Selective sweep at the Rpv3 locus during grapevine breeding for downy mildew resistance

The Rpv3 locus is a major determinant of downy mildew resistance in grapevine (Vitis spp.). A selective sweep at this locus was revealed by the DNA genotyping of 580 grapevines, which include a highly diverse set of 265 European varieties that predated the spread of North American mildews, 82 accessions of wild species, and 233 registered breeding lines with North American ancestry produced in the past 150?years. Artificial hybridisation and subsequent phenotypic selection favoured a few Rpv3 haplotypes that were introgressed from wild vines and retained in released varieties. Seven conserved haplotypes in five descent groups of resistant varieties were traced back to their founders: (1) 'Munson', a cross between two of Hermann Jaeger's selections of V. rupestris and V. lincecumii made in the early 1880s in Missouri, (2) V. rupestris 'Ganzin', first utilised for breeding in 1879 by Victor Ganzin in France, (3) 'Noah', selected in 1869 from intermingled accessions of V. riparia and V. labrusca by Otto Wasserzieher in Illinois, (4) 'Bayard', a V. rupestris?×?V. labrusca offspring generated in 1882 by George Couderc in France, and (5) a wild form closely related to V. rupestris accessions in the Midwestern United States and introgressed into 'Seibel 4614' in the 1880s by Albert Seibel in France. Persistence of these Rpv3 haplotypes across many of the varieties generated by human intervention indicates that a handful of vines with prominent resistance have laid the foundation for modern grape breeding. A rampant hot spot of NB-LRR genes at the Rpv3 locus has provided a distinctive advantage for the adaptation of native North American grapevines to withstand downy mildew. The coexistence of multiple resistance alleles or paralogues in the same chromosomal region but in different haplotypes counteracts efforts to pyramidise them in a diploid individual via conventional breeding.     

Genomic selection for growth and wood quality in Eucalyptus: capturing the missing heritability and accelerating breeding for complex traits in forest trees

? Genomic selection (GS) is expected to cause a paradigm shift in tree breeding by improving its speed and efficiency. By fitting all the genome-wide markers concurrently, GS can capture most of the 'missing heritability' of complex traits that quantitative trait locus (QTL) and association mapping classically fail to explain. Experimental support of GS is now required. ? The effectiveness of GS was assessed in two unrelated Eucalyptus breeding populations with contrasting effective population sizes (N(e) = 11 and 51) genotyped with > 3000 DArT markers. Prediction models were developed for tree circumference and height growth, wood specific gravity and pulp yield using random regression best linear unbiased predictor (BLUP). ? Accuracies of GS varied between 0.55 and 0.88, matching the accuracies achieved by conventional phenotypic selection. Substantial proportions (74-97%) of trait heritability were captured by fitting all genome-wide markers simultaneously. Genomic regions explaining trait variation largely coincided between populations, although GS models predicted poorly across populations, likely as a result of variable patterns of linkage disequilibrium, inconsistent allelic effects and genotype × environment interaction. ? GS brings a new perspective to the understanding of quantitative trait variation in forest trees and provides a revolutionary tool for applied tree improvement. Nevertheless population-specific predictive models will likely drive the initial applications of GS in forest tree breeding.     

Contact stresses and fatigue life in a knee prosthesis: comparison between in vitro measurements and computational simulations

The evaluation of contact areas and pressures in total knee prosthesis is a key issue to prevent early failure. The first part of this study is based on the hypothesis that the patterns of contact stresses on the tibial insert of a knee prosthesis at different stages of the gait cycle could be an indicator of the wear performances of a knee prosthesis. Contact stresses were calculated for a mobile bearing knee prosthesis by means of finite element method (FEM). Contact areas and stresses were also measured through in vitro tests using Fuji Prescale film in order to support the FEM findings.The second part of this study addresses the long-term structural integrity of metal tibial components in terms of fatigue life by means of experimental tests and FEM simulations. Fatigue experimental evaluations were performed on Cr-Co alloy tibial tray, based on ISO standards. FEM models were used to calculate the stress patterns. The failure risk was estimated with a standard fatigue criterion on the basis of the results obtained from the FEM calculations. Experimental and computational results showed a positive matching.     

