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G3BP, vigilin and TSC2 colocalize in stress granules.

Selected list of putative interacting TSC2 partners identified by yeast 2-hybrid analysis.

Tuberous sclerosis complex (TSC) is caused by mutations of either the TSC1 or TSC2 tumor suppressor gene. TSC causes tumors of the brain, heart, kidney, skin and lymphangioleiomyomatosis (LAM). Here we report that the TSC2 protein physically binds to high-density lipoprotein binding protein (HDLBP), also called vigilin, a core stress granule (SG) protein, and that TSC2 localizes to SGs. SGs contain mRNAs and translation initiation complexes, and regulate gene expression by sequestering specific transcripts, thereby serving a cytoprotective role. TSC2 has never before been shown to localize to SGs and knocking down vigilin impacts SG translocation of TSC2. TSC2-deficient cells showed a striking increase in the number of SGs after thermal shock and arsenite treatment relative to Tsc2-expressing cells. Our findings also show that murine kidney lysates from a model of TSC have increased levels of SG components including G3BP1 and Caprin1. G3BP1 and Caprin are elevated in renal angiomyolipomas (a renal tumor common in patients with TSC) compared with control normal kidney. G3BP1 is also elevated in TSC-associated subependymal giant cell astrocytomas. We found that genetic inhibition of G3BP1 inhibits the proliferation of TSC2-deficient cells in vitro. Finally, in a mouse model of TSC, genetic inhibition of SGs suppresses cell growth, suggesting that targeting SGs may have efficacy in the therapy of TSC.Implications:This study demonstrates that TSC2 physically interacts with HDLBP/vigilin, a component of SGs, that TSC2 localizes to SG and that TSC2-deficient cells have more SGs, suggesting that SGs represent a novel therapeutic target in TSC.

Biogenesis of different classes of eukaryotic RNAs proceeds via different pathways that require strict spatiotemporal resolution. The intracellular organization has evolved to provide order for RNA processing to coordinate different maturation steps with specific enzymatic reaction. In higher eukaryotes, processing of transfer RNAs (tRNAs) is postulated to be almost entirely intranuclear, while in lower eukaryotes like yeast, tRNA maturation is both nuclear and cytoplasmic. Here, we show that tRNA processing is largely cytosolic event in human cells. After transcription, unprocessed precursors of tRNAs (pre-tRNAs) bound by La protein are exported from the nucleus into the cytoplasm. Using cell fractionation analysis and pre-tRNA-specific fluorescence in situ hybridization (FISH) protocol, we show tRNA splicing/ligation and end-processing takes place in the cytoplasm where majority of processing enzymes is also located. We propose here a model where processing of intron-less and intron-containing pre-tRNAs is cytoplasmic similarly to the observed in lower eukaryotes, although tRNA splicing precedes 5’- and 3’-end processing in human cells unlike in yeast.

Although racial and ethnic identities are associated with a multitude of disparate medical outcomes, surveillance of these subpopulations in the occupational clinic setting could benefit enormously from a more detailed and nuanced recognition of racial and ethnic identity.The research group designed a brief questionnaire to capture several dimensions of this identity and collected data from patients seen for work-related conditions in four occupational medicine clinics from May 2019 through March 2020. Responses were used to calculate the sensitivity and specificity of extant racial/ethnic identity data within our electronic health records system, and were compared to participants' self-reported industry and occupation, coded according to North American Industry Classification System and Standard Occupational Classification System listings.Our questionnaire permitted collection of data that defined our patients' specific racial/ethnic identity with far greater detail, identified patients with multiple ethnic identities, and elicited their preferred language. Response rate was excellent (94.2%, n = 773). Non-White participants frequently selected a racial/ethnic subcategory (78.1%-92.2%). Using our race/ethnicity data as a referent, the electronic health record (EHR) had a high specificity (87.1%), widely variable sensitivity (11.8%-82.2%), and poorer response rates (75.1% for race, 82.5% for ethnicity, as compared to 93.8% with our questionnaire). Additional analyses revealed some industries and occupations disproportionately populated by patients of particular racial/ethnic identities.Our project demonstrates the usefulness of a questionnaire which more effectively identifies racial/ethnic subpopulations in an occupational medicine clinic, permitting far more detailed characterization of their occupations, industries, and diagnoses.

