CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung transplantation

Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, while a CD11b agonist, leukadherin-1, administered only to the donor lung prior to lung transplantation, abrogated CXCL2 production and PGD. The damage-associated molecular pattern molecule HMGB1 was increased in peripheral blood samples from patients undergoing lung transplantation after reperfusion and induced CXCL2 production in nonclassical monocytes via TLR4/MyD88. An inhibitor of HMGB1 administered to the donor and recipient prior to lung transplantation attenuated PGD. Our findings suggest that CD11b acts as a molecular brake to prevent neutrophil recruitment by nonclassical monocytes following lung transplantation, revealing an attractive therapeutic target in the donor lung to prevent PGD in lung transplant recipients

Invasion of the Red Seaweed \u3cem\u3eHeterosiphonia japonica\u3c/em\u3e Spans Biogeographic Provinces in the Western North Atlantic Ocean

The recent invasion of the red alga Heterosiphonia japonica in the western North Atlantic Ocean has provided a unique opportunity to study invasion dynamics across a biogeographical barrier. Native to the western North Pacific Ocean, initial collections in 2007 and 2009 restricted the western North Atlantic range of this invader to Rhode Island, USA. However, through subtidal community surveys, we document the presence of Heterosiphonia in coastal waters from Maine to New York, USA, a distance of more than 700 km. This geographical distribution spans a well-known biogeographical barrier at Cape Cod, Massachusetts. Despite significant differences in subtidal community structure north and south of Cape Cod, Heterosiphonia was found at all but two sites surveyed in both biogeographic provinces, suggesting that this invader is capable of rapid expansion over broad geographic ranges. Across all sites surveyed, Heterosiphonia comprised 14% of the subtidal benthic community. However, average abundances of nearly 80% were found at some locations. As a drifting macrophyte, Heterosiphonia was found as intertidal wrack in abundances of up to 65% of the biomass washed up along beaches surveyed. Our surveys suggest that the high abundance of Heterosiphonia has already led to marked changes in subtidal community structure; we found significantly lower species richness in recipient communities with higher Heterosiphona abundances. Based on temperature and salinity tolerances of the European populations, we believe Heterosiphonia has the potential to invade and alter subtidal communities from Florida to Newfoundland in the western North Atlantic

Cognition and bimanual performance in children with unilateral cerebral palsy: Protocol for a multicentre, cross-sectional study

© 2018 The Author(s). Background: Motor outcomes of children with unilateral cerebral palsy are clearly documented and well understood, yet few studies describe the cognitive functioning in this population, and the associations between the two is poorly understood. Using two hands together in daily life involves complex motor and cognitive processes. Impairment in either domain may contribute to difficulties with bimanual performance. Research is yet to derive whether, and how, cognition affects a child's ability to use their two hands to perform bimanual tasks. Methods/Design: This study will use a prospective, cross-sectional multi-centre observational design. Children (aged 6-12 years) with unilateral cerebral palsy will be recruited from one of five Australian treatment centres. We will examine associations between cognition, bimanual performance and brain neuropathology (lesion type and severity) in a sample of 131 children. The primary outcomes are: Motor - the Assisting Hand Assessment; Cognitive - Executive Function; and Brain - lesion location on structural MRI. Secondary data collected will include: Motor - Box and Blocks, ABILHAND- Kids, Sword Test; Cognitive - standard neuropsychological measures of intelligence. We will use generalized linear modelling and structural equation modelling techniques to investigate relationships between bimanual performance, executive function and brain lesion location. Discussion: This large multi-centre study will examine how cognition affects bimanual performance in children with unilateral cerebral palsy. First, it is anticipated that distinct relationships between bimanual performance and cognition (executive function) will be identified. Second, it is anticipated that interrelationships between bimanual performance and cognition will be associated with common underlying neuropathology. Findings have the potential to improve the specificity of existing upper limb interventions by providing more targeted treatments and influence the development of novel methods to improve both cognitive and motor outcomes in children with unilateral cerebral palsy

