The Role of FMRP in Ethanol-Induced Homeostatic Plasticity in the Hippocampus

Exposure to chronic ethanol induces homeostatic alterations in glutamatergic signaling and actin polymerization that may have an important role in the development of ethanol-seeking behaviors. Acute ethanol exposure promotes excitation and dampens inhibition while extended periods of exposure induce long-term adaptations in neuronal function that require new protein synthesis to maintain homeostasis. These adaptations include not only transcription and somatic protein synthesis, but also local dendritic protein translation. One of the major mediators of activity-dependent translation is the mTORC1 signaling pathway and its downstream substrates that include kinases and mRNA-binding proteins, such as p70 S6 kinase 1 (S6K1) and fragile X mental retardation protein (FMRP). FMRP is an mRNA-binding protein that interacts with mRNAs to suppress translation. FMRP also interacts with several different mRNAs that code for proteins that are necessary for synaptic plasticity, and it may also have an important role in regulating ethanol-induced alterations in homeostasis in dendrites and dendritic spines. This dissertation addresses the hypothesis that FMRP is necessary for activity-dependent homeostatic alterations in protein expression and spine morphology following chronic ethanol exposure. First, western blot analysis was used to investigate ethanol-induced alterations in expression of FMRP and proteins that are key mediators of dendritic excitability. These studies revealed an increase in FMRP phosphorylation as well as alterations in the A-type K+-channel Kv4.2, KChIP3 and NMDA receptor subunits. Further studies examining changes in FMRP interactions with Kv4.2, KChIP3, and NMDA mRNAs showed chronic ethanol-induced changes in FMRP-mRNA binding. Additionally, inhibition of FMRP phosphorylation prevented these alterations in protein expression and FMRP-mRNA interactions following chronic ethanol exposure. Studies included in this dissertation also addressed whether alterations in protein expression are accompanied by changes in actin polymerization and spine morphology. These experiments utilized two different sub-strains of C57BL/6 mice with different polymorphisms in cyfip2, a protein regulating actin polymerization that is also implicated in regulation of protein translation. A two-bottle choice/CIE exposure paradigm revealed alterations in ethanol consumption between the two strains as well as differences in ethanol-induced changes in protein expression and spine morphology. Taken together, this dissertation reveals an integral role for FMRP in mediating ethanol-induced alterations in homeostatic protein expression, and that these alterations may influence actin polymerization and drinking behaviors

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient\u27s progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. ©2017 AACR

Burden of injury along the development spectrum: Associations between the socio-demographic Index and disability-adjusted life year estimates from the global burden of disease study 2017

Background: The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates.Methods: Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm-the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate.Results: For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced.Conclusions: The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum

Girls Are Good At STEM: Opening Minds And Providing Evidence Reduce Boys\u27 Stereotyping Of Girls\u27 STEM Ability

Girls and women face persistent negative stereotyping within STEM (science, technology, engineering, mathematics). This field intervention was designed to improve boys\u27 perceptions of girls\u27 STEM ability. Boys (N = 667; mostly White and East Asian) aged 9-15 years in Canadian STEM summer camps (2017-2019) had an intervention or control conversation with trained camp staff. The intervention was a multi-stage persuasive appeal: a values affirmation, an illustration of girls\u27 ability in STEM, a personalized anecdote, and reflection. Control participants discussed general camp experiences. Boys who received the intervention (vs. control) had more positive perceptions of girls\u27 STEM ability, d = 0.23, an effect stronger among younger boys. These findings highlight the importance of engaging elementary-school-aged boys to make STEM climates more inclusive

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

Population distribution and burden of acute gastrointestinal illness in British Columbia, Canada

BACKGROUND: In developed countries, gastrointestinal illness (GI) is typically mild and self-limiting, however, it has considerable economic impact due to high morbidity. METHODS: The magnitude and distribution of acute GI in British Columbia (BC), Canada was evaluated via a cross-sectional telephone survey of 4,612 randomly selected residents, conducted from June 2002 to June 2003. Respondents were asked if they had experienced vomiting or diarrhoea in the 28 days prior to the interview. RESULTS: A response rate of 44.3% was achieved. A monthly prevalence of 9.2% (95%CI 8.4 – 10.0), an incidence rate of 1.3 (95% CI 1.1–1.4) episodes of acute GI per person-year, and an average probability that an individual developed illness in the year of 71.6% (95% CI 68.0–74.8), weighted by population size were observed. The average duration of illness was 3.7 days, translating into 19.2 million days annually of acute GI in BC. CONCLUSION: The results corroborate those from previous Canadian and international studies, highlighting the substantial burden of acute GI