Tackling the phosphoproteome: tools and strategies

Characterization of post-translational modifications in proteins is one of the major tasks that is to be accomplished in the post-genomic era. Phosphorylation is a key reversible modification that regulates enzymatic activity, subcellular localization, complex formation and degradation of proteins. Rapid advances in mass spectrometry instrumentation coupled to the development of analytical methods over the past several years now allow us to investigate the phosphoproteome on a global scale.     

Fluorescence Behavioral Imaging (FBI) Tracks Identity in Heterogeneous Groups of Drosophila

Distinguishing subpopulations in group behavioral experiments can reveal the impact of differences in genetic, pharmacological and life-histories on social interactions and decision-making. Here we describe Fluorescence Behavioral Imaging (FBI), a toolkit that uses transgenic fluorescence to discriminate subpopulations, imaging hardware that simultaneously records behavior and fluorescence expression, and open-source software for automated, high-accuracy determination of genetic identity. Using FBI, we measure courtship partner choice in genetically mixed groups of Drosophila.     

EMG-Driven Forward-Dynamic Estimation of Muscle Force and Joint Moment about Multiple Degrees of Freedom in the Human Lower Extremity

This work examined if currently available electromyography (EMG) driven models, that are calibrated to satisfy joint moments about one single degree of freedom (DOF), could provide the same musculotendon unit (MTU) force solution, when driven by the same input data, but calibrated about a different DOF. We then developed a novel and comprehensive EMG-driven model of the human lower extremity that used EMG signals from 16 muscle groups to drive 34 MTUs and satisfy the resulting joint moments simultaneously produced about four DOFs during different motor tasks. This also led to the development of a calibration procedure that allowed identifying a set of subject-specific parameters that ensured physiological behavior for the 34 MTUs. Results showed that currently available single-DOF models did not provide the same unique MTU force solution for the same input data. On the other hand, the MTU force solution predicted by our proposed multi-DOF model satisfied joint moments about multiple DOFs without loss of accuracy compared to single-DOF models corresponding to each of the four DOFs. The predicted MTU force solution was (1) a function of experimentally measured EMGs, (2) the result of physiological MTU excitation, (3) reflected different MTU contraction strategies associated to different motor tasks, (4) coordinated a greater number of MTUs with respect to currently available single-DOF models, and (5) was not specific to an individual DOF dynamics. Therefore, our proposed methodology has the potential of producing a more dynamically consistent and generalizable MTU force solution than was possible using single-DOF EMG-driven models. This will help better address the important scientific questions previously approached using single-DOF EMG-driven modeling. Furthermore, it might have applications in the development of human-machine interfaces for assistive devices.     

Vorinostat Eliminates Multicellular Resistance of Mesothelioma 3D Spheroids via Restoration of Noxa Expression

When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies.     

What was I thinking? Eye-tracking experiments underscore the bias that architecture exerts on nuclear grading in prostate cancer

We previously reported that nuclear grade assignment of prostate carcinomas is subject to a cognitive bias induced by the tumor architecture. Here, we asked whether this bias is mediated by the non-conscious selection of nuclei that "match the expectation" induced by the inadvertent glance at the tumor architecture. 20 pathologists were asked to grade nuclei in high power fields of 20 prostate carcinomas displayed on a computer screen. Unknown to the pathologists, each carcinoma was shown twice, once before a background of a low grade, tubule-rich carcinoma and once before the background of a high grade, solid carcinoma. Eye tracking allowed to identify which nuclei the pathologists fixated during the 8 second projection period. For all 20 pathologists, nuclear grade assignment was significantly biased by tumor architecture. Pathologists tended to fixate on bigger, darker, and more irregular nuclei when those were projected before kigh grade, solid carcinomas than before low grade, tubule-rich carcinomas (and vice versa). However, the morphometric differences of the selected nuclei accounted for only 11% of the architecture-induced bias, suggesting that it can only to a small part be explained by the unconscious fixation on nuclei that "match the expectation". In conclusion, selection of ? matching nuclei ? represents an unconscious effort to vindicate the gravitation of nuclear grades towards the tumor architecture.     

