Analysis of the Macaca mulatta transcriptome and the sequence divergence between Macaca and human

We report the initial sequencing and comparative analysis of the Macaca mulatta transcriptome. Cloned sequences from 11 tissues, nine animals, and three species (M. mulatta, M. fascicularis, and M. nemestrina) were sampled, resulting in the generation of 48,642 sequence reads. These data represent an initial sampling of the putative rhesus orthologs for 6,216 human genes. Mean nucleotide diversity within M. mulatta and sequence divergence among M. fascicularis, M. nemestrina, and M. mulatta are also reported

The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase

AbstractBackground: The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1 β and tumor necrosis factor α, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.Results: We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.Conclusions: Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme

ICAM-reg: Interpretable Classification and Regression with Feature Attribution for Mapping Neurological Phenotypes in Individual Scans

An important goal of medical imaging is to be able to precisely detect patterns of disease specific to individual scans; however, this is challenged in brain imaging by the degree of heterogeneity of shape and appearance. Traditional methods, based on image registration to a global template, historically fail to detect variable features of disease, as they utilise population-based analyses, suited primarily to studying group-average effects. In this paper we therefore take advantage of recent developments in generative deep learning to develop a method for simultaneous classification, or regression, and feature attribution (FA). Specifically, we explore the use of a VAE-GAN translation network called ICAM, to explicitly disentangle class relevant features from background confounds for improved interpretability and regression of neurological phenotypes. We validate our method on the tasks of Mini-Mental State Examination (MMSE) cognitive test score prediction for the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, as well as brain age prediction, for both neurodevelopment and neurodegeneration, using the developing Human Connectome Project (dHCP) and UK Biobank datasets. We show that the generated FA maps can be used to explain outlier predictions and demonstrate that the inclusion of a regression module improves the disentanglement of the latent space. Our code is freely available on Github https://github.com/CherBass/ICAM

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip

DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken

Post-release reforms for short prison sentences: re-legitimising and widening the net of punishment

Transforming Rehabilitation (TR) promised a ‘revolution’ in the way offenders are managed, providing a renewed focus on short sentence prisoners. The TR reforms extends mandatory post-release supervision and tailored through-the-gate resettlement provisions to a group that has predominately faced a ‘history of neglect’ yet often present with the most acute needs within the criminal justice system. However, existing literature underlines that serving short sentences lack ‘utility’ and can be counter-productive to facilitating effective rehabilitation. This article explores the purposes of providing post release supervision for short sentences, firstly exploring a previous attempt to reform short sentences; (the now defunct) ‘Custody Plus’ within the 2003 Criminal Justice Act and then the Offender Rehabilitation Act 2014 within the TR reforms. This article contends that both post release reforms have sought to re-affirm and re-legitimise prison as the dominant form of punishment in society- or what Carlen refers to as ‘carceral clawback’. This article will also use Cohen’s analysis on social control to establish that post release supervision will serve to ‘widen the net’ extend the period of punishment and oversight and will only reinforce a form of enforced ‘state obligated rehabilitation’ that will undermine efforts made to resettle short sentence prisoners

Obesity prevention in child care: A review of U.S. state regulations

<p>ABSTRACT</p> <p>Objective</p> <p>To describe and contrast individual state nutrition and physical activity regulations related to childhood obesity for child care centers and family child care homes in the United States.</p> <p>Methods</p> <p>We conducted a review of regulations for child care facilities for all 50 states and the District of Columbia. We examined state regulations and recorded key nutrition and physical activity items that may contribute to childhood obesity. Items included in this review were: 1) Water is freely available; 2) Sugar-sweetened beverages are limited; 3) Foods of low nutritional value are limited; 4) Children are not forced to eat; 5) Food is not used as a reward; 6) Support is provided for breastfeeding and provision of breast milk; 7) Screen time is limited; and 8) Physical activity is required daily.</p> <p>Results</p> <p>Considerable variation exists among state nutrition and physical activity regulations related to obesity. Tennessee had six of the eight regulations for child care centers, and Delaware, Georgia, Indiana, and Nevada had five of the eight regulations. Conversely, the District of Columbia, Idaho, Nebraska and Washington had none of the eight regulations. For family child care homes, Georgia and Nevada had five of the eight regulations; Arizona, Mississippi, North Carolina, Oregon, Tennessee, Texas, Vermont, and West Virginia had four of the eight regulations. California, the District of Columbia, Idaho, Iowa, Kansas, and Nebraska did not have any of the regulations related to obesity for family child care homes.</p> <p>Conclusion</p> <p>Many states lack specific nutrition and physical activity regulations related to childhood obesity for child care facilities. If widely implemented, enhancing state regulations could help address the obesity epidemic in young children in the United States.</p

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC / BCL2 double-hit

Abstract: Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour

Prioritising the protection of habitat utilised by southern cassowaries Casuarius casuarius johnsonii

The southern cassowary Casuarius casuarius johnsonii L. is an endangered flightless bird from northern Australia. The cassowaries' rainforest habitat has been extensively cleared, and the population primarily exists within discrete protected areas. They do, however, venture outside the reserves into modified landscapes, and it is here they are exposed to threatening processes. We used GPS-based telemetry and the adaptive local convex hull (a-LoCoH) non-parametric kernel method to define the relationship between cassowary home range (HR) and a protection- area network. The study showed that: (1) females had a larger HR than males; (2) overlapping HR occurred between but not within the sexes; (3) HRs of the same sex partitioned along defined boundaries; and (4) the current protected areas only encompassed core HR for the inhabiting cassowaries. This information was incorporated within a spatial-conservation-prioritisation analysis to define the relative cost:benefit relationship for protecting the currently non-protected land utilised by the cassowaries. The results showed that the current reserve system may accommodate up to 24 adult cassowaries, only offering HR protection at the 40 to 60% a-LoCoH. This could be raised, relatively cheaply (1.2-fold the current costs), to 70% a-LoCoH for all birds by protecting adjacent forested areas on private land. Protection beyond the 70% a-LoCoH, however, required protection of large expanses of agricultural land, resulting in an exponential increase in monetary cost (5.1-fold). We argue that total HR protection for the cassowaries was an unfeasible conservation option, but protection of core habitat was achieved relatively cheaply. Combining core HS protection with target incentives to landowners of adjacent cleared land may be the most costeffective conservation strategy for C.c. johnsonii