Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Complex Deleterious Interactions Associated with Malic Enzyme May Contribute to Reproductive Isolation in the Copepod Tigriopus californicus

Dobzhansky-Muller incompatibilities can result from the interactions of more than a single pair of interacting genes and there are several different models of how such complex interactions can be structured. Previous empirical work has identified complex conspecific epistasis as a form of complex interaction that has contributed to postzygotic reproductive isolation between taxa, but other forms of complexity are also possible. Here, I probe the genetic basis of reproductive isolation in crosses of the intertidal copepod Tigriopus californicus by looking at the impact of markers in genes encoding metabolic enzymes in F2 hybrids. The region of the genome associated with the locus ME2 is shown to have strong, repeatable impacts on the fitness of hybrids in crosses and epistatic interactions with another chromosomal region marked by the GOT2 locus in one set of crosses. In a cross between one of these populations and a third population, these two regions do not appear to interact despite the continuation of a large effect of the ME2 region itself in both crosses. The combined results suggest that the ME2 chromosomal region is involved in incompatibilities with several unique partners. If these deleterious interactions all stem from the same factor in this region, that would suggest a different form of complexity from complex conspecific epistasis, namely, multiple independent deleterious interactions stemming from the same factor. Confirmation of this idea will require more fine-scale mapping of the interactions of the ME2 region of the genome

Observation of the Fractional Quantum Hall Effect in Graphene

When electrons are confined in two dimensions and subjected to strong magnetic fields, the Coulomb interactions between them become dominant and can lead to novel states of matter such as fractional quantum Hall liquids. In these liquids electrons linked to magnetic flux quanta form complex composite quasipartices, which are manifested in the quantization of the Hall conductivity as rational fractions of the conductance quantum. The recent experimental discovery of an anomalous integer quantum Hall effect in graphene has opened up a new avenue in the study of correlated 2D electronic systems, in which the interacting electron wavefunctions are those of massless chiral fermions. However, due to the prevailing disorder, graphene has thus far exhibited only weak signatures of correlated electron phenomena, despite concerted experimental efforts and intense theoretical interest. Here, we report the observation of the fractional quantum Hall effect in ultraclean suspended graphene, supporting the existence of strongly correlated electron states in the presence of a magnetic field. In addition, at low carrier density graphene becomes an insulator with an energy gap tunable by magnetic field. These newly discovered quantum states offer the opportunity to study a new state of matter of strongly correlated Dirac fermions in the presence of large magnetic fields

Asymmetric Expansion of the Youngest Galactic Supernova Remnant G1.9+0.3

The youngest Galactic supernova remnant (SNR) G1.9+0.3, produced by a (probable) SN Ia that exploded ~1900 CE, is strongly asymmetric at radio wavelengths, much brighter in the north, but bilaterally symmetric in X-rays. We present the results of X-ray expansion measurements that illuminate the origin of the radio asymmetry. We confirm the mean expansion rate (2011–2015) of 0.58% yr$^{−1}$, but large spatial variations are present. Using the nonparametric "Demons" method, we measure the velocity field throughout the entire SNR, finding that motions vary by a factor of 5, from 0\buildrel{\prime\prime}\over{.} 09 to 0\buildrel{\prime\prime}\over{.} 44 yr−1. The slowest shocks are at the outer boundary of the bright northern radio rim, with velocities v s as low as 3600 km s$^{−1}$ (for an assumed distance of 8.5 kpc), much less than v $_{s}$ = 12,000–13,000 km s$^{−1}$ along the X-ray-bright major axis. Such strong deceleration of the northern blast wave most likely arises from the collision of SN ejecta with a much denser than average ambient medium there. This asymmetric ambient medium naturally explains the radio asymmetry. In several locations, significant morphological changes and strongly nonradial motions are apparent. The spatially integrated X-ray flux continues to increase with time. Based on Chandra observations spanning 8.3 yr, we measure its increase at $1.3 \% \pm 0.8 \%$ yr$^{−1}$. The SN ejecta are likely colliding with the asymmetric circumstellar medium ejected by the SN progenitor prior to its explosion.We acknowledge support by NASA through Chandra General Observer Program grants SAO GO5-16069A—C

Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action

Background Patterns of food intake and prevalent osteoarthritis of the hand, hip, and knee were studied using the twin design to limit the effect of confounding factors. Compounds found in associated food groups were further studied in vitro. Methods Cross-sectional study conducted in a large population-based volunteer cohort of twins. Food intake was evaluated using the Food Frequency Questionnaire; OA was determined using plain radiographs. Analyses were adjusted for age, BMI and physical activity. Subsequent in vitro studies examined the effects of allium-derived compounds on the expression of matrix-degrading proteases in SW1353 chondrosarcoma cells. Results Data were available, depending on phenotype, for 654-1082 of 1086 female twins (median age 58.9 years; range 46-77). Trends in dietary analysis revealed a specific pattern of dietary intake, that high in fruit and vegetables, showed an inverse association with hip OA (p = 0.022). Consumption of 'non-citrus fruit' (p = 0.015) and 'alliums' (p = 0.029) had the strongest protective effect. Alliums contain diallyl disulphide which was shown to abrogate cytokine-induced matrix metalloproteinase expression. Conclusions Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action

Unexpected features of branched flow through high-mobility two-dimensional electron gases

GaAs-based two-dimensional electron gases (2DEGs) show a wealth of remarkable electronic states, and serve as the basis for fast transistors, research on electrons in nanostructures, and prototypes of quantum-computing schemes. All these uses depend on the extremely low levels of disorder in GaAs 2DEGs, with low-temperature mean free paths ranging from microns to hundreds of microns. Here we study how disorder affects the spatial structure of electron transport by imaging electron flow in three different GaAs/AlGaAs 2DEGs, whose mobilities range over an order of magnitude. As expected, electrons flow along narrow branches that we find remain straight over a distance roughly proportional to the mean free path. We also observe two unanticipated phenomena in high-mobility samples. In our highest-mobility sample we observe an almost complete absence of sharp impurity or defect scattering, indicated by the complete suppression of quantum coherent interference fringes. Also, branched flow through the chaotic potential of a high-mobility sample remains stable to significant changes to the initial conditions of injected electrons.Comment: 22 pages, 4 figures, 1 tabl

Change in diet, physical activity, and body weight among young-adults during the transition from high school to college

<p>Abstract</p> <p>Background</p> <p>The freshmen year of college is likely a critical period for risk of weight gain among young-adults.</p> <p>Methods</p> <p>A longitudinal observational study was conducted to examine changes in weight, dietary intake, and other health-related behaviors among first-year college students (n = 186) attending a public University in the western United States. Weight was measured at the beginning and end of fall semester (August – December 2005). Participants completed surveys about dietary intake, physical activity and other health-related behaviors during the last six months of high school (January – June 2005) in August 2005 and during their first semester of college (August – December 2005) in December 2005.</p> <p>Results</p> <p>159 students (n = 102 women, 57 men) completed both assessments. The average BMI at the baseline assessment was 23.0 (standard deviation (SD) 3.8). Although the average amount of weight gained during the 15-week study was modest (1.5 kg), 23% of participants gained ≥ 5% of their baseline body weight. Average weight gain among those who gained ≥ 5% of baseline body weight was 4.5 kg. Those who gained ≥ 5% of body weight reported less physical activity during college than high school, were more likely to eat breakfast, and slept more than were those who did not gain ≥ 5% of body weight.</p> <p>Conclusion</p> <p>Almost one quarter of students gained a significant amount of weight during their first semester of college. This research provides further support for the implementation of education or other strategies aimed at helping young-adults entering college to achieve or maintain a healthy body weight.</p

High Diet Quality Is Associated with a Lower Risk of Cardiovascular Disease and All-Cause Mortality in Older Men