Prevalence and antibiotic resistance of Staphylococcus aureus associated with a college-aged cohort: life-style factors that contribute to nasal carriage

Staphylococcus aureus is an opportunistic human pathogen that can frequently be found at various body locations, such as the upper respiratory tract, nostrils, skin, and perineum. S. aureus is responsible for causing a variety of conditions, which range from minor skin infections and food poisoning to life-threatening sepsis and endocarditis. Furthermore, S. aureus has developed resistance to numerous antimicrobial agents, which has made treatment of S. aureus infections difficult. In the present study, we examined lifestyle factors that could increase the likelihood of S. aureus carriage, the overall prevalence of S. aureus, as well as assessed the antibiotic resistance profiles of the S. aureus isolates among a population of college students. Five hundred nasal samples were collected and analyzed via selective growth media, coagulase and protein A testing, as well as polymerase chain reaction and DNA sequencing. One hundred four out of the 500 samples collected (21%) were identified as containing S. aureus. The S. aureus isolates were resistant to penicillin (74%), azithromycin (34%), cefoxitin (5%), ciprofloxacin (5%), tetracycline (4%), and trimethoprim (1%), but sensitive to gentamicin and rifampin. Lastly, we identified several lifestyle factors (i.e., pet exposure, time spent at the university recreational facility, musical instrument usage, and tobacco usage) positively correlated with S. aureus nasal colonization

"The extreme penalty of the law": mercy and the death penalty as aspects of state power in colonial Nyasaland, c. 1903-47

Open access article.Capital punishment was the pinnacle of the colonial judicial system and its use of state violence, but has previously been neglected as a topic of historical research in Africa. This article is based on the case files and legal records of over 800 capital trials – predominantly for murder – dating between 1900 and 1947. It outlines the functioning of the legal system in Nyasaland and the tensions between “violence” and “humanitarianism” in the use and reform of the death penalty. Capital punishment was a political penalty as much as a judicial punishment, with both didactic and deterrent functions: it operated through mercy and the sparing of condemned lives as well as through executions. Mercy in Nyasaland was consistent with colonial political objectives and cultural values: it was decided not only on the facts of cases, but according to British conceptions of “justice”, “order”, “criminality”, and “African” behaviour. This article analyses the use of mercy in Nyasaland to provide a lens on the nature of colonial governance, and the tensions between African and colonial understandings of violence.Arts and Humanities Research Council (UK) and the Beit Fund, University of Oxfor

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

BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers.

Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin. Melanosomes and other lysosome-related organelles obtain cargoes from early endosomes, but the fusion machinery involved and its recycling pathway are unknown. Here, we show that the v-SNARE VAMP7 mediates fusion of melanosomes with tubular transport carriers that also carry the cargo protein TYRP1 and that require BLOC-1 for their formation. Using live-cell imaging, we identify a pathway for VAMP7 recycling from melanosomes that employs distinct tubular carriers. The recycling carriers also harbor the VAMP7-binding scaffold protein VARP and the tissue-restricted Rab GTPase RAB38. Recycling carrier formation is dependent on the RAB38 exchange factor BLOC-3. Our data suggest that VAMP7 mediates fusion of BLOC-1-dependent transport carriers with melanosomes, illuminate SNARE recycling from melanosomes as a critical BLOC-3-dependent step, and likely explain the distinct hypopigmentation phenotypes associated with BLOC-1 and BLOC-3 deficiency in Hermansky-Pudlak syndrome variants.This work was supported by grants from the National Institutes of Health, National Eye Institute (R01 EY015625, to M.S. Marks and G.  Raposo), National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR048155, to M.S. Marks, and F32 AR062476, to M.K. Dennis), National Institute of General Medical Sciences (R01 GM108807, to M.S. Marks); Fondation pour la Recherche Médicale (to T.  Galli); the UK Medical Research Council (G0900113, to J.P. Luzio); and the Wellcome Trust (108429, to E.V. Sviderskaya and D.C. Bennett). This work was also supported by a Canadian Institutes of Health Research Fellowship (to G.G.  Hesketh) and a Fondation pour la Recherche Médicale grant from Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Curie, and Fondation pour la Recherche Médicale (DEQ20140329491 Team label, to G. Raposo).This is the final version of the article. It first appeared from Rockefeller University Press via http://dx.doi.org/10.1083/jcb.20160509

