Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

Competing biosecurity and risk rationalities in the Chittagong poultry commodity chain, Bangladesh

This paper anthropologically explores how key actors in the Chittagong live bird trading network perceive biosecurity and risk in relation to avian influenza between production sites, market maker scenes and outlets. They pay attention to the past and the present, rather than the future, downplaying the need for strict risk management, as outbreaks have not been reported frequently for a number of years. This is analysed as ‘temporalities of risk perception regarding biosecurity’, through Black Swan theory, the idea that unexpected events with major effects are often inappropriately rationalized (Taleb in The Black Swan. The impact of the highly improbable, Random House, New York, 2007). This incorporates a sociocultural perspective on risk, emphasizing the contexts in which risk is understood, lived, embodied and experienced. Their risk calculation is explained in terms of social consent, practical intelligibility and convergence of constraints and motivation. The pragmatic and practical orientation towards risk stands in contrast to how risk is calculated in the avian influenza preparedness paradigm. It is argued that disease risk on the ground has become a normalized part of everyday business, as implied in Black Swan theory. Risk which is calculated retrospectively is unlikely to encourage investment in biosecurity and, thereby, points to the danger of unpredictable outlier events

Bacterial microevolution and the Pangenome

The comparison of multiple genome sequences sampled from a bacterial population reveals considerable diversity in both the core and the accessory parts of the pangenome. This diversity can be analysed in terms of microevolutionary events that took place since the genomes shared a common ancestor, especially deletion, duplication, and recombination. We review the basic modelling ingredients used implicitly or explicitly when performing such a pangenome analysis. In particular, we describe a basic neutral phylogenetic framework of bacterial pangenome microevolution, which is not incompatible with evaluating the role of natural selection. We survey the different ways in which pangenome data is summarised in order to be included in microevolutionary models, as well as the main methodological approaches that have been proposed to reconstruct pangenome microevolutionary history

Strain-Dependent Differences in Bone Development, Myeloid Hyperplasia, Morbidity and Mortality in Ptpn2-Deficient Mice

Single nucleotide polymorphisms in the gene encoding the protein tyrosine phosphatase TCPTP (encoded by PTPN2) have been linked with the development of autoimmunity. Here we have used Cre/LoxP recombination to generate Ptpn2ex2−/ex2− mice with a global deficiency in TCPTP on a C57BL/6 background and compared the phenotype of these mice to Ptpn2−/− mice (BALB/c-129SJ) generated previously by homologous recombination and backcrossed onto the BALB/c background. Ptpn2ex2−/ex2− mice exhibited growth retardation and a median survival of 32 days, as compared to 21 days for Ptpn2−/− (BALB/c) mice, but the overt signs of morbidity (hunched posture, piloerection, decreased mobility and diarrhoea) evident in Ptpn2−/− (BALB/c) mice were not detected in Ptpn2ex2−/ex2− mice. At 14 days of age, bone development was delayed in Ptpn2−/− (BALB/c) mice. This was associated with increased trabecular bone mass and decreased bone remodeling, a phenotype that was not evident in Ptpn2ex2−/ex2− mice. Ptpn2ex2−/ex2− mice had defects in erythropoiesis and B cell development as evident in Ptpn2−/− (BALB/c) mice, but not splenomegaly and did not exhibit an accumulation of myeloid cells in the spleen as seen in Ptpn2−/− (BALB/c) mice. Moreover, thymic atrophy, another feature of Ptpn2−/− (BALB/c) mice, was delayed in Ptpn2ex2−/ex2− mice and preceded by an increase in thymocyte positive selection and a concomitant increase in lymph node T cells. Backcrossing Ptpn2−/− (BALB/c) mice onto the C57BL/6 background largely recapitulated the phenotype of Ptpn2ex2−/ex2− mice. Taken together these results reaffirm TCPTP's important role in lymphocyte development and indicate that the effects on morbidity, mortality, bone development and the myeloid compartment are strain-dependent

Fabry Disease in Latin America: Data from the Fabry Registry

The purpose of these analyses was to characterize demographic and baseline clinical characteristics of Latin American patients with Fabry disease compared to that of patients in the rest of the world. Observational data reported to the Fabry Registry were obtained from untreated patients or prior to treatment with enzyme replacement therapy. As of October 1, 2010, 3,752 patients were enrolled in the Fabry Registry worldwide, including 333 patients within Latin America. Latin American patients tended to be younger than Fabry Registry patients enrolled in the rest of the world: mean current age 35.5 years versus 39.2 years for men (p < 0.05 by t-test), mean age 37.8 years versus 43.6 years for women (p < 0.05 by t-test). A smaller percentage of Latin American patients have received enzyme replacement therapy, compared to patients in the rest of the world: 67% versus 80% for men, and 19% versus 39% of women, respectively. Thirty-one percent of men and 22% of women in Latin America reported experiencing a significant cardiovascular, renal, or cerebrovascular event, at a mean age of 35 ± 12.6 years in men and 44 ± 12.3 years in women. Cardiovascular events were the most common type of initial clinical event among men and women in Latin America. The medical community in Latin America should be aware of Fabry disease as a possible cause of renal or cardiac dysfunction. Increased awareness will facilitate prompt diagnosis and initiation of treatment