Although diet quality is implicated in cardiovascular disease (CVD) risk, few studies have investigated the relation between diet quality and the risks of CVD and mortality in older adults. This study examined the prospective associations between dietary scores and risk of CVD and all-cause mortality in older British men. A total of 3328 men (aged 60–79 y) from the British Regional Heart Study, free from CVD at baseline, were followed up for 11.3 y for CVD and mortality. Baseline food-frequency questionnaire data were used to generate 2 dietary scores: the Healthy Diet Indicator (HDI), based on WHO dietary guidelines, and the Elderly Dietary Index (EDI), based on a Mediterranean-style dietary intake, with higher scores indicating greater compliance with dietary recommendations. Cox proportional hazards regression analyses assessed associations between quartiles of HDI and EDI and risk of all-cause mortality, CVD mortality, CVD events, and coronary heart disease (CHD) events. During follow-up, 933 deaths, 327 CVD deaths, 582 CVD events, and 307 CHD events occurred. Men in the highest compared with the lowest EDI quartile had significantly lower risks of all-cause mortality (HR:0.75; 95% CI: 0.60, 0.94; P-trend = 0.03), CVD mortality (HR: 0.63; 95% CI: 0.42, 0.94; P-trend = 0.03), and CHD events(HR: 0.66; 95% CI: 0.45,0.97; P-trend = 0.05) but not CVD events (HR: 0.79; 95% CI: 0.60, 1.05;P-trend = 0.16) after adjustment for sociodemographic, behavioral, and cardiovascular risk factors. The HDI was not significantly associated with any of the outcomes. The EDI appears to be more useful than the HDI for assessing diet quality in relation to CVD and morality risk in older men. Encouraging older adults to adhere to the guidelines inherent in the EDI criteria may have public health benefit

Genetic diversity and population structure of Glossina pallidipes in Uganda and western Kenya

<p>Abstract</p> <p>Background</p> <p><it>Glossina pallidipes </it>has been implicated in the spread of sleeping sickness from southeastern Uganda into Kenya. Recent studies indicated resurgence of <it>G. pallidipes </it>in Lambwe Valley and southeastern Uganda after what were deemed to be effective control efforts. It is unknown whether the <it>G. pallidipes </it>belt in southeastern Uganda extends into western Kenya. We investigated the genetic diversity and population structure of <it>G. pallidipes </it>in Uganda and western Kenya.</p> <p>Results</p> <p>AMOVA indicated that differences among sampling sites explained a significant proportion of the genetic variation. Principal component analysis and Bayesian assignment of microsatellite genotypes identified three distinct clusters: western Uganda, southeastern Uganda/Lambwe Valley, and Nguruman in central-southern Kenya. Analyses of mtDNA confirmed the results of microsatellite analysis, except in western Uganda, where Kabunkanga and Murchison Falls populations exhibited haplotypes that differed despite homogeneous microsatellite signatures. To better understand possible causes of the contrast between mitochondrial and nuclear markers we tested for sex-biased dispersal. Mean pairwise relatedness was significantly higher in females than in males within populations, while mean genetic distance was lower and relatedness higher in males than females in between-population comparisons. Two populations sampled on the Kenya/Uganda border, exhibited the lowest levels of genetic diversity. Microsatellite alleles and mtDNA haplotypes in these two populations were a subset of those found in neighboring Lambwe Valley, suggesting that Lambwe was the source population for flies in southeastern Uganda. The relatively high genetic diversity of <it>G. pallidipes </it>in Lambwe Valley suggest large relict populations remained even after repeated control efforts.</p> <p>Conclusion</p> <p>Our research demonstrated that <it>G. pallidipes </it>populations in Kenya and Uganda do not form a contiguous tsetse belt. While Lambwe Valley appears to be a source population for flies colonizing southeastern Uganda, this dispersal does not extend to western Uganda. The complicated phylogeography of <it>G. pallidipes </it>warrants further efforts to distinguish the role of historical and modern gene flow and possible sex-biased dispersal in structuring populations.</p

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas