The Extracellular Vesicles of the Helminth Pathogen, Fasciola hepatica: Biogenesis Pathways and Cargo Molecules Involved in Parasite Pathogenesis

Extracellular vesicles (EVs) released by parasites have important roles in establishing and maintaining infection. Analysis of the soluble and vesicular secretions of adult Fasciola hepatica has established a definitive characterization of the total secretome of this zoonotic parasite. Fasciola secretes at least two subpopulations of EVs that differ according to size, cargo molecules and site of release from the parasite. The larger EVs are released from the specialized cells that line the parasite gastrodermus and contain the zymogen of the 37 kDa cathepsin L peptidase that performs a digestive function. The smaller exosome-like vesicle population originate from multivesicular bodies within the tegumental syncytium and carry many previously described immunomodulatory molecules that could be delivered into host cells. By integrating our proteomics data with recently available transcriptomic data sets we have detailed the pathways involved with EV biogenesis in F. hepatica and propose that the small exosome biogenesis occurs via ESCRT-dependent MVB formation in the tegumental syncytium before being shed from the apical plasma membrane. Furthermore, we found that the molecular "machinery" required for EV biogenesis is constitutively expressed across the intramammalian development stages of the parasite. By contrast, the cargo molecules packaged within the EVs are developmentally regulated, most likely to facilitate the parasites migration through host tissue and to counteract host immune attack

Genome-wide Association and Population Genetic Analysis of C-Reactive Protein in African American and Hispanic American Women

C-reactive protein (CRP) is a systemic inflammation marker that predicts future cardiovascular risk. CRP levels are higher in African Americans and Hispanic Americans than in European Americans, but the genetic determinants of CRP in these admixed United States minority populations are largely unknown. We performed genome-wide association studies (GWASs) of 8,280 African American (AA) and 3,548 Hispanic American (HA) postmenopausal women from the Women's Health Initiative SNP Health Association Resource. We discovered and validated a CRP-associated variant of triggering receptors expressed by myeloid cells 2 (TREM2) in chromosomal region 6p21 (p = 10−10). The TREM2 variant associated with higher CRP is common in Africa but rare in other ancestral populations. In AA women, the CRP region in 1q23 contained a strong admixture association signal (p = 10−17), which appears to be related to several independent CRP-associated alleles; the strongest of these is present only in African ancestral populations and is associated with higher CRP. Of the other genomic loci previously associated with CRP through GWASs of European populations, most loci (LEPR, IL1RN, IL6R, GCKR, NLRP3, HNF1A, HNF4A, and APOC1) showed consistent patterns of association with CRP in AA and HA women. In summary, we have identified a common TREM2 variant associated with CRP in United States minority populations. The genetic architecture underlying the CRP phenotype in AA women is complex and involves genetic variants shared across populations, as well as variants specific to populations of African descent

Implementation of a Shared Data Repository and Common Data Dictionary for Fetal Alcohol Spectrum Disorders Research

Many previous attempts by fetal alcohol spectrum disorders researchers to compare data across multiple prospective and retrospective human studies have failed due to both structural differences in the collected data as well as difficulty in coming to agreement on the precise meaning of the terminology used to describe the collected data. Although some groups of researchers have an established track record of successfully integrating data, attempts to integrate data more broadly amongst different groups of researchers have generally faltered. Lack of tools to help researchers share and integrate data has also hampered data analysis. This situation has delayed improving diagnosis, intervention, and treatment before and after birth. We worked with various researchers and research programs in the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CI-FASD) to develop a set of common data dictionaries to describe the data to be collected, including definitions of terms and specification of allowable values. The resulting data dictionaries were the basis for creating a central data repository (CI-FASD Central Repository) and software tools to input and query data. Data entry restrictions ensure that only data which conform to the data dictionaries reach the CI-FASD Central Repository. The result is an effective system for centralized and unified management of the data collected and analyzed by the initiative, including a secure, long-term data repository. CI-FASD researchers are able to integrate and analyze data of different types, collected using multiple methods, and collected from multiple populations, and data are retained for future reuse in a secure, robust repository

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Phylogenomic classification and the evolution of Clonal complex 5 methicillin-resistant Staphylococcus aureus in the Western Hemisphere

