Mechanistically informed predictions of binding modes for carbocation intermediates of a sesquiterpene synthase reaction.

Sesquiterpenoids comprise a class of terpenoid natural products with thousands of compounds that are highly diverse in structure, generally containing a polycyclic carbon backbone that is constructed by a sesquiterpene synthase. Decades of experimental and computational studies have demonstrated that these enzymes generate a carbocation in the active site, which undergoes a series of structural rearrangements until a product is formed via deprotonation or nucleophile attack. However, for the vast majority of these enzymes the productive binding orientation of the intermediate carbocations has remained unclear. In this work, a method that combines quantum mechanics and computational docking is used to generate an all-atom model of every putative intermediate formed in the context of the enzyme active site for tobacco epi-aristolochene synthase (TEAS). This method identifies a single pathway that links the first intermediate to the last, enabling us to propose the first high-resolution model for the reaction intermediates in the active site of TEAS, and providing testable predictions

Multiple QTL-effects of wheat Gpc-B1 locus on grain protein and micronutrient concentrations

Micronutrient malnutrition afflicts over three billion peopleworldwide and the numbers are continuously increasing. Developing genetically micronutrientenriched cereals, which are the predominant source of human dietary, is essential to alleviate malnutrition worldwide. Wheat chromosome 6B derived from wild emmerwheat [Triticum turgidum ssp. dicoccoides (Körn.) Thell] was previously reported to be a source for high Zn concentration in the grain. In the present study, recombinant chromosome substitution lines (RSLs), previously constructed for genetic and physical maps of Gpc-B1 (a 250-kb locus affecting grain protein concentration), were used to identify the effects of the Gpc-B1 locus on grain micronutrient concentrations. RSLs carrying the Gpc-B1 allele of T. dicoccoides accumulated on average 12% higher concentration of Zn, 18% higher concentration of Fe, 29% higher concentration of Mn and 38% higher concentration of protein in the grain as compared with RSLs carrying the allele from cultivated wheat (Triticum durum). Furthermore, the high grain Zn, Fe and Mn concentrations were consistently expressed in five different environments with an absence of genotype by environment interaction. The results obtained in the present study also confirmed the previously reported effect of the wild-type allele of Gpc-B1 on earlier senescence of flag leaves. We suggest that the Gpc-B1 locus is involved in more efficient remobilization of protein, zinc, iron and manganese from leaves to the grains, in addition to its effect on earlier senescence of the green tissues

In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings.

In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future tau research, including (a) longitudinal imaging in preclinical dementia, (b) multi-modal mapping of tau pathology onto other pathological processes such as neuroinflammation, and (c) the need for more validation studies against post-mortem samples of the same subjects.The study is supported by the UK National Institute of Health Research Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia. JBR is supported by the Wellcome Trust (103838). EM is in receipt of a Gates Cambridge scholarship and an Alzheimer’s Research UK Research Grant

Focusing the Neuroscience and Societal Implications of Cognitive Enhancers.

Cognitive enhancement can benefit the individual and society, but also has associated risks and ethical concerns. Cognitive-enhancing drugs are used in the treatment of neuropsychiatric disorders. Nonpharmacological strategies are also emerging, which have the potential to improve motivational deficits associated with neuropsychiatric symptoms and should be prioritized for development. The increasing lifestyle use of "smart" and other drugs indicates the desire for healthy people to improve themselves. Safety and ethical implications are discussed.Janssen/J&J, Wallitt FoundationThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/cpt.45

On the experimental verification of quantum complexity in linear optics

The first quantum technologies to solve computational problems that are beyond the capabilities of classical computers are likely to be devices that exploit characteristics inherent to a particular physical system, to tackle a bespoke problem suited to those characteristics. Evidence implies that the detection of ensembles of photons, which have propagated through a linear optical circuit, is equivalent to sampling from a probability distribution that is intractable to classical simulation. However, it is probable that the complexity of this type of sampling problem means that its solution is classically unverifiable within a feasible number of trials, and the task of establishing correct operation becomes one of gathering sufficiently convincing circumstantial evidence. Here, we develop scalable methods to experimentally establish correct operation for this class of sampling algorithm, which we implement with two different types of optical circuits for 3, 4, and 5 photons, on Hilbert spaces of up to 50,000 dimensions. With only a small number of trials, we establish a confidence >99% that we are not sampling from a uniform distribution or a classical distribution, and we demonstrate a unitary specific witness that functions robustly for small amounts of data. Like the algorithmic operations they endorse, our methods exploit the characteristics native to the quantum system in question. Here we observe and make an application of a "bosonic clouding" phenomenon, interesting in its own right, where photons are found in local groups of modes superposed across two locations. Our broad approach is likely to be practical for all architectures for quantum technologies where formal verification methods for quantum algorithms are either intractable or unknown.Comment: Comments welcom

Hookworm Infection and Environmental Factors in Mbeya Region, Tanzania: A Cross-sectional, Population-based study.

