Prediction of 10-fold coordinated TiO2 and SiO2 structures at multimegabar pressures.

We predict by first-principles methods a phase transition in TiO2 at 6.5 Mbar from the Fe2P-type polymorph to a ten-coordinated structure with space group I4/mmm. This is the first report, to our knowledge, of the pressure-induced phase transition to the I4/mmm structure among all dioxide compounds. The I4/mmm structure was found to be up to 3.3% denser across all pressures investigated. Significant differences were found in the electronic properties of the two structures, and the metallization of TiO2 was calculated to occur concomitantly with the phase transition to I4/mmm. The implications of our findings were extended to SiO2, and an analogous Fe2P-type to I4/mmm transition was found to occur at 10 TPa. This is consistent with the lower-pressure phase transitions of TiO2, which are well-established models for the phase transitions in other AX2 compounds, including SiO2. As in TiO2, the transition to I4/mmm corresponds to the metallization of SiO2. This transformation is in the pressure range reached in the interiors of recently discovered extrasolar planets and calls for a reformulation of the equations of state used to model them.We gratefully acknowledge financial support from the Engineering and Physical Sciences Research Council (EPSRC) of the UK and Peterhouse, Cambridge. Computational resources were provided by the High Performance Computing Service (HPCS) at the University of Cambridge and the Archer facility of the UK’s national high-performance computing service for which access was obtained via the UKCP consortium.This is the accepted manuscript of a paper published in the Proceedings of the National Academy of Sciences (Lyle MJ, Pickard CJ, Needs RJ, Proceedings of the National Academy of Sciences, 2015, 112, 6898-6901, doi:10.1073/pnas.1500604112). The final version is available at http://dx.doi.org/10.1073/pnas.150060411

Expression Profiling the Temperature-Dependent Amphibian Response to Infection by Batrachochytrium dendrobatidis

Amphibians are experiencing a panzootic of unprecedented proportions caused by the emergence of Batrachochytrium dendrobatidis (Bd). However, all species are not equally at risk of infection, and risk is further modified by environmental variables, specifically temperature. In order to understand how, and when, hosts mount a response to Bd we analysed infection dynamics and patterns of gene expression in the model amphibian species Silurana (Xenopus) tropicalis. Mathematical modelling of infection dynamics demonstrate the existence of a temperature-dependent protective response that is largely independent of the intrinsic growth-rate of Bd. Using temporal expression-profiling by microarrays and qRT-PCR, we characterise this response in the main amphibian lymphoid tissue, the spleen. We demonstrate that clearance of Bd at the host-optimal temperature is not clearly associated with an adaptive immune response, but rather is correlated with the induction of components of host innate immunity including the expression of genes that are associated with the production of the antimicrobial skin peptide preprocareulein (PPCP) as well as inflammatory responses. We find that adaptive immunity appears to be lacking at host-optimal temperatures. This suggests that either Bd does not stimulate, or suppresses, adaptive immunity, or that trade-offs exist between innate and adaptive limbs of the amphibian immune system. At cold temperatures, S. tropicalis loses the ability to mount a PPCP-based innate response, and instead manifests a more pronounced inflammatory reaction that is characterised by the production of proteases and higher pathogen burdens. This study demonstrates the temperature-dependency of the amphibian response to infection by Bd and indicates the influence that changing climates may exert on the ectothermic host response to pathogens

Computational approaches for understanding the diagnosis and treatment of Parkinson's disease

This study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson’s disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring. New results are presented that demonstrate how EAs can also be used to classify fruit flies with and without genetic mutations that cause Parkinson’s by using measurements of the proboscis extension reflex. The case is made for a computational approach that can be applied across human and animal studies of PD and lays the way for evaluation of existing and new drug therapies in a truly objective way

Genome-wide associations of gene expression variation in humans

The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs) with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis-) to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I) HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level

B cells enhance early innate immune responses during bacterial sepsis

Type I interferon–responsive B cells provide early protection against bacterial sepsis

Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe)

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study. Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×$10^{−6}$. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts. Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis

Implementing Community-Created Self-Management Support Tools in Primary Care Practices: Multimethod Analysis From the INSTTEPP Study

