation revealed a further reduction in LBF area under the curve in DU (-13 ± 83 ml) versus non-DU (91 ± 102 ml) patients. Biomarkers of inflammation (C-reactive protein) and oxidative stress (malondialdehyde and protein carbonyl) were all elevated in SSc (C-reactive protein, 3299 ± 2372 versus 984 ± 565 ng ml -1 ; malondialdehyde, 3.2 ± 1.1 versus 1.1 ± 0.7 μm; and protein carbonyl, 0.15 ± 0.05 versus 0.12 ± 0.03 nmol mg -1 ), and C-reactive protein was further elevated in patients with a history of DU (4551 ± 2752 versus 2047 ± 1019 ng ml -1 ) compared with non-DU, although these were not individually correlated with changes in LBF. These findings of impaired NO-mediated vascular function, linked to DU and a milieu of inflammation and oxidative stress, suggest that redox balance plays an important, but not necessarily deterministic, role in the vascular pathophysiology of SSc., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Background: While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated., Methods: Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case-cohort design., Results: With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7-1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11-0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: -0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose., Conclusion: Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.

Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m 2 increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m 2 of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.

The overall light energy to biomass conversion efficiency of plant photosynthesis is generally regarded as low. Forward genetic screens in Arabidopsis have yielded very few mutants with substantially enhanced photochemistry. Here, we report the isolation of a novel Arabidopsis mutant with a high operating efficiency of Photosystem II (φPSII) and low chlorophyll fluorescence from a library of lines harboring T-DNA constructs encoding artificial transcription factors. This mutant was named Low Chlorophyll Fluorescence 1 (LCF1). Only a single T-DNA insertion was detected in LCF1, which interrupted the expression of the full length mRNA of the gene At4g36280 (MORC2). We demonstrate that the high φPSII and low levels of chlorophyll fluorescence were due to a decrease in PSII:PSI ratio. Although LCF1 plants had decreased rosette surface area and biomass under normal growth conditions, they contained more starch per gram fresh weight. The growth defect of LCF1 was alleviated by low light and short day conditions, and growth could even be enhanced after a period of dark-induced senescence, showing that the plant can utilize its excess photosynthetic conversion capacity as a resource when needed.

Hybrid magic-angle spinning (MAS) NMR spectroscopy and TEM were demonstrated for de novo structure determination of para-crystalline materials with a bioinspired fused naphthalene diimide (NDI)-salphen-phenazine prototype light-harvesting compound. Starting from chiral building blocks with C 2 molecular symmetry, the asymmetric unit was determined by MAS NMR spectroscopy, index low-resolution TEM diffraction data, and resolve reflection conditions, and for the first time the ability to determine the space group from reciprocal space data using this hybrid approach was shown. Transfer of molecular C 2 symmetry into P2/c packing symmetry provided a connection across length scales to overcome both lack of long-range order and missing diffraction-phase information. Refinement with heteronuclear distance constraints confirmed the racemic P2/c packing that was scaffolded by molecular recognition of salphen zinc in a pseudo-octahedral environment with bromide and with alkyl chains folding along the phenazine. The NDI light-harvesting stacks ran orthogonal to the intermolecular electric dipole moment present in the solid. Finally, the orientation of flexible lamellae on an electrode surface was determined., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) are retinal-based light-driven proton pumps that absorb visible light (maxima at 520-540 nm). Shifting the action spectra of these proton pumps beyond 700 nm would generate new prospects in optogenetics, membrane sensor technology, and complementation of oxygenic phototrophy. We therefore investigated the effect of red-shifting analogues of retinal, combined with red-shifting mutations, on the spectral properties and pump activity of the resulting pigments. We investigated a variety of analogues, including many novel ones. One of the novel analogues we tested, 3-methylamino-16-nor-1,2,3,4-didehydroretinal (MMAR), produced exciting results. This analogue red-shifted all of the rhodopsin variants tested, accompanied by a strong broadening of the absorbance band, tailing out to 850-950 nm. In particular, MMAR showed a strong synergistic effect with the PR-D212N,F234S double mutant, inducing an astonishing 200 nm red shift in the absorbance maximum. To our knowledge, this is by far the largest red shift reported for any retinal protein. Very importantly, all MMAR-containing holoproteins are the first rhodopsins retaining significant pump activity under near-infrared illumination (730 nm light-emitting diode). Such MMAR-based rhodopsin variants present very promising opportunities for further synthetic biology modification and for a variety of biotechnological and biophysical applications.

