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Recent studies suggest that Sirt inhibition may have beneficial effects on several human diseases such as neurodegenerative diseases and cancer. Coffee is one of most popular beverages with several positive health effects. Therefore, in this paper, potential Sirt inhibitors were screened using coffee extract. First, HPLC was utilized to fractionate coffee extract, then screened using a Sirt1/2 inhibition assay. The screening led to the isolation of a potent Sirt1/2 inhibitor, whose structure was determined as javamide-II (N-caffeoyltryptophan) by NMR. For confirmation, the amide was chemically synthesized and its capacity of inhibiting Sirt1/2 was also compared with the isolated amide. Javamide-II inhibited Sirt2 (IC50; 8.7 μM) better than Sirt1(IC50; 34μM). Since javamide-II is a stronger inhibitor for Sirt2 than Sirt1. The kinetic study was performed against Sirt2. The amide exhibited noncompetitive Sirt2 inhibition against the NAD+ (Ki = 9.8 μM) and showed competitive inhibition against the peptide substrate (Ki = 5.3 μM). Also, a docking simulation showed stronger binding pose of javamide-II to Sirt2 than AGK2. In cellular levels, javamide-II was able to increase the acetylation of total lysine, cortactin and histone H3 in neuronal NG108-15 cells. In the same cells, the amide also increased the acetylation of lysine (K382) in p53, but not (K305). This study suggests that Javamide-II found in coffee may be a potent Sirt1/2 inhibitor, probably with potential use in some conditions of human diseases.

The third affiliation in the paper was incorrect and has now been corrected to “Tyndall Centre for Climate Change Research, School of International Development, University of East Anglia, Norwich, NR4 7TJ, UK”. Furthermore, the initial of the author D. Guan has been corrected.

Safe mountain hiking requires precise control of dynamic foot–ground interactions. In addition to vision and vestibular afferents, limb proprioception, sensorimotor control loops, and reflex responses are used to adapt to the specific nature of the ground contact. Diminished leg dexterity and balance during downhill walking is usually attributed to fatigue. We investigated the supplementary hypothesis that the eccentric contractions inherent to downhill walking can also disrupt muscle proprioception, as well as the sensorimotor control loops and reflex responses that depend on it. In this study, we measured leg dexterity (LD), anterior–posterior (AP) and medio–lateral (ML) bipedal balance, and maximal voluntary leg extension strength in young and healthy participants before and after 30 min of simulated downhill walking at a natural pace on a treadmill at a 20° decline. Post–pre comparisons of LD (p < 0.001) and AP balance (p = 0.001) revealed significant reductions in dynamic foot–ground interactions after eccentric exercise without an accompanying reduction in leg extension strength. We conclude that eccentric contractions during downhill walking can disrupt the control of dynamic foot–ground interactions independently of fatigue. We speculate that mountaineering safety could be improved by increasing conscious attention to compensate for unadjusted proprioception weighting, especially in the descent.

This work was supported by the following grants: T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain and in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain (J.M.). R.B. is supported by the I3P Consejo Superior de Investigaciones Científicas program funded by the 'Fondo Social Europeo'. B.Z.A. is supported by the Netherlands Organization for Health Research and Development (ZonMW grant 016.096.121). B.K. is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). Genotyping of the Dutch control samples was sponsored by US National Insitutes of Mental Health funding, R01 MH078075 (R.O.A.). The German controls were from the PopGen biobank (to B.K.). Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors. 4 páginas, 2 figuras, 2 tablas.-- Spanish Scleroderma Group. Peer reviewed

[1] The Budyko framework elegantly reduces the complex spatial patterns of actual evapotranspiration and runoff to a general function of two variables: mean annual precipitation (MAP) and net radiation. While the methodology has first-order skill, departures from a globally averaged curve can be significant and may be usefully attributed to additional controls such as vegetation type. This paper explores the magnitude of such departures as detected from flux tower measurements of ecosystem-scale evapotranspiration, and investigates their attribution to site characteristics (biome, seasonal rainfall distribution, and frozen precipitation). The global synthesis (based on 167 sites with 764 tower-years) shows smooth transition from water-limited to energy-limited control, broadly consistent with catchment-scale relations and explaining 62% of the across site variation in evaporative index (the fraction of MAP consumed by evapotranspiration). Climate and vegetation types act as additional controls, combining to explain an additional 13% of the variation in evaporative index. Warm temperate winter wet sites (Mediterranean) exhibit a reduced evaporative index, 9% lower than the average value expected based on dryness index, implying elevated runoff. Seasonal hydrologic surplus explains a small but significant fraction of variance in departures of evaporative index from that expected for a given dryness index. Surprisingly, grasslands on average have a higher evaporative index than forested landscapes, with 9% more annual precipitation consumed by annual evapotranspiration compared to forests. In sum, the simple framework of supply- or demand-limited evapotranspiration is supported by global FLUXNET observations but climate type and vegetation type are seen to exert sizeable additional controls.

Background: The COVID-19 pandemic reduced the number of skin cancer diagnoses, potentially causing a progression to unfavourable tumour stages. Objectives: To identify the impact of delayed diagnostics on primary invasive melanoma and cutaneous squamous cell carcinoma (cSCC) by comparing tumour (pT) stage, Breslow thickness and invasion depth from before to after the first and second lockdown periods. Methods: In this population-based cohort study, histopathology reports registered between 1 January 2018 and 22 July 2021 were obtained from the nationwide histopathology registry in the Netherlands. The Breslow thickness of melanomas, invasion depth of cSCCs, and pT stage for both tumour types were compared across five time periods: (i) pre-COVID, (ii) first lockdown, (iii) between first and second lockdowns, (iv) second lockdown and (v) after second lockdown. Breslow thickness was compared using an independent t-test. pT-stage groups were compared using a χ2-test. Outcomes were corrected for multiple testing using the false discovery rate. Results: In total, 20 434 primary invasive melanomas and 68 832 cSCCs were included in this study. The mean primary melanoma Breslow thickness of the prepandemic era (period i) and the following time periods (ii–v) showed no significant difference. A small shift was found towards unfavourable pT stages during the first lockdown compared with the pre-COVID period: pT1 52·3% vs. 58·6%, pT2 18·9% vs. 17·8%, pT3 13·2% vs. 11·0%, pT4 9·1% vs. 7·3% (P = 0·001). No relevant changes were seen in subsequent periods. No significant change in pT stage distribution was observed between the pre-COVID (i) and COVID-affected periods (ii–v) for cSCCs. Conclusions: To date, the diagnostic delay caused by COVID-19 has not resulted in relatively more unfavourable primary tumour characteristics of melanoma or cSCC. Follow-up studies in the coming years are needed to identify a potential impact on staging distribution and survival in the long term.

Abstract. Ambient pine forest air was oxidized by OH, O3, or NO3 radicals using an oxidation flow reactor (OFR) during the BEACHON-RoMBAS (Bio–hydro–atmosphere interactions of Energy, Aerosols, Carbon, H2O, Organics and Nitrogen – Rocky Mountain Biogenic Aerosol Study) campaign to study biogenic secondary organic aerosol (SOA) formation and organic aerosol (OA) aging. A wide range of equivalent atmospheric photochemical ages was sampled, from hours up to days (for O3 and NO3) or weeks (for OH). Ambient air processed by the OFR was typically sampled every 20–30 min, in order to determine how the availability of SOA precursor gases in ambient air changed with diurnal and synoptic conditions, for each of the three oxidants. More SOA was formed during nighttime than daytime for all three oxidants, indicating that SOA precursor concentrations were higher at night. At all times of day, OH oxidation led to approximately 4 times more SOA formation than either O3 or NO3 oxidation. This is likely because O3 and NO3 will only react with gases containing C = C bonds (e.g., terpenes) to form SOA but will not react appreciably with many of their oxidation products or any species in the gas phase that lacks a C = C bond (e.g., pinonic acid, alkanes). In contrast, OH can continue to react with compounds that lack C = C bonds to produce SOA. Closure was achieved between the amount of SOA formed from O3 and NO3 oxidation in the OFR and the SOA predicted to form from measured concentrations of ambient monoterpenes and sesquiterpenes using published chamber yields. This is in contrast to previous work at this site (Palm et al., 2016), which has shown that a source of SOA from semi- and intermediate-volatility organic compounds (S/IVOCs) 3.4 times larger than the source from measured VOCs is needed to explain the measured SOA formation from OH oxidation. This work suggests that those S/IVOCs typically do not contain C = C bonds. O3 and NO3 oxidation produced SOA with elemental O : C and H : C similar to the least-oxidized OA observed in local ambient air, and neither oxidant led to net mass loss at the highest exposures, in contrast to OH oxidation. An OH exposure in the OFR equivalent to several hours of atmospheric aging also produced SOA with O : C and H : C values similar to ambient OA, while higher aging (days–weeks) led to formation of SOA with progressively higher O : C and lower H : C (and net mass loss at the highest exposures). NO3 oxidation led to the production of particulate organic nitrates (pRONO2), while OH and O3 oxidation (under low NO) did not, as expected. These measurements of SOA formation provide the first direct comparison of SOA formation potential and chemical evolution from OH, O3, and NO3 oxidation in the real atmosphere and help to clarify the oxidation processes that lead to SOA formation from biogenic hydrocarbons.

Contains fulltext : 202702.pdf (Publisher’s version ) (Open Access) In the past few decades, cardiac ultrasound has become a widely available, easy-to-use diagnostic tool in many scenarios in acute cardiac care. The introduction of microbubbles extended its diagnostic value. Not long thereafter, several investigators explored the therapeutic potential of contrast ultrasound on thrombus dissolution. Despite large improvements in therapeutic options, acute ST elevation myocardial infarction remains one of the main causes of mortality and morbidity in the western world. The therapeutic effect of contrast ultrasound on thrombus dissolution might prove to be a new, effective treatment strategy in this group of patients. With the recent publication of human studies scrutinising the therapeutic options of ultrasound and microbubbles in ST elevation myocardial infarction, we have entered a new stage in this area of research. This therapeutic effect is based on biochemical effects both at macrovascular and microvascular levels, of which the exact working mechanisms remain to be elucidated in full. This review will give an up-to-date summary of our current knowledge of the therapeutic effects of contrast ultrasound and its potential application in the field of ST elevation myocardial infarction, along with its future developments.