Negative frequency-dependent preferences and variation in male facial hair

Negative frequency-dependent sexual selection maintains striking polymorphisms in secondary sexual traits in several animal species. Here, we test whether frequency of beardedness modulates perceived attractiveness of men''s facial hair, a secondary sexual trait subject to considerable cultural variation. We first showed participants a suite of faces, within which we manipulated the frequency of beard thicknesses and then measured preferences for four standard levels of beardedness. Women and men judged heavy stubble and full beards more attractive when presented in treatments where beards were rare than when they were common, with intermediate preferences when intermediate frequencies of beardedness were presented. Likewise, clean-shaven faces were least attractive when clean-shaven faces were most common and more attractive when rare. This pattern in preferences is consistent with negative frequency-dependent selection.     

Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety.     

Cleavage specificity of the subtilisin-like protease C1 from soybean

The cleavage specificity of protease C1, isolated from soybean (Glycine max (L.) Merrill) seedling cotyledons, was examined using oligopeptide substrates in an HPLC based assay. A series of peptides based on the sequence Ac-KVEKEESEEGE-NH2 was used, mimicking a natural cleavage site of protease C1 in the alpha subunit of the storage protein beta-conglycinin. A study of substrate peptides truncated from either the N- or C-terminus indicates that the minimal requirements for cleavage by protease C2 are three residues N-terminal to the cleaved bond, and two residues C-terminal (i.e. P3-P2'). The maximal rate of cleavage is reached with substrates containing four to five residues N-terminal to the cleaved bond and four residues C-terminal (i.e. P4 or P5 to P4'). The importance of Glu residues at the P1, P1', and P4 positions was examined using a series of substituted nonapeptides (P5-P4') with a base sequence of Ac-KVEKEESEE-NH2. At the P1 position, the relative ranking, based on kcat/Km, was E>Q>K>A>D>F>S. Substitutions at the P1' position yield the ranking E congruent withQ>A>S>D>K>F, while those at P4' had less effect on kcat/Km, yielding the ranking F congruent with S congruent with E congruent withD>K>A congruent withQ. These data show that protease C1 prefers to cleave at Glu-Glu and Glu-Gln bonds, and that the nature of the P4' position is less important. The fact that there is specificity in the cleavage of the oligopeptides suggests that the more limited specific cleavage of the alpha and alpha' subunits of beta-conglycinin by protease C1 is due to a combination of the sequence cleavage specificity of the protease and the accessibility of appropriate scissile peptide bonds on the surface of the substrate protein.     

Potential sites of bioactive gibberellin production during reproductive growth in Arabidopsis

Gibberellin 3-oxidase (GA3ox) catalyzes the final step in the synthesis of bioactive gibberellins (GAs). We examined the expression patterns of all four GA3ox genes in Arabidopsis thaliana by promoter-beta-glucuronidase gene fusions and by quantitative RT-PCR and defined their physiological roles by characterizing single, double, and triple mutants. In developing flowers, GA3ox genes are only expressed in stamen filaments, anthers, and flower receptacles. Mutant plants that lack both GA3ox1 and GA3ox3 functions displayed stamen and petal defects, indicating that these two genes are important for GA production in the flower. Our data suggest that de novo synthesis of active GAs is necessary for stamen development in early flowers and that bioactive GAs made in the stamens and/or flower receptacles are transported to petals to promote their growth. In developing siliques, GA3ox1 is mainly expressed in the replums, funiculi, and the silique receptacles, whereas the other GA3ox genes are only expressed in developing seeds. Active GAs appear to be transported from the seed endosperm to the surrounding maternal tissues where they promote growth. The immediate upregulation of GA3ox1 and GA3ox4 after anthesis suggests that pollination and/or fertilization is a prerequisite for de novo GA biosynthesis in fruit, which in turn promotes initial elongation of the silique.     

Does the {Delta}F508-CFTR mutation induce a proinflammatory response in human airway epithelial cells?

