The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex

Phosphoinositide (PI) 3-kinase is required for most insulin and insulin-like growth factor (IGF) 1–dependent cellular responses. The p85 regulatory subunit of PI 3-kinase is required to mediate the insulin-dependent recruitment of PI 3-kinase to the plasma membrane, yet mice with reduced p85 expression have increased insulin sensitivity. To further understand the role of p85, we examined IGF-1–dependent translocation of p85α by using a green fluorescence protein (GFP)–tagged p85α (EGFP–p85α). In response to IGF-1, but not to PDGF signaling, EGFP–p85α translocates to discrete foci in the cell. These foci contain the insulin receptor substrate (IRS) 1 adaptor molecule, and their formation requires the binding of p85 to IRS-1. Surprisingly, monomeric p85 is preferentially localized to these foci compared with the p85–p110 dimer, and these foci are not sites of phosphatidylinositol-3,4,5-trisphosphate production. Ultrastructural analysis reveals that p85–IRS-1 foci are cytosolic protein complexes devoid of membrane. These results suggest a mechanism of signal down-regulation of IRS-1 that is mediated by monomeric p85 through the formation of a sequestration complex between p85 and IRS-1

Dissemination of Evidence-based Atypical Antipsychotic Information to Nursing Homes

Background: Accumulating evidence demonstrates minimal benefit and increased risk of off-label use of atypical antipsychotic medications for dementia-related behaviors. Optimal strategy for disseminating evidence-based guides to nursing home (NH) stakeholders is unclear. Our objective is to describe the impact of differing dissemination efforts in Connecticut NHs. Methods: Forty-three Connecticut NHs were randomized to one of 3 arms receiving incrementally intensive dissemination strategies of the Agency for Healthcare Research and Quality Comparative Effectiveness Review Summary Guide on the off-label use of atypical antipsychotic drugs, which was included in a toolkit informed by a needs assessment of NHs. All NHs received the paper-based toolkit and notifications regarding the online toolkit. Additionally, Arm 2 received individualized quarterly audit and feedback reports with atypical antipsychotic prescribing rates; Arm 3 received in-person educational visits and audit and feedback reports. Toolkit reach was assessed using interviews with NH leadership and staff. Online toolkit use was assessed using Google analytics. Results: Eighty leaders and 222 direct care staff were interviewed. Leadership and direct care staff in Arm 3 NHs were more likely to be familiar with the toolkit that those in Arm 1 (p=0.008) and Arm 2 (p Conclusions: Intensive dissemination, using multi-pronged approach including academic detailing and direct care staff trainings, appeared to be associated with higher familiarity with paper-based toolkit, but not Internet-based use of the toolkit in the NH setting

Discovery and Implications of C₂ and C₃ Perfluoroalkyl Sulfonates in Aqueous Film-Forming Foams and Groundwater

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.Historically, 3M aqueous film-forming foams (AFFFs) were released at U.S. military and civilian sites to extinguish hydrocarbon-based fuel fires. To date, only C₄–C₁₀ homologues of the perfluoroalkyl sulfonic acids (PFSAs) are documented in 3M AFFFs. Perfluoroethanesulfonate (PFEtS) and perfluoropropanesulfonate (PFPrS), two ultra-short-chain PFSAs, were discovered by liquid chromatography (LC) quadrupole time-of-flight mass spectrometry. Once they were identified, PFEtS and PFPrS were then quantified in five 3M AFFFs and in one groundwater sample from each of 11 U.S. military bases by LC tandem mass spectrometry. Concentrations of PFEtS and PFPrS in the five AFFFs ranged from 7 to 13 mg/L and from 120 to 270 mg/L, respectively. For the groundwater, PFEtS was quantified in 8 of the 11 samples (11–7500 ng/L) and PFPrS in all samples (19–63000 ng/L). The high water solubility, mobility, and detection frequency of these ultra-short-chain PFSAs indicate that groundwater contaminant plumes may be larger than previously believed, and their removal by conventional activated carbon will be challenging

Differential Gene Expression in Primary Breast Tumors Associated with Lymph Node Metastasis

