A Genomic-Based Approach Combining In Vivo Selection in Mice to Identify a Novel Virulence Gene in Leishmania

Parasites of the genus Leishmania cause a variety of human diseases that range from destructive skin lesions caused by L. major to visceral infections of the liver and spleen caused by L. donovani that result in death. The Leishmania genes responsible for these different pathologies are not known. In the present study, we used a comparative genome-based approach to introduce and over-express L. donovani genes in L. major to determine whether this results in increased virulence of L. major in visceral organs of infected mice. Through this approach, a novel gene termed Li1040 was identified that is potentially involved in protein transport and was shown to increase pathogenesis in the visceral organs in mice. The Li1040 gene may therefore represent a Leishmania virulence gene that has the potential to regulate the pathology of infection in the mammalian host. These observations help to define how Leishmania causes fatal infections in humans and therefore provide a parasite-specific target for therapy

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

Multilocation Corn Stover Harvest Effects on Crop Yields and Nutrient Removal

Corn (Zea mays L.) stover was identified as an important feedstock for cellulosic bioenergy production because of the extensive area upon which the crop is already grown. This report summarizes 239 site-years of field research examining effects of zero, moderate, and high stover removal rates at 36 sites in seven different states. Grain and stover yields from all sites as well as N, P, and K removal from 28 sites are summarized for nine longitude and six latitude bands, two tillage practices (conventional vs no tillage), two stover-harvest methods (machine vs calculated), and two crop rotations {continuous corn (maize) vs corn/soybean [Glycine max (L.) Merr.]}. Mean grain yields ranged from 5.0 to 12.0 Mg ha−1 (80 to 192 bu ac−1). Harvesting an average of 3.9 or 7.2 Mg ha−1(1.7 or 3.2 tons ac−1) of the corn stover resulted in a slight increase in grain yield at 57 and 51 % of the sites, respectively. Average no-till grain yields were significantly lower than with conventional tillage when stover was not harvested, but not when it was collected. Plant samples collected between physiological maturity and combine harvest showed that compared to not harvesting stover, N, P, and K removal was increased by 24, 2.7, and 31 kg ha−1, respectively, with moderate (3.9 Mg ha−1) harvest and by 47, 5.5, and 62 kg ha−1, respectively, with high (7.2 Mg ha−1) removal. This data will be useful for verifying simulation models and available corn stover feedstock projections, but is too variable for planning site-specific stover harvest

Combining Free Text and Structured Electronic Medical Record Entries to Detect Acute Respiratory Infections

The electronic medical record (EMR) contains a rich source of information that could be harnessed for epidemic surveillance. We asked if structured EMR data could be coupled with computerized processing of free-text clinical entries to enhance detection of acute respiratory infections (ARI).A manual review of EMR records related to 15,377 outpatient visits uncovered 280 reference cases of ARI. We used logistic regression with backward elimination to determine which among candidate structured EMR parameters (diagnostic codes, vital signs and orders for tests, imaging and medications) contributed to the detection of those reference cases. We also developed a computerized free-text search to identify clinical notes documenting at least two non-negated ARI symptoms. We then used heuristics to build case-detection algorithms that best combined the retained structured EMR parameters with the results of the text analysis.An adjusted grouping of diagnostic codes identified reference ARI patients with a sensitivity of 79%, a specificity of 96% and a positive predictive value (PPV) of 32%. Of the 21 additional structured clinical parameters considered, two contributed significantly to ARI detection: new prescriptions for cough remedies and elevations in body temperature to at least 38°C. Together with the diagnostic codes, these parameters increased detection sensitivity to 87%, but specificity and PPV declined to 95% and 25%, respectively. Adding text analysis increased sensitivity to 99%, but PPV dropped further to 14%. Algorithms that required satisfying both a query of structured EMR parameters as well as text analysis disclosed PPVs of 52-68% and retained sensitivities of 69-73%.Structured EMR parameters and free-text analyses can be combined into algorithms that can detect ARI cases with new levels of sensitivity or precision. These results highlight potential paths by which repurposed EMR information could facilitate the discovery of epidemics before they cause mass casualties

Public Access to Genome-Wide Data: Five Views on Balancing Research with Privacy and Protection

Introductory paragraph: Just over twelve months ago, PLoS Genetics published a paper [1] demonstrating that, given genome-wide genotype data from an individual, it is, in principle, possible to ascertain whether that individual is a member of a larger group defined solely by aggregate genotype frequencies, such as a forensic sample or a cohort of participants in a genome-wide association study (GWAS). As a consequence, the National Institutes of Health (NIH) and Wellcome Trust agreed to shut down public access not just to individual genotype data but even to aggregate genotype frequency data from each study published using their funding. Reactions to this decision span the full breadth of opinion, from ‘‘too little, too late—the public trust has been breached’’ to ‘‘a heavy-handed bureaucratic response to a practically minimal risk that will unnecessarily inhibit scientific research.’’ Scientific concerns have also been raised over the conditions under which individual identity can truly be accurately determined from GWAS data. These concerns are addressed in two papers published in this month’s issue of PLoS Genetics [2,3]. We received several submissions on this topic and decided to assemble these viewpoints as a contribution to the debate and ask readers to contribute their thoughts through the PLoS online commentary features. Five viewpoints are included. The Public Population Project in Genomics (P3G) is calling for a universal researcher ID with an access permit mechanism for bona fide researchers. The contribution by Catherine Heeney, Naomi Hawkins, Jantina de Vries, Paula Boddington, and Jane Kaye of the University of Oxford Ethox Centre outlines some of the concerns over possible misuse of individual identification in conjunction with medical and family history data, and points out that if geneticists mishandle public trust, it will backfire on their ability to conduct further research. George Church posits that actions directed toward restricting data access are likely to exclude researchers who might provide the most novel insights into the data and instead makes the argument that full disclosure and consent to the release of genomic information should be sought from study participants, rather than making difficult-to-guarantee promises of anonymity. Martin Bobrow weighs the risks and benefits and proposes four steps that represent a middle ground: Retain restricted access for now, make malicious de-identification practices illegal, increase public awareness of the issues, and encourage recognition that scientists have a special professional relationship of trust with study participants. Finally, Bruce Weir provides a commentary on the contribution of the two research articles from Braun et al. [2] and Visscher and Hill [3]

Small Scattered Fragments Do Not a Dwarf Make: Biological and Archaeological Data Indicate that Prehistoric Inhabitants of Palau Were Normal Sized

Current archaeological evidence from Palau in western Micronesia indicates that the archipelago was settled around 3000–3300 BP by normal sized populations; contrary to recent claims, they did not succumb to insular dwarfism

Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014