3,153 research outputs found

    1,5-asymmetric induction in the boron-mediated aldol reactions of beta-oxygenated methyl ketones

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    High levels of substrate-based 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of P-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate pi-facial selectivity critically dependent upon the nature of the beta-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on a hydrogen bonding between the alkoxy oxygen and the formyl hydrogen has been recently proposed.3082007201

    Searching for sterile neutrinos in ice

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    Oscillation interpretation of the results from the LSND, MiniBooNE and some other experiments requires existence of sterile neutrino with mass 1\sim 1 eV and mixing with the active neutrinos Uμ02(0.020.04)|U_{\mu 0}|^2 \sim (0.02 - 0.04). It has been realized some time ago that existence of such a neutrino affects significantly the fluxes of atmospheric neutrinos in the TeV range which can be tested by the IceCube Neutrino Observatory. In view of the first IceCube data release we have revisited the oscillations of high energy atmospheric neutrinos in the presence of one sterile neutrino. Properties of the oscillation probabilities are studied in details for various mixing schemes both analytically and numerically. The energy spectra and angular distributions of the νμ\nu_\mu-events have been computed for the simplest νs\nu_s-mass, and νsνμ\nu_s - \nu_\mu mixing schemes and confronted with the IceCube data. An illustrative statistical analysis of the present data shows that in the νs\nu_s-mass mixing case the sterile neutrinos with parameters required by LSND/MiniBooNE can be excluded at about 3σ3\sigma level. The νsνμ\nu_s- \nu_\mu mixing scheme, however, can not be ruled out with currently available IceCube data.Comment: 41 pages, 16 figures. Accepted for publication in JHEP. Minor changes from the previous versio

    The prevalence of chronic diseases and major disease risk factors at different ages among 150 000 men and women living in Mexico City: cross-sectional analyses of a prospective study

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    <p>Abstract</p> <p>Background</p> <p>While most of the global burden from chronic diseases, and especially vascular diseases, is now borne by low and middle-income countries, few large-scale epidemiological studies of chronic diseases in such countries have been performed.</p> <p>Methods</p> <p>From 1998–2004, 52 584 men and 106 962 women aged ≥35 years were visited in their homes in Mexico City. Self reported diagnoses of chronic diseases and major disease risk factors were ascertained and physical measurements taken. Age- and sex-specific prevalences and means were analysed.</p> <p>Results</p> <p>After about age 50 years, diabetes was extremely common – for example, 23.8% of men and 26.9% of women aged 65–74 reported a diagnosis. By comparison, ischaemic heart disease was reported by 4.8% of men and 3.0% of women aged 65–74, a history of stroke by 2.8% and 2.3%, respectively, and a history of cancer by 1.3% and 2.1%. Cancer history was generally more common among women than men – the excess being largest in middle-age, due to breast and cervical cancer. At older ages, the gap narrowed because of an increasing prevalence of prostate cancer. 51% of men and 25% of women aged 35–54 smoked cigarettes, while 29% of men and 41% of women aged 35–54 were obese (i.e. BMI ≥30 kg/m<sup>2</sup>). The prevalence of treated hypertension or measured blood pressure ≥140/90 mmHg increased about 50% more steeply with age among women than men, to 66% of women and 58% of men aged 65–74. Physical inactivity was highly prevalent but daily alcohol drinking was relatively uncommon.</p> <p>Conclusion</p> <p>Diabetes, obesity and tobacco smoking are highly prevalent among adults living in Mexico City. Long-term follow-up of this and other cohorts will establish the relevance of such factors to the major causes of death and disability in Mexico.</p

    Attitudes About COVID-19 and Health (ATTACH): Online Survey and Mixed Methods Study

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    Background: Behavioral mitigation strategies to slow the spread of COVID-19 have resulted in sweeping lifestyle changes, with short- and long-term psychological, well-being, and quality of life implications. The Attitudes About COVID-19 and Health (ATTACH) study focuses on understanding attitudes and beliefs while considering the impact on mental and physical health and the influence of broader demographic and geographic factors on attitudes, beliefs, and mental health burden. / Objective: In this assessment of our first wave of data collection, we provide baseline cohort description of the ATTACH study participants in the United Kingdom, the United States, and Mexico. Additionally, we assess responses to daily poll questions related to COVID-19 and conduct a cross-sectional analysis of baseline assessments collected in the UK between June 26 and October 31, 2020. / Methods: The ATTACH study uses smartphone app technology and online survey data collection. Participants completed poll questions related to COVID-19 2 times daily and a monthly survey assessing mental health, social isolation, physical health, and quality of life. Poll question responses were graphed using 95% Clopper–Pearson (exact) tests with 95% CIs. Pearson correlations, hierarchical linear regression analyses, and generalized linear models assessed relationships, predictors of self-reported outcomes, and group differences, respectively. / Results: By October 31, 2020, 1405, 80, and 90 participants had consented to participate in the UK, United States, and Mexico, respectively. Descriptive data for the UK daily poll questions indicated that participants generally followed social distancing measures, but worry and negative impacts on families increased as the pandemic progressed. Although participants generally reported feeling that the reasons for current measures had been made clear, there was low trust that the government was doing everything in its power to meet public needs. In the UK, 1282 participants also completed a monthly survey (94.99% [1326/1396] White, 72.22% [1014/1404] female, and 20.12% [277/1377] key or essential workers); 18.88% (242/1282) of UK participants reported a preexisting mental health disorder, 31.36% (402/1282) reported a preexisting chronic medical illness, and 35.11% (493/1404) were aged over 65; 57.72% (740/1282) of participants reported being more sedentary since the pandemic began, and 41.89% (537/1282) reported reduced access to medical care. Those with poorer mental health outcomes lived in more deprived neighborhoods, in larger households (Ps<.05), had more preexisting mental health disorders and medical conditions, and were younger than 65 years (all Ps<.001). / Conclusions: Communities who have been exposed to additional harm during the COVID-19 pandemic were experiencing worse mental outcomes. Factors including having a medical condition, or living in a deprived neighborhood or larger household were associated with heightened risk. Future longitudinal studies should investigate the link between COVID-19 exposure, mental health, and sociodemographic and residential characteristics

    Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets

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    <div><p>Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway <i>i</i>.<i>e</i>., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3–38 times <i>vs</i>. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.</p></div

    Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

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    Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD
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