Age-associated changes in synaptic lipid raft proteins revealed by two-dimensional fluorescence difference gel electrophoresis

Brain aging is associated with a progressive decline in cognitive function though the molecular mechanisms remain unknown. Functional changes in brain neurons could be due to age-related alterations in levels of specific proteins critical for information processing. Specialized membrane microdomains known as ‘lipid rafts’ contain protein complexes involved in many signal transduction processes. This study was undertaken to determine if two-dimensional fluorescence difference gel electrophoresis (2D DIGE) analysis of proteins in synaptic membrane lipid rafts revealed age-dependent alterations in levels of raft proteins. Five pairs of young and aged rat synaptic membrane rafts were subjected to DIGE separation, followed by image analysis and identification of significantly altered proteins. Of 1046 matched spots on DIGE gels, 94 showed statistically significant differences in levels between old and young rafts, and 87 of these were decreased in aged rafts. The 41 most significantly altered (p < 0.03) proteins included several synaptic proteins involved in energy metabolism, redox homeostasis, and cytoskeletal structure. This may indicate a disruption in bioenergetic balance and redox homeostasis in synaptic rafts with brain aging. Differential levels of representative identified proteins were confirmed by immunoblot analysis. Our findings provide novel pathways in investigations of mechanisms that may contribute to altered neuronal function in aging brain

Profiles in Community-Engaged Learning

To provide a snapshot of the many impressive manifestations of community-engaged learning at the University of San Francisco, a 2014-2015 Faculty Learning Community (FLC), supported by the Center for Teaching Excellence (CTE), has collected the following profiles of selected faculty members across all the schools and colleges. This report was prepared by members of the CTE’s Faculty Learning Community on Community-Engaged Learning: Kevin D. Lo, Facilitator (School of Management), Emma Fuentes (School of Education), David Holler (College of Arts and Sciences), Tim Iglesias (School of Law), Susan Roberta Katz (School of Education), Star Moore (Leo T. McCarthy Center for Public Service and the Common Good), Chenit Ong-Flaherty (School of Nursing and Health Professions), Jennifer Parlamis (School of Management) Susan Pauly-O’Neill (School of Nursing and Health Professions). Our intent with this report is to offer USF administrators and incoming faculty members a sense of what’s being done well in community-engaged learning (CEL), while also pointing out what challenges remain as we establish our identity as a university that prioritizes community engagement. (Incidentally, we prefer the term “community-engaged learning” to “service-learning,” which we feel more precisely defines the scope of our activities. For more about this designation, please see the Executive Report on Community Engaged Learning issued by this same committee in June 2015.) Community-engaged learning as defined by Eyler and Giles is “a form of experiential education where learning occurs through a cycle of action and reflection as students . . . seek to achieve real objectives for the community and deeper understanding and skills for themselves. In the process, students link personal and social development with academic and cognitive development . . . experience enhances understanding; understanding leads to more effective action.” (qtd. in Bandy, Vanderbilt Center for Teaching, “What Is Service Learning or Community Engagement?”). We invited at least two faculty members from each school/college to answer several questions about the application of CEL in their courses. After providing a brief overview of activities in each course, we asked each professor what works well and what challenges persist. The successes and the challenges, as you’ll see, vary widely, and yet they clearly delineate, limited though our present sample size is, the great variety and energy and commitment our faculty have demonstrated in working with community partners and students. It is our hope that this report is merely the beginning of a much more ambitious project to be taken up by the McCarthy Center which will provide many more profiles of professors in the months and years to come

Worldwide genetic diversity for mineral element concentrations in rice grain

With the aim of identifying rice (Oryza spp.) germplasm having enhanced grain nutritional value, the mineral nutrient and trace element concentrations (or ionome) of whole (unmilled) grains from a set of 1763 rice accessions of diverse geographic and genetic origin were evaluated. Seed for analysis of P, Mg, K, S, Ca, As, Cd, Co, Cu, Fe, Mn, Mo, Ni, Rb, Sr, and Zn concentrations by inductively coupled plasma mass spectrometry was produced over 2 yr in Beaumont, TX, under both flooded and unflooded watering regimes. The distributions of all element concentrations analyzed were skewed toward higher concentration. A significant portion of this ionomic variation has a genetic basis (broad sense heritabilities 0.14–0.75), indicating an ability to breed for improved grain concentration of all elements except possibly Ni. Variation in grain elemental concentrations was not strongly associated with plant height, heading time, or grain shape, suggesting these physiological factors are not of primary importance in controlling ionomic variation in rice grain. Accessions high in specific elements were sometimes found to have similar genetic or geographic origins, suggesting they share a heritable mechanism underlying their enhanced ionomes. For example, accessions with high Ca, Mg, or K were more common in the indica than in the japonica subgroup; low As was most common among temperate japonica accessions; and several lines high in Mo originated in Malaysia or adjacent Brunei

Comprehensiveness of HIV care provided at global HIV treatment sites in the IeDEA consortium: 2009 and 2014.

INTRODUCTION An important determinant of the effectiveness of HIV treatment programs is the capacity of sites to implement recommended services and identify systematic changes needed to ensure that invested resources translate into improved patient outcomes. We conducted a survey in 2014 of HIV care and treatment sites in the seven regions of the International epidemiologic Database to Evaluate AIDS (IeDEA) Consortium to evaluate facility characteristics, HIV prevention, care and treatment services provided, laboratory capacity, and trends in the comprehensiveness of care compared to data obtained in the 2009 baseline survey. METHODS Clinical staff from 262 treatment sites in 45 countries in IeDEA completed a site survey from September 2014 to January 2015, including Asia-Pacific with Australia ( = 50), Latin America and the Caribbean ( = 11), North America ( = 45), Central Africa ( = 17), East Africa ( = 36), Southern Africa ( = 87), and West Africa ( = 16). For the 55 sites with complete data from both the 2009 and 2014 survey, we evaluated change in comprehensiveness of care. RESULTS The majority of the 262 sites (61%) offered seven essential services (ART adherence, nutritional support, PMTCT, CD4+ cell count testing, tuberculosis screening, HIV prevention, and outreach). Sites that were publicly funded (64%), cared for adults and children (68%), low or middle Human Development Index (HDI) rank (68%, 68%), and received PEPFAR support (71%) were most often fully comprehensive. CD4+ cell count testing was universally available (98%) but only 62% of clinics offered it onsite. Approximately two-thirds (69%) of sites reported routine viral load testing (44-100%), with 39% having it onsite. Laboratory capacity to monitor antiretroviral-related toxicity and diagnose opportunistic infections varied widely by testing modality and region. In the subgroup of 55 sites with two surveys, comprehensiveness of services provided significantly increased across all regions from 2009 to 2014 (5.7 to 6.5, < 0.001). CONCLUSION The availability of viral load monitoring remains suboptimal and should be a focus for site capacity, particularly in East and Southern Africa, where the majority of those initiating on ART reside. However, the comprehensiveness of care provided increased over the past 5 years and was related to type of funding received (publicly funded and PEPFAR supported)

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Spatially-coordinated airborne data and complementary products for aerosol, gas, cloud, and meteorological studies: The NASA ACTIVATE dataset

The NASA Aerosol Cloud meTeorology Interactions oVer the western ATlantic Experiment (ACTIVATE) produced a unique dataset for research into aerosol-cloud-meteorology interactions. An HU-25 Falcon and King Air conducted systematic and spatially coordinated flights over the northwest Atlantic Ocean. This paper describes the ACTIVATE flight strategy, instrument and complementary dataset products, data access and usage details, and data application notes

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts