Subunit interactions influence the biochemical and biological properties of Hsp104

Point mutations in either of the two nucleotide-binding domains (NBD) of Hsp104 (NBD1 and NBD2) eliminate its thermotolerance function in vivo. In vitro, NBD1 mutations virtually eliminate ATP hydrolysis with little effect on hexamerization; analogous NBD2 mutations reduce ATPase activity and severely impair hexamerization. We report that high protein concentrations overcome the assembly defects of NBD2 mutants and increase ATP hydrolysis severalfold, changing V(max) with little effect on K(m). In a complementary fashion, the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate inhibits hexamerization of wild-type (WT) Hsp104, lowering V(max) with little effect on K(m). ATP hydrolysis exhibits a Hill coefficient between 1.5 and 2, indicating that it is influenced by cooperative subunit interactions. To further analyze the effects of subunit interactions on Hsp104, we assessed the effects of mutant Hsp104 proteins on WT Hsp104 activities. An NBD1 mutant that hexamerizes but does not hydrolyze ATP reduces the ATPase activity of WT Hsp104 in vitro. In vivo, this mutant is not toxic but specifically inhibits the thermotolerance function of WT Hsp104. Thus, interactions between subunits influence the ATPase activity of Hsp104, play a vital role in its biological functions, and provide a mechanism for conditionally inactivating Hsp104 function in vivo

Examination of Differential Validity of MMPI-2-RF Scores by Gender and Ethnicity in Predicting Future Suicidal and Violent Behaviors in a Forensic Sample

Given the diversity of individuals who undergo psychological assessment, examining whether cultural bias exists in psychological assessment instruments (i.e., differential validity) is crucial. This issue occurs when a measure systematically over- or underpredicts a criterion across demographic groups or is associated with the criterion unequally across the groups. We tested the differential validity of a widely used psychological test, the Minnesota Multiphasic Personality Inventory (MMPI)-2-Restructured Form (MMPI-2-RF), as a function of gender (male, female) and ethnicity (Caucasian, African American, and Hispanic/Latino American) in large samples of forensic psychiatric inpatients. Regression models were estimated in a multigroup framework. The analyses yielded negligible to small statistical evidence of differential validity in MMPI-2-RF scores predicting the number of future suicidal behaviors and violent behaviors in the samples. This evidence supports use of the MMPI-2-RF as a generally unbiased instrument for predicting key criteria across genders and ethnicities in a forensic psychiatric population

New Reports of Exotic and Native Ambrosia and Bark Beetle Species (Coleoptera: Curculionidae: Scolytinae) From Ohio

In a 2007 survey of ambrosia and bark beetles (Coleoptera: Curculionidae: Scolytinae) along a transect in northeastern Ohio, we collected six exotic and three native species not previously reported from the state. These species include the exotic ambrosia beetles Ambrosiodmus rubricollis (Eichhoff), Dryoxylon onoharaensum (Murayama), Euwallacea validus (Eichhoff), Xyleborus californicus Wood, Xyleborus pelliculosusEichhoff, and Xylosandrus crassiusculus (Motschulsky). The native ambrosia beetle Corthylus columbianus Hopkins, and the native bark beetles Dryocoetes autographus (Ratzeburg) and Hylastes tenuis Eichhoff are also reported from Ohio for the first time. Our study suggests a northward range expansion for five of the six exotic species including, X. crassiusculus, which is an important pest of nursery and orchard crops in the southeastern United States

Anti-polyQ antibodies recognize a short polyQ stretch in both normal and mutant huntingtin exon 1