The vasodilatory response to passive leg movement (PLM) appears to provide a novel, noninvasive assessment of vascular function. However, PLM has yet to be compared with the established noninvasive assessment of vascular health, flow-mediated dilation (FMD). Therefore, as an initial evaluation of the construct validity of PLM and upright seated and supine PLM as well as brachial (BA) and superficial femoral (SFA) artery FMDs were performed in 10 young (22 ± 1) and 30 old (73 ± 2) subjects. During upright seated PLM, the peak change in leg blood flow (ΔLBF) and leg vascular conductance (ΔLVC) was significantly correlated with BA (r = 0.57 and r = 0.66) and SFA (r = 0.44 and r = 0.41, ΔLBF and ΔLVC, respectively) FMD. Furthermore, although the relationships were not as strong, the supine PLM response was also significantly correlated with BA (r = 0.38 and r = 0.35) and SFA (r = 0.39 and r = 0.35, ΔLBF and ΔLVC, respectively) FMD. Examination of the young and old separately, however, revealed that significant relationships persisted in both groups only for the upright seated PLM response and BA FMD (young: r = 0.73 and r = 0.77; old: r = 0.35 and r = 0.45, ΔLBF and ΔLVC, respectively). Normalizing FMD for shear rate during PLM abrogated all significant relationships between the PLM and FMD response, suggesting a role for nitric oxide (NO) in these associations. Collectively, these data indicate that PLM, particularly upright seated PLM, likely provides an index of vascular health analogous to the traditional FMD test. Given the relative ease of PLM implementation, these data have important positive implications for PLM as a clinical vascular health assessment.

Arabidopsis thaliana is the most widely used model organism for research in plant biology. While significant advances in understanding plant growth and development have been made by focusing on the molecular genetics of Arabidopsis, extracting and understanding the functional framework of metabolism is challenging, both from a technical perspective due to losses and modification during extraction of metabolites from the leaves, and from the biological perspective, due to random variation obscuring how well the function is performed. The purpose of this work is to establish the in vivo metabolic profile directly from the Arabidopsis thaliana leaves without metabolite extraction, to reduce the complexity of the results by multivariate analysis, and to unravel the mitigation of cellular complexity by predominant functional periodicity. To achieve this, we use the circadian cycle that strongly influences metabolic and physiological processes and exerts control over the photosynthetic machinery. High resolution-magic angle spinning nuclear magnetic resonance (HR-MAS NMR) was applied to obtain the metabolic profile directly from intact Arabidopsis leaves. Combining one- and two-dimensional 1H HR-MAS NMR allowed the identification of several metabolites including sugars and amino acids in intact leaves. Multivariate analysis on HR-MAS NMR spectra of leaves throughout the circadian cycle revealed modules of primary metabolites with significant and consistent variations of their molecular components at different time points of the circadian cycle. Since robust photosynthetic performance in plants relies on the functional periodicity of the circadian rhythm, our results show that HR-MAS NMR promises to be an important non-invasive method that can be used for metabolomics of the Arabidopsis thaliana mutants with altered physiology and photosynthetic efficiency., Competing Interests: The authors have declared that no competing interests exist.

In electrocatalytic water splitting systems pursuing for renewable energy using sunlight, developing robust, stable and easily accessible materials operating under mild chemical conditions is pivotal. We present here a unique nanoparticulate type silver-oxide (AgOx-NP) based robust and highly stable electrocatalyst for efficient water oxidation. The AgOx-NP is generated in situ in a HCO3(-)/CO2 system under benign conditions. Micrographs show that they exhibit a nanoscale box type squared nano-bipyramidal configuration. The oxygen generation is initiated at low overpotential, and a sustained O2 evolution current density of >1.1 mA cm(-2) is achieved during prolonged-period water electrolysis. The AgOx-NP electrocatalyst performs exceptionally well in metal-ion free neutral or near-neutral carbonate, phosphate and borate buffers relative to recently reported Co-oxide and Ni-oxide based heterogeneous electrocatalysts, which are unstable in metal-ion free electrolytes and tend to deactivate with time and lose catalytic performance during long-term experimental tests.

Introduction: Because of reduced nitric oxide (NO) bioavailability with age, passive leg movement (PLM)-induced vasodilation is attenuated in older sedentary subjects and, unlike the young subjects, cannot be augmented by posture-induced elevations in femoral perfusion pressure. However, whether vasodilator function assessed with PLM, and therefore NO bioavailability, is preserved in older individuals with greater physical activity and fitness is unknown., Methods: PLM was performed on four subject groups: young sedentary (Y, 23 ± 1 yr, n = 12), old sedentary (OS, 73 ± 2 yr, n = 12), old active (OA, 71 ± 2 yr, n = 10), and old endurance trained (OT, 72 ± 1 yr, n = 10) in the supine and upright-seated posture. Hemodynamics were measured using ultrasound Doppler and finger photoplethysmography., Results: In the supine posture, PLM-induced peak change in leg vascular conductance was significantly attenuated in the OS compared with the young subjects (OS = 4.9 ± 0.5, Y = 6.9 ± 0.7 mL·min·mm Hg) but was not different from the young in the OA and OT (OA = 5.9 ± 1.0, OT = 5.4 ± 0.4 mL·min·mm Hg). The upright-seated posture significantly augmented peak change in leg vascular conductance in all but the OS (OS = 4.9 ± 0.5, Y = 11.8 ± 1.3, OA = 7.3 ± 0.8, OT = 8.1 ± 0.8 mL·min·mm Hg), revealing a significant vasodilatory reserve capacity in the other groups (Y = 4.92 ± 1.18, OA = 1.37 ± 0.55, OT = 2.76 ± 0.95 mL·min·mm Hg)., Conclusions: As PLM predominantly reflects NO-mediated vasodilation, these findings support the idea that augmenting physical activity and fitness can protect NO bioavailability, attenuating the deleterious effects of advancing age on vascular function.