Purpose: With one-half of Americans projected to be living with at least one chronic condition before 2020, enhancing patient self-management support (SMS) may improve health-related behaviors and clinical outcomes. Routine SMS implementation in primary care settings is difficult. Little is known about the practice conditions required for successful implementation of SMS tools. Methods: Four primary care practice-based research networks (PBRNs) recruited 16 practices to participate in a boot camp translation process to adapt patient-centered SMS tools. Boot camp translation sessions were held over a 2-month period with 2 patients, a clinician, and a care manager from each practice. Qualitative case comparison and qualitative comparative analysis were used to examine practice conditions needed to implement SMS tools. The Consolidated Framework for Implementation Research guided data collection and analysis. Results: Four different practice conditions affected the implementation of new SMS tools: functional practice organization; system that enables innovation and change; presence of a visible, activated champion; and synergy and alignment of SMS changes with other work. Qualitative comparative analysis suggested that it was necessary to have an enabling system, a visible champion, and synergy for a practice to at least minimally implement the SMS tools. Sufficiency testing, however, failed to show robust consistency to satisfactorily explain conditions required to implement new SMS tools. Conclusions: To implement tailored self-management support tools relatively rapidly, the minimum necessary conditions include a system that enables innovation and change, presence of a visible champion, and alignment of SMS changes with other work; yet, these alone are insufficient to ensure successful implementation

Adapting Boot Camp Translation Methods to Engage Clinician/Patient Research Teams Within Practice-Based Research Networks

Purpose: Boot camp translation is a proven process to engage community members and health professionals in translating and disseminating evidence-based “best practices” models for health prevention and chronic illness care. Primary care practice improvement studies, particularly involving patient-driven change, as seen with self-management support (SMS), require engaged practice teams that include patients. Models of engagement such as boot camp translation may be effective. Methods: Four geographically dispersed practice-based research networks (PBRNs) from the Meta-LARC consortium engaged 16 practices to form SMS implementation teams involving a clinician, care manager, and 2 patients in each team. Our study adapted the boot camp translation model to engage the implementation teams in describing patient SMS, studying the Agency for Healthcare Research and Quality’s SMS Resource Library, and adapting and implementing self-management tools at each practice site. Testimonials and quotes were collected across the 4 PBRNs through a facilitated brainstorming discussion and consensus model at each PBRN kickoff meeting to address the focused question, “What do patients want and need in order to self-manage their chronic illnesses?” Results: Testimonials collected across the 4 PBRNs and participation levels indicated there was a high degree of engagement in the boot camp translation process across the PBRNs and the practices. Each PBRN developed themes expressed by patients and the practices regarding what patients want and need to self-manage their illnesses. Each practice selected, adapted, and implemented an SMS tool. Conclusions: Results suggest that adapted boot camp translation was effective in guiding multiple practices to implement self-management support tools for the INSTTEPP trial. Additional study of the adapted boot camp translation process in practice quality improvement and practice redesign studies is needed

How to Translate Self-Management Support Tools Into Clinical Practice

Purpose: Patient self-management is an inevitable part of the work of being a patient, and self-management support (SMS) has become increasingly important in chronic disease management. However, the majority of SMS resources available in the Agency for Healthcare Research and Quality SMS Resource Library were developed without explicit collaboration between clinicians and patients. Methods: Translation of SMS tools derived from the library into primary care practices occurred utilizing boot camp translation in four different practice-based research networks (PBRNs). The typical model of boot camp translation was adapted for the purpose of the Implementing Networks’ Self-management Tools Through Engaging Patients and Practices (INSTTEPP) study to develop SMS tools for implementation in the participating practices. Clinicians, clinic staff members, and patients were involved throughout the translation process. Existing resources from the SMS library were reviewed and adapted by each boot camp translation group to create tools unique to the patients in each network. Results: There was no preexisting resource within the library that was deemed suitable for implementation without modification. Each network adapted tools from the SMS library to create different products. Common themes emerged from each network’s translation process that highlighted the importance of patient engagement in the translation process. Boot camp translation, in conjunction with PBRNs, can be implemented to adapt SMS tools for implementation in member practices. Conclusions: Boot camp translation with a combination of practices and patients can be implemented to facilitate a process of local adaptation that improves the local applicability of SMS tools in primary care clinics