Paradoxical CD4 Lymphopenia in Autoimmune Lymphoproliferative Syndrome (ALPS)

Autoimmune lymphoproliferative syndrome (ALPS) is caused by germline or somatic loss of function FAS mutations resulting in impaired apoptosis and consequent expansion of T-lymphocytes causing organomegaly and autoimmune anemia, neutropenia and thrombocytopenia. Herein, we report on a case of disseminated varicella zoster infection after post-partum vaccination in a patient found to have CD4 lymphopenia and eventually diagnosed with ALPS caused by a novel germline missense mutation in FAS death-domain. A subsequent retrospective analysis of 169 patients of the NIH ALPS-FAS cohort, revealed that CD4-T-cells lymphopenia (&lt; 300 cells/μl) may occur in 5% of ALPS-FAS patients irrespectively of the underlying genetic defect, organomegaly or immunosuppressive treatment. Although immunophenotyping did not show depletion of specific CD4-T-cells subpopulations, CD4-lymphopenic ALPS-FAS subjects had an expansion of a subset of circulating T-follicular-helper (cTfh) cells, associated with autoantibody production (CCR7lowPD-1high). Furthermore, autoantibodies binding on CD4-T-cells were detected in 50% of the CD4-lymphopenic ALPS-FAS patients and caused cytotoxicity in a natural killer (NK)-mediated antibody-dependent-cellular cytotoxicity assay. Such autoantibodies can therefore be associated with CD4-T-cell death, impaired activation induced proliferation or impaired trafficking. The expansion of autoreactive T-cells in ALPS-FAS is known to be associated with autoimmune clinical manifestations, however our study reveals that ALPS-FAS can also be associated with a paradoxical depletion of CD4-T-cells due to the presence of autoantibodies on the surface of CD4-T-cells which can in turn result in increased susceptibility to opportunistic infections. These novel findings have implications for the diagnosis, clinical monitoring, and management of patients with ALPS-FAS

Evidence in the learning organization

<p>Abstract</p> <p>Background</p> <p>Organizational leaders in business and medicine have been experiencing a similar dilemma: how to ensure that their organizational members are adopting work innovations in a timely fashion. Organizational leaders in healthcare have attempted to resolve this dilemma by offering specific solutions, such as evidence-based medicine (EBM), but organizations are still not systematically adopting evidence-based practice innovations as rapidly as expected by policy-makers (the knowing-doing gap problem). Some business leaders have adopted a systems-based perspective, called the learning organization (LO), to address a similar dilemma. Three years ago, the Society of General Internal Medicine's Evidence-based Medicine Task Force began an inquiry to integrate the EBM and LO concepts into one model to address the knowing-doing gap problem.</p> <p>Methods</p> <p>During the model development process, the authors searched several databases for relevant LO frameworks and their related concepts by using a broad search strategy. To identify the key LO frameworks and consolidate them into one model, the authors used consensus-based decision-making and a narrative thematic synthesis guided by several qualitative criteria. The authors subjected the model to external, independent review and improved upon its design with this feedback.</p> <p>Results</p> <p>The authors found seven LO frameworks particularly relevant to evidence-based practice innovations in organizations. The authors describe their interpretations of these frameworks for healthcare organizations, the process they used to integrate the LO frameworks with EBM principles, and the resulting Evidence in the Learning Organization (ELO) model. They also provide a health organization scenario to illustrate ELO concepts in application.</p> <p>Conclusion</p> <p>The authors intend, by sharing the LO frameworks and the ELO model, to help organizations identify their capacities to learn and share knowledge about evidence-based practice innovations. The ELO model will need further validation and improvement through its use in organizational settings and applied health services research.</p