Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

Money, Fame and the Allocation of Talent: Brain Drain, the Matthew Effect and the Institution of Science

The earning structure in science is known to be flat relative to the one in the private sector, which could cause a brain drain toward the private sector. In this paper, we assume that agents value both money and fame and study the role of the institution of science in the allocation of talent between the science sector and the private sector. Following works on the Sociology of Science, we model the institution of science as a mechanism distributing fame (i.e. peer recognition). We show that since the intrinsic performance is less noisy signal of talent in the science sector than in the private sector, a good institution of science can mitigate the brain drain. We also find that providing extra monetary incentives through the market might undermine the incentives provided by the institution and thereby worsen the brain drain. Finally, we study the optimal balance between monetary and non-monetary incentives in science.

Identification of novel elements of the Drosophila blisterome sheds light on potential pathological mechanisms of several human diseases.

Main developmental programs are highly conserved among species of the animal kingdom. Improper execution of these programs often leads to progression of various diseases and disorders. Here we focused on Drosophila wing tissue morphogenesis, a fairly complex developmental program, one of the steps of which - apposition of the dorsal and ventral wing sheets during metamorphosis - is mediated by integrins. Disruption of this apposition leads to wing blistering which serves as an easily screenable phenotype for components regulating this process. By means of RNAi-silencing technique and the blister phenotype as readout, we identify numerous novel proteins potentially involved in wing sheet adhesion. Remarkably, our results reveal not only participants of the integrin-mediated machinery, but also components of other cellular processes, e.g. cell cycle, RNA splicing, and vesicular trafficking. With the use of bioinformatics tools, these data are assembled into a large blisterome network. Analysis of human orthologues of the Drosophila blisterome components shows that many disease-related genes may contribute to cell adhesion implementation, providing hints on possible mechanisms of these human pathologies.

Ankle-Brachial Index: Nurses Strategy To Cardiovascular Disease Risk Factors Identification

Elevated risk of fatal and non-fatal cardiovascular events is associated with high prevalence of peripheral arterial disease, with assessment through the ankle-brachial index (ABI). This study aimed to demonstrate that the ABI and the Edinburgh Claudication Questionnaire are tools to be used by nurses in prevention and/or treatment of CVD (cardiovascular disease). A cross-sectional study was carried out with patients from a cardiovascular clinic. The Edinburgh Claudication Questionnaire was applied and the ABI was measured with the formula (ABI= Blood Pressure Ankle/Blood Pressure Brachial). A total of 115 patients were included, most were females (57.4%), aged 60.6 ± 12.5 years. The most prevalent risk factors were hypertension (64.3%), physical inactivity (48.7%) and family history (58.3%). The study showed that abnormal ABI was frequently found and 42.6% of the patients with abnormal ABI showed intermittent claudication. The method to evaluate the ABI associated to the Edinburg Claudication Questionnaire, can be easily used by nurses in the clinical evaluation of asymptomatic and symptomatic CVD patients.

Identification of a key lysine residue in heat shock protein 90 required for azole and echinocandin resistance in Aspergillus fumigatus.

Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced Aspergillus fumigatus virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in A. fumigatus. Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylation-mimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in Candida albicans, the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against A. fumigatus and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in A. fumigatus and that deacetylase inhibition may represent an adjunctive anti-Aspergillus strategy.

Identification of care needs of patients with and without the use of a classification instrument

Objective: To analyze the agreement and disagreement between the assessments by applying or not a patient classification instrument, and to investigate the association between the agreement and personal and professional characteristics of the evaluators. Method: This is a descriptive exploratory study. 105 patients were hospitalized in a teaching hospital in the state of Sao Paulo, using the kappa statistic (weighted) and the Bootstrap method. Results: The agreement between the assessments were​​: kw 0.87 (instrument x internal evaluator), kw 0.78 (instrument x external evaluator) and kw 0.76 (between evaluators) and the influence of some personal and professional characteristics. The assessments conducted through the use of an instrument contemplated a greater number of areas of care in relation to when the instrument was not applied. Conclusion: The use of this instrument is recommended in order to more effectively identify care needs of patients.




Structural and Resting State Functional Connectivity of the Subthalamic Nucleus: Identification of Motor STN Parts and the Hyperdirect Pathway.