Post-cuff occlusion flow-mediated dilation (FMD) is a proposed indicator of nitric oxide (NO) bioavailability and vascular function. FMD is reduced in patients with sepsis and may be a marker of end organ damage and mortality. However, FMD likely does not solely reflect NO-mediated vasodilation, is technically challenging, and often demonstrates poor reproducibility. In contrast, passive leg movement (PLM), a novel methodology to assess vascular function, yields a hyperemic response that is predominately NO-dependent, reproducible, and easily measured. This study evaluated PLM as an approach to assess NO-mediated vascular function in patients with sepsis. We hypothesized that PLM-induced hyperemia, quantified by the increase in leg blood flow (LBF), would be attenuated in sepsis. In a cross-sectional study, 17 subjects in severe sepsis or septic shock were compared with 16 matched healthy controls. Doppler ultrasound was used to assess brachial artery FMD and the hyperemic response to PLM in the femoral artery. FMD was attenuated in septic compared with control subjects (1.1 ± 1.7% vs. 6.8 ± 1.3%; values are means ± SD). In terms of PLM, baseline LBF (196 ± 33 ml/min vs. 328 ± 20 ml/min), peak change in LBF from baseline (133 ± 28 ml/min vs. 483 ± 86 ml/min), and the LBF area under the curve (16 ± 8.3 vs. 143 ± 33) were all significantly attenuated in septic subjects. Vascular function, as assessed by both FMD and PLM, is attenuated in septic subjects compared with controls. These data support the concept that NO bioavailability is attenuated in septic subjects, and PLM appears to be a novel and feasible approach to assess NO-mediated vascular function in sepsis.

Background: Sensitization of mechanosensitive afferents, which contribute to the exercise pressor reflex, has been recognized as a characteristic of patients with heart failure (HF); however, the hemodynamic implications of this hypersensitivity are unclear., Objectives: The present study used passive leg movement (PLM) and intrathecal injection of fentanyl to blunt the afferent portion of this reflex arc to better understand the role of the mechanoreflex on central and peripheral hemodynamics in HF., Methods: Femoral blood flow (FBF), mean arterial pressure, femoral vascular conductance, HR, stroke volume, cardiac output, ventilation, and muscle oxygenation of the vastus lateralis were assessed in 10 patients with New York Heart Association class II HF at baseline and during 3 min of PLM both with fentanyl and without (control)., Results: Fentanyl had no effect on baseline measures but increased (control vs fentanyl, P < 0.05) the peak PLM-induced change in FBF (493 ± 155 vs 804 ± 198 ΔmL·min(-1)) and femoral vascular conductance (4.7 ± 2 vs 8.5 ± 3 ΔmL·min(-1)·mm Hg)(-1) while norepinephrine spillover (103% ± 19% vs 58% ± 17%Δ) and retrograde FBF (371 ± 115 vs 260 ± 68 ΔmL·min(-1)) tended to be reduced (P < 0.10). In addition, fentanyl administration resulted in greater PLM-induced increases in muscle oxygenation, suggestive of increased microvascular perfusion. Fentanyl had no effect on the ventilation, mean arterial pressure, HR, stroke volume, or cardiac output response to PLM., Conclusions: Although movement-induced central hemodynamics were unchanged by afferent blockade, peripheral hemodynamic responses were significantly enhanced. Thus, in patients with HF, a heightened mechanoreflex seems to augment peripheral sympathetic vasoconstriction in response to movement, a phenomenon that may contribute to exercise intolerance in this population.

