Subduction initiation and ophiolite crust: new insights from IODP drilling

International Ocean Discovery Program (IODP) Expedition 352 recovered a high-fidelity record of volcanism related to subduction initiation in the Bonin fore-arc. Two sites (U1440 and U1441) located in deep water nearer to the trench recovered basalts and related rocks; two sites (U1439 and U1442) located in shallower water further from the trench recovered boninites and related rocks. Drilling in both areas ended in dolerites inferred to be sheeted intrusive rocks. The basalts apparently erupted immediately after subduction initiation and have compositions similar to those of the most depleted basalts generated by rapid sea-floor spreading at mid-ocean ridges, with little or no slab input. Subsequent melting to generate boninites involved more depleted mantle and hotter and deeper subducted components as subduction progressed and volcanism migrated away from the trench. This volcanic sequence is akin to that recorded by many ophiolites, supporting a direct link between subduction initiation, fore-arc spreading, and ophiolite genesis

Principles of early human development and germ cell program from conserved model systems

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during week 2-3 of early postimplantation development(1). Using in vitro models of hPGC induction(2-4), recent studies suggest striking mechanistic differences in specification of human and mouse PGCs(5). This may partly be due to the divergence in their pluripotency networks, and early postimplantation development(6-8). Since early human embryos are inaccessible for direct studies, we considered alternatives, including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs (pPGCs) originate from the posterior pre-primitive streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. Together with human and monkey in vitro models simulating peri-gastrulation development, we show conserved principles for epiblast development for competency for PGC fate, followed by initiation of the epigenetic program(9-11), regulated by a balanced SOX17–BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models, provides synthetic insights on early human development

Systematic identification of conserved motif modules in the human genome

<p>Abstract</p> <p>Background</p> <p>The identification of motif modules, groups of multiple motifs frequently occurring in DNA sequences, is one of the most important tasks necessary for annotating the human genome. Current approaches to identifying motif modules are often restricted to searches within promoter regions or rely on multiple genome alignments. However, the promoter regions only account for a limited number of locations where transcription factor binding sites can occur, and multiple genome alignments often cannot align binding sites with their true counterparts because of the short and degenerative nature of these transcription factor binding sites.</p> <p>Results</p> <p>To identify motif modules systematically, we developed a computational method for the entire non-coding regions around human genes that does not rely upon the use of multiple genome alignments. First, we selected orthologous DNA blocks approximately 1-kilobase in length based on discontiguous sequence similarity. Next, we scanned the conserved segments in these blocks using known motifs in the TRANSFAC database. Finally, a frequent pattern mining technique was applied to identify motif modules within these blocks. In total, with a false discovery rate cutoff of 0.05, we predicted 3,161,839 motif modules, 90.8% of which are supported by various forms of functional evidence. Compared with experimental data from 14 ChIP-seq experiments, on average, our methods predicted 69.6% of the ChIP-seq peaks with TFBSs of multiple TFs. Our findings also show that many motif modules have distance preference and order preference among the motifs, which further supports the functionality of these predictions.</p> <p>Conclusions</p> <p>Our work provides a large-scale prediction of motif modules in mammals, which will facilitate the understanding of gene regulation in a systematic way.</p

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Sub-Optimal Vitamin B-12 Levels among ART-Naïve HIV-Positive Individuals in an Urban Cohort in Uganda

Malnutrition is common among HIV-infected individuals and is often accompanied by low serum levels of micronutrients. Vitamin B-12 deficiency has been associated with various factors including faster HIV disease progression and CD4 depletion in resource-rich settings. To describe prevalence and factors associated with sub-optimal vitamin B-12 levels among HIV-infected antiretroviral therapy (ART) naïve adults in a resource-poor setting, we performed a cross-sectional study with a retrospective chart review among individuals attending either the Mulago-Mbarara teaching hospitals’ Joint AIDS Program (MJAP) or the Infectious Diseases Institute (IDI) clinics, in Kampala, Uganda. Logistic regression was used to determine factors associated with sub-optimal vitamin B-12. The mean vitamin B-12 level was 384 pg/ml, normal range (200–900). Sub-optimal vitamin B-12 levels (<300 pg/ml) were found in 75/204 (36.8%). Twenty-one of 204 (10.3%) had vitamin B-12 deficiency (<200 pg/ml) while 54/204 (26.5%) had marginal depletion (200–300 pg/ml). Irritable mood was observed more among individuals with sub-optimal vitamin B-12 levels (OR 2.5, 95% CI; 1.1–5.6, P = 0.03). Increasing MCV was associated with decreasing serum B-12 category; 86.9 fl (±5.1) vs. 83 fl (±8.4) vs. 82 fl (±8.4) for B-12 deficiency, marginal and normal B-12 categories respectively (test for trend, P = 0.017). Compared to normal B-12, individuals with vitamin B-12 deficiency had a longer known duration of HIV infection: 42.2 months (±27.1) vs. 29.4 months (±23.8; P = 0.02). Participants eligible for ART (CD4<350 cells/µl) with sub-optimal B-12 had a higher mean rate of CD4 decline compared to counterparts with normal B-12; 118 (±145) vs. 22 (±115) cells/µl/year, P = 0.01 respectively. The prevalence of a sub-optimal vitamin B-12 was high in this HIV-infected, ART-naïve adult clinic population in urban Uganda. We recommend prospective studies to further clarify the causal relationships of sub-optimal vitamin B-12, and explore the role of vitamin B-12 supplementation in immune recovery

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Effect of sedation with detomidine and butorphanol on pulmonary gas exchange in the horse

<p>Abstract</p> <p>Background</p> <p>Sedation with α₂-agonists in the horse is reported to be accompanied by impairment of arterial oxygenation. The present study was undertaken to investigate pulmonary gas exchange using the Multiple Inert Gas Elimination Technique (MIGET), during sedation with the α₂-agonist detomidine alone and in combination with the opioid butorphanol.</p> <p>Methods</p> <p>Seven Standardbred trotter horses aged 3–7 years and weighing 380–520 kg, were studied. The protocol consisted of three consecutive measurements; in the unsedated horse, after intravenous administration of detomidine (0.02 mg/kg) and after subsequent butorphanol administration (0.025 mg/kg). Pulmonary function and haemodynamic effects were investigated. The distribution of ventilation-perfusion ratios (V_A/Q) was estimated with MIGET.</p> <p>Results</p> <p>During detomidine sedation, arterial oxygen tension (PaO₂) decreased (12.8 ± 0.7 to 10.8 ± 1.2 kPa) and arterial carbon dioxide tension (PaCO₂) increased (5.9 ± 0.3 to 6.1 ± 0.2 kPa) compared to measurements in the unsedated horse. Mismatch between ventilation and perfusion in the lungs was evident, but no increase in intrapulmonary shunt could be detected. Respiratory rate and minute ventilation did not change. Heart rate and cardiac output decreased, while pulmonary and systemic blood pressure and vascular resistance increased. Addition of butorphanol resulted in a significant decrease in ventilation and increase in PaCO₂. Alveolar-arterial oxygen content difference P(A-a)O₂remained impaired after butorphanol administration, the V_A/Q distribution improved as the decreased ventilation and persistent low blood flow was well matched. Also after subsequent butorphanol no increase in intrapulmonary shunt was evident.</p> <p>Conclusion</p> <p>The results of the present study suggest that both pulmonary and cardiovascular factors contribute to the impaired pulmonary gas exchange during detomidine and butorphanol sedation in the horse.</p