Lymph node status remains one of the most useful prognostic indicators in breast cancer; however, current methods to assess nodal status disrupt the lymphatic system and may lead to secondary complications. Identification of molecular signatures discriminating lymph node-positive from lymph node-negative primary tumors would allow for stratification of patients requiring surgical assesment of lymph nodes. Primary breast tumors from women with negative (n = 41) and positive (n = 35) lymph node status matched for possible confounding factors were subjected to laser microdissection and gene expression data generated. Although ANOVA analysis (P < .001, fold-change >1.5) revealed 13 differentially expressed genes, hierarchical clustering classified 90% of node-negative but only 66% of node-positive tumors correctly. The inability to derive molecular profiles of metastasis in primary tumors may reflect tumor heterogeneity, paucity of cells within the primary tumor with metastatic potential, influence of the microenvironment, or inherited host susceptibility to metastasis

Using wastewater-based epidemiology to estimate drug consumption—Statistical analyses and data presentation

Aim Analysis of wastewater samples can be used to assess population drug use, but reporting and statistical issues have limited the utility of the approach for epidemiology due to analytical results that are below the limit of quantification or detection. Unobserved or non-quantifiable—censored—data are common and likely to persist as the methodology is applied to more municipalities and a broader array of substances. We demonstrate the use of censored data techniques and account for measurement errors to explore distributions and annual estimates of the daily mean level of drugs excreted per capita. Measurements Daily 24-hour composite wastewater samples for 56 days in 2009 were obtained using a random sample stratified by day of week and season for 19 municipalities in the Northwest region of the U.S. Methods Methamphetamine, benzoylecgonine (cocaine metabolite), 3,4-ethylenedioxymethamphetamine (MDMA), methadone, oxycodone and hydrocodone were identified and quantified in wastewater samples. Four statistical approaches (reporting censoring, maximum likelihood estimation, Kaplan-Meier estimates, or complete data calculations) were used to estimate an annual average, including confidence bounds where appropriate, dependent upon the amount of censoring in the data. Findings The proportion of days within a year with censored data varied greatly by drug across the 19 municipalities, with MDMA varying the most (4% to 94% of observations censored). The different statistical approaches each needed to be used given the levels of censoring of measured drug concentrations. Figures incorporating confidence bounds allow visualization of the data that facilitates appropriate comparisons across municipalities. Conclusions Results from wastewater sampling that are below detection or quantification limits contain important information and can be incorporated to create a more complete and valid estimate of drug excretion

Trends in North American net primary productivity derived from satellite observations, 1982-1998

Net primary productivity (NPP) in North America was computed for the years 1982–1998 using the Carnegie‐Ames‐Stanford approach (CASA) carbon cycle model. CASA was driven by a new, corrected satellite record of the normalized difference vegetation index at 8‐km spatial resolution. Regional trends in the 17‐year NPP record varied substantially across the continent. Croplands and grasslands of the Central Plains and eastern Canadian forests experienced summer increases in NPP. Peak NPP trends in Alaska and western Canada occurred in late spring or early summer, suggesting an earlier onset of the growing season in these regions. Forests and woodlands of the southeastern United States showed NPP increases in spring and fall, also suggesting an increase in the length of the growing season. An analysis of climate variables showed that summer precipitation increased in the Central Plains, indicating that climate changes probably play some role in increasing NPP in this region, though intensive management of agricultural ecosystems has also increased productivity. Similarly, increased summer precipitation possibly increased NPP in eastern Canada, but another possible explanation is forest recovery after insect damage. NPP in the southeastern United States increased in the absence of climate variation. Much of this region consists of aggressively managed forests, with young stand ages and intensive silviculture resulting in increased NPP. The high latitudes of western Canada and Alaska experienced spring warming that could have increased NPP in late spring or early summer

Hookworm secreted extracellular vesicles interact with host cells and prevent inducible colitis in mice

