Structure of a Novel Shoulder-to-Shoulder p24 Dimer in Complex with the Broad-Spectrum Antibody A10F9 and Its Implication in Capsid Assembly

10.1371/journal.pone.0061314PLoS ONE84

Intensity Modulated Radiotherapy (IMRT) and Fractionated Stereotactic Radiotherapy (FSRT) for children with head-and-neck-rhabdomyosarcoma

<p>Abstract</p> <p>Background</p> <p>The present study evaluates the outcome of 19 children with rhabdomyosarcoma of the head-and-neck region treated with Intensity Modulated Radiotherapy (IMRT) or Fractionated Stereotactic Radiotherapy (FSRT) between August 1995 and November 2005.</p> <p>Methods</p> <p>We treated 19 children with head-and-neck rhabdomyosarcoma with FSRT (n = 14) or IMRT (n = 5) as a part of multimodal therapy. Median age at the time of radiation therapy was 5 years (range 2–15 years). All children received systemic chemotherapy according to the German Soft Tissue Sarcoma Study protocols.</p> <p>Median size of treatment volume for RT was 93,4 ml. We applied a median total dose of 45 Gy (range 32 Gy – 54 Gy) using a median fractionation of 5 × 1,8 Gy/week (range 1,6 Gy – 1,8 Gy).</p> <p>The median time interval between primary diagnosis and radiation therapy was 5 months (range 3–9 months).</p> <p>Results</p> <p>After RT, the 3- and 5-year survival rate was 94%. The 3- and 5-year actuarial local control rate after RT was 89%.</p> <p>The actuarial freedom of distant metastases rate at 3- and 5-years was 89% for all patients.</p> <p>Radiotherapy was well tolerated in all children and could be completed without interruptions > 4 days. No toxicities >CTC grade 2 were observed. The median follow-up time after RT was 17 months.</p> <p>Conclusion</p> <p>IMRT and FSRT lead to excellent outcome in children with head-and-neck RMS with a low incidence of treatment-related side effects.</p

The Trypanosoma cruzi Virulence Factor Oligopeptidase B (OPBTc) Assembles into an Active and Stable Dimer

Oligopeptidase B, a processing enzyme of the prolyl oligopeptidase family, is considered as an important virulence factor in trypanosomiasis. Trypanosoma cruzi oligopeptidase B (OPBTc) is involved in host cell invasion by generating a Ca2+-agonist necessary for recruitment and fusion of host lysosomes at the site of parasite attachment. The underlying mechanism remains unknown and further structural and functional characterization of OPBTc may help clarify its physiological function and lead to the development of new therapeutic molecules to treat Chagas disease. In the present work, size exclusion chromatography and analytical ultracentrifugation experiments demonstrate that OPBTc is a dimer in solution, an association salt and pH-resistant and independent of intermolecular disulfide bonds. The enzyme retains its dimeric structure and is fully active up to 42°C. OPBTc is inactivated and its tertiary, but not secondary, structure is disrupted at higher temperatures, as monitored by circular dichroism and fluorescence spectroscopy. It has a highly stable secondary structure over a broad range of pH, undergoes subtle tertiary structure changes at low pH and is less stable under moderate ionic strength conditions. These results bring new insights into the structural properties of OPBTc, contributing to future studies on the rational design of OPBTc inhibitors as a promising strategy for Chagas disease chemotherapy

Maintaining and breaking symmetry in homomeric coiled-coil assemblies

Higher order coiled coils with five or more helices can form α-helical barrels. Here the authors show that placing β-branched aliphatic residues along the lumen yields stable and open α-helical barrels, which is of interest for the rational design of functional proteins; whereas, the absence of β-branched side chains leads to unusual low-symmetry α-helical bundles

Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone

Mineralized bone forms when collagen-containing osteoid accrues mineral crystals. This is initiated rapidly (primary mineralization), and continues slowly (secondary mineralization) until bone is remodeled. The interconnected osteocyte network within the bone matrix differentiates from bone-forming osteoblasts; although osteoblast differentiation requires EphrinB2, osteocytes retain its expression. Here we report brittle bones in mice with osteocyte-targeted EphrinB2 deletion. This is not caused by low bone mass, but by defective bone material. While osteoid mineralization is initiated at normal rate, mineral accrual is accelerated, indicating that EphrinB2 in osteocytes limits mineral accumulation. No known regulators of mineralization are modified in the brittle cortical bone but a cluster of autophagy-associated genes are dysregulated. EphrinB2-deficient osteocytes displayed more autophagosomes in vivo and in vitro, and EphrinB2-Fc treatment suppresses autophagy in a RhoA-ROCK dependent manner. We conclude that secondary mineralization involves EphrinB2-RhoA-limited autophagy in osteocytes, and disruption leads to a bone fragility independent of bone mass

Fluctuating Environments, Sexual Selection and the Evolution of Flexible Mate Choice in Birds

Environmentally-induced fluctuation in the form and strength of natural selection can drive the evolution of morphology, physiology, and behavior. Here we test the idea that fluctuating climatic conditions may also influence the process of sexual selection by inducing unexpected reversals in the relative quality or sexual attractiveness of potential breeding partners. Although this phenomenon, known as ‘ecological cross-over’, has been documented in a variety of species, it remains unclear the extent to which it has driven the evolution of major interspecific differences in reproductive behavior. We show that after controlling for potentially influential life history and demographic variables, there are significant positive associations between the variability and predictability of annual climatic cycles and the prevalence of infidelity and divorce within populations of a taxonomically diverse array of socially monogamous birds. Our results are consistent with the hypothesis that environmental factors have shaped the evolution of reproductive flexibility and suggest that in the absence of severe time constraints, secondary mate choice behaviors can help prevent, correct, or minimize the negative consequences of ecological cross-overs. Our findings also illustrate how a basic evolutionary process like sexual selection is susceptible to the increasing variability and unpredictability of climatic conditions that is resulting from climate change

The Things You Do:Internal Models of Others' Expected Behaviour Guide Action Observation

Predictions allow humans to manage uncertainties within social interactions. Here, we investigate how explicit and implicit person models-how different people behave in different situations-shape these predictions. In a novel action identification task, participants judged whether actors interacted with or withdrew from objects. In two experiments, we manipulated, unbeknownst to participants, the two actors action likelihoods across situations, such that one actor typically interacted with one object and withdrew from the other, while the other actor showed the opposite behaviour. In Experiment 2, participants additionally received explicit information about the two individuals that either matched or mismatched their actual behaviours. The data revealed direct but dissociable effects of both kinds of person information on action identification. Implicit action likelihoods affected response times, speeding up the identification of typical relative to atypical actions, irrespective of the explicit knowledge about the individual's behaviour. Explicit person knowledge, in contrast, affected error rates, causing participants to respond according to expectations instead of observed behaviour, even when they were aware that the explicit information might not be valid. Together, the data show that internal models of others' behaviour are routinely re-activated during action observation. They provide first evidence of a person-specific social anticipation system, which predicts forthcoming actions from both explicit information and an individuals' prior behaviour in a situation. These data link action observation to recent models of predictive coding in the non-social domain where similar dissociations between implicit effects on stimulus identification and explicit behavioural wagers have been reported

Antiviral Silencing and Suppression of Gene Silencing in Plants

RNA silencing is an evolutionary conserved sequence-specific gene inactivation mechanism that contributes to the control of development, maintains heterochromatin, acts in stress responses, DNA repair and defends against invading nucleic acids like transposons and viruses. In plants RNA silencing functions as one of the main immune systems. RNA silencing process involves the small RNAs and trans factor components like Dicers, Argonautes and RNA-dependent RNA poly- merases. To deal with host antiviral silencing responses viruses evolved mecha- nisms to avoid or counteract this, most notably through expression of viral suppressors of RNA silencing. Due to the overlap between endogenous and antiviral silencing pathways while blocking antiviral pathways viruses also impact endogenous silencing processes. Here we provide an overview of antiviral silencing pathway, host factors implicated in it and the crosstalk between antiviral and endogenous branches of silencing. We summarize the current status of knowledge about the viral counter-defense strategies acting at various steps during virus infection in plants with the focus on representative, well studied silencing suppres- sor proteins. Finally we discuss future challenges of the antiviral silencing and counter-defense research field

Development of the Stanford Social Dimensions Scale: initial validation in autism spectrum disorder and in neurotypicals.

Background: The aim of this paper was to provide an initial validation of a newly developed parent questionnaire-the Stanford Social Dimensions Scale (SSDS), designed to capture individual differences across several key social dimensions including social motivation in children and adolescents with and without psychiatric disorders. Methods: The initial validation sample was comprised of parents of 175 individuals with autism spectrum disorder (ASD) (35 females, 140 males; M age = 7.19 years, SD age = 3.96) and the replication sample consisted of 624 parents of children who were either typically developing or presented with a range of neurodevelopmental and neuropsychiatric disorders (302 females, 322 males; M age = 11.49 years, SDage = 4.48). Parents from both samples completed the SSDS and the Social Responsiveness Scale (SRS-2). Results: Exploratory Structural Equation Modeling indicated that a 5-factor model provided adequate to excellent fit to the data in the initial ASD sample (comparative fit index [CFI] = .940, Tucker-Lewis Index [TLI] = .919, root mean square error of approximation [RMSEA] = .048, standardized root mean square residual [SRMR] = .038). The identified factors were interpreted as Social Motivation, Social Affiliation, Expressive Social Communication, Social Recognition, and Unusual Approach. This factor structure was further confirmed in Sample 2 (CFI = 946, TLI = .930, RMSEA = .044, SRMR = .026). Internal consistency for all subscales was in the good to excellent range across both samples as indicated by Composite Reliability scores of ≥ .72. Convergent and divergent validity was strong as indexed by the pattern of correlations with relevant SRS-2 and Child Behavior Checklist domains and with verbal and non-verbal intellectual functioning scores in Sample 1 and with the Need to Belong Scale and Child Social Preference Scale scores in Sample 2. Across both samples, females had higher social motivation and expressive social communication scores. Discriminant validity was strong given that across all SSDS subscales, the ASD sample had significantly higher impairment than both the typically developing group and the group with other clinical conditions, which in turn, had significantly higher impairment than the typically developing group. Conclusions: Our findings provide initial validation of a new scale designed to comprehensively capture individual differences in social motivation and other key social dimensions in ASD