27 research outputs found
12-h clock regulation of genetic information flow by XBP1s
© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Pan, Y., Ballance, H., Meng, H., Gonzalez, N., Kim, S., Abdurehman, L., York, B., Chen, X., Schnytzer, Y., Levy, O., Dacso, C. C., McClung, C. A., O'Malley, B. W., Liu, S., & Zhu, B. 12-h clock regulation of genetic information flow by XBP1s. Plos Biology, 18(1), (2020): e3000580, doi:10.1371/journal.pbio.3000580.Our group recently characterized a cell-autonomous mammalian 12-h clock independent from the circadian clock, but its function and mechanism of regulation remain poorly understood. Here, we show that in mouse liver, transcriptional regulation significantly contributes to the establishment of 12-h rhythms of mRNA expression in a manner dependent on Spliced Form of X-box Binding Protein 1 (XBP1s). Mechanistically, the motif stringency of XBP1s promoter binding sites dictates XBP1sâs ability to drive 12-h rhythms of nascent mRNA transcription at dawn and dusk, which are enriched for basal transcription regulation, mRNA processing and export, ribosome biogenesis, translation initiation, and protein processing/sorting in the Endoplasmic Reticulum (ER)-Golgi in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). We further identified GA-binding proteins (GABPs) as putative novel transcriptional regulators driving 12-h rhythms of gene expression with more diverse phases. These 12-h rhythms of gene expression are cell autonomous and evolutionarily conserved in marine animals possessing a circatidal clock. Our results demonstrate an evolutionarily conserved, intricate network of transcriptional control of the mammalian 12-h clock that mediates diverse biological pathways. We speculate that the 12-h clock is coopted to accommodate elevated gene expression and processing in mammals at the two rush hours, with the particular genes processed at each rush hour regulated by the circadian and/or tissue-specific pathways.This study was supported by the American Diabetes Association junior faculty development award 1-18-JDF-025 to B.Z., by funding from National Institute of Health HD07879 and 1P01DK113954 to B.W.O, by funding from National Science Foundation award 1703170 to C.C.D. and B.Z., and by funding from Brockman Foundation to C.C.D and B.W.O. This work was further supported by the UPMC Genome Center with funding from UPMCâs Immunotherapy and Transplant Center. This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Research reported in this publication was further supported by the National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under award number P30DK120531 to Pittsburgh Liver Research Center, in which both S.L. and B.Z. are members. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Examining Implicit Attitudes towards Exercisers with a Physical Disability
Background. Using measures of explicit attitudes, physical activity status has been established as a factor that reduces the stigma able-bodied people hold towards people with physical disabilities. This phenomenon is called the exerciser stereotype. However, whether the exerciser stereotype exists when using measures of implicit attitudes remains unknown. Objective. The aims of this study were to evaluate the prevalence of negative implicit attitudes towards people with physical disabilities and determine whether implicit attitudes towards people with physical disabilities were influenced by the exerciser stereotype. Methods. One hundred able-bodied participants (82 females, 18 males) completed two implicit association tests (IATs): the Disability-Attitudes IAT and the Disability-Activity IAT. The Disability-Attitudes IAT measured implicit attitudes towards people who were not disabled relative to disabled; the Disability-Activity IAT measured attitudes towards people with a physical disability who were active relative to inactive. Results. Results revealed that 83.8% of participants had negative implicit attitudes towards people with a disability. Participants held more positive attitudes towards active versus inactive people with a physical disability. Conclusions. The study findings indicate that the exerciser stereotype exists implicitly and may undermine negative attitudes towards people with physical disabilities
Scn1b deletion in adult mice results in seizures and SUDEP
Pathogenic lossĂą ofĂą function variants in SCN1B are linked to Dravet syndrome (DS). Previous work suggested that neuronal pathfinding defects underlie epileptogenesis and SUDEP in the Scn1b null mouse model of DS. We tested this hypothesis by inducing Scn1b deletion in adult mice that had developed normally. Epilepsy and SUDEP, which occur by postnatal day 21 in Scn1b null animals, were observed within 20ĂÂ days of induced Scn1b deletion in adult mice, suggesting that epileptogenesis in SCN1BĂą DS does not result from defective brain development. Thus, the developmental brain defects observed previously in Scn1b null mice may model other coĂą morbidities of DS.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149575/1/acn3785.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149575/2/acn3785_am.pd
Incidence and Symptoms of High Altitude Illness in South Pole Workers: Antarctic Study of Altitude Physiology (ASAP)