Both photosystem I and photosystem II are considerably similar in molecular architecture but they operate at very different electrochemical potentials. The origin of the different redox properties of these RCs is not yet clear. In recent years, insight was gained into the electronic structure of photosynthetic cofactors through the application of photochemically induced dynamic nuclear polarization (photo-CIDNP) with magic-angle spinning NMR (MAS NMR). Non-Boltzmann populated nuclear spin states of the radical pair lead to strongly enhanced signal intensities that allow one to observe the solid-state photo-CIDNP effect from both photosystem I and II from isolated reaction center of spinach (Spinacia oleracea) and duckweed (Spirodela oligorrhiza) and from the intact cells of the cyanobacterium Synechocystis by (13)C and (15)N MAS NMR. This review provides an overview on the photo-CIDNP MAS NMR studies performed on PSI and PSII that provide important ingredients toward reconstruction of the electronic structures of the donors in PSI and PSII., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Studies examining the effect of aging on skeletal muscle oxidative capacity have yielded equivocal results; however, these investigations may have been confounded by differences in oxygen (O(2)) delivery, physical activity, and small numbers of participants. Therefore, we evaluated skeletal muscle oxidative capacity and O(2) delivery in a relatively large group (N = 40) of young (22 ± 2 years) and old (73 ± 7 years) participants matched for physical activity. After submaximal dynamic plantar flexion exercise, phosphocreatine (PCr) resynthesis ((31)P magnetic resonance spectroscopy), muscle reoxygenation (near-infrared spectroscopy), and popliteal artery blood flow (Doppler ultrasound) were measured. The phosphocreatine recovery time constant (Tau) (young: 33 ± 16; old: 30 ± 11 seconds), maximal rate of adenosine triphosphate (ATP) synthesis (young: 25 ± 9; old: 27 ± 8 mM/min), and muscle reoxygenation rates determined by the deoxyhemoglobin/myoglobin recovery Tau (young: 48 ± 5; old: 47 ± 9 seconds) were similar between groups. Similarly, although tending to be higher in the old, there were no significant age-related differences in postexercise popliteal blood flow (area under the curve: young: 1,665 ± 227 vs old: 2,404 ± 357 mL, p = .06) and convective O(2) delivery (young: 293 ± 146 vs old: 404 ± 191 mL, p = .07). In conclusion, when physical activity and O(2) delivery are similar, oxidative capacity in the plantar flexors is not affected by aging. These findings reveal that diminished skeletal muscle oxidative capacity is not an obligatory accompaniment to the aging process., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Passive leg movement (PLM), an assessment of predominantly nitric oxide-dependent vasodilation, is decreased with age and cannot be augmented by posture-induced increases in femoral perfusion pressure in older men. However, this novel method of assessing vascular function has yet to be used to evaluate alterations in nitric oxide-dependent vasodilation with age in females. PLM was performed in 10 young (20 ± 1 yr) and 10 old (73 ± 2 yr) women in both the supine and upright-seated postures, whereas central and peripheral hemodynamic measurements were acquired second by second using noninvasive techniques (finger photoplethysmography and Doppler ultrasound, respectively). The heart rate response to PLM was attenuated in the old compared with the young in both the supine (young, 10 ± 1; and old, 5 ± 1 beats/min; P < 0.05) and upright-seated posture (young, 10 ± 2; and old, 5 ± 1 beats/min; P < 0.05), leading to a blunted cardiac output response in the old in the upright-seated posture (young, 1.0 ± 0.2; and old, 0.3 ± 0.1 l/min; P < 0.05). The PLM-induced peak change in leg vascular conductance was lower in the old compared with the young in both postures (young supine, 5.7 ± 0.5; old supine, 2.6 ± 0.3; young upright, 9.2 ± 0.7; and old upright, 2.2 ± 0.4 ml·min(-1)·mmHg(-1); P < 0.05) and was significantly augmented by the upright-seated posture in the young only, revealing a vasodilatory reserve capacity in the young (3.5 ± 0.6 ml·min(-1)·mmHg(-1), P < 0.05) that was absent in the old (-0.5 ± 0.3 ml·min(-1)·mmHg(-1), P = 0.18). These data support previous literature demonstrating attenuated PLM-induced vasodilation with age and extend these findings to include the female population, thus bolstering the utility of PLM as a novel assessment of vascular function across the life span in humans., (Copyright © 2015 the American Physiological Society.)

The passive leg movement (PLM) model is a novel approach to assess vascular function. Increasing femoral perfusion pressure (FPP) by moving from the supine to the upright-seated posture augments the vasodilatory response to PLM in the young, with no effect in the old, but whether this augmented vasodilatation is nitric oxide (NO) dependent is unknown. Using an intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) to inhibit nitric oxide synthase (NOS), the posture-induced increases in the PLM responses in the young were nearly ablated, with no effect of NOS inhibition in the old. Therefore, PLM in combination with alterations in posture can be used to determine changes in NO-mediated vasodilatation with age, and thus, may be a clinically useful tool for assessing NO bioavailability across the human lifespan. We sought to better understand the contribution of nitric oxide (NO) to passive leg movement (PLM)-induced vasodilatation with age, with and without a posture-induced increase in femoral perfusion pressure (FPP). PLM was performed in eight young (24 ± 1 years) and eight old (74 ± 3 years) healthy males, with and without NO synthase inhibition via intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) into the common femoral artery in both the supine and upright-seated posture. Central and peripheral haemodynamic responses were determined second-by-second with finger photoplethysmography and Doppler ultrasound, respectively. PLM-induced increases in heart rate, stroke volume, cardiac output and reductions in mean arterial pressure were similar between age groups and conditions. In the young, L -NMMA attenuated the peak change in leg vascular conductance (ΔLVCpeak ) in both the supine (control: 7.4 ± 0.9; L -NMMA: 5.2 ± 1.1 ml min(-1) mmHg(-1) , P < 0.05) and upright-seated (control: 12.3 ± 2.0; L -NMMA: 6.4 ± 1.0 ml min(-1) mmHg(-1) , P < 0.05) posture, with no significant change in the old (supine control: 4.2 ± 1.3; supine L -NMMA: 3.4 ± 0.8; upright-seated control: 4.5 ± 0.8; upright-seated L -NMMA: 3.4 ± 0.8 ml min(-1) mmHg(-1) , P > 0.05). Increased FPP augmented the ΔLVCpeak in the young control condition only (P < 0.05). In the upright-seated posture, NOS inhibition attenuated the FPP-induced augmentation of rapid vasodilatation in the young (control: 1.25 ± 0.23; L -NMMA: 0.74 ± 0.11 ml min(-1) mmHg(-1) s(-1) ; P < 0.05), but not the old (control: 0.37 ± 0.07; L -NMMA: 0.25 ± 0.07 ml ml min(-1) mmHg(-1) s(-1) ; P > 0.05). These data reveal that greater FPP increases the role of NO in PLM-induced vasodilatation in the young, but not the old, due to reduced NO bioavailability with age. Therefore, PLM involving alterations in posture may be useful to determine changes in NO bioavailability with age., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Objectives: Using flow-mediated vasodilation (FMD) and reactive hyperemia (RH), this study aimed to provide greater insight into left ventricular assist device (LVAD)-induced changes in peripheral vascular function., Background: Peripheral endothelial function is recognized to be impaired in patients with heart failure with reduced ejection fraction (HFrEF), but the peripheral vascular effects of continuous-flow LVAD implantation, now used as either a bridge to transplantation or as a destination therapy, remain unclear., Methods: Sixty-eight subjects (13 New York Heart Association [NYHA] functional class II HFrEF patients, 19 NYHA functional class III/IV HFrEF patients, 20 NYHA functional class III/IV HFrEF patients post-LVAD implantation, and 16 healthy age-matched control subjects) underwent FMD and RH testing in the brachial artery with blood flow velocity, artery diameters, and pulsatility index (PI) assessed by ultrasound Doppler., Results: PI was significantly lower in the LVAD group (2.0 ± 0.4) compared with both the HFrEF II (8.6 ± 0.8) and HFrEF III/IV (8.1 ± 0.9) patients, who, in turn, had significantly lower PI than the control subjects (12.8 ± 0.9). Likewise, LVAD %FMD/shear rate (0.09 ± 0.01 %Δ/s(-1)) was significantly reduced compared with all other groups (control subjects, 0.24 ± 0.03; HFrEF II, 0.17 ± 0.02; and HFrEF III/IV, 0.13 ± 0.02 %Δ/s(-1)), and %FMD/shear rate significantly correlated with PI (r = 0.45). RH was unremarkable across groups., Conclusions: Although central hemodynamics are improved in patients with HFrEF by a continuous-flow LVAD, peripheral vascular function is further compromised, which is likely due, at least in part, to the reduction in pulsatility that is a characteristic of such a mechanical assist device., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age.

