CIB2 Interacts with TMC1 and TMC2 and is Essential for Mechanotransduction in Auditory Hair Cells

Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of both Cib2 mutants. Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia

The Grizzly, December 1, 1989

Curriculum in Transition • Armstrong\u27s Talk a Trauma • Letters: Maturity Decides Right Choice; Everybody\u27s a Critic; Championship Cycling; PDA Pooh-Poohed; Pro-Choice Rally Ironic • Aquatic Lady Bears Stroke Strongly • Hoopsters Hopeful • Women\u27s Track Looks to Season • Congrats to Athletes • Shoudt to Return Next Fall • X-Country Wrap-Up • Swimmers Victorious • Down with Frats • Faith-Leaps Abound • EPA: Not a Joking Matter • What Can Clamer Claim? • Victims of Fishy Business • Corsonites Fashion Comatose • Greeks Promote Sexism • U.C. Honors Spotlight • Final Exam Schedulehttps://digitalcommons.ursinus.edu/grizzlynews/1248/thumbnail.jp

Identification of Class I HLA T Cell Control Epitopes for West Nile Virus

The recent West Nile virus (WNV) outbreak in the United States underscores the importance of understanding human immune responses to this pathogen. Via the presentation of viral peptide ligands at the cell surface, class I HLA mediate the T cell recognition and killing of WNV infected cells. At this time, there are two key unknowns in regards to understanding protective T cell immunity: 1) the number of viral ligands presented by the HLA of infected cells, and 2) the distribution of T cell responses to these available HLA/viral complexes. Here, comparative mass spectroscopy was applied to determine the number of WNV peptides presented by the HLA-A*11:01 of infected cells after which T cell responses to these HLA/WNV complexes were assessed. Six viral peptides derived from capsid, NS3, NS4b, and NS5 were presented. When T cells from infected individuals were tested for reactivity to these six viral ligands, polyfunctional T cells were focused on the GTL9 WNV capsid peptide, ligands from NS3, NS4b, and NS5 were less immunogenic, and two ligands were largely inert, demonstrating that class I HLA reduce the WNV polyprotein to a handful of immune targets and that polyfunctional T cells recognize infections by zeroing in on particular HLA/WNV epitopes. Such dominant HLA/peptide epitopes are poised to drive the development of WNV vaccines that elicit protective T cells as well as providing key antigens for immunoassays that establish correlates of viral immunity. © 2013 Kaabinejadian et al

Tyramine acts downstream of neuronal XBP-1s to coordinate inter-tissue UPRER activation and behavior in C. elegans

In C. elegans, expression of the UPRER transcription factor xbp-1s in neurons cell non-autonomously activates the UPRER in the intestine, leading to enhanced proteostasis and lifespan. To better understand this signaling pathway, we isolated neurons from animals expressing neuronal xbp-1s for transcriptomic analysis, revealing a striking remodeling of transcripts involved in neuronal signaling. We then identified signaling molecules required for cell non-autonomous intestinal UPRER activation, including the biogenic amine tyramine. Expression of xbp-1s in just two pairs of neurons that synthesize tyramine, the RIM and RIC interneurons, induced intestinal UPRER activation and extended longevity, and exposure to stress led to splicing and activation of xbp-1 in these neurons. In addition, we found that neuronal xbp-1s modulates feeding behavior and reproduction, dependent upon tyramine synthesis. XBP-1s therefore remodels neuronal signaling to coordinately modulate intestinal physiology and stress-responsive behavior, functioning as a global regulator of organismal responses to stress

Maternal–Fetal Microtransfusions and HIV-1 Mother-to-Child Transmission in Malawi