Background Minnesota has an ethnically diverse labor force, with the largest number of refugees per capita in the United States. In recent years, Minnesota has been and continues to be a major site for immigrant and refugee resettlement in the United States, with a large population of both immigrant and native born Hmong, Hispanic, and East Africans. This study seeks to evaluate the injury risk among the evolving minority workforce in the Minnesota Twin Cities region. Methods A retrospective cohort study identifying work-related injuries following pre-employment examinations was performed using electronic health records from a large multi-clinic occupational medicine practice. Preplacement examinations and subsequent work-related injuries were pulled from the electronic health record using representative ICD-10 codes for surveillance examinations and injuries. This study included patient records collected over a 2-year period from January 1, 2015, through December, 2016. The patients in this cohort worked in a wide-array of occupations including production, assembly, construction, law enforcement, among others. Results Hispanic minority workers were twice as likely to be injured at work compared with White workers. Hispanics were 2.89 times more likely to develop back injuries compared with non-Hispanic workers, and 1.86 times more likely to develop upper extremity injuries involving the hand, wrist, or elbow. Conclusion Clinical practice data shows that Hispanic workers are at increased risk for work-related injuries in Minnesota. They were especially susceptible to back and upper extremity injuries. Lower injury rates in non-Hispanic minority workers, may be the result of injury underreporting and require further investigation.

Introduction The purpose of this study was to identify the predictors of personal flotation device (PFD) use among workers in the Alaska commercial fishing industry. Methods This study analyzed data from a questionnaire administered to fishing industry workers on four types of commercial fishing vessels in Alaska. Workers' risk perceptions of falling overboard, attitudes regarding PFDs, and other factors were compared using Chi-square tests. A forward stepwise procedure was used to fit multivariate logistic regression models predicting PFD use. Results PFD usage ranged from 0% reporting always using a PFD among longliners to 51% among trawlers. Among the statistically significant predictors of PFD use identified in multivariate models, the belief that PFDs were an entanglement hazard was inversely associated with any use of PFDs among longliners (OR 0.38; 95% CI: 0.20, 0.73) and gillnetters (OR 0.38; 95% CI: 0.19, 0.76). The belief that PFDs interfered with work was inversely associated with high use of PFDs among crabbers (OR 0.16; 95% CI: 0.06, 0.45) and with always using PFDs among trawlers (OR 0.35; 95% CI: 0.16, 0.78). Other significant predictors were specific to each vessel type. Conclusions Interventions to increase PFD use in the fishing industry should be tailored to each vessel type and focus on addressing the significant barriers to PFD use. Workers may increase PFD usage if they are familiarized with newer PFDs that have been tested and accepted by their peers.

Nicole M Herman,1 Diane E Grill,2 Paul J Anderson,1 Andrew D Miller,1 Jacob B Johnson,1 Kathy A O’Malley,1 Maile L Ceridon Richert,1 Bruce D Johnson1 1Department of Cardiovascular Diseases, 2Department of Biostatistics, Mayo Clinic Rochester, MN, USA Abstract: Although mechanisms of high altitude illness have been studied extensively, the processes behind the development of these conditions are still unclear. Few genome-wide studies on rapid exposure to high altitude have been performed. Each year, scientists and support workers are transferred by plane from McMurdo Station in Antarctica (sea level) to the Amundsen-Scott South Pole Station at 2,835 meters. This uniform and rapid transfer to altitude provides a unique opportunity to study the effects of hypobaric hypoxia on gene expression that may help illustrate the body's adaptations to these conditions. We hypothesized that an extensive number of genes would change with rapid exposure to altitude and further expected that these genes would correspond to inflammatory pathways proposed as a mechanism in development of acute mountain sickness. Peripheral venous blood samples were drawn from 98 healthy subjects at sea level and again on day two at altitude. Microarray analysis was performed on these samples. In total, 1,118 probe sets with significant P-values and fold changes (90% upregulated) were identified and entered into MetaCore™ software. Several pathways, including oxidative phosphorylation, cytoskeleton remodeling, and platelet aggregation, were significantly represented by the data set and all were upregulated. Many genes changed expression, and the vast majority of these increased. Increased metabolism in peripheral blood mononuclear cells suggests increased inflammatory activity. Keywords: peripheral blood mononuclear cells, microarray, gene expression, acute mountain sickness

A shift in ocean climate during the late 1970s triggered a reorganization of community structure in the Gulf of Alaska ecosystem, as evidenced in changing catch composi- tion on long-term (1953-1997) small-mesh trawl surveys. Forage species such as pandalid shrimp and capelin declined because of recruitment failure and predation, and populations have not yet recovered. Total trawl catch biomass declined > 50% and remained low through the 1980s. In contrast, recruitment of high trophic-level groundfish improved during the 1980s, yielding a > 250% increase in catch biomass during the 1990s. This trophic reorganization apparently had negative effects on piscivorus sea birds and marine mammals.