We investigate the electron injection from a terrylene-based chromophore to the TiO2 semiconductor bridged by a recently proposed phenyl-amide-phenyl molecular rectifier. The mechanism of electron transfer is studied by means of quantum dynamics simulations using an extended Hückel Hamiltonian. It is found that the inclusion of the nuclear motion is necessary to observe the photoinduced electron transfer. In particular, the fluctuations of the dihedral angle between the terrylene and the phenyl ring modulate the localization and thus the electronic coupling between the donor and acceptor states involved in the injection process. The electron propagation shows characteristic oscillatory features that correlate with interatomic distance fluctuations in the bridge, which are associated with the vibrational modes driving the process. The understanding of such effects is important for the design of functional dyes with optimal injection and rectification properties.

This contribution discusses why we should consider developing artificial photosynthesis with the tandem approach followed by the Dutch BioSolar Cells consortium, a current operational paradigm for a global artificial photosynthesis project. We weigh the advantages and disadvantages of a tandem converter against other approaches, including biomass. Owing to the low density of solar energy per unit area, artificial photosynthetic systems must operate at high efficiency to minimize the land (or sea) area required. In particular, tandem converters are a much better option than biomass for densely populated countries and use two photons per electron extracted from water as the raw material into chemical conversion to hydrogen, or carbon-based fuel when CO2 is also used. For the average total light sum of 40 mol m(-2) d(-1) for The Netherlands, the upper limits are many tons of hydrogen or carbon-based fuel per hectare per year. A principal challenge is to forge materials for quantitative conversion of photons to chemical products within the physical limitation of an internal potential of ca 2.9 V. When going from electric charge in the tandem to hydrogen and back to electricity, only the energy equivalent to 1.23 V can be stored in the fuel and regained. A critical step is then to learn from nature how to use the remaining difference of ca 1.7 V effectively by triple use of one overpotential for preventing recombination, kinetic stabilization of catalytic intermediates and finally generating targeted heat for the release of oxygen. Probably the only way to achieve this is by using bioinspired responsive matrices that have quantum-classical pathways for a coherent conversion of photons to fuels, similar to what has been achieved by natural selection in evolution. In appendix A for the expert, we derive a propagator that describes how catalytic reactions can proceed coherently by a convergence of time scales of quantum electron dynamics and classical nuclear dynamics. We propose that synergy gains by such processes form a basis for further progress towards high efficiency and yield for a global project on artificial photosynthesis. Finally, we look at artificial photosynthesis research in The Netherlands and use this as an example of how an interdisciplinary approach is beneficial to artificial photosynthesis research. We conclude with some of the potential societal consequences of a large-scale roll out of artificial photosynthesis.