BACKGROUND: Between 25% and 35% of infants born to HIV-infected mothers become HIV-1 infected. One potential route of mother-to-child transmission (MTCT) could be through a breakdown in the placental barrier (i.e., maternal–fetal microtransfusions). METHODS AND FINDINGS: Placental alkaline phosphatase (PLAP) is a 130-kD maternal enzyme that cannot cross the intact placental barrier. We measured PLAP activity in umbilical vein serum as an indicator of maternal–fetal microtransfusion, and related this to the risk of HIV-1 MTCT. A case-cohort study was conducted of 149 women randomly selected from a cohort of HIV-1-infected pregnant Malawians; these women served as a reference group for 36 cases of in utero MTCT and 43 cases of intrapartum (IP) MTCT. Cord PLAP activity was measured with an immunocatalytic assay. Infant HIV status was determined by real-time PCR. The association between cord PLAP activity and HIV-1 MTCT was measured with logistic regression using generalized estimating equations. Among vaginal deliveries, PLAP was associated with IP MTCT (risk ratio, 2.25 per log(10) ng/ml PLAP; 95% confidence interval, 0.95–5.32) but not in utero MTCT. In a multivariable model adjusted for HIV-1 RNA load, chorioamnionitis, and self-reported fever, the risk of IP MTCT almost tripled for every log(10) increase in cord PLAP activity (risk ratio, 2.87; 95% confidence interval, 1.05–7.83). CONCLUSION: These results suggest that during vaginal deliveries, placental microtransfusions are a risk factor for IP HIV-1 MTCT. Future studies are needed to identify factors that increase the risk for microtransfusions in order to prevent IP HIV-1 MTCT

Conduct disorder in girls: neighborhoods, family characteristics, and parenting behaviors

<p>Abstract</p> <p>Background</p> <p>Little is known about the social context of girls with conduct disorder (CD), a question of increasing importance to clinicians and researchers. The purpose of this study was to examine the associations between three social context domains (neighborhood, family characteristics, and parenting behaviors) and CD in adolescent girls, additionally testing for race moderation effects. We predicted that disadvantaged neighborhoods, family characteristics such as parental marital status, and parenting behaviors such as negative discipline would characterize girls with CD. We also hypothesized that parenting behaviors would mediate the associations between neighborhood and family characteristics and CD.</p> <p>Methods</p> <p>We recruited 93 15–17 year-old girls from the community and used a structured psychiatric interview to assign participants to a CD group (n = 52) or a demographically matched group with no psychiatric disorder (n = 41). Each girl and parent also filled out questionnaires about neighborhood, family characteristics, and parenting behaviors.</p> <p>Results</p> <p>Neighborhood quality was not associated with CD in girls. Some family characteristics (parental antisociality) and parenting behaviors (levels of family activities and negative discipline) were characteristic of girls with CD, but notll. There was no moderation by race. Our hypothesis that the association between family characteristics and CD would be mediated by parenting behaviors was not supported.</p> <p>Conclusion</p> <p>This study expanded upon previous research by investigating multiple social context domains in girls with CD and by selecting a comparison group who were not different in age, social class, or race. When these factors are thus controlled, CD in adolescent girls is not significantly associated with neighborhood, but is associated with some family characteristics and some types of parental behaviors. However, the mechanisms underlying these relationships need to be further investigated. We discuss possible explanations for our findings and suggest directions for future research.</p

The effects of economic deprivation on psychological well-being among the working population of Switzerland

BACKGROUND: The association between poverty and mental health has been widely investigated. There is, however, limited evidence of mental health implications of working poverty, despite its representing a rapidly expanding segment of impoverished populations in many developed nations. In this study, we examined whether working poverty in Switzerland, a country with substantial recent growth among the working poor, was correlated with two dependent variables of interest: psychological health and unmet mental health need. METHODS: This cross-sectional study used data drawn from the first 3 waves (1999–2001) of the Swiss Household Panel, a nationally representative sample of the permanent resident population of Switzerland. The study sample comprised 5453 subjects aged 20–59 years. We used Generalized Estimating Equation models to investigate the association between working poverty and psychological well-being; we applied logistic regression models to analyze the link between working poverty and unmet mental health need. Working poverty was represented by dummy variables indicating financial deficiency, restricted standard of living, or both conditions. RESULTS: After controlling other factors, restricted standard of living was significantly (p < .001) negatively correlated with psychological well-being; it was also associated with approximately 50% increased risk of unmet mental health need (OR = 1.55; 95% CI 1.17 – 2.06). CONCLUSION: The findings of this study contribute to our understanding of the potential psychological impact of material deprivation on working Swiss citizens. Such knowledge may aid in the design of community intervention programs to help reduce the individual and societal burdens of poverty in Switzerland

SN 2010jl: Optical to Hard X-ray Observations Reveal an Explosion Embedded In a Ten Solar Mass Cocoon

