EXCITATION CONDITIONS IN THE MULTI-COMPONENT SUBMILLIMETER GALAXY SMM J00266+1708

We present multiline CO observations of the complex submillimeter galaxy SMMJ00266+1708. Using the Zpectrometer on the Green Bank Telescope, we provide the first precise spectroscopic measurement of its redshift (z = 2.742). Based on followup CO(1–0), CO(3–2), and CO(5–4) mapping, SMMJ00266+1708 appears to have two distinct components separated by ∼ 500 kms−1 that are nearly coincident along our line of sight. The two components show hints of different kinematics, with the blue-shifted component dispersion-dominated and the red-shifted component showing a clear velocity gradient. CO line ratios differ slightly between the two components, indicating that the physical conditions in their molecular gas may not be alike. We tentatively infer that SMMJ00266+1708 is an on going merger with a mass ratio of (7.8±4.0)/ sin2(i), with its overall size and surface brightness closely resembling that of other merging systems. We perform large velocity gradient modeling of the CO emission from both components and find that each component’s properties are consistent with a single phase of molecular gas (i.e., a single temperatures and density); additional multi-phase modelling of the red-shifted component, although motivated by a CO(1–0) size larger than the CO(3–2) size, is inconclusive. SMMJ00266+1708 provides evidence of early stage mergers within the submillimeter galaxy population. Continuum observations of J00266 at the ∼ 1′′ resolution of our observations could not have distinguished between the two components due to their separation (0.′′73 ± 0.′′06), illustrating that the additional velocity information provided by spectral line studies is important for addressing the prevalence of unresolved galaxy pairs in low-resolution submillimeter surveys

Excitation Conditions in the Multi-component Submillimeter Galaxy SMM J00266+1708

We present multiline CO observations of the complex submillimeter galaxy SMM J00266+1708. Using the Zpectrometer on the Green Bank Telescope, we provide the first precise spectroscopic measurement of its redshift (z=2.742). Based on followup CO(1-0), CO(3-2), and CO(5-4) mapping, SMM J00266+1708 appears to have two distinct components separated by ~500 km/s that are nearly coincident along our line of sight. The two components show hints of different kinematics, with the blue-shifted component dispersion-dominated and the red-shifted component showing a clear velocity gradient. CO line ratios differ slightly between the two components, indicating that the physical conditions in their molecular gas may not be alike. We tentatively infer that SMM J00266+1708 is an ongoing merger with a mass ratio of (7.8+/-4.0)/sin^2(i), with its overall size and surface brightness closely resembling that of other merging systems. We perform large velocity gradient modeling of the CO emission from both components and find that each component's properties are consistent with a single phase of molecular gas (i.e., a single temperatures and density); additional multi-phase modeling of the red-shifted component, although motivated by a CO(1-0) size larger than the CO(3-2) size, is inconclusive. SMM J00266+1708 provides evidence of early stage mergers within the submillimeter galaxy population. Continuum observations of J00266 at the ~1" resolution of our observations could not have distinguished between the two components due to their separation (0.73" +/- 0.06"), illustrating that the additional velocity information provided by spectral line studies is important for addressing the prevalence of unresolved galaxy pairs in low-resolution submillimeter surveys

A DYNC1H1 mutation in autosomal dominant spinal muscular atrophy shows the potential of pharmacological inhibition of histone deacetylase 6 as a treatment for disease associated cellular phenotypes

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Targeted hepatitis C antibody testing interventions: a systematic review and meta-analysis

Testing for hepatitis C virus (HCV) infection may reduce the risk of liver-related morbidity, by facilitating earlier access to treatment and care. This review investigated the effectiveness of targeted testing interventions on HCV case detection, treatment uptake, and prevention of liver-related morbidity. A literature search identified studies published up to 2013 that compared a targeted HCV testing intervention (targeting individuals or groups at increased risk of HCV) with no targeted intervention, and results were synthesised using meta-analysis. Exposure to a targeted testing intervention, compared to no targeted intervention, was associated with increased cases detected [number of studies (n) = 14; pooled relative risk (RR) 1.7, 95 % CI 1.3, 2.2] and patients commencing therapy (n = 4; RR 3.3, 95 % CI 1.1, 10.0). Practitioner-based interventions increased test uptake and cases detected (n = 12; RR 3.5, 95 % CI 2.5, 4.8; and n = 10; RR 2.2, 95 % CI 1.4, 3.5, respectively), whereas media/information-based interventions were less effective (n = 4; RR 1.5, 95 % CI 0.7, 3.0; and n = 4; RR 1.3, 95 % CI 1.0, 1.6, respectively). This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. It is recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

Interventions encouraging the use of systematic reviews by health policymakers and managers: A systematic review

<p>Abstract</p> <p>Background</p> <p>Systematic reviews have the potential to inform decisions made by health policymakers and managers, yet little is known about the impact of interventions to increase the use of systematic reviews by these groups in decision making.</p> <p>Methods</p> <p>We systematically reviewed the evidence on the impact of interventions for seeking, appraising, and applying evidence from systematic reviews in decision making by health policymakers or managers. Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment Database, and LISA were searched from the earliest date available until April 2010. Two independent reviewers selected studies for inclusion if the intervention intended to increase seeking, appraising, or applying evidence from systematic reviews by a health policymaker or manager. Minimum inclusion criteria were a description of the study population and availability of extractable data.</p> <p>Results</p> <p>11,297 titles and abstracts were reviewed, leading to retrieval of 37 full-text articles for assessment; four of these articles met all inclusion criteria. Three articles described one study where five systematic reviews were mailed to public health officials and followed up with surveys at three months and two years. The articles reported from 23% to 63% of respondents declaring they had used systematic reviews in policymaking decisions. One randomised trial indicated that tailored messages combined with access to a registry of systematic reviews had a significant effect on policies made in the area of healthy body weight promotion in health departments.</p> <p>Conclusions</p> <p>The limited empirical data renders the strength of evidence weak for the effectiveness and the types of interventions that encourage health policymakers and managers to use systematic reviews in decision making.</p

Catalytic Function of PLA2G6 Is Impaired by Mutations Associated with Infantile Neuroaxonal Dystrophy but Not Dystonia-Parkinsonism

Mutations in the PLA2G6 gene have been identified in autosomal recessive neurodegenerative diseases classified as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and dystonia-parkinsonism. These clinical syndromes display two significantly different disease phenotypes. NBIA and INAD are very similar, involving widespread neurodegeneration that begins within the first 1-2 years of life. In contrast, patients with dystonia-parkinsonism present with a parkinsonian movement disorder beginning at 15 to 30 years of age. The PLA2G6 gene encodes the PLA2G6 enzyme, also known as group VIA calcium-independent phospholipase A(2), which has previously been shown to hydrolyze the sn-2 acyl chain of phospholipids, generating free fatty acids and lysophospholipids.We produced purified recombinant wildtype (WT) and mutant human PLA2G6 proteins and examined their catalytic function using in vitro assays with radiolabeled lipid substrates. We find that human PLA2G6 enzyme hydrolyzes both phospholipids and lysophospholipids, releasing free fatty acids. Mutations associated with different disease phenotypes have different effects on catalytic activity. Mutations associated with INAD/NBIA cause loss of enzyme activity, with mutant proteins exhibiting less than 20% of the specific activity of WT protein in both lysophospholipase and phospholipase assays. In contrast, mutations associated with dystonia-parkinsonism do not impair catalytic activity, and two mutations produce a significant increase in specific activity for phospholipid but not lysophospholipid substrates.These results indicate that different alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids, which predicts accumulation of PLA2G6 phospholipid substrates and provides a mechanistic explanation for the accumulation of membranes in neuroaxonal spheroids previously observed in histopathological studies of INAD/NBIA. In contrast, dystonia-parkinsonism mutations do not appear to directly impair catalytic function, but may modify substrate preferences or regulatory mechanisms for PLA2G6

A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation

Background: A sterilizing cure of HIV-1 infection has been reported in 2 persons living with HIV-1 who underwent allogeneic hematopoietic stem cell transplantations from donors who were homozygous for the CCR5D32 gene polymorphism. However, this has been considered elusive during natural infection. Objective: To evaluate persistent HIV-1 reservoir cells in an elite controller with undetectable HIV-1 viremia for more than 8 years in the absence of antiretroviral therapy. Design: Detailed investigation of virologic and immunologic characteristics. Setting: Tertiary care centers in Buenos Aires, Argentina, and Boston, Massachusetts. Patient: A patient with HIV-1 infection and durable drug-free suppression of HIV-1 replication. Measurements: Analysis of genome-intact and replication-competent HIV-1 using near-full-length individual proviral sequencing and viral outgrowth assays, respectively; analysis of HIV-1 plasma RNA by ultrasensitive HIV-1 viral load testing. Results: No genome-intact HIV-1 proviruses were detected in analysis of a total of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissues. Seven defective proviruses, some of them derived from clonally expanded cells, were detected. A viral outgrowth assay failed to retrieve replication-competent HIV-1 from 150 million resting CD4+ T cells. No HIV-1 RNA was detected in 4.5 mL of plasma. Limitations: Absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses. A sterilizing cure of HIV-1 can never be empirically proved. Conclusion: Genome-intact and replication-competent HIV-1 were not detected in an elite controller despite analysis of massive numbers of cells from blood and tissues, suggesting that this patient may have naturally achieved a sterilizing cure of HIV-1 infection. These observations raise the possibility that a sterilizing cure may be an extremely rare but possible outcome of HIV-1 infection.Fil: Turk, Gabriela Julia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Seiger, Kyra. Massachusetts Institute of Technology; Estados UnidosFil: Lian, Xiaodong. Massachusetts Institute of Technology; Estados UnidosFil: Sun, Weiwei. Massachusetts Institute of Technology; Estados UnidosFil: Parsons, Elizabeth M.. Massachusetts Institute of Technology; Estados UnidosFil: Gao, Ce. Massachusetts Institute of Technology; Estados UnidosFil: Rassadkina, Yelizaveta. Massachusetts Institute of Technology; Estados UnidosFil: Polo, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Czernikier, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Ghiglione, Yanina Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Vellicce, Alejandra Fabiana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Varriale, Joseph. No especifíca;Fil: Lai, Jun. No especifíca;Fil: Yuki, Yuko. No especifíca;Fil: Martin, Maureen. No especifíca;Fil: Rhodes, Ajantha. University of Melbourne; AustraliaFil: Lewin, Sharon R.. University of Melbourne; Australia. Monash University; AustraliaFil: Walker, Bruce D.. Massachusetts Institute of Technology; Estados UnidosFil: Carrington, Mary. Massachusetts Institute of Technology; Estados UnidosFil: Siliciano, Robert. No especifíca;Fil: Siliciano, Janet. No especifíca;Fil: Lichterfeld, Mathias. Massachusetts Institute of Technology; Estados UnidosFil: Laufer, Natalia Lorna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Yu, Xu G.. Massachusetts Institute of Technology; Estados Unido