Background . Many nations routinely include health impact assessments (HIA) in public policy decisions. Institutionalization of HIA formally integrates health considerations into a governmental decision-making process. We describe an example of institutionalization in the United States through Alaska's early experience with institutionalization of HIA. Literature review . HIA arose from a series of health conferences in the 1970s that affirmed the importance of “health for all.” A number of key milestones eventually defined HIA as a unique field of impact assessment. There are several approaches to institutionalization, and one common approach in the United States is through the National Environmental Policy Act (NEPA). NEPA formed the basis for the earliest HIAs in Alaska. Program description . Early HIAs in Alaska led to conferences, working groups, a state guidance document and the institutionalization of a HIA program within the Department of Health and Social Services in 2010. A medical epidemiologist staffs the program, which utilizes contractors to meet rising demand for HIA. The HIA program has sustainable funding from the state budget and from the state's natural resource permitting process. The HIA document is the main deliverable, but the program performs other tasks, including fieldwork and technical reviews. The HIA program works closely with a host of collaborative partners. Conclusion . Alaska's institutionalized HIA program benefits from sustainable funding that promotes continuous quality improvement and involves the program in the entire life cycle of a development project. The program structure adapts well to variations in workflow and supports a host of quality control activities. Currently, the program focuses on HIAs for natural resource development projects. Keywords: health impact assessment; institutionalization; Alaska (Published: 5 August 2013) This paper is part of Supplement 1, 2013, ICCH15 Proceedings . More papers from this Supplement can be found here . Citation: Int J Circumpolar Health 2013, 72 : 22101 - http://dx.doi.org/10.3402/ijch.v72i0.22101

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/m2) 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.

We have previously reported results for treatment of adenocarcinomas and squamous cell carcinomas of the mid and distal esophagus as well as the use of intraluminal high-dose rate radiation (HDR-RT) for palliation of carcinoma of the esophagus. In this report we describe the results of a chemotherapy/HDR-RT/esophagectomy management program. Examination of the surgical specimens revealed a complete response in only 13% of patients and locoregional recurrence was disappointing. There were no operative deaths nor were there major complications attributable to the preoperative treatment. Two-year survival was 33%, only slightly better than that previously achieved by us with either primary surgery or primary external beam radiation among “curative” candidates with locoregional disease. HDR in combination with our selected chemotherapy regimen is insufficient for locoregional control and must be supplemented either by esophagectomy or external beam radiation for even modest long-term survival. © 1993 Wiley-Liss, Inc.

There is an increasing challenge for chemical industry and research institutions to find cost-efficient and environmentally sound methods of converting natural resources into fuels chemicals and energy. Catalysts are essential to these processes and the Catalysis Specialist Periodical Report series serves to highlight major developments in this area. This series provides systematic and detailed reviews of topics of interest to scientists and engineers in the catalysis field. The coverage includes all major areas of heterogeneous and homogeneous catalysis and also specific applications of catalysis such as NOx control kinetics and experimental techniques such as microcalorimetry. Each chapter is compiled by recognised experts within their specialist fields and provides a summary of the current literature. This series will be of interest to all those in academia and industry who need an up-to-date critical analysis and summary of catalysis research and applications. Catalysis will be of interest to anyone working in academia and industry that needs an up-to-date critical analysis and summary of catalysis research and applications. Specialist Periodical Reports provide systematic and detailed review coverage in major areas of chemical research. Compiled by teams of leading experts in their specialist fields, this series is designed to help the chemistry community keep current with the latest developments in their field. Each volume in the series is published either annually or biennially and is a superb reference point for researchers. www.rsc.org/spr

Three independent autopsy samples of brains without apparent neuropathology were studied to ascertain whether there was sexual dimorphism in the human corpus callosum (CC). Using planimetric measurements on midsagittal brain sections, several morphometric features of the CC were studied: total callosal area, maximum dorsoventral splenial width, the posterior one fifth of the total area of the CC (mostly splenium), and brain weight. Ratio data correcting for brain size were also studied. In all samples, absolute brain size was larger in males, and significantly so. Measurements of splenial dorsoventral width were higher in females than males, but not significantly, except in the Australian sample. Total callosal area was absolutely higher in the Australian female sample than in males, and almost equal in the two American samples, without statistically significant differences. The posterior one-fifth area (splenium) was larger for females in each of the samples. The variables which were corrected for brain size were usually significantly larger in females, although this pattern varied in each sample. The statistical pattern of sexual dimorphism for the human CC differs from that found in most other neural structures, such as the amygdaloid nucleus, cerebellum, hippocampus, and thalamus. The absolute sizes of these structures are always significantly larger in males. When corrected for brain size, the relative sizes are not significantly larger. The CC is the only structure to show a larger set of relative measures in females.