Some supernovae (SNe) may be powered by the interaction of the SN ejecta with a large amount of circumstellar matter (CSM). However, quantitative estimates of the CSM mass around such SNe are missing when the CSM material is optically thick. Specifically, current estimators are sensitive to uncertainties regarding the CSM density profile and the ejecta velocity. Here we outline a method to measure the mass of the optically thick CSM around such SNe. We present new visible-light and X-ray observations of SN 2010jl (PTF 10aaxf), including the first detection of an SN in the hard X-ray band using NuSTAR. The total radiated luminosity of SN 2010jl is extreme—at least 9 × 1050 erg. By modeling the visible-light data, we robustly show that the mass of the circumstellar material within ~1016 cm of the progenitor of SN 2010jl was in excess of 10 M☉. This mass was likely ejected tens of years prior to the SN explosion. Our modeling suggests that the shock velocity during shock breakout was ~6000 km s–1, decelerating to ~2600 km s–1 about 2 yr after maximum light. Furthermore, our late-time NuSTAR and XMM spectra of the SN presumably provide the first direct measurement of SN shock velocity 2 yr after the SN maximum light—measured to be in the range of 2000-4500 km s–1 if the ions and electrons are in equilibrium, and ≳2000 km s–1 if they are not in equilibrium. This measurement is in agreement with the shock velocity predicted by our modeling of the visible-light data. Our observations also show that the average radial density distribution of the CSM roughly follows an r–2 law. A possible explanation for the ≳10 M☉ of CSM and the wind-like profile is that they are the result of multiple pulsational pair instability events prior to the SN explosion, separated from each other by years

Biogeochemical and climate drivers of wetland phosphorus and nitrogen release: implications for nutrient legacies and eutrophication risk

The dynamics and processes of nutrient cycling and release were examined for a lowland wetland‐pond system, draining woodland in southern England. Hydrochemical and meteorological data were analyzed from 1997 to 2017, along with high‐resolution in situ sensor measurements from 2016 to 2017. The results showed that even a relatively pristine wetland can become a source of highly bioavailable phosphorus (P), nitrogen (N), and silicon (Si) during low‐flow periods of high ecological sensitivity. The drivers of nutrient release were primary production and accumulation of biomass, which provided a carbon (C) source for microbial respiration and, via mineralization, a source of bioavailable nutrients for P and N co‐limited microorganisms. During high‐intensity nutrient release events, the dominant N‐cycling process switched from denitrification to nitrate ammonification, and a positive feedback cycle of P and N release was sustained over several months during summer and fall. Temperature controls on microbial activity were the primary drivers of short‐term (day‐to‐day) variability in P release, with subdaily (diurnal) fluctuations in P concentrations driven by water body metabolism. Interannual relationships between nutrient release and climate variables indicated “memory” effects of antecedent climate drivers through accumulated legacy organic matter from the previous year's biomass production. Natural flood management initiatives promote the use of wetlands as “nature‐based solutions” in climate change adaptation, flood management, and soil and water conservation. This study highlights potential water quality trade‐offs and shows how the convergence of climate and biogeochemical drivers of wetland nutrient release can amplify background nutrient signals by mobilizing legacy nutrients, causing water quality impairment and accelerating eutrophication risk

Inositol 1,4,5-Trisphosphate Signalling Regulates the Avoidance Response to Nose Touch in Caenorhabditis elegans

When Caenorhabditis elegans encounters an unfavourable stimulus at its anterior, it responds by initiating an avoidance response, namely reversal of locomotion. The amphid neurons, ASHL and ASHR, are polymodal in function, with roles in the avoidance responses to high osmolarity, nose touch, and both volatile and non-volatile repellents. The mechanisms that underlie the ability of the ASH neurons to respond to such a wide range of stimuli are still unclear. We demonstrate that the inositol 1,4,5-trisphosphate receptor (IP3R), encoded by itr-1, functions in the reversal responses to nose touch and benzaldehyde, but not in other known ASH-mediated responses. We show that phospholipase Cβ (EGL-8) and phospholipase Cγ (PLC-3), which catalyse the production of IP3, both function upstream of ITR-1 in the response to nose touch. We use neuron-specific gene rescue and neuron-specific disruption of protein function to show that the site of ITR-1 function is the ASH neurons. By rescuing plc-3 and egl-8 in a neuron-specific manner, we show that both are acting in ASH. Imaging of nose touch–induced Ca2+ transients in ASH confirms these conclusions. In contrast, the response to benzaldehyde is independent of PLC function. Thus, we have identified distinct roles for the IP3R in two specific responses mediated by ASH