Deep brain stimulation (DBS) for Parkinson's disease often alleviates the motor symptoms, but causes cognitive and emotional side effects in a substantial number of cases. Identification of the motor part of the subthalamic nucleus (STN) as part of the presurgical workup could minimize these adverse effects. In this study, we assessed the STN's connectivity to motor, associative, and limbic brain areas, based on structural and functional connectivity analysis of volunteer data. For the structural connectivity, we used streamline counts derived from HARDI fiber tracking. The resulting tracks supported the existence of the so-called "hyperdirect" pathway in humans. Furthermore, we determined the connectivity of each STN voxel with the motor cortical areas. Functional connectivity was calculated based on functional MRI, as the correlation of the signal within a given brain voxel with the signal in the STN. Also, the signal per STN voxel was explained in terms of the correlation with motor or limbic brain seed ROI areas. Both right and left STN ROIs appeared to be structurally and functionally connected to brain areas that are part of the motor, associative, and limbic circuit. Furthermore, this study enabled us to assess the level of segregation of the STN motor part, which is relevant for the planning of STN DBS procedures.

Identification and characterization of the members of the pho1 gene family in moss and rice

Inorganic phosphate (Pi) is one of the main nutrients limiting plant growth anddevelopment in many agro-ecosystems. In plants, phosphate is acquired from the soil by theroots, and is then transferred to the shoot via the xylem. In the model plant Arabidopsisthaliana, PHO1 was previously identified as being involved in loading Pi into the xylem ofroots. AtPHO1, belongs to a multigenic family composed of 10 additional members, namelyAtPHO1;H1 to AtPHO1;10. In this study, we aimed at further investigating the role of thePHO1 gene family in Pi homeostasis in plants, and to this end we isolated and characterizedthe PHO1 members of two main model plants, the moss Physcomitrella patens and the riceOryza sativa.In the bryophyte P. patens, bioinformatic analyses revealed the presence of seven AtPHO1homologues, highly similar to AtPHO1. The seven moss PHO1 genes, namely PpPHO1;1 toPpPHO1;7 appeared to be differentially regulated, both at the tissue level and in response toPi status. However only PpPHO1;1 and PpPHO1;7 were specifically up-regulated upon Pistarvation, suggesting a potential role in Pi homeostasis. We also characterized the responseof P. patens to Pi starvation, showing that higher and lower plants share some commonstrategies to adapt to Pi-deficiency.In the second part, focusing on the monocotyledon rice, we showed the existence of threePHO1 homologues OsPHO1;1 to OsPHO1;3, with the unique particularity of each havingNatural Antisense Transcripts (NATs). Molecular analyses revealed that both the sense andthe antisense OsPHO1;2 transcripts were by far the most abundantly expressed transcripts ofthe family, preferentially expressed in the roots. The stable expression of OsPHO1;2 in allconditions tested, in opposition with the highly induced antisense transcript upon Pistarvation, suggest a putative role for the antisense in regulating the sense transcript.Moreover, mutant analyses revealed that OsPHO1;2 plays a key role in Pi homeostasis, intransferring Pi from the root to the shoot. Finally, complementing the pho1 mutant inArabidopsis, characterized by low Pi in the shoot and reduced growth, with the riceOsPHO1;2 gene revealed a new role for PHO1 in Pi signaling. Indeed, the complementedplants showed normal growth, with however low Pi content.

Identification of naturally processed hepatitis C virus-derived major histocompatibility complex class I ligands.

Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS3₁₄₀₆₋₁₄₁₅ and NS5B₂₅₉₄₋₂₆₀₂). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.

Mutation identification by direct comparison of whole-genome sequencing data from mutant and wild-type individuals using k-mers.

Genes underlying mutant phenotypes can be isolated by combining marker discovery, genetic mapping and resequencing, but a more straightforward strategy for mapping mutations would be the direct comparison of mutant and wild-type genomes. Applying such an approach, however, is hampered by the need for reference sequences and by mutational loads that confound the unambiguous identification of causal mutations. Here we introduce NIKS (needle in the k-stack), a reference-free algorithm based on comparing k-mers in whole-genome sequencing data for precise discovery of homozygous mutations. We applied NIKS to eight mutants induced in nonreference rice cultivars and to two mutants of the nonmodel species Arabis alpina. In both species, comparing pooled F2 individuals selected for mutant phenotypes revealed small sets of mutations including the causal changes. Moreover, comparing M3 seedlings of two allelic mutants unambiguously identified the causal gene. Thus, for any species amenable to mutagenesis, NIKS enables forward genetics without requiring segregating populations, genetic maps and reference sequences.