TESS discovery of a super-Earth and two sub-Neptunes orbiting the bright, nearby, Sun-like star HD 22946

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of a three-planet system around the bright Sun-like star HD~22946(V=8.3 mag),also known as TIC~100990000, located 63 parsecs away.The system was observed by TESS in Sectors 3, 4, 30 and 31 and two planet candidates, labelled TESS Objects of Interest (TOIs) 411.01 (planet $c$) and 411.02 (planet $b$), were identified on orbits of 9.57 and 4.04 days, respectively. In this work, we validate the two planets and recover an additional single transit-like signal in the light curve, which suggests the presence of a third transiting planet with a longer period of about 46 days.We assess the veracity of the TESS transit signals and use follow-up imaging and time series photometry to rule out false positive scenarios, including unresolved binary systems, nearby eclipsing binaries or background/foreground stars contaminating the light curves. Parallax measurements from Gaia EDR3, together with broad-band photometry and spectroscopic follow-up by TFOP allowed us to constrain the stellar parameters of TOI-411, including its radius of$1.157\pm0.025R_\odot$. Adopting this value, we determined the radii for the three exoplanet candidates and found that planet $b$ is a super-Earth, with a radius of $1.72\pm0.10R_\oplus$, while planet $c$ and $d$ are sub-Neptunian planets, with radii of$2.74\pm0.14R_\oplus$ and $3.23\pm0.19R_\oplus$ respectively. By using dynamical simulations, we assessed the stability of the system and evaluated the possibility of the presence of other undetected, non-transiting planets by investigating its dynamical packing. We find that the system is dynamically stable and potentially unpacked, with enough space to host at least one more planet between $c$ and $d$.(Abridged)Comment: 21 pages, 12 figures. Accepted for publication on A&

Genetic Testing for Early Detection of Individuals at Risk of Coronary Heart Disease and Monitoring Response to Therapy: Challenges and Promises

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient’s lifetime, can help guide therapy selection, and may be of utility in family counseling

The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): illuminating the functional diversity of eukaryotic life in the oceans through transcriptome sequencing

International audienceCurrent sampling of genomic sequence data from eukaryotes is relatively poor, biased, and inadequate to address important questions about their biology, evolution, and ecology; this Community Page describes a resource of 700 transcriptomes from marine microbial eukaryotes to help understand their role in the world's oceans

Power efficiency of outer hair cell somatic electromotility

© 2009 Rabbitt et al. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS Computational Biology 5 (2009): e1000444, doi:10.1371/journal.pcbi.1000444.Cochlear outer hair cells (OHCs) are fast biological motors that serve to enhance the vibration of the organ of Corti and increase the sensitivity of the inner ear to sound. Exactly how OHCs produce useful mechanical power at auditory frequencies, given their intrinsic biophysical properties, has been a subject of considerable debate. To address this we formulated a mathematical model of the OHC based on first principles and analyzed the power conversion efficiency in the frequency domain. The model includes a mixture-composite constitutive model of the active lateral wall and spatially distributed electro-mechanical fields. The analysis predicts that: 1) the peak power efficiency is likely to be tuned to a specific frequency, dependent upon OHC length, and this tuning may contribute to the place principle and frequency selectivity in the cochlea; 2) the OHC power output can be detuned and attenuated by increasing the basal conductance of the cell, a parameter likely controlled by the brain via the efferent system; and 3) power output efficiency is limited by mechanical properties of the load, thus suggesting that impedance of the organ of Corti may be matched regionally to the OHC. The high power efficiency, tuning, and efferent control of outer hair cells are the direct result of biophysical properties of the cells, thus providing the physical basis for the remarkable sensitivity and selectivity of hearing.This work was supported by NIDCD R01 DC04928 (Rabbitt), NIDCD R01 DC00384 (Brownell) and NASA Ames GSRA56000135 (Breneman)