Huntington's disease is caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. A structural basis for the apparent transition between normal and disease-causing expanded polyQ repeats of huntingtin is unknown. The “linear lattice” model proposed random-coil structures for both normal and expanded polyQ in the preaggregation state. Consistent with this model, the affinity and stoichiometry of the anti-polyQ antibody MW1 increased with the number of glutamines. An opposing “structural toxic threshold” model proposed a conformational change above the pathogenic polyQ threshold resulting in a specific toxic conformation for expanded polyQ. Support for this model was provided by the anti-polyQ antibody 3B5H10, which was reported to specifically recognize a distinct pathologic conformation of soluble expanded polyQ. To distinguish between these models, we directly compared binding of MW1 and 3B5H10 to normal and expanded polyQ repeats within huntingtin exon 1 fusion proteins. We found similar binding characteristics for both antibodies. First, both antibodies bound to normal, as well as expanded, polyQ in huntingtin exon 1 fusion proteins. Second, an expanded polyQ tract contained multiple epitopes for fragments antigen-binding (Fabs) of both antibodies, demonstrating that 3B5H10 does not recognize a single epitope specific to expanded polyQ. Finally, small-angle X-ray scattering and dynamic light scattering revealed similar binding modes for MW1 and 3B5H10 Fab–huntingtin exon 1 complexes. Together, these results support the linear lattice model for polyQ binding proteins, suggesting that the hypothesized pathologic conformation of soluble expanded polyQ is not a valid target for drug design

Feasibility, psychosocial effects, influence, and perception of elastic band resistance balance training in older adults

This study utilised feedback from older adults during balance-challenging, elastic band resistance exercises to design a physical activity (PA) intervention. Methods: Twenty-three active participants, aged 51 – 81 years, volunteered to perform a mini balance evaluation test and falls efficacy scale, and completed a daily living questionnaire. Following a 10 min warm-up, participants performed eight pre-selected exercises (1 × set, 8 – 12 repetitions) using elastic bands placed over the hip or chest regions in a randomised, counterbalanced order with 15 min seated rests between interventions. Heart rate (HR) and rate of perceived exertion (RPE) were measured throughout. Participant interview responses were used to qualify the experiences and opinions of the interventions including likes, dislikes, comfort, and exercise difficulty. Results: Similar significant (p \u3c 0.01) increases in HR (pre- = 83 – 85 bpm, mid- = 85 – 88 bpm, post-intervention = 88 – 89 bpm; 5 – 6 %) and RPE (pre- = 8 – 9, mid- = 10, post-intervention = 10 – 11) were detected during the PA interventions (hip and chest regions). Interview data revealed that participants thought the PA interventions challenged balance, that the exercises would be beneficial for balance, and that the exercises were suitable for themselves and others. Participants reported a positive experience when using the PA interventions with an elastic band placed at the hip or chest and would perform the exercises again, preferably in a group, and that individual preference and comfort would determine the placement of the elastic band at either the hip or chest. Conclusion: These positive outcomes confirm the feasibility of a resistance band balance program and will inform intervention design and delivery in future studies

Increasing the use of evidence in health policy: practice and views of policy makers and researchers

Background: Better communication is often suggested as fundamental to increasing the use of research evidence in policy, but little is known about how researchers and policy makers work together or about barriers to exchange. This study explored the views and practice of policy makers and researchers regarding the use of evidence in policy, including: (i) current use of research to inform policy; (ii) dissemination of and access to research findings for policy; (iii) communication and exchange between researchers and policy makers; and (iv) incentives for increasing the use of research in policy. Methods: Separate but similar interview schedules were developed for policy makers and researchers. Senior policy makers from NSW Health and senior researchers from public health and health service research groups in NSW were invited to participate. Consenting participants were interviewed by an independent research company. Results: Thirty eight policy makers (79% response rate) and 41 researchers (82% response rate) completed interviews. Policy makers reported rarely using research to inform policy agendas or to evaluate the impact of policy; research was used more commonly to inform policy content. Most researchers reported that their research had informed local policy, mainly by increasing awareness of an issue. Policy makers reported difficulty in accessing useful research syntheses, and only a third of researchers reported developing targeted strategies to inform policy makers of their findings. Both policy makers and researchers wanted more exchange and saw this as important for increasing the use of research evidence in policy; however, both groups reported a high level of involvement by policy makers in research. Conclusion: Policy makers and researchers recognise the potential of research to contribute to policy and are making significant attempts to integrate research into the policy process. These findings suggest four strategies to assist in increasing the use of research in policy: making research findings more accessible to policy makers; increasing opportunities for interaction between policy makers and researchers; addressing structural barriers such as research receptivity in policy agencies and a lack of incentives for academics to link with policy; and increasing the relevance of research to policy. © 2009 Campbell et al; licensee BioMed Central Ltd

Utility of clinical features with fine needle aspiration biopsy for diagnosis of Warthin tumor.