Hookworm disease is one of the most common infections and cause of a high disease burden in the tropics and subtropics. Remotely sensed ecological data and model-based geostatistics have been used recently to identify areas in need for hookworm control. Cross-sectional interview data and stool samples from 6,375 participants from nine different sites in Mbeya region, south-western Tanzania, were collected as part of a cohort study. Hookworm infection was assessed by microscopy of duplicate Kato-Katz thick smears from one stool sample from each participant. A geographic information system was used to obtain remotely sensed environmental data such as land surface temperature (LST), vegetation cover, rainfall, and elevation, and combine them with hookworm infection data and with socio-demographic and behavioral data. Uni- and multivariable logistic regression was performed on sites separately and on the pooled dataset. Univariable analyses yielded significant associations for all ecological variables. Five ecological variables stayed significant in the final multivariable model: population density (odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.63-0.73), mean annual vegetation density (OR = 0.11; 95% CI = 0.06-0.18), mean annual LST during the day (OR = 0.81; 95% CI = 0.75-0.88), mean annual LST during the night (OR = 1.54; 95% CI = 1.44-1.64), and latrine coverage in household surroundings (OR = 1.02; 95% CI = 1.01-1.04). Interaction terms revealed substantial differences in associations of hookworm infection with population density, mean annual enhanced vegetation index, and latrine coverage between the two sites with the highest prevalence of infection. This study supports previous findings that remotely sensed data such as vegetation indices, LST, and elevation are strongly associated with hookworm prevalence. However, the results indicate that the influence of environmental conditions can differ substantially within a relatively small geographic area. The use of large-scale associations as a predictive tool on smaller scales is therefore problematic and should be handled with care

Alcohol use among amateur sportsmen in Ireland

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to establish baseline data on alcohol consumption patterns, behaviours and harms among amateur sportsmen in the Republic of Ireland.</p> <p>Findings</p> <p>The study presents findings from the baseline survey for a cluster randomised controlled trial to evaluate the effectiveness of a community intervention programme to reduce problem alcohol use among a representative sample of Gaelic Athletic Association (GAA) clubs in two counties in the Republic of Ireland. Self reported alcohol use, prevalence of binge drinking, AUDIT scores and alcohol-related harms were assessed in amateur GAA sportsmen aged 16 years and over.</p> <p>Nine hundred and sixty (960) players completed questionnaires (72% response rate). Mean age was 24.0 years (S.D. 5.2). Of those aged 18 years or over, 75% had post-primary education; most (864, 90%) were current drinkers and 8.2% were regular smokers. The self-reported average yearly alcohol consumption was 12.5 litres. Almost one third (31%) of current drinkers reported drinking over the recommended limit of 21 standard drinks per week and just over half (54.3%) reported drinking 6 or more standard drinks in a row at least once a week (regular binge drinking). Of those who (self) completed the Alcohol Use Disorder Identification Test (AUDIT) questionnaire, three-quarters (74.7%) had a score of 8 or more; 11.5% had a score of 20 or above warranting referral for diagnostic evaluation and treatment. Almost all (87.6%) of the 864 drinkers reported experiencing at least one harm due to their drinking. These alcohol misuse outcomes were higher than those found in a nationally representative sample of males of a similar age. There were strong associations between regular binge drinking and reporting harms such as being in a fight (adjusted odds ratio (OR) 2.02, p < 0.001), missing time from work or college (adjusted OR 1.39, p = 0.04) or being in an accident (adjusted OR 1.78, p = 0.04).</p> <p>Conclusions</p> <p>These male amateur sportsmen reported high rates of alcohol consumption and alcohol-related harm.</p

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Past Achievements and Future Challenges in 3D Photonic Metamaterials

Photonic metamaterials are man-made structures composed of tailored micro- or nanostructured metallo-dielectric sub-wavelength building blocks that are densely packed into an effective material. This deceptively simple, yet powerful, truly revolutionary concept allows for achieving novel, unusual, and sometimes even unheard-of optical properties, such as magnetism at optical frequencies, negative refractive indices, large positive refractive indices, zero reflection via impedance matching, perfect absorption, giant circular dichroism, or enhanced nonlinear optical properties. Possible applications of metamaterials comprise ultrahigh-resolution imaging systems, compact polarization optics, and cloaking devices. This review describes the experimental progress recently made fabricating three-dimensional metamaterial structures and discusses some remaining future challenges

Energy drink use, problem drinking and drinking motives in a diverse sample of Alaskan college students

Background. Recent research has identified the use of caffeinated energy drinks as a common, potentially risky behaviour among college students that is linked to alcohol misuse and consequences. Research also suggests that energy drink consumption is related to other risky behaviours such as tobacco use, marijuana use and risky sexual activity. Objective. This research sought to examine the associations between frequency of energy drink consumption and problematic alcohol use, alcohol-related consequences, symptoms of alcohol dependence and drinking motives in an ethnically diverse sample of college students in Alaska. We also sought to examine whether ethnic group moderated these associations in the present sample of White, Alaska Native/American Indian and other ethnic minority college students. Design. A paper-and-pencil self-report questionnaire was completed by a sample of 298 college students. Analysis of covariance (ANCOVA) was used to examine the effects of energy drink use, ethnic group and energy drink by ethnic group interactions on alcohol outcomes after controlling for variance attributed to gender, age and frequency of binge drinking. Results. Greater energy drink consumption was significantly associated with greater hazardous drinking, alcohol consequences, alcohol dependence symptoms, drinking for enhancement motives and drinking to cope. There were no main effects of ethnic group, and there were no significant energy drink by ethnic group interactions. Conclusion. These findings replicate those of other studies examining the associations between energy drink use and alcohol problems, but contrary to previous research we did not find ethnic minority status to be protective. It is possible that energy drink consumption may serve as a marker for other health risk behaviours among students of various ethnic groups