Revising the Cannabis Use Disorders Identification Test (CUDIT) by means of Item Response Theory.

Cannabis use among adolescents and young adults has become a major public health challenge. Several European countries are currently developing short screening instruments to identify 'problematic' forms of cannabis use in general population surveys. One such instrument is the Cannabis Use Disorders Identification Test (CUDIT), a 10-item questionnaire based on the Alcohol Use Disorders Identification Test. Previous research found that some CUDIT items did not perform well psychometrically. In the interests of improving the psychometric properties of the CUDIT, this study replaces the poorly performing items with new items that specifically address cannabis use. Analyses are based on a sub-sample of 558 recent cannabis users from a representative population sample of 5722 individuals (aged 13-32) who were surveyed in the 2007 Swiss Cannabis Monitoring Study. Four new items were added to the original CUDIT. Psychometric properties of all 14 items, as well as the dimensionality of the supplemented CUDIT were then examined using Item Response Theory. Results indicate the unidimensionality of CUDIT and an improvement in its psychometric performance when three original items (usual hours being stoned; injuries; guilt) are replaced by new ones (motives for using cannabis; missing out leisure time activities; difficulties at work/school). However, improvements were limited to cannabis users with a high problem score. For epidemiological purposes, any further revision of CUDIT should therefore include a greater number of 'easier' items.

Identification of a new oncofoetal antigen associated with several types of human carcinomas.

In experimental animals, oncofoetal antigens1 have been found to be associated with both chemical-2 and virus-induced tumours3. In man the two best known oncofoetal antigens are the α-foetoprotein (AFP) described by both Abelev4 and Tatarinov5 and the carcinoembryonic antigen (CEA) of the human digestive system identified by Gold and Freedman6. We describe here a different human oncofoetal antigen, common to several types of carcinomas and various foetal organs. This antigen has been identified by rabbit antisera raised against semipurified fractions of colon carcinoma soluble extracts. Because of its β-immunoelectrophoretic mobility, this antigen will be referred to as β-oncofoetal antigen (BOFA).

The distribution of talent across contests

Do the contests with the largest prizes attract the most able contestants? Towhat extent do contestants avoid competition? In this paper, we show, theoreticallyand empirically, that the distribution of abilities plays a crucial role in determiningcontest choice. Sorting exists only when the proportion of high-ability contestantsis sufficiently small. As this proportion increases, contestants shy away from competitionand sorting decreases, such that, reverse sorting becomes a possibility. Wetest our theoretical predictions using a large panel data set containing contest choiceover three decades. We use exogenous variation in the participation of highly-ablecompetitors to provide empirical evidence for the relationship among prizes, competition,and sorting.

Identification of three Sorex species with microsatellite markers

Three sibling species of shrews, the common shrew (Sorex araneus), the Valais shrew (S. antinorii) and the Jersey shrew (S. coronatus) are morphologically similar. Different techniques based on karyorypes, morphology, biochemistry and genetic markers have been developed to identify individuals from these taxa. In this paper, we have used multiple microsatellite markers (L13, L14 and L99) to identify 55 dead animals coming from the Tarentaise Valley in France. As some individuals showed an unclear pattern with loci previously thought to be diagnostic (Lugon-Moulin et al. 2000), we have used morphologic measurements (Hausser et al. 1991) to confirm the status of these animals. This analysis clearly showed the limitations of the use of genetic diagnostic markers that have been designed in local populations and then applied to a wider scale. Even if these markers have great advantages over other techniques (i.e. simple to use and do not require samples from living animals), they should always be used with caution. There is always a risk of a locus not being diagnostic in the sampling region or in finding individuals with hybrid genotypes. Additional genetic markers should then be used, simultaneously with other identification techniques, to be sure of the status of the individuals.