Orbital Dimer Model for Spin-Glass State in Y2_2Mo2_2O7_7

The formation of a spin glass usually requires both structural disorder and frustrated magnetic interactions. Consequently, the origin of spin-glass behaviour in Y$_2$Mo$_2$O$_7$ $-$ in which magnetic Mo$^{4+}$ ions occupy a frustrated pyrochlore lattice with minimal compositional disorder $-$ has been a longstanding question. Here, we use neutron and X-ray pair-distribution function (PDF) analysis to develop a disorder model that resolves apparent incompatibilities between previously-reported PDF, EXAFS and NMR studies and provides a new and physical mechanism for spin-glass formation. We show that Mo$^{4+}$ ions displace according to a local "2-in/2-out" rule on each Mo$_4$ tetrahedron, driven by orbital dimerisation of Jahn-Teller active Mo$^{4+}$ ions. Long-range orbital order is prevented by the macroscopic degeneracy of dimer coverings permitted by the pyrochlore lattice. Cooperative O$^{2-}$ displacements yield a distribution of Mo$-$O$-$Mo angles, which in turn introduces disorder into magnetic interactions. Our study demonstrates experimentally how frustration of atomic displacements can assume the role of compositional disorder in driving a spin-glass transition.Comment: 6 pages, 3 figure

Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest

Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation

Investigating the effectiveness and acceptability of oral health and related health behaviour interventions in adults with severe and multiple disadvantage:Protocol for a mixed-methods systematic review

Increasing numbers of people in England experience homelessness, substance use, and repeated offending (known as ‘severe and multiple disadvantage’; SMD). Populations experiencing SMD often have extremely poor oral health, which is closely inter-linked with high levels of substance use, smoking, and poor diet. This study aims to undertake an evidence synthesis to identify the effectiveness, resource requirements, and factors influencing the implementation and acceptability of oral health and related health behaviour interventions in adults experiencing SMD. Two systematic reviews will be conducted using mixed-methods. Review 1 will investigate the effectiveness and resource implications of oral health and related health behaviours (substance use, smoking, diet) interventions; Review 2 will investigate factors influencing the implementation of such interventions. The population includes adults (≥18 years) experiencing SMD. Standard review methods in terms of searches, screening, data extraction, and quality appraisal will be conducted. Narrative syntheses will be conducted. If feasible, a meta-analysis will be conducted for Review 1 and a thematic synthesis for Review 2. Evidence from the two reviews will then be synthesised together. Input from people with experience of SMD will be sought throughout to inform the reviews. An initial logic model will be iteratively refined during the review.</jats:p

Robust Detection of Hierarchical Communities from Escherichia coli Gene Expression Data

Determining the functional structure of biological networks is a central goal of systems biology. One approach is to analyze gene expression data to infer a network of gene interactions on the basis of their correlated responses to environmental and genetic perturbations. The inferred network can then be analyzed to identify functional communities. However, commonly used algorithms can yield unreliable results due to experimental noise, algorithmic stochasticity, and the influence of arbitrarily chosen parameter values. Furthermore, the results obtained typically provide only a simplistic view of the network partitioned into disjoint communities and provide no information of the relationship between communities. Here, we present methods to robustly detect coregulated and functionally enriched gene communities and demonstrate their application and validity for Escherichia coli gene expression data. Applying a recently developed community detection algorithm to the network of interactions identified with the context likelihood of relatedness (CLR) method, we show that a hierarchy of network communities can be identified. These communities significantly enrich for gene ontology (GO) terms, consistent with them representing biologically meaningful groups. Further, analysis of the most significantly enriched communities identified several candidate new regulatory interactions. The robustness of our methods is demonstrated by showing that a core set of functional communities is reliably found when artificial noise, modeling experimental noise, is added to the data. We find that noise mainly acts conservatively, increasing the relatedness required for a network link to be reliably assigned and decreasing the size of the core communities, rather than causing association of genes into new communities.Comment: Due to appear in PLoS Computational Biology. Supplementary Figure S1 was not uploaded but is available by contacting the author. 27 pages, 5 figures, 15 supplementary file

Development of the Critical Thinking Toolkit (CriTT): a measure of student attitudes and beliefs about critical thinking

Critical thinking is an important focus in higher education and is essential for good academic achievement. We report the development of a tool to measure critical thinking for three purposes: (i) to evaluate student perceptions and attitudes about critical thinking, (ii) to identify students in need of support to develop their critical thinking, and (iii) to predict academic performance. Seventy-seven items were generated from focus groups, interviews and the critical thinking literature. Data were collected from 133 psychology students. Factor Analysis revealed three latent factors based on a reduced set of 27 items. These factors were characterised as: Confidence in Critical Thinking; Valuing Critical Thinking; and Misconceptions. Reliability analysis demonstrated that the sub-scales were reliable. Convergent validity with measures of grade point average and argumentation skill was shown, with significant correlations between subscales and validation measures. Most notably, in multiple regression analysis, the three sub-scales from the new questionnaire substantially increased the variance in grade point average accounted for by measures of reflective thinking and argumentation. To sum, the resultant scale offers a measure that is simple to administer, can be used as a diagnostic tool to identify students who need support in developing their critical thinking skills, and can also predict academic performance

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies

The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

Although the canonical transforming growth factor &beta; signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin&ndash;dependent process, whereas increased BMP&ndash;Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders

The Value of Intraoperative Parathyroid Hormone Monitoring in Localized Primary Hyperparathyroidism: A Cost Analysis

Minimally invasive parathyroidectomy (MIP) is the preferred approach to primary hyperparathyroidism (PHPT) when a single adenoma can be localized preoperatively. The added value of intraoperative parathyroid hormone (IOPTH) monitoring remains debated because its ability to prevent failed parathyroidectomy due to unrecognized multiple gland disease (MGD) must be balanced against assay-related costs. We used a decision tree and cost analysis model to examine IOPTH monitoring in localized PHPT. Literature review identified 17 studies involving 4,280 unique patients, permitting estimation of base case costs and probabilities. Sensitivity analyses were performed to evaluate the uncertainty of the assumptions associated with IOPTH monitoring and surgical outcomes. IOPTH cost, MGD rate, and reoperation cost were varied to evaluate potential cost savings from IOPTH. The base case assumption was that in well-localized PHPT, IOPTH monitoring would increase the success rate of MIP from 96.3 to 98.8%. The cost of IOPTH varied with operating room time used. IOPTH reduced overall treatment costs only when total assay-related costs fell below $110 per case. Inaccurate localization and high reoperation cost both independently increased the value of IOPTH monitoring. The IOPTH strategy was cost saving when the rate of unrecognized MGD exceeded 6$12,000 (compared with initial MIP cost of $3733). Setting the positive predictive value of IOPTH at 100% and reducing the false-negative rate to 0% did not substantially alter these findings. Institution-specific factors influence the value of IOPTH. In this model, IOPTH increased the cure rate marginally while incurring approximately 4% additional cost