Clonal complex 5 methicillin-resistant Staphylococcus aureus (CC5-MRSA) includes multiple prevalent clones that cause hospital-associated infections in the Western Hemisphere. Here, we present a phylogenomic study of these MRSA to reveal their phylogeny, spatial and temporal population structure, and the evolution of selected traits. We studied 598 genome sequences, including 409 newly generated sequences, from 11 countries in Central, North, and South America, and references from Asia and Europe. An early-branching CC5-Basal clade is well-dispersed geographically, is methicillin-susceptible and MRSA predominantly of ST5-IV such as the USA800 clone, and includes separate subclades for avian and porcine strains. In the early 1970s and early 1960s, respectively, two clades appeared that subsequently underwent major expansions in the Western Hemisphere: a CC5-I clade in South America and a CC5-II clade largely in Central and North America. The CC5-I clade includes the ST5-I Chilean/Cordobes clone, and the ST228-I South German clone as an early offshoot, but is distinct from other ST5-I clones from Europe that nest within CC5-Basal. The CC5-II clade includes divergent strains of the ST5-II USA100 clone, various other clones, and most known vancomycin-resistant strains of S. aureus, but is distinct from ST5-II strain N315 from Japan that nests within CC5-Basal. The recombination rate of CC5 was much lower than has been reported for other S. aureus genetic backgrounds, which indicates that recurrence of vancomycin resistance in CC5 is not likely due to an enhanced promiscuity. An increased number of antibiotic resistances and decreased number of toxins with distance from the CC5 tree root were observed. Of note, the expansions of the CC5-I and CC5-II clades in the Western Hemisphere were preceded by convergent gains of resistance to fluoroquinolone, macrolide, and lincosamide antibiotics, and convergent losses of the staphylococcal enterotoxin p (sep) gene from the immune evasion gene cluster of phage ΦSa3. Unique losses of surface proteins were also noted for these two clades. In summary, our study has determined the relationships of different clades and clones of CC5 and has revealed genomic changes for increased antibiotic resistance and decreased virulence associated with the expansions of these MRSA in the Western Hemisphere.Fil: Challagundla, Lavanya. University of Mississippi; Estados UnidosFil: Reyes, Jinnethe. Universidad El Bosque; ColombiaFil: Rafiqullah, Iftekhar. University of Mississippi; Estados UnidosFil: Sordelli, Daniel Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Echaniz-Aviles, Gabriela. Instituto Nacional de Salud Pùblica; MéxicoFil: Velazquez-Meza, Maria E.. Instituto Nacional de Salud Pública; MéxicoFil: Castillo-Ramírez, Santiago. Universidad Nacional Autónoma de México; MéxicoFil: Fittipaldi, Nahuel. University of Toronto; Canadá. Public Health Ontario Laboratory; CanadáFil: Feldgarden, Michael. National Institutes of Health; Estados UnidosFil: Chapman, Sinéad B.. Broad Institute of MIT and Harvard; Estados UnidosFil: Calderwood, Michael S.. Dartmouth–Hitchcock Medical Center; Estados UnidosFil: Carvajal, Lina P.. Universidad El Bosque; ColombiaFil: Rincon, Sandra. Universidad El Bosque; ColombiaFil: Blake, Hanson. University of Texas; Estados UnidosFil: Planet, Paul J.. University of Pennsylvania; Estados UnidosFil: Arias, Cesar A.. Universidad El Bosque; Colombia. University of Texas; Estados UnidosFil: Diaz, Lorena. Universidad El Bosque; ColombiaFil: Robinson, D. Ashley. University of Mississippi; Estados Unido

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Efficacy of antibiotic prophylaxis in patients with cancer and hematopoietic stem cell transplantation recipients : A systematic review of randomized trials

