PHOENIX: Public Health and Obesity in England – the New Infrastructure eXamined First interim report: the scoping review

The PHOENIX project aims to examine the impact of structural changes to the health and care system in England on the functioning of the public health system, and on the approaches taken to improving the public’s health. The scoping review has now been completed. During this phase we analysed: Department of Health policy documents (2010-2013), as well as responses to those documents from a range of stakeholders; data from 22 semi-structured interviews with key informants; and the oral and written evidence presented at the House of Commons Communities and Local Government Committee on the role of local authorities in health issues. We also gathered data from local authority (LA) and Health and Wellbeing Board (HWB) websites and other sources to start to develop a picture of how the new structures are developing, and to collate demographic and other data on local authorities. A number of important themes were identified and explored during this phase. In summary, some key points related to three themes - governance, relationships and new ways of working - were: The reforms have had a profound effect on leadership within the public health system. Whilst LAs are now the local leaders for public health, in a more fragmented system, leadership for public health appears to be more dispersed amongst a range of organisations and a range of people within the LA. At national level, the leadership role is complex and not yet developed (from a local perspective). Accountability mechanisms have changed dramatically within public health, and many people still seem to be unclear about them. Some performance management mechanisms have disappeared, and much accountability now appears to rely on transparency and the democratic accountability that this would (theoretically) enable. The extent to which ‘system leaders’ within PHE are able to influence local decisions and performance will depend on the strength of relationships principally between the LA and the local Public Health England centre. These relationships will take time to develop. Many people have faced new ways of working, in new settings, and with new relationships to build. Public health teams in LAs have faced the most profound of these changes, having gone from a position of ‘expert voice’ to a position where they must defend their opinions and activities in the context of competing demands and severely restricted resources. Public health staff may require new skills, and may need to seek new ‘allies’ to thrive in the new environment. HWBs could be crucial in bringing together a fragmented system and dispersed leadership. The next phase of data collection will begin in March with the initiation of case study work. National surveys will be conducted in June/July this year (2014), and at the same time the following year. In this work, we will further explore the following themes: relationships, governance, decision making, new ways of working, and opportunities and difficulties

MMBIRFinder: A Tool to Detect Microhomology-Mediated Break-Induced Replication

The introduction of next-generation sequencing technologies has radically changed the way we view structural genetic events. Microhomology-mediated break-induced replication (MMBIR) is just one of the many mechanisms that can cause genomic destabilization that may lead to cancer. Although the mechanism for MMBIR remains unclear, it has been shown that MMBIR is typically associated with template-switching events. Currently, to our knowledge, there is no existing bioinformatics tool to detect these template-switching events. We have developed MMBIRFinder, a method that detects template-switching events associated with MMBIR from whole-genome sequenced data. MMBIRFinder uses a half-read alignment approach to identify potential regions of interest. Clustering of these potential regions helps narrow the search space to regions with strong evidence. Subsequent local alignments identify the template-switching events with single-nucleotide accuracy. Using simulated data, MMBIRFinder identified 83 percent of the MMBIR regions within a five nucleotide tolerance. Using real data, MMBIRFinder identified 16 MMBIR regions on a normal breast tissue data sample and 51 MMBIR regions on a triple-negative breast cancer tumor sample resulting in detection of 37 novel template-switching events. Finally, we identified template-switching events residing in the promoter region of seven genes that have been implicated in breast cancer

Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver

Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition

Utilization of Probabilistic Models in Short Read Assembly from Second-Generation Sequencing

With the advent of cheaper and faster DNA sequencing technologies, assembly methods have greatly changed. Instead of outputting reads that are thousands of base pairs long, new sequencers parallelize the task by producing read lengths between 35 and 400 base pairs. Reconstructing an organism’s genome from these millions of reads is a computationally expensive task. Our algorithm solves this problem by organizing and indexing the reads using n-grams, which are short, fixed-length DNA sequences of length n. These n-grams are used to efficiently locate putative read joins, thereby eliminating the need to perform an exhaustive search over all possible read pairs. Our goal was develop a novel n-gram method for the assembly of genomes from next-generation sequencers. Specifically, a probabilistic, iterative approach was utilized to determine the most likely reads to join through development of a new metric that models the probability of any two arbitrary reads being joined together. Tests were run using simulated short read data based on randomly created genomes ranging in lengths from 10,000 to 100,000 nucleotides with 16 to 20x coverage. We were able to successfully re-assemble entire genomes up to 100,000 nucleotides in length

Conserved community structure and simultaneous divergence events in the fig wasps associated with Ficus benjamina in Australia and China

Localised patterns of species diversity can be influenced by many factors, including regional species pools, biogeographic features and interspecific interactions. Despite recognition of these issues, we still know surprisingly little about how invertebrate biodiversity is structured across geographic scales. In particular, there have been few studies of how insect communities vary geographically while using the same plant host. We compared the composition (species, genera) and functional structure (guilds) of the chalcid wasp communities associated with the widespread fig tree, Ficus benjamina, towards the northern (Hainan province, China) and southern (Queensland, Australia) edges of its natural range. Sequence data were generated for nuclear and mtDNA markers and used to delimit species, and Bayesian divergence analyses were used to test patterns of community cohesion through evolutionary time. Both communities host at least 14 fig wasp species, but no species are shared across continents. Community composition is similar at the genus level, with six genera shared although some differ in species diversity between China and Australia; a further three genera occur in only China or Australia. Community functional structure remains very similar in terms of numbers of species in each ecological guild despite community composition differing a little (genera) or a lot (species), depending on taxonomic level. Bayesian clustering analyses favour a single community divergence event across continents over multiple events for different ecological guilds. Molecular dating estimates of lineage splits between nearest inter-continental species pairs are broadly consistent with a scenario of synchronous community divergence from a shared "ancestral community". Fig wasp community structure and genus-level composition are largely conserved in a wide geographic comparison between China and Australia. Moreover, dating analyses suggest that the functional community structure has remained stable for long periods during historic range expansions. This suggests that ecological interactions between species may play a persistent role in shaping these communities, in contrast to findings in some comparable temperate systems