Introduction Each year, the US Antarctic Program rapidly transports scientists and support personnel from sea level (SL) to the South Pole (SP, 2835 m) providing a unique natural laboratory to quantify the incidence of acute mountain sickness (AMS), patterns of altitude related symptoms and the field effectiveness of acetazolamide in a highly controlled setting. We hypothesized that the combination of rapid ascent (3 hr), accentuated hypobarism (relative to altitude), cold, and immediate exertion would increase altitude illness risk. Methods Medically screened adults (N = 246, age = 37 ± 11 yr, 30% female, BMI = 26 ± 4 kg/m 2 ) were recruited. All underwent SL and SP physiological evaluation, completed Lake Louise symptom questionnaires (LLSQ, to define AMS), and answered additional symptom related questions (eg, exertional dyspnea, mental status, cough, edema and general health), during the 1st week at altitude. Acetazolamide, while not mandatory, was used by 40% of participants. Results At SP, the barometric pressure resulted in physiological altitudes that approached 3400 m, while T ° C averaged -42, humidity 0.03%. Arterial oxygen saturation averaged 89% ± 3%. Overall, 52% developed LLSQ defined AMS. The most common symptoms reported were exertional dyspnea-(87%), sleeping difficulty-(74%), headache-(66%), fatigue-(65%), and dizziness/lightheadedness-(46%). Symptom severity peaked on days 1-2, yet in >20% exertional dyspnea, fatigue and sleep problems persisted through day 7. AMS incidence was similar between those using acetazolamide and those abstaining (51 vs. 52%, P = 0.87). Those who used acetazolamide tended to be older, have less altitude experience, worse symptoms on previous exposures, and less SP experience. Conclusion The incidence of AMS at SP tended to be higher than previously reports in other geographic locations at similar altitudes. Thus, the SP constitutes a more intense altitude exposure than might be expected considering physical altitude alone. Many symptoms persist, possibly due to extremely cold, arid conditions and the benefits of acetazolamide appeared negligible, though it may have prevented more severe symptoms in higher risk subjects
The impact of a physician detailing and sampling program for generic atorvastatin: an interrupted time series analysis
Life and death in the Chicxulub impact crater: a record of the PaleoceneâEocene Thermal Maximum
latitudes, with sea surface temperatures at some localities exceeding the 35ââC at which marine organisms experience heat stress. Relatively few equivalent terrestrial sections have been identified, and the response of land plants to this extreme heat is still poorly understood. Here, we present a new record of the PETM from the peak ring of the Chicxulub impact crater that has been identified based on nannofossil biostratigraphy, an acme of the dinoflagellate genus Apectodinium, and a negative carbon isotope excursion. Geochemical and microfossil proxies show that the PETM is marked by elevated TEXH86-based sea surface temperatures (SSTs) averaging âŒ37.8ââC, an increase in terrestrial input and surface productivity, salinity stratification, and bottom water anoxia, with biomarkers for green and purple sulfur bacteria indicative of photic zone euxinia in the early part of the event. Pollen and plants spores in this core provide the first PETM floral assemblage described from Mexico, Central America, and the northern Caribbean. The source area was a diverse coastal shrubby tropical forest with a remarkably high abundance of fungal spores, indicating humid conditions. Thus, while seafloor anoxia devastated the benthic marine biota and dinoflagellate assemblages were heat-stressed, the terrestrial plant ecosystem thrived
A further examination of the lexical-processing stages hypothesized by the E-Z Reader model
Proteome specialization of anaerobic fungi during ruminal degradation of recalcitrant plant fiber
publishedVersio
Electronic health record tools to assist with childrenâs insurance coverage: a mixed methods study
Abstract Background Children with health insurance have increased access to healthcare and receive higher quality care. However, despite recent initiatives expanding childrenâs coverage, many remain uninsured. New technologies present opportunities for helping clinics provide enrollment support for patients. We developed and tested electronic health record (EHR)-based tools to help clinics provide childrenâs insurance assistance. Methods We used mixed methods to understand tool adoption, and to assess impact of tool use on insurance coverage, healthcare utilization, and receipt of recommended care. We conducted intent-to-treat (ITT) analyses comparing pediatric patients in 4 intervention clinics (nâ=â15,024) to those at 4 matched control clinics (nâ=â12,227). We conducted effect-of-treatment-on-the-treated (ETOT) analyses comparing intervention clinic patients with tool use (nâ=â2240) to intervention clinic patients without tool use (nâ=â12,784). Results Tools were used for only 15% of eligible patients. Qualitative data indicated that tool adoption was limited by: (1) concurrent initiatives that duplicated the work associated with the tools, and (2) inability to obtain accurate insurance coverage data and end dates. The ITT analyses showed that intervention clinic patients had higher odds of gaining insurance coverage (adjusted odds ratio [aOR]â=â1.32, 95% confidence interval [95%CI] 1.14â1.51) and lower odds of losing coverage (aORâ=â0.77, 95%CI 0.68â0.88), compared to control clinic patients. Similarly, ETOT findings showed that intervention clinic patients with tool use had higher odds of gaining insurance (aORâ=â1.83, 95%CI 1.64â2.04) and lower odds of losing coverage (aORâ=â0.70, 95%CI 0.53â0.91), compared to patients without tool use. The ETOT analyses also showed higher rates of receipt of return visits, well-child visits, and several immunizations among patients for whom the tools were used. Conclusions This pragmatic trial, the first to evaluate EHR-based insurance assistance tools, suggests that it is feasible to create and implement tools that help clinics provide insurance enrollment support to pediatric patients. While ITT findings were limited by low rates of tool use, ITT and ETOT findings suggest tool use was associated with better odds of gaining and keeping coverage. Further, ETOT findings suggest that use of such tools may positively impact healthcare utilization and quality of pediatric care. Trial registration ClinicalTrials.gov, NCT02298361; retrospectively registered on November 5, 2014