Endogenous Wnt/β-Catenin Signaling Is Required for Cardiac Differentiation in Human Embryonic Stem Cells

Wnt/beta-catenin signaling is an important regulator of differentiation and morphogenesis that can also control stem cell fates. Our group has developed an efficient protocol to generate cardiomyocytes from human embryonic stem (ES) cells via induction with activin A and BMP4.We tested the hypothesis that Wnt/beta-catenin signals control both early mesoderm induction and later cardiac differentiation in this system. Addition of exogenous Wnt3a at the time of induction enhanced cardiac differentiation, while early inhibition of endogenous Wnt/beta-catenin signaling with Dkk1 inhibited cardiac differentiation, as indicated by quantitative RT-PCR analysis for beta-myosin heavy chain (beta-MHC), cardiac troponin T (cTnT), Nkx2.5, and flow cytometry analysis for sarcomeric myosin heavy chain (sMHC). Conversely, late antagonism of endogenously produced Wnts enhanced cardiogenesis, indicating a biphasic role for the pathway in human cardiac differentiation. Using quantitative RT-PCR, we show that canonical Wnt ligand expression is induced by activin A/BMP4 treatment, and the extent of early Wnt ligand expression can predict the subsequent efficiency of cardiogenesis. Measurement of Brachyury expression showed that addition of Wnt3a enhances mesoderm induction, whereas blockade of endogenously produced Wnts markedly inhibits mesoderm formation. Finally, we show that Wnt/beta-catenin signaling is required for Smad1 activation by BMP4.Our data indicate that induction of mesoderm and subsequent cardiac differentiation from human ES cells requires fine-tuned cross talk between activin A/BMP4 and Wnt/beta-catenin pathways. Controlling these pathways permits efficient generation of cardiomyocytes for basic studies or cardiac repair applications

The ACCESS study a Zelen randomised controlled trial of a treatment package including problem solving therapy compared to treatment as usual in people who present to hospital after self-harm: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>People who present to hospital after intentionally harming themselves pose a common and important problem. Previous reviews of interventions have been inconclusive as existing trials have been under powered and done on unrepresentative populations. These reviews have however indicated that problem solving therapy and regular written communications after the self-harm attempt may be an effective treatment. This protocol describes a large pragmatic trial of a package of measures which include problem solving therapy, regular written communication, patient support, cultural assessment, improved access to primary care and a risk management strategy in people who present to hospital after self-harm using a novel design.</p> <p>Methods</p> <p>We propose to use a double consent Zelen design where participants are randomised prior to giving consent to enrol a large representative cohort of patients. The main outcome will be hospital attendance following repetition of self-harm, in the 12 months after recruitment with secondary outcomes of self reported self-harm, hopelessness, anxiety, depression, quality of life, social function and hospital use at three months and one year.</p> <p>Discussion</p> <p>A strength of the study is that it is a pragmatic trial which aims to recruit large numbers and does not exclude people if English is not their first language. A potential limitation is the analysis of the results which is complex and may underestimate any effect if a large number of people refuse their consent in the group randomised to problem solving therapy as they will effectively cross over to the treatment as usual group. However the primary analysis is a true intention to treat analysis of everyone randomised which includes both those who consent and do not consent to participate in the study. This provides information about how the intervention will work in practice in a representative population which is a major advance in this study compared to what has been done before.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000641291.aspx">ACTRN12609000641291</a></p