Proteorhodopsins are heptahelical membrane proteins which function as light-driven proton pumps. They use all-trans-retinal A1 as a ligand and chromophore and absorb visible light (520-540 nm). In the present paper, we describe modulation of the absorbance band of the proteorhodopsin from Monterey Bay SAR 86 gammaproteobacteria (PR), its red-shifted double mutant PR-D212N/F234S (PR-DNFS) and Gloeobacter rhodopsin (GR). This was approached using three analogues of all-trans-retinal A1, which differ in their electronic and conformational properties: all-trans-6,7-s-trans-locked retinal A1, all-trans-phenyl-retinal A1 and all-trans-retinal A2. We further probed the effect of these retinal analogues on the proton pump activity of the proteorhodopsins. Our results indicate that, whereas the constraints of the retinal-binding pocket differ for the proteorhodopsins, at least two of the retinal analogues are capable of shifting the absorbance bands of the pigments either bathochromically or hypsochromically, while maintaining their proton pump activity. Furthermore, the shifts implemented by the analogues add up to the shift induced by the double mutation in PR-DNFS. This type of chromophore substitution may present attractive applications in the field of optogenetics, towards increasing the flexibility of optogenetic tools or for membrane potential probes.

In young healthy men, passive leg movement (PLM) elicits a robust nitric oxide (NO)-dependent increase in leg blood flow (LBF), thus providing a novel approach to assess NO-mediated vascular function. While the magnitude of the LBF response to PLM is markedly reduced with age, the role of NO in this attenuated response in the elderly is unknown. Therefore, this study sought to determine the contribution of NO in the PLM-induced LBF with age. Fourteen male subjects (7 young, 24 ± 1 yr; and 7 old, 75 ± 3 yr) underwent PLM with and without NO synthase (NOS) inhibition achieved by intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central hemodynamics were measured by finger photoplethysmography. NOS inhibition blunted the PLM-induced peak increase in LBF in the young (control: 668 ± 106;, L-Nmma: 431 ± 95 Δml/min; P = 0.03) but had no effect in the old (control: 266 ± 98;, L-Nmma: 251 ± 92 Δml/min; P = 0.59). Likewise, the magnitude of the reduction in the overall (i.e., area under the curve) PLM-induced LBF response to NOS inhibition was less in the old (LBF: -31 ± 18 ml) than the young (LBF: -129 ± 21 ml; P < 0.01). These findings suggest that the age-associated reduction in PLM-induced LBF in the elderly is primarily due to a reduced contribution to vasodilation from NO and therefore support the use of PLM as a novel approach to assess NO-mediated vascular function across the lifespan.

Background: The complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls., Methods: Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM., Results: The FBF response (area under the curve; AUC) to 60s of continuous PLM was attenuated in the HFrEF (25±15ml AUC) compared to controls (199±34ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (-9±10ml AUC) in contrast to the controls (43±25ml AUC)., Conclusions: These data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation., (Published by Elsevier Ireland Ltd.)

The corpus callosum is the largest commissural fiber connecting left and right hemisphere of the brain. Emerging evidence suggests that a variety of abnormalities detected in the microstructure of this white matter fiber can be an early event in Alzheimer's disease (AD) pathology. However, little is known about tissue characteristics of these abnormalities and how these abnormalities evolve during AD progression. In this study, we measured in vivo magnetic resonance transverse relaxation times (T2) to longitudinally monitor changes in tissue integrity and abnormalities related to myelination and demyelination processes in corpus callosum of AD mouse models. The most striking finding of our study was a significant elongation of T2 values in the corpus callosum at 10, 14, 16 and 18 months of age compared to age-matched wild-type mice. In contrast, the gray matter regions surrounding the corpus callosum, such as the cortex and hippocampus, showed a significant T2 decrease compared to wild-type mice. Histological analyses clearly revealed demyelination, gliosis and amyloid-plaque deposition in the corpus callosum. Our results suggest that demyelinating and inflammatory pathology may result in prolonged relaxation time during AD progression. To our knowledge, this is the first in vivo T2 study assessing the microstructural changes with age in the corpus callosum of the Tg2576 mouse model and it demonstrates the application of T2 measurement to noninvasively detect tissue integrity of the corpus callosum, which can be an early event in disease progression.

Lipids play an important role in many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Zebrafish models for these diseases have been recently developed. The detailed brain lipid composition of the adult zebrafish is not known, and therefore, the representativeness of these models cannot be properly evaluated. In this study, we characterized the total lipid composition of healthy adult zebrafish using (1)H nuclear magnetic resonance spectroscopy. A close resemblance of the zebrafish brain composition is shown in comparison to the human brain. Moreover, several lipids involved in the pathogenesis of neurodegenerative diseases (i.e., cholesterol, phosphatidylcholine, docosahexaenoic acid, and further, polyunsaturated fatty acids) are detected and quantified. These lipids might represent useful biomarkers in future research toward human therapies. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry coupled with high-performance thin-layer chromatography was used for further characterization of zebrafish brain lipids. Our results show that the lipid composition of the zebrafish brain is rather similar to the human brain and thus confirms that zebrafish represents a good model for studying various brain diseases.