Gastrointestinal (GI) parasites, hookworms in particular, have evolved to cause minimal harm to their hosts, allowing them to establish chronic infections. This is mediated by creating an immunoregulatory environment. Indeed, hookworms are such potent sup-pressors of inflammation that they have been used in clinical trials to treat inflammatory bowel diseases (IBD) and celiac disease. Since the recent description of helminths (worms) secreting extracellular vesicles (EVs), exosome-like EVs from different helminths have been characterized and their salient roles in parasite-host interactions have been highlighted. Here, we analyze EVs from the rodent parasite Nippostrongylus brasiliensis, which has been used as a model for human hookworm infection. N. brasiliensis EVs (Nb-EVs) are actively internalized by mouse gut organoids, indicating a role in driving parasitism. We used proteomics and RNA-Seq to profile the molecular composition of Nb-EVs. We identified 81 proteins, including proteins frequently present in exosomes (like tetraspanin, enolase, 14-3-3 protein, and heat shock proteins), and 27 sperm-coating protein-like extracellular proteins. RNA-Seq analysis revealed 52 miRNA species, many of which putatively map to mouse genes involved in regulation of inflammation. To determine whether GI nematode EVs had immunomodulatory properties, we assessed their potential to suppress GI inflammation in a mouse model of inducible chemical colitis. EVs from N. brasiliensis but not those from the whipworm Trichuris muris or control vesicles from grapes protected against colitic inflammation in the gut of mice that received a single intraperitoneal injection of EVs. Key cytokines associated with colitic pathology (IL-6, IL-1 beta, IFN gamma, and IL-17a) were significantly suppressed in colon tissues from EV-treated mice. By contrast, high levels of the anti-inflammatory cytokine IL-10 were detected in Nb-EV-treated mice. Proteins and miRNAs contained within helminth EVs hold great potential application in development of drugs to treat helminth infections as well as chronic non-infectious diseases resulting from a dysregulated immune system, such as IBD

A Mixed-Methods Study To Characterize Pharmaceutical Marketing in the Nursing Home Setting: Off-Label Use of Atypical Antipsychotics

Background: Despite FDA warnings that atypical antipsychotic medications are associated with an increased risk of death when used to treat behavioral disorders in older adults with dementia, they are prescribed to nearly one-third of older U.S. nursing home (NH) residents. Reasons for their high use in NHs are poorly understood, but may include pharmaceutical marketing efforts in the NH setting. Methods: This study is nested within an ongoing cluster randomized trial to improve the use of atypical antipsychotics in NHs. We analyzed semistructured interviews (n = 36) and surveys (n = 139) of administrators, directors of nursing and medical directors from 62 NHs in Connecticut. Using prescription drug claims from a national long-term care pharmacy, we arrayed study NHs into lowest to highest tertile of atypical antipsychotic use. We tested for differences in the receipt of information or clinical tools from pharmaceutical company representatives (PCRs) to manage dementia-related behaviors by medication use tertiles, adjusting for NH profit status, size, quality (overall, health inspections, staffing) and staffing measures (daily nurse hours per resident). Results: Average baseline use of atypical antipsychotics ranged from 6.6 to 44.3 percent of all residents in the facility. Approximately one-quarter of NH leaders presently receive information on dementia-related behavioral management strategies from PCRs through detailing, in-service training, written or Web-based material or sponsorship as speakers. However, we did not detect statistically significant differences in the receipt of information by level of atypical antipsychotic use, NH characteristics, quality and staffing measures. Conclusions: This first attempt to characterize pharmaceutical marketing within the NH setting did not find differences among reports of marketing efforts with respect to medication use and facility-level characteristics. However, studies across a wider geographic area should continue investigating the possible role of marketing efforts on overall use and choice of atypical antipsychotics in the NH setting

Satellite-derived increases in net primary productivity across North America, 1982-1998

We used a new 17‐year, high spatial resolution satellite record and a carbon cycle model to explore how changing net primary productivity (NPP) contributed to a proposed carbon (C) sink in North America. We found a small but significant increase in NPP, 0.03 Pg C yr^(−2) or 8% over 17 years, that could explain a substantial fraction of the C sink. The largest increases occurred in the central and southeastern United States, eastern Canada, and northwestern North America, and were consistent with NPP trends derived from forest inventories and crop yields. Interannual NPP variability was small, implying that the large interannual variability in the C sink found in previous studies were driven by changes in heterotrophic respiration