Envelope Structure of Starless Core L694-2 Derived from a Near-Infrared Extinction Map

We present a near-infrared extinction study of the dark globule L694-2, a starless core that shows strong evidence for inward motions in molecular line profiles. The J,H, and K band data were taken using the European Southern Observatory New Technology Telescope. The best fit simple spherical power law model has index p=2.6 +/- 0.2, over the 0.036--0.1 pc range in radius sampled in extinction. This power law slope is steeper than the value of p=2 for a singular isothermal sphere, the initial condition of the inside-out model for protostellar collapse. Including an additional extinction component along the line of sight further steepens the inferred profile. Fitting a Bonnor-Ebert sphere results in a super-critical value of the dimensionless radius xi_max=25 +/- 3. The unstable configuration of material may be related to the observed inward motions. The Bonnor-Ebert model matches the shape of the observed profile, but significantly underestimates the amount of extinction (by a factor of ~4). This discrepancy in normalization has also been found for the nearby protostellar core B335 (Harvey et al. 2001). A cylindrical density model with scale height H=0.0164+/- 0.002 pc viewed at a small inclination to the cylinder axis provides an equally good radial profile as a power law model, and reproduces the asymmetry of the core remarkably well. In addition, this model provides a basis for understanding the discrepancy in the normalization of the Bonnor-Ebert model, namely that L694-2 has prolate structure, with the full extent (mass) of the core being missed by assuming symmetry between the profiles in the plane of the sky and along the line-of-sight. If the core is sufficiently magnetized then fragmentation may be avoided, and later evolution might produce a protostar similar to B335.Comment: 38 pages, 7 figures, accepted to Astrophysical Journa

The organization of the transcriptional network in specific neuronal classes

Genome-wide expression profiling has aided the understanding of the molecular basis of neuronal diversity, but achieving broad functional insight remains a considerable challenge. Here, we perform the first systems-level analysis of microarray data from single neuronal populations using weighted gene co-expression network analysis to examine how neuronal transcriptome organization relates to neuronal function and diversity. We systematically validate network predictions using published proteomic and genomic data. Several network modules of co-expressed genes correspond to interneuron development programs, in which the hub genes are known to be critical for interneuron specification. Other co-expression modules relate to fundamental cellular functions, such as energy production, firing rate, trafficking, and synapses, suggesting that fundamental aspects of neuronal diversity are produced by quantitative variation in basic metabolic processes. We identify two transcriptionally distinct mitochondrial modules and demonstrate that one corresponds to mitochondria enriched in neuronal processes and synapses, whereas the other represents a population restricted to the soma. Finally, we show that galectin-1 is a new interneuron marker, and we validate network predictions in vivo using Rgs4 and Dlx1/2 knockout mice. These analyses provide a basis for understanding how specific aspects of neuronal phenotypic diversity are organized at the transcriptional level

Epistatic Interactions Between Mutations of Deoxyribonuclease 1-Like 3 and the Inhibitory Fc Gamma Receptor IIB Result in Very Early and Massive Autoantibodies Against Double-Stranded DNA

Autoantibodies against double-stranded DNA (anti-dsDNA) are a hallmark of systemic lupus erythematosus (SLE). It is well documented that anti-dsDNA reactive B lymphocytes are normally controlled by immune self-tolerance mechanisms operating at several levels. The evolution of high levels of IgG anti-dsDNA in SLE is dependent on somatic hypermutation and clonal selection, presumably in germinal centers from non-autoreactive B cells. Twin studies as well as genetic studies in mice indicate a very strong genetic contribution for the development of anti-dsDNA as well as SLE. Only few single gene defects with a monogenic Mendelian inheritance have been described so far that are directly responsible for the development of anti-dsDNA and SLE. Recently, among other mutations, rare null-alleles for the deoxyribonuclease 1 like 3 (DNASE1L3) and the Fc gamma receptor IIB (FCGR2B) have been described in SLE patients and genetic mouse models. Here, we demonstrate that double Dnase1l3- and FcgR2b-deficient mice in the C57BL/6 background exhibit a very early and massive IgG anti-dsDNA production. Already at 10 weeks of age, autoantibody production in double-deficient mice exceeds autoantibody levels of diseased 9-month-old NZB/W mice, a long established multigenic SLE mouse model. In single gene-deficient mice, autoantibody levels were moderately elevated at early age of the mice. Premature autoantibody production was accompanied by a spontaneous hyperactivation of germinal centers, early expansions of T follicular helper cells, and elevated plasmablasts in the spleen. Anti-dsDNA hybridomas generated from double-deficient mice show significantly elevated numbers of arginines in the CDR3 regions of the heavy-chain as well as clonal expansions and diversification of B cell clones with moderate numbers of somatic mutations. Our findings show a strong epistatic interaction of two SLE-alleles which prevent early and high-level anti-dsDNA autoantibody production. Both genes apparently synergize to keep in check excessive germinal center reactions evolving into IgG anti-dsDNA antibody producing B cells

Spectral Evolution of Energetic Neutral Atom Emissions at the Heliospheric Poles as Measured by \u3ci\u3eIBEX\u3c/i\u3e during its First Three Yeras

The Interstellar Boundary Explorer (IBEX) mission continues to measure energetic neutral atom (ENA) emissions produced by charge exchange between solar wind (SW) protons and interstellar neutrals at the edge of our heliosphere. Using the first 3 yr of IBEX-Hi ENA measurements (2009-2011), we examined the spectral evolution of ~0.5-6 keV ENAs at the polar regions (above 60°). We found the following: (1) pixels with a characteristic ankle spectra (lower spectral index at higher energies) increase by ~5% in 2010 and ~10% in 2011 compared to 2009. (2) The averaged spectral index in 2011 is smaller than that of 2009. (3) The slope of the ENA spectrum above ~1.7 keV is more variable than the slope below ~1.7 keV. The lower spectral index at higher energies of the spectrum does not appear to be caused by an increase of the ENA production at these energies, but rather from a consistent decrease at lower energies. (4) The decrease in polar ENA fluxes does not correlate significantly with the averaged SW dynamic pressure, back-traced in time to 1 AU along the flow streamlines (originating between 10° and 30° for slow SW, and 60° and 80°for fast SW), assuming these are the respective conditions of ENA progenitors back in time. These results provide insights into the complexity of relating the slow and fast SW contributions to polar ENAs and shed light on how the solar output and the resulting change in the global heliospheric structure possibly affect the heliohealth (HS) populations

Elemental and Isotopic Analysis of Uranium Oxide an NIST Glass Standards by FEMTOSECOND-LA-ICP-MIC-MS

The objective of this work was to test and demonstrate the analytical figures of merit of a femtosecond-laser ablation (fs-LA) system coupled with an inductively coupled plasma-multi-ion collector-mass spectrometer (ICP-MIC-MS). The mobile fs-LA sampling system was designed and assembled at Ames Laboratory and shipped to Oak Ridge National Laboratory (ORNL), where it was integrated with an ICP-MIC-MS. The test period of the integrated systems was February 2-6, 2009. Spatially-resolved analysis of particulate samples is accomplished by 100-shot laser ablation using a fs-pulsewidth laser and monitoring selected isotopes in the resulting ICP-MS transient signal. The capability of performing high sensitivity, spatially resolved, isotopic analyses with high accuracy and precision and with virtually no sample preparation makes fs-LA-ICP-MIC-MS valuable for the measurement of actinide isotopes at low concentrations in very small samples for nonproliferation purposes. Femtosecond-LA has been shown to generate particles from the sample that are more representative of the bulk composition, thereby minimizing weaknesses encountered in previous work using nanosecond-LA (ns-LA). The improvement of fs- over ns-LA sampling arises from the different mechanisms for transfer of energy into the sample in these two laser pulse-length regimes. The shorter duration fs-LA pulses induce less heating and cause less damage to the sample than the longer ns pulses. This results in better stoichiometric sampling (i.e., a closer correlation between the composition of the ablated particles and that of the original solid sample), which improves accuracy for both intra- and inter-elemental analysis. The primary samples analyzed in this work are (a) solid uranium oxide powdered samples having different {sup 235}U to {sup 238}U concentration ratios, and (b) glass reference materials (NIST 610, 612, 614, and 616). Solid uranium oxide samples containing {sup 235}U in depleted, natural, and enriched abundances were analyzed as particle aggregates immobilized in a collodion substrate. The uranium oxide samples were nuclear reference materials (CRMs U0002, U005-A, 129-A, U015, U030-A, and U050) obtained from New Brunswick Laboratory-USDOE

MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia

BACKGROUND: The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). METHODS AND FINDINGS: DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9–4.0 × 10 (12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. CONCLUSIONS: Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD

For whom does it work? Moderators of outcome on the effect of a transdiagnostic internet-based maintenance treatment after inpatient psychotherapy: Randomized controlled trial

Background: Recent studies provide evidence for the effectiveness of Internet-based maintenance treatments for mental disorders. However, it is still unclear which participants might or might not profit from this particular kind of treatment delivery. Objective: The study aimed to identify moderators of treatment outcome in a transdiagnostic Internet-based maintenance treatment (TIMT) offered to patients after inpatient psychotherapy for mental disorders in routine care. Methods: Using data from a randomized controlled trial (N=400) designed to test the effectiveness of TIMT, we performed secondary analyses to identify factors moderating the effects of TIMT (intervention) when compared with those of a treatment-as-usual control condition. TIMT involved an online self-management module, asynchronous patient-therapist communication, a peer support group, and online-based progress monitoring. Participants in the control condition had unstructured access to outpatient psychotherapy, standardized outpatient face-to-face continuation treatment, and psychotropic management. Self-reports of psychopathological symptoms and potential moderators were assessed at the start of inpatient treatment (T1), at discharge from inpatient treatment/start of TIMT (T2), and at 3-month (T3) and 12-month follow-up (T4). Results: Education level, positive outcome expectations, and diagnoses significantly moderated intervention versus control differences regarding changes in outcomes between T2 and T3. Only education level moderated change differences between T2 and T4. The effectiveness of the intervention (vs control) was more pronounced among participants with a low (vs high) education level (T2-T3: B=-0.32, SE 0.16, P=.049; T2-T4: B=-0.42, SE 0.21, P=.049), participants with high (vs low) positive outcome expectations (T2-T3: B=-0.12, SE 0.05, P=.02) and participants with anxiety disorder (vs mood disorder) (T2-T3: B=-0.43, SE 0.21, P=.04). Simple slope analyses revealed that despite some subgroups benefiting less from the intervention than others, all subgroups still benefited significantly. Conclusions: This transdiagnostic Internet-based maintenance treatment might be suitable for a wide range of participants differing in various clinical, motivational, and demographic characteristics. The treatment is especially effective for participants with low education levels. These findings may generalize to other Internet-based maintenance treatments. Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 28632626; http://www.controlled-trials.com/isrctn/pf/ 28632626 (Archived by WebCite at http://www.webcitation.org/6IqZjTLrx). © David Daniel Ebert, Mario Gollwitzer, Heleen Riper, Pim Cuijpers, Harald Baumeister, Matthias Berking

Disruption of DNA methylation-dependent long gene repression in Rett syndrome

Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism1. MECP2 encodes a methyl-DNA-binding protein2 that has been proposed to function as a transcriptional repressor, but despite numerous studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 regulates transcription3–9. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain

Overfishing Drives Over One-Third of All Sharks and Rays Toward a Global Extinction Crisis

The scale and drivers of marine biodiversity loss are being revealed by the International Union for Conservation of Nature (IUCN) Red List assessment process. We present the first global reassessment of 1,199 species in Class Chondrichthyes-sharks, rays, and chimeras. The first global assessment (in 2014) concluded that one-quarter (24%) of species were threatened. Now, 391 (32.6%) species are threatened with extinction. When this percentage of threat is applied to Data Deficient species, more than one-third (37.5%) of chondrichthyans are estimated to be threatened, with much of this change resulting from new information. Three species are Critically Endangered (Possibly Extinct), representing possibly the first global marine fish extinctions due to overfishing. Consequently, the chondrichthyan extinction rate is potentially 25 extinctions per million species years, comparable to that of terrestrial vertebrates. Overfishing is the universal threat affecting all 391 threatened species and is the sole threat for 67.3% of species and interacts with three other threats for the remaining third: loss and degradation of habitat (31.2% of threatened species), climate change (10.2%), and pollution (6.9%). Species are disproportionately threatened in tropical and subtropical coastal waters. Science-based limits on fishing, effective marine protected areas, and approaches that reduce or eliminate fishing mortality are urgently needed to minimize mortality of threatened species and ensure sustainable catch and trade of others. Immediate action is essential to prevent further extinctions and protect the potential for food security and ecosystem functions provided by this iconic lineage of predators

Carcharhinus hemiodon Pondicherry Shark

The Pondicherry Shark (Carcharhinus hemiodon) is a small (to 102 cm total length) and very rare Indo- West Pacific whaler shark. It has a wide historic range from Oman to southern China, but known records are scattered, and it has only been reliably verified from a handful of countries. It appears to occur in shallow coastal waters, and has also been reported to enter rivers, although this has not been verified. The contemporary range of this species is poorly defined and museum specimens were collected pre- 1960. There are reports from 1979, the 1990s, and 2000, but none of these could be verified. Its identification is problematic, and it is easily confused with a number of other Carcharhinus species (for example, recent putative records from Sri Lanka)