Temporal and spatial changes in cartilage-matrix-specific gene expression in mesenchymal stem cells in response to dynamic compression.

Various forms of mechanical stimulation have been shown to enhance chondrogenesis of mesenchymal stem cells (MSCs). However, the response of MSCs undergoing chondrogenesis to such signals has been shown to depend on the temporal application of loading. The objective of this study was to determine the effect of dynamic compression on cartilage-matrix-specific gene expression and to relate this response to the local biochemical environment and cell phenotype at the time of loading. At 0, 7, 14, and 21 days extracellular matrix (ECM) deposition within MSC-seeded agarose hydrogels due to transforming growth factor-β3 stimulation was determined biochemically and histologically, and then reverse transcription-polymerase chain reaction was used to examine the effects of dynamic compression on cartilage-matrix-specific gene expression. The results of these experiments show that the local environment in the core of the constructs is more favorable for chondrogenesis in comparison to the annulus, as evident from both ECM synthesis and gene expression. Additionally, we found that the response of the cells to mechanical stimulus varied with both the spatial region within the constructs and the temporal application of loading. Dynamic compression applied at day 21 was found to enhance levels of cartilage matrix gene expression following a peak in expression levels at day 14 in free swelling constructs, suggesting that mechanical signals play a key role in the maintenance of a chondrogenic phenotype. The application of mechanical stimulus to enhance cartilage ECM synthesis may be an important tool in regenerative medicine-based cartilage repair. The results of this study suggest that a chondrogenic phenotype and/or a well-developed pericellular matrix must first be established before dynamic compression can have a positive effect on cartilage-matrix-specific gene expression

The response of North Sea ecosystem functional groups to warming and changes in fishing

Achieving Good Environmental Status (GES) requires managing ecosystems subject to a variety of pressures such as climate change, eutrophication, and fishing. However, ecosystem models are generally much better at representing top-down impacts from fishing than bottom-up impacts due to warming or changes in nutrient loading. Bottom-up processes often have to be parameterised with little data or worse still taken as a system input rather than being represented explicitly. In this study we use an end-to-end ecosystem model (StrathE2E2) for the North Sea with 18 broad functional groups, five resource pools, and representations of feeding, metabolism, reproduction, active migrations, advection, and mixing. Environmental driving data include temperature, irradiance, hydrodynamics, and nutrient inputs from rivers, atmosphere, and ocean boundaries, so the model is designed to evaluate rigorously top-down and bottom-up impacts and is ideal for looking at possible changes in energy flows and “big picture” ecosystem function. In this study we considered the impacts of warming (2 and 4°C) and various levels of fishing, by demersal and pelagic fleets, on the structure and function of the foodweb. A key aim is to demonstrate whether monitoring of broad ecosystem groups could assist in deciding whether GES was being achieved. We found that warming raised primary productivity and increased the size (total biomass) of the ecosystem. Warming raised metabolic demands on omnivorous zooplankton and reduced their abundance, thus favouring benthivorous and piscivorous demersal fish at the expense of planktivorous pelagic fish but otherwise had modest effects on energy pathways and top predators, whereas changes in fishing patterns could materially alter foodweb function and the relative outcomes for top predators. We suggest that GES should be defined in terms of an unfished state and that abundances of broad groupings and the balance between them can help to assess whether indicator outcomes were consistent with GES. Our findings underwrite the need for an ecosystem approach for the management of human activities supported by relevant monitoring. We also highlight the need to improve our basic understanding of bottom-up processes, improve their representation within models, and ensure that our ecosystem models can capture growth limitation by nitrogen and other elements, and not just food/energy uptake

Formation of a conceptual framework during the development of a patient-reported outcome measure for early gastrointestinal recovery: Phase I of the PRO-diGi study

Aim: Patients admitted to hospital for abdominal surgery often experience gastrointestinal dysfunction. Many studies have reported outcomes following gastrointestinal dysfunction, yet there is no unified definition of recovery or a validated patient-reported outcome measure (PROM). The first stage of PROM development requires formation of a conceptual framework to identify key themes to patients. The aim of this study was to utilize semistructured interviews to identify core themes and concepts relevant to patients to facilitate development of a conceptual framework. Method: Adult patients admitted to hospital for major gastrointestinal, urological or gynaecological surgery, in an emergency or elective setting, were eligible to participate. Patients treated nonoperatively for small bowel obstruction were also eligible. Interviews were conducted by telephone, audio-recorded, transcribed, coded and analysed using NVivo software by two researchers and reviewed by lay members of the steering group. Interviews continued until data saturation was reached. Ethical approval was gained prior to interviews (21/WA/0231). Results: Twenty nine interviews were completed (17 men, median age 64 years) across three specialties (20 gastrointestinal, six gynaecological, three urological). Two overarching themes of ‘general recovery’ and ‘gastrointestinal symptoms’ were identified. General recovery included three themes: ‘life impact’, ‘mental impact’, including anxiety, and ‘physical impact’, including fatigue. Gastrointestinal symptoms included three themes: ‘abdominal symptoms’ such as pain, ‘diet and appetite’ and ‘expulsory function’, such as stool frequency. A total of 18 gastrointestinal symptoms were identified during patient recovery—many of which lasted several weeks following discharge. Conclusion: This study reports a range of gastrointestinal and nongastrointestinal symptoms experienced by patients during early gastrointestinal recovery. Identified symptoms have been synthesized into a conceptual framework to enable development of a definitive PROM for early gastrointestinal recovery