In the clinical setting, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene enhance the inflammatory response in the lung to Pseudomonas aeruginosa (P. aeruginosa) infection. However, studies on human airway epithelial cells in vitro have produced conflicting results regarding the effect of mutations in CFTR on the inflammatory response to P. aeruginosa, and there are no comprehensive studies evaluating the effect of P. aeruginosa on the inflammatory response in airway epithelial cells with the ΔF508/ΔF508 genotype and their matched CF cell line rescued with wild-type (wt)-CFTR. CFBE41o- cells (ΔF508/ΔF508) and CFBE41o- cells complemented with wt-CFTR (CFBE-wt-CFTR) have been used extensively as an experimental model to study CF. Thus the goal of this study was to examine the effect of P. aeruginosa on gene expression and cytokine/chemokine production in this pair of cells. P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL1, CXCL2 and TNF-α) in CFBE-wt-CFTR cells compared with CFBE-ΔF508-CFTR cells. These results demonstrate that CFBE41o- cells complemented with wt-CFTR mount a more robust inflammatory response to P. aeruginosa than CFBE41o-ΔF508/ΔF508-CFTR cells. Taken together with other published studies, our data demonstrate that there is no compelling evidence to support the view that mutations in CFTR induce a hyperinflammatory response in human airway epithelial cells in vivo. Although the lungs of patients with CF have abundant levels of proinflammatory cytokines and chemokines, because the lung is populated by immune cells and epithelial cells there is no way to know, a priori, whether airway epithelial cells in the CF lung in vivo are hyperinflammatory in response to P. aeruginosa compared with non-CF lung epithelial cells. Thus studies on human airway epithelial cell lines and primary cells in vitro that propose to examine the effect of mutations in CFTR on the inflammatory response to P. aeruginosa have uncertain clinical significance with regard to CF.     

Discovery of 2-Aminothiazoles as Potent Antiprion Compounds

Prion diseases are fatal, untreatable neurodegenerative diseases caused by the accumulation of the misfolded, infectious isoform of the prion protein (PrP), termed PrP^Sc. In an effort to identify novel inhibitors of prion formation, we utilized a high-throughput enzyme-linked immunosorbent assay (ELISA) to evaluate PrP^Sc reduction in prion-infected neuroblastoma cell lines (ScN2a). We screened a library of ∼10,000 diverse small molecules in 96-well format and identified 121 compounds that reduced PrP^Sc levels at a concentration of 5 μM. Four chemical scaffolds were identified as potential candidates for chemical optimization based on the presence of preliminary structure-activity relationships (SAR) derived from the primary screening data. A follow-up analysis of a group of commercially available 2-aminothiazoles showed this class as generally active in ScN2a cells. Our results establish 2-aminothiazoles as promising candidates for efficacy studies of animals and validate our drug discovery platform as a viable strategy for the identification of novel lead compounds with antiprion properties.Prion diseases belong to a class of neurodegenerative, protein-conformation disorders whose unifying pathological mechanism is the misprocessing and aggregation of normally benign soluble proteins. These “proteinopathies,” which include Alzheimer''s, Parkinson''s, and Huntington''s diseases, as well as the frontotemporal dementias—including Pick''s disease—and amyotrophic lateral sclerosis (ALS), are uniformly fatal after a period of neurodegeneration, characterized clinically by dementia and motor dysfunction (20). Prion diseases, which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy, are characterized by the formation of “spongiform” vacuolation of the brain (13). Disease onset is caused by the accumulation of a β-sheet-rich, infectious isoform of the prion protein, termed PrP^Sc (1, 16, 19, 20), which is formed from the α-helix-rich cellular prion protein, termed PrP^C. This conversion can occur spontaneously or be induced by the presence of a number of different autosomally dominant mutations of the PrP gene (8, 21). Alternatively, prion disease can result from exogenous exposure to PrP^Sc (20). The infectious nature of prions results from the ability of PrP^Sc to induce its own production by stimulating the alternative folding of PrP^C (18). Although PrP^Sc formation has been demonstrated to be the primary pathogenic event in prion disease, the precise mechanism that features in its formation and the ensuing neurodegeneration remains largely unknown.Despite the lack of a detailed understanding of the cellular mechanism of prion propagation, numerous studies have been directed toward development of therapeutics targeting prions. Screenings utilizing prion-infected cell lines have identified a number of compounds that reduce the level of PrP^Sc in culture. These include pentosan polysulfate (PPS), dextran sulfate (DS), HPA-23, Congo red, suramin, dendritic polyamines, and quinacrine, among others; for a comprehensive review, see reference 22. However, none of these have been shown to be effective against a broad range of prion strains in animal models when administered after clinical signs manifest, and none have been shown to modify the disease course in human clinical studies (22).The current array of antiprion compounds has been discovered mostly by ad hoc, low-throughput screening of small sets of known bioactive compounds. Most antiprion compounds that are active in prion-infected cell lines have failed in vivo, which highlights the need for a sustained, high-throughput drug discovery effort. Such studies need to rapidly screen large libraries of new chemical entities in vitro, analyze the pharmacokinetic and pharmacodynamic properties of the primary hits in vivo, and optimize the chemical properties of lead compounds. In two semi-high-throughput screenings for antiprion compounds, an analysis of ∼2,000-member compound libraries of known drugs and natural products identified sets of 17 and 8 active compounds (10). None of these have been reported to be effective in vivo.In the present study, we assessed the antiprion activity of ∼10,000 compounds encompassing a diverse set of chemical entities and identified a set of 121 compounds that induce the clearance of PrP^Sc. Subsequent analysis of a number of compounds with the 2-aminothiazole scaffold informed the structure-activity relationship (SAR) of this lead class.     