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11−/−) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11−/− mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11−/− mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11−/− female mice are infertile. Unlike Il11ra1−/− mice, Il11−/− mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling

Advancement into the Arctic Region for Bioactive Sponge Secondary Metabolites

Porifera have long been a reservoir for the discovery of bioactive compounds and drug discovery. Most research in the area has focused on sponges from tropical and temperate waters, but more recently the focus has shifted to the less accessible colder waters of the Antarctic and, to a lesser extent, the Arctic. The Antarctic region in particular has been a more popular location for natural products discovery and has provided promising candidates for drug development. This article reviews groups of bioactive compounds that have been isolated and reported from the southern reaches of the Arctic Circle, surveys the known sponge diversity present in the Arctic waters, and details a recent sponge collection by our group in the Aleutian Islands, Alaska. The collection has yielded previously undescribed sponge species along with primary activity against opportunistic infectious diseases, malaria, and HCV. The discovery of new sponge species and bioactive crude extracts gives optimism for the isolation of new bioactive compounds from a relatively unexplored source

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter

Evaluating the effects of increasing physical activity to optimize rehabilitation outcomes in hospitalized older adults (MOVE Trial): Study protocol for a randomized controlled trial

Background: Older adults who have received inpatient rehabilitation often have significant mobility disability at discharge. Physical activity levels in rehabilitation are also low. It is hypothesized that providing increased physical activity to older people receiving hospital-based rehabilitation will lead to better mobility outcomes at discharge. Methods/Design: A single blind, parallel-group, multisite randomized controlled trial with blinded assessment of outcome and intention-to-treat analysis. The cost effectiveness of the intervention will also be examined. Older people (age &gt;60 years) undergoing inpatient rehabilitation to improve mobility will be recruited from geriatric rehabilitation units at two Australian hospitals. A computer-generated blocked stratified randomization sequence will be used to assign 198 participants in a 1:1 ratio to either an 'enhanced physical activity' (intervention) group or a 'usual care plus' (control) group for the duration of their inpatient stay. Participants will receive usual care and either spend time each week performing additional physical activities such as standing or walking (intervention group) or performing an equal amount of social activities that have minimal impact on mobility such as card and board games (control group). Self-selected gait speed will be measured using a 6-meter walk test at discharge (primary outcome) and 6 months follow-up (secondary outcome). The study is powered to detect a 0.1 m/sec increase in self-selected gait speed in the intervention group at discharge. Additional measures of mobility (Timed Up and Go, De Morton Mobility Index), function (Functional Independence Measure) and quality of life will be obtained as secondary outcomes at discharge and tertiary outcomes at 6 months follow-up. The trial commenced recruitment on 28 January 2014. Discussion: This study will evaluate the efficacy and cost effectiveness of increasing physical activity in older people during inpatient rehabilitation. These results will assist in the development of evidenced-based rehabilitation programs for this population. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12613000884707(Date of registration 08 August 2013); ClinicalTrials.gov Identifier NCT01910740(Date of registration 22 July 2013)

Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates

Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative clonal mapping with 3D reconstruction of adult human prostates, we show that multipotent basal stem cells, confined to discrete niches in juxta-urethral ducts, generate bipotent basal progenitors in directed epithelial migration streams. Basal progenitors are then dispersed throughout the entire glandular network, dividing and differentiating to replenish the loss of apoptotic luminal cells. Rare lineage-restricted luminal stem cells, and their progeny, are confined to proximal ducts and provide only minor contribution to epithelial homeostasis. In situ cell capture from clonal maps identified delta homolog 1 (DLK1) enrichment of basal stem cells, which was validated in functional spheroid assays. This study establishes significant insights into niche organization and function of prostate stem and progenitor cells, with implications for disease.This work was supported by grants from The Royal College of Surgeons of England and a Cancer Research UK Clinician Scientist Fellowship (C10169/A12173). This work was also supported by the Wellcome Trust (grant 098357/Z/12/Z to B.D.S. and grant 110326/Z/15/Z to E.H.). E.H. is funded by a Junior Research Fellowship from Trinity College, Cambridge, a Sir Henry Wellcome Fellowship from the Wellcome Trust and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. L.C.G., D.M.T., and R.W.T. are supported by the Wellcome Trust Centre Strategic Award (096919/Z/11/Z). R.W.T. is also supported by the Medical Research Council (MRC) Centre for Neuromuscular Diseases (G0601943), the Lily Foundation, and the UK National Health Service (NHS) Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service. L.C.G. and D.M.T. receive support from the Newcastle University Centre for Ageing and Vitality funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC), and MRC as part of the cross-council Lifelong Health and Wellbeing Initiative