Reduced shear stress and augmented oscillatory shear rate are associated with the proatherogenic phenotype observed with aging. To date, mechanisms contributing to the age-related alterations in shear rate in humans have only been examined in the conduit vessels of the arm. Therefore, this study sought to examine the contribution of nitric oxide (NO) bioavailability to age-related alterations in shear rate and the impact of common body positions (supine and seated) in the atherosclerotic-prone conduit artery of the leg. Inhibition of NO synthase (NOS) was accomplished by intra-arterial infusion of N(G)-monomethyl-l-arginine (L-NMMA), and common femoral artery diameter and blood velocity were measured by Doppler ultrasound in healthy young (n=8, 24±1 years) and old (n=8, 75±3 years) men. Old subjects exhibited reduced mean shear rate in the supine (18±3 s(-1)) and seated positions (17±3 s(-1)) compared with young subjects (supine: 42±6 s(-1); seated: 32±4 s(-1)). This reduced mean shear in the old was driven by attenuated antegrade shear as there were no differences in retrograde shear. Inhibition of NOS reduced antegrade shear in the young such that age-related differences were abolished. In contrast, NOS-induced reductions in retrograde shear rate were similar between groups. The seated position reduced mean shear rate in the young to that normally observed in old. Overall, this study reveals that age-related reductions in mean shear rate, assessed in the atherosclerotic-prone vasculature of the leg, are largely explained by reductions in antegrade shear as a result of reduced NO bioavailability in the elderly.

Exercise-induced hyperemia is often normalized for muscle mass, and this value is sometimes evaluated at relative exercise intensities to take muscle recruitment into account. Therefore, this study sought to better understand the impact of muscle mass on leg blood flow (LBF) during exercise. LBF was assessed by Doppler ultrasound in 27 young healthy male subjects performing knee-extensor (KE) exercise at three absolute (5, 15, and 25 W) and three relative [20, 40, and 60% of maximum KE (KEmax)] workloads. Thigh muscle mass (5.2-8.1 kg) and LBF were significantly correlated at rest (r = 0.54; P = 0.004). Exercise-induced hyperemia was linearly related to absolute workload, but revealed substantial between-subject variability, documented by the coefficient of variation (5 W: 17%; 15 W: 16%; 25 W: 16%). Quadriceps muscle mass (1.5-2.7 kg) and LBF were not correlated at 5, 15, or 25 W (r = 0.09-0.01; P = 0.7-0.9). Normalizing blood flow for quadriceps muscle mass did not improve the coefficient of variation at each absolute workload (5 W: 21%; 15 W: 21%; 25 W: 22%), while the additional evaluation at relative exercise intensities resulted in even greater variance (20% KEmax: 29%; 40% KEmax: 29%; 60% KEmax: 27%). Similar findings were documented when subjects were parsed into high and low aerobic capacity. Thus, in contrast to rest, blood flow during exercise is unrelated to muscle mass, and simply normalizing for muscle mass or comparing normalized blood flow at a given relative exercise intensity has no effect on the inherent blood flow variability. Therefore, during exercise, muscle mass does not appear to be a determinant of the hyperemic response.

Impaired skeletal muscle efficiency potentially contributes to the age-related decline in exercise capacity and may explain the altered haemodynamic response to exercise in the elderly. Thus we examined whether (i) the ATP cost of contraction increases with age, and (ii) this results in altered convective O(2) delivery to maintain microvascular oxygenation in the calf muscle. To this aim, we used an integrative experimental approach combining (31)P-MRS (magnetic resonance spectroscopy), Doppler ultrasound imaging and NIRS (near-IR spectroscopy) during dynamic plantar flexion exercise at 40% of WR(max) (maximal power output) in 20 healthy young and 20 older subjects matched for physical activity. The ATP cost of contraction was significantly higher in the old (7.2±4.1 mM/min per W) compared with the young (2.4±1.9 mM/min per W; P<0.05) and this was only significantly correlated with the plantar flexion WR(max) value in the old subjects (r=-0.52; P<0.05). Even when differences in power output were taken into account, end-exercise blood flow (old, 259±168 ml/min per W and young, 134±40 ml/min per W; P<0.05) and convective O(2) delivery (old, 0.048±0.031 l/min per W and young, 0.026±0.008 l/min per W; P<0.05) were greater in the old in comparison with the young subjects. In contrast, the NIRS oxyhaemoglobin, deoxyhaemoglobin and microvascular oxygenation indices were not significantly different between the groups (P>0.05). Therefore the present study reveals that, although the peripheral haemodynamic responses to plantar flexion exercise appear to be appropriate, the elevated energy cost of contraction and associated reduction in the WR(max) value in this muscle group may play a role in limiting exercise capacity with age.