PURPOSE: To determine the efficacy and safety of different prophylactic systemic antibiotics in adult and pediatric patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a systematic review and performed searches of Ovid MEDLINE, MEDLINE in-process and Embase; and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were HSCT recipients with anticipated neutropenia, and the intervention was systemic antibacterial prophylaxis. Strategies synthesized included fluoroquinolone vs no antibiotic/nonabsorbable antibiotic; fluoroquinolone vs trimethoprim-sulfamethoxazole; trimethoprim-sulfamethoxazole vs no antibiotic; and cephalosporin vs. no antibiotic. Fluoroquinolone vs cephalosporin and levofloxacin vs ciprofloxacin were compared by network meta-analysis. Primary outcome was bacteremia. RESULTS: Of 20 984 citations screened, 113 studies comparing prophylactic antibiotic to control were included. The following were effective in reducing bacteremia: fluoroquinolone vs no antibiotic/nonabsorbable antibiotic (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.41-0.76), trimethoprim-sulfamethoxazole vs no antibiotic (RR 0.59, 95% CI 0.41-0.85) and cephalosporin vs no antibiotic (RR 0.30, 95% CI 0.16-0.58). Fluoroquinolone was not significantly associated with increased Clostridium difficile infection (RR 0.62, 95% CI 0.31-1.24) or invasive fungal disease (RR 1.28, 95% CI 0.79-2.08) but did increase resistance to fluoroquinolone among bacteremia isolates (RR 3.35, 95% CI 1.12 to 10.03). Heterogeneity in fluoroquinolone effect on bacteremia was not explained by evaluated study, population, or methodological factors. Network meta-analysis revealed no direct comparisons for pre-specified analyses; superior regimens were not identified. CONCLUSIONS: Fluoroquinolone, trimethoprim-sulfamethoxazole, and cephalosporin prophylaxis reduced bacteremia. A clinical practice guideline to facilitate prophylactic antibiotic decision-making is required

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

The Transcription Factor Ultraspiracle Influences Honey Bee Social Behavior and Behavior-Related Gene Expression

Behavior is among the most dynamic animal phenotypes, modulated by a variety of internal and external stimuli. Behavioral differences are associated with large-scale changes in gene expression, but little is known about how these changes are regulated. Here we show how a transcription factor (TF), ultraspiracle (usp; the insect homolog of the Retinoid X Receptor), working in complex transcriptional networks, can regulate behavioral plasticity and associated changes in gene expression. We first show that RNAi knockdown of USP in honey bee abdominal fat bodies delayed the transition from working in the hive (primarily “nursing” brood) to foraging outside. We then demonstrate through transcriptomics experiments that USP induced many maturation-related transcriptional changes in the fat bodies by mediating transcriptional responses to juvenile hormone. These maturation-related transcriptional responses to USP occurred without changes in USP's genomic binding sites, as revealed by ChIP–chip. Instead, behaviorally related gene expression is likely determined by combinatorial interactions between USP and other TFs whose cis-regulatory motifs were enriched at USP's binding sites. Many modules of JH– and maturation-related genes were co-regulated in both the fat body and brain, predicting that usp and cofactors influence shared transcriptional networks in both of these maturation-related tissues. Our findings demonstrate how “single gene effects” on behavioral plasticity can involve complex transcriptional networks, in both brain and peripheral tissues

Development of an online information and support resource for adolescent idiopathic scoliosis patients considering surgery: perspectives of health care providers

<p>Abstract</p> <p>Background</p> <p>Adolescents with idiopathic scoliosis who are considering spinal surgery face a major decision that requires access to in-depth information and support. Unfortunately, most online resources provide incomplete and inconsistent information and minimal social support. The aim of this study was to develop an online information and support resource for adolescent idiopathic scoliosis (AIS) patients considering spinal surgery. Prior to website development, a user-based needs assessment was conducted. The needs assessment involved a total of six focus groups with three stakeholder groups: (1) post-operative AIS patients or surgical candidates (10-18 years) (n = 11), (2) their parents (n = 6) and (3) health care providers (n = 11). This paper reports on the findings from focus groups with health care providers.</p> <p>Methods</p> <p>Focus group methodology was used to invite a range of perspectives and stimulate discussion. During audio-recorded focus groups, an emergent table of website content was presented to participants for assessment of relevance, viability and comprehensiveness in targeting global domains of need. Specifically, effective presentation of content, desired aspects of information and support, and discussions about the value of peer support and the role of health professionals were addressed. Focus group transcripts were then subject to content analysis through a constant comparative review and analysis.</p> <p>Results</p> <p>Two focus groups were held with health care providers, consisting of 5 and 6 members respectively. Clinicians provided their perceptions of the information and support needs of surgical patients and their families and how this information and support should be delivered using internet technology. Health care providers proposed four key suggestions to consider in the development of this online resource: (1) create the website with the target audience in mind; (2) clearly state the purpose of the website and organize website content to support the user; (3) offer a professionally-moderated interactive support component; and (4) ensure accessibility of website information and support by considering the age, gender, reading level and geographic location of potential users.</p> <p>Conclusions</p> <p>Health care providers collectively identified the need for the development of an online information and support resource for adolescents considering surgery for AIS and their families and described the proposed website as a positive and needed adjunct to current clinical care.</p