BACKGROUND:Conservative management of Warthin tumor (WT) may be a viable alternative to surgery, but there are concerns of missed malignancies on fine needle aspiration biopsy (FNAB). The purpose of this study is to measure the sensitivity and positive predictive value of FNAB for WT, and to identify clinical features associated with WT that can aid in this diagnosis. METHODS: Retrospective analysis of patients from January 1, 2006 to April 30, 2017 at a tertiary care center in London, Ontario, Canada. All patients with a diagnosis of WT on FNAB or resection were included. Electronic medical records were identified for 177 patients that fit the criteria. Study outcomes included the sensitivity and positive predictive value of FNAB alone for WT, and, when including clinical features associated with WT. RESULTS: The mean age of patients in this study was 63.2 years (SD 10.4); 115 (65%) were male, and 157 (89%) were past or present smokers. The measured sensitivity and positive predictive value of FNAB for WT were 95.8 and 97.2% respectively. Two cases were classified as WT on FNAB but confirmed at resection as mucoepidermoid carcinoma and acinic cell carcinoma. When only patients with multifocal, bilateral or incidental tumors were assessed, sensitivities and positive predictive values for each were 100%. Isolating for inferior pole location also resulted in a positive predictive value of 100%. CONCLUSIONS: The sensitivity and positive predictive value of FNAB for WT in this study are high, with two false negatives on FNAB. Multifocal, bilateral, incidentaloma and inferior pole location were identified as potential clinical features that may increase the diagnostic confidence for WT, strengthening the argument for conservative management in these patients. Overall, this study serves as an initial exploration into whether clinical features may be included with FNAB results to improve the sensitivity and positive predictive value of diagnosing WT. Further research is necessary before these findings can be translated into clinical practice

A gene × gene interaction between DRD2 and DRD4 is associated with conduct disorder and antisocial behavior in males

<p>Abstract</p> <p>Background</p> <p>Antisocial behaviors are complex polygenic phenotypes that are due to a multifactorial arrangement of genetic polymorphisms. Little empirical research, however, has been undertaken that examines gene × gene interactions in the etiology of conduct disorder and antisocial behavior. This study examined whether adolescent conduct disorder and adult antisocial behavior were related to the dopamine D2 receptor polymorphism (DRD2) and the dopamine D4 receptor polymorphism (DRD4).</p> <p>Methods</p> <p>A sample of 872 male participants from the National Longitudinal Study of Adolescent Health (Add Health) completed self-report questionnaires that tapped adolescent conduct disorder and adult antisocial behavior. DNA was genotyped for DRD2 and DRD4.</p> <p>Results</p> <p>Multivariate regression analysis revealed that neither DRD2 nor DRD4 had significant independent effects on conduct disorder or antisocial behavior. However, DRD2 interacted with DRD4 to predict variation in adolescent conduct disorder and in adult antisocial behavior.</p> <p>Conclusion</p> <p>The results suggest that a gene × gene interaction between DRD2 and DRD4 is associated with the development of conduct disorder and adult antisocial behavior in males.</p

Neuroendocrine and neurotrophic signaling in Huntington\u27s disease: Implications for pathogenic mechanisms and treatment strategies

Huntington\u27s disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways

TNF-α/TNFR1 Signaling Is Required for the Development and Function of Primary Nociceptors

SummaryPrimary nociceptors relay painful touch information from the periphery to the spinal cord. Although it is established that signals generated by receptor tyrosine kinases TrkA and Ret coordinate the development of distinct nociceptive circuits, mechanisms modulating TrkA or Ret pathways in developing nociceptors are unknown. We have identified tumor necrosis factor (TNF) receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and nonpeptidergic nociceptors. Specifically, TrkA+ peptidergic nociceptors require TNF-α-TNFR1 forward signaling to suppress nerve growth factor (NGF)-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNF-α reverse signaling augments the neurite growth and excitability of Ret+ nonpeptidergic nociceptors. The developmental and functional nociceptive defects associated with loss of TNFR1 signaling manifest behaviorally as lower pain thresholds caused by increased sensitivity to NGF. Thus, TNFR1 exerts a dual role in nociceptor information processing by suppressing TrkA and enhancing Ret signaling in peptidergic and nonpeptidergic nociceptors, respectively