A hydrogeomorphological context for ecological research on alpine glacial rivers

1. This paper presents a framework for the analysis of glacial stream ecosystems based upon the hierarchy of physical processes that operate over timescales varying from diel to millennial. Linked conceptual models propose interrelationships between climate, hydrology and fluvial geomorphology in alpine catchments.
2. These conceptual models are illustrated using data from the Taillon/Gabiétous catchment, French Pyrénées. Secondary sources provide information concerning the long-term sequence of climatic and geomorphological controls on contemporary catchment processes. Detailed hydrogeomorphological field data collected over three consecutive summer melt seasons (1995–97) permit identification of marked changes in shorter-term (diel, seasonal and inter-annual) physical processes.
3. Clear differences in the response of water quality and quantity variables were observed between years as climatic conditions varied. In two of the three study years, a precipitation-driven regime was imposed upon the typical ablation-driven river discharge pattern in alpine streams. Clear changes in water quality and quantity were evident with increasing distance from the glacier: (i) discharge increased although specific discharge decreased markedly, (ii) the mean and variability in water temperature increased, and (iii) base concentrations of suspended solids decreased.
4. The physical processes incorporated in the conceptual models presented in this paper have ecological implications because they underpin a nested suite of disturbance regimes operating over timescales from diel to millennial.     

Genome annotation of a 1.5 Mb region of human chromosome 6q23 encompassing a quantitative trait locus for fetal hemoglobin expression in adults

Background  

Heterocellular hereditary persistence of fetal hemoglobin (HPFH) is a common multifactorial trait characterized by a modest increase of fetal hemoglobin levels in adults. We previously localized a Quantitative Trait Locus for HPFH in an extensive Asian-Indian kindred to chromosome 6q23. As part of the strategy of positional cloning and a means towards identification of the specific genetic alteration in this family, a thorough annotation of the candidate interval based on a strategy ofin silico/ wet biology approach with comparative genomics was conducted.     

A Study of Platelet Inhibition,Using a ‘Point of Care’ Platelet Function Test,following Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction [PINPOINT-PPCI]

Background

Rapid coronary recanalization following ST-elevation myocardial infarction (STEMI) requires effective anti-platelet and anti-thrombotic therapies. This study tested the impact of door to end of procedure (‘door-to-end’) time and baseline platelet activity on platelet inhibition within 24hours post-STEMI.

Methods and Findings

108 patients, treated with prasugrel and procedural bivalirudin, underwent Multiplate® platelet function testing at baseline, 0, 1, 2 and 24hours post-procedure. Major adverse cardiac events (MACE), bleeding and stent thrombosis (ST) were recorded. Baseline ADP activity was high (88.3U [71.8–109.0]), procedural time and consequently bivalirudin infusion duration were short (median door-to-end time 55minutes [40–70] and infusion duration 30minutes [20–42]). Baseline ADP was observed to influence all subsequent measurements of ADP activity, whereas door-to-end time only influenced ADP immediately post-procedure. High residual platelet reactivity (HRPR ADP>46.8U) was observed in 75% of patients immediately post-procedure and persisted in 24% of patients at 2hours. Five patients suffered in-hospital MACE (4.6%). Acute ST occurred in 4 patients, all were <120mins post-procedure and had HRPR. No significant bleeding was observed. In a post-hoc analysis, pre-procedural morphine use was associated with significantly higher ADP activity following intervention.

Conclusions

Baseline platelet function, time to STEMI treatment and opiate use all significantly influence immediate post-procedural platelet activity.