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity

Land Cover and Rainfall Interact to Shape Waterbird Community Composition

Human land cover can degrade estuaries directly through habitat loss and fragmentation or indirectly through nutrient inputs that reduce water quality. Strong precipitation events are occurring more frequently, causing greater hydrological connectivity between watersheds and estuaries. Nutrient enrichment and dissolved oxygen depletion that occur following these events are known to limit populations of benthic macroinvertebrates and commercially harvested species, but the consequences for top consumers such as birds remain largely unknown. We used non-metric multidimensional scaling (MDS) and structural equation modeling (SEM) to understand how land cover and annual variation in rainfall interact to shape waterbird community composition in Chesapeake Bay, USA. The MDS ordination indicated that urban subestuaries shifted from a mixed generalist-specialist community in 2002, a year of severe drought, to generalist-dominated community in 2003, of year of high rainfall. The SEM revealed that this change was concurrent with a sixfold increase in nitrate-N concentration in subestuaries. In the drought year of 2002, waterbird community composition depended only on the direct effect of urban development in watersheds. In the wet year of 2003, community composition depended both on this direct effect and on indirect effects associated with high nitrate-N inputs to northern parts of the Bay, particularly in urban subestuaries. Our findings suggest that increased runoff during periods of high rainfall can depress water quality enough to alter the composition of estuarine waterbird communities, and that this effect is compounded in subestuaries dominated by urban development. Estuarine restoration programs often chart progress by monitoring stressors and indicators, but rarely assess multivariate relationships among them. Estuarine management planning could be improved by tracking the structure of relationships among land cover, water quality, and waterbirds. Unraveling these complex relationships may help managers identify and mitigate ecological thresholds that occur with increasing human land cover

Physical and biogeochemical controls on the variability in surface pH and calcium carbonate saturation states in the Atlantic sectors of the Arctic and Southern Oceans

Polar oceans are particularly vulnerable to ocean acidification due to their low temperatures and reduced buffering capacity, and are expected to experience extensive low pH conditions and reduced carbonate mineral saturations states (Ω) in the near future. However, the impact of anthropogenic CO2 on pH and Ω will vary regionally between and across the Arctic and Southern Oceans. Here we investigate the carbonate chemistry in the Atlantic sector of two polar oceans, the Nordic Seas and Barents Sea in the Arctic Ocean, and the Scotia and Weddell Seas in the Southern Ocean, to determine the physical and biogeochemical processes that control surface pH and Ω. High-resolution observations showed large gradients in surface pH (0.10–0.30) and aragonite saturation state (Ωar) (0.2–1.0) over small spatial scales, and these were particularly strong in sea-ice covered areas (up to 0.45 in pH and 2.0 in Ωar). In the Arctic, sea-ice melt facilitated bloom initiation in light-limited and iron replete (dFe>0.2 nM) regions, such as the Fram Strait, resulting in high pH (8.45) and Ωar (3.0) along the sea-ice edge. In contrast, accumulation of dissolved inorganic carbon derived from organic carbon mineralisation under the ice resulted in low pH (8.05) and Ωar (1.1) in areas where thick ice persisted. In the Southern Ocean, sea-ice retreat resulted in bloom formation only where terrestrial inputs supplied sufficient iron (dFe>0.2 nM), such as in the vicinity of the South Sandwich Islands where enhanced pH (8.3) and Ωar (2.3) were primarily due to biological production. In contrast, in the adjacent Weddell Sea, weak biological uptake of CO2 due to low iron concentrations (dFe<0.2 nM) resulted in low pH (8.1) and Ωar (1.6). The large spatial variability in both polar oceans highlights the need for spatially resolved surface data of carbonate chemistry variables but also nutrients (including iron) in order to accurately elucidate the large gradients experienced by marine organisms and to understand their response to increased CO2 in the future