Mood Disorders and Risk of Lung Cancer in the EAGLE Case-Control Study and in the U.S. Veterans Affairs Inpatient Cohort

Background

Mood disorders may affect lung cancer risk. We evaluated this hypothesis in two large studies.

Methodology/Principal Findings

We examined 1,939 lung cancer cases and 2,102 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in Italy (2002–2005), and 82,945 inpatients with a lung cancer diagnosis and 3,586,299 person-years without a lung cancer diagnosis in the U.S. Veterans Affairs Inpatient Cohort (VA study), composed of veterans with a VA hospital admission (1969–1996). In EAGLE, we calculated odds ratios (ORs) and 95% confidence intervals (CI), with extensive adjustment for tobacco smoking and multiple lifestyle factors. In the VA study, we estimated lung cancer relative risks (RRs) and 95% CIs with time-dependent Poisson regression, adjusting for attained age, calendar year, hospital visits, time within the study, and related previous medical diagnoses. In EAGLE, we found decreased lung cancer risk in subjects with a personal history of mood disorders (OR: 0.59, 95% CI: 0.44–0.79, based on 121 lung cancer incident cases and 192 controls) and family history of mood disorders (OR: 0.62, 95% CI: 0.50–0.77, based on 223 lung cancer cases and 345 controls). The VA study analyses yielded similar results (RR: 0.74, 95% CI: 0.71–0.77, based on 2,304 incident lung cancer cases and 177,267 non-cancer person-years) in men with discharge diagnoses for mood disorders. History of mood disorders was associated with nicotine dependence, alcohol and substance use and psychometric scales of depressive and anxiety symptoms in controls for these studies.

Conclusions/Significance

The consistent finding of a relationship between mood disorders and lung cancer risk across two large studies calls for further research into the complex interplay of risk factors associated with these two widespread and debilitating diseases. Although we adjusted for smoking effects in EAGLE, residual confounding of the results by smoking cannot be ruled out.     

Herniation pits in human mummies: a CT investigation in the Capuchin Catacombs of Palermo, Sicily

Herniation pits (HPs) of the femoral neck were first described in a radiological publication in 1982 as round to oval radiolucencies in the proximal superior quadrant of the femoral neck on anteroposterior radiographs of adults. In following early clinical publications, HPs were generally recognized as an incidental finding. In contrast, in current clinical literature they are mentioned in the context of femoroacetabular impingement (FAI) of the hip joint, which is known to cause osteoarthritis (OA). The significance of HPs in chronic skeletal disorders such as OA is still unclear, but they are discussed as a possible radiological indicator for FAI in a large part of clinical studies.In this paleoradiological study we examined a sample of mummies from the Capuchin Catacombs of Palermo, Sicily, by a mobile computed tomography (CT) scanner. Evaluation of the CT examinations revealed HPs in six out of 16 (37.5%) adult male mummies.The first aim of this study was to compare the characteristics of HPs shown in our mummy collection to the findings described in clinical literature. Thereby CT evaluation revealed that their osseous imaging characteristics are in accordance, consisting of round to oval subcortical lesions at the anterior femoral neck, clearly demarcated by a sclerotic margin.The second aim was to introduce HPs to the paleoradiological and paleopathological methodology as an entity that underwent a renaissance from an incidental finding to a possible radiological indicator of FAI in the clinical situation. As FAI plays an important role in the development of OA of the hip, which is a very common finding in human skeletal remains, HPs should always be considered in paleoradiological evaluation of hip joint diseases.