Layer upon layer: Solar-to-fuel conversion through water splitting is among the most challenging and growing fields in present day science. Herein, a report is highlighted that successfully demonstrates an efficient photoanodic system utilizing simple and low-cost tungsten-doped bismuth vanadate on single- or double-junction amorphous silicon photovoltaic in a tandem configuration., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chronic obstructive pulmonary disease (COPD) is associated with systemic oxidative stress and skeletal muscle dysfunction. The purpose of this study was to examine the impact of intravenous ascorbate administration (AO) on biological markers of antioxidant capacity and oxidative stress, and subsequently skeletal muscle function during dynamic, small muscle mass exercise in patients with COPD. Ten patients with spirometric evidence of COPD performed single-leg knee extensor (KE) trials matched for intensity and time (isotime) following intravenous ascorbate (2 g) or saline infusion (PL). Quadriceps fatigue was quantified by changes in force elicited by maximal voluntary contraction (MVC) and magnetic femoral nerve stimulation (Qtw,pot). AO administration significantly increased antioxidant capacity, as measured by the ferric-reducing ability of plasma (PL: 1 ± 0.1 vs. AO: 5 ± 0.2 mM), and significantly reduced malondialdehyde levels (PL: 1.16 ± 0.1 vs. AO: 0.97 ± 0.1 mmol). Additionally, resting blood pressure was significantly reduced (PL: 104 ± 4 vs. AO: 93 ± 6 mmHg) and resting femoral vascular conductance was significantly elevated after AO (PL: 2.4 ± 0.2 vs. AO: 3.6 ± 0.4 ml·min(-1)·mmHg(-1)). During isotime exercise, the AO significantly attenuated both the ventilatory and metabolic responses, and patients accumulated significantly less peripheral quadriceps fatigue, as illustrated by less of a fall in MVC (PL: -11 ± 2% vs. AO: -5 ± 1%) and Qtw,pot (PL: -37 ± 1% vs. AO: -30 ± 2%). These data demonstrate a beneficial role of AO administration on skeletal muscle fatigue in patients with COPD and further implicate systemic oxidative stress as a causative factor in the skeletal muscle dysfunction observed in this population.

Purpose: To establish regional T1 and T2 values of the healthy mouse brain at ultra-high magnetic field strength of 17.6 T and to follow regional brain T1 and T2 changes with age., Methods: In vivo T1 and T2 values in the C57BL/6J mouse brain were followed with age using multislice-multiecho sequence and multiple spin echo saturation recovery with variable repetition time sequence, respectively, at 9.4 and 17.6 T. Gadolinium-tetra-azacyclo-dodecane-tetra-acetic acid phantoms were used to validate in vivo T2 measurements. Student's t-test was used to compare mean relaxation values., Results: A field-dependent decrease in T2 is shown and validated with phantom measurements. T2 values at 17.6 T typically increased with age in multiple brain regions except in the hypothalamus and the caudate-putamen, where a slight decrease was observed. Furthermore, T1 values in various brain regions of young and old mice are presented at 17.6 T. A large gain in signal-to-noise ratio was observed at 17.6 T., Conclusions: This study establishes for the first time the normative T1 and T2 values at 17.6 T over different mouse brain regions with age. The estimates of in vivo T1 and T2 will be useful to optimize pulse sequences for optimal image contrast at 17.6 T and will serve as baseline values against which disease-related relaxation changes can be assessed in mice., (Copyright © 2012 Wiley Periodicals, Inc.)

Using first-principles molecular dynamics (AIMD) and constrained density functional theory (CDFT) we identify the pathway of primary electron transfer in the R. Sphaeroides reaction center from the special pair excited state (P*) to the accessory bacteriochlorophyll (BA). Previous AIMD simulations on the special pair (PLPM) predicted a charge-transfer intermediate formation through the excited-state relaxation along a reaction coordinate characterized by the rotation of an axial histidine (HisM202). To account for the full electron transfer we extend the model to include the primary acceptor BA. In this extended model, the LUMO is primarily localized on the acceptor BA and extends over an interstitial water (water A) that is known to influence the rate of electron transfer (Potter et al. Biochemistry 2005 280, 27155-27164). A vibrational analysis of the dynamical trajectories gives a frequency of 30-35 cm(-1) for a molecular motion involving the hydrogen-bond network around water A, in good agreement with experimental findings (Yakovlev et al. Biochemistry, 2003, 68, 603-610). In its binding pocket water A can act as a switch by breaking and forming hydrogen bonds. With CDFT we calculate the energy required to the formation of the charge-separated state and find it to decrease along the predicted anisotropic reaction coordinate. Furthermore, we observe an increased coupling between the ground and charge-separated state. Water A adapts its hydrogen-bonding network along this reaction coordinate and weakens the hydrogen bond with HisM202. We also present AIMD simulations on the radical cation (P(•+)) showing a weakening of the hydrogen bond between HisL168 and the 3(1)-acetyl of PL. This work demonstrates how proton displacements are crucially coupled to the primary electron transfer and characterizes the reaction coordinate of the initial photoproduct formation.

The molecular stacking of an artificial light-harvesting antenna self-assembled from 3(1)-aminofunctionalized zinc-chlorins was determined by solid-state NMR in combination with quantum-chemical and molecular-mechanics modeling. A library of trial molecular stacking arrangements was generated based on available structural data for natural and semisynthetic homologues of the Zn-chlorins. NMR assignments obtained for the monomer in solution were validated for self-assembled aggregates and refined with (1)H-(13)C heteronuclear correlation spectroscopy data collected from samples with (13)C at natural abundance. Solid-state ring-current shifts for the (1)H provided spatial constraints to determine the molecular overlap. This procedure allows for a discrimination between different self-assembled structures and a classification of the stacking mode in terms of electric dipole alignment and π-π interactions, parameters that determine the functional properties of light-harvesting assemblies and conducting nanowires. The combination with quantum-mechanical modeling then allowed building a low-resolution packing model in silico from molecular stacks. The method allows for moderate disorder and residual polymorphism at the stack or molecular level and is generally applicable to determine molecular packing structures of aromatic molecules with structural asymmetry, such as is commonly provided by functionalized side chains that serve to tune the self-assembly process.