The Relationship Between Molecular Gas, HI, and Star Formation in the Low-Mass, Low-Metallicity Magellanic Clouds

The Magellanic Clouds provide the only laboratory to study the effect of metallicity and galaxy mass on molecular gas and star formation at high (~20 pc) resolution. We use the dust emission from HERITAGE Herschel data to map the molecular gas in the Magellanic Clouds, avoiding the known biases of CO emission as a tracer of H$_{2}$. Using our dust-based molecular gas estimates, we find molecular gas depletion times of ~0.4 Gyr in the LMC and ~0.6 SMC at 1 kpc scales. These depletion times fall within the range found for normal disk galaxies, but are shorter than the average value, which could be due to recent bursts in star formation. We find no evidence for a strong intrinsic dependence of the molecular gas depletion time on metallicity. We study the relationship between gas and star formation rate across a range in size scales from 20 pc to ~1 kpc, including how the scatter in molecular gas depletion time changes with size scale, and discuss the physical mechanisms driving the relationships. We compare the metallicity-dependent star formation models of Ostriker, McKee, and Leroy (2010) and Krumholz (2013) to our observations and find that they both predict the trend in the data, suggesting that the inclusion of a diffuse neutral medium is important at lower metallicity.Comment: 24 pages, 14 figures, accepted for publication in ApJ. FITS files of the dust-based estimates of the H2 column densities for the LMC and SMC (shown in Figures 2 and 3) will be available online through Ap

Allele-specific transcriptional elongation regulates monoallelic expression of the IGF2BP1 gene

<p>Abstract</p> <p>Background</p> <p>Random monoallelic expression contributes to phenotypic variation of cells and organisms. However, the epigenetic mechanisms by which individual alleles are randomly selected for expression are not known. Taking cues from chromatin signatures at imprinted gene loci such as the insulin-like growth factor 2 gene 2 (<it>IGF2</it>), we evaluated the contribution of CTCF, a zinc finger protein required for parent-of-origin-specific expression of the <it>IGF2 </it>gene, as well as a role for allele-specific association with DNA methylation, histone modification and RNA polymerase II.</p> <p>Results</p> <p>Using array-based chromatin immunoprecipitation, we identified 293 genomic loci that are associated with both CTCF and histone H3 trimethylated at lysine 9 (H3K9me3). A comparison of their genomic positions with those of previously published monoallelically expressed genes revealed no significant overlap between allele-specifically expressed genes and colocalized CTCF/H3K9me3. To analyze the contributions of CTCF and H3K9me3 to gene regulation in more detail, we focused on the monoallelically expressed <it>IGF2BP1 </it>gene. <it>In vitro </it>binding assays using the CTCF target motif at the <it>IGF2BP1 </it>gene, as well as allele-specific analysis of cytosine methylation and CTCF binding, revealed that CTCF does not regulate mono- or biallelic <it>IGF2BP1 </it>expression. Surprisingly, we found that RNA polymerase II is detected on both the maternal and paternal alleles in B lymphoblasts that express <it>IGF2BP1 </it>primarily from one allele. Thus, allele-specific control of RNA polymerase II elongation regulates the allelic bias of <it>IGF2BP1 </it>gene expression.</p> <p>Conclusions</p> <p>Colocalization of CTCF and H3K9me3 does not represent a reliable chromatin signature indicative of monoallelic expression. Moreover, association of individual alleles with both active (H3K4me3) and silent (H3K27me3) chromatin modifications (allelic bivalent chromatin) or with RNA polymerase II also fails to identify monoallelically expressed gene loci. The selection of individual alleles for expression occurs in part during transcription elongation.</p

Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements

Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Here we present a high-throughput 3C approach, 3C-Carbon Copy (5C), that employs microarrays or quantitative DNA sequencing using 454-technology as detection methods. We applied 5C to analyze a 400-kb region containing the human beta-globin locus and a 100-kb conserved gene desert region. We validated 5C by detection of several previously identified looping interactions in the beta-globin locus. We also identified a new looping interaction in K562 cells between the beta-globin Locus Control Region and the gamma-beta-globin intergenic region. Interestingly, this region has been implicated in the control of developmental globin gene switching. 5C should be widely applicable for large-scale mapping of cis- and trans- interaction networks of genomic elements and for the study of higher-order chromosome structure

First Results from the HerschelHerschel and ALMA Spectroscopic Surveys of the SMC: The Relationship Between [CII]-bright Gas and CO-bright Gas at Low Metallicity

The Small Magellanic Cloud (SMC) provides the only laboratory to study the structure of molecular gas at high resolution and low metallicity. We present results from the Herschel Spectroscopic Survey of the SMC (HS$^{3}$), which mapped the key far-IR cooling lines [CII], [OI], [NII], and [OIII] in five star-forming regions, and new ALMA 7m-array maps of $^{12}$CO and $^{13}$CO $(2-1)$ with coverage overlapping four of the five HS$^{3}$ regions. We detect [CII] and [OI] throughout all of the regions mapped. The data allow us to compare the structure of the molecular clouds and surrounding photodissociation regions using $^{13}$CO, CO, [CII], and [OI] emission at $<10$" ($<3$ pc) scales. We estimate Av using far-IR thermal continuum emission from dust and find the CO/[CII] ratios reach the Milky Way value at high A$_{V}$ in the centers of the clouds and fall to $\sim{1/5-1/10}\times$ the Milky Way value in the outskirts, indicating the presence of translucent molecular gas not traced by bright CO emission. We estimate the amount of molecular gas traced by bright [CII] emission at low A$_{V}$ and bright CO emission at high A$_{V}$. We find that most of the molecular gas is at low A$_{V}$ and traced by bright [CII] emission, but that faint CO emission appears to extend to where we estimate the H$_{2}$-to-HI transition occurs. By converting our H$_{2}$ gas estimates to a CO-to-H$_{2}$ conversion factor ($X_{CO}$), we show that $X_{CO}$ is primarily a function of A$_{V}$, consistent with simulations and models of low metallicity molecular clouds.Comment: Accepted for publication in Ap

PHANGS-JWST First Results: A Global and Moderately Resolved View of Mid-Infrared and CO Line Emission from Galaxies at the Start of the JWST Era

We explore the relationship between mid-infrared (mid-IR) and CO rotational line emission from massive star-forming galaxies, which is one of the tightest scalings in the local universe. We assemble a large set of unresolved and moderately ($\sim 1$ kpc) spatially resolved measurements of CO (1-0) and CO (2-1) intensity, $I_{\rm CO}$, and mid-IR intensity, $I_{\rm MIR}$, at 8, 12, 22, and 24$\mu$m. The $I_{\rm CO}$ vs. $I_{\rm MIR}$ relationship is reasonably described by a power law with slopes $0.7{-}1.2$ and normalization $I_{\rm CO} \sim 1$ K km s$^{-1}$ at $I_{\rm MIR} \sim 1$ MJy sr$^{-1}$. Both the slopes and intercepts vary systematically with choice of line and band. The comparison between the relations measured for CO~(1-0) and CO (2-1) allow us to infer that $R_{21} \propto I_{\rm MIR}^{0.2}$, in good agreement with other work. The $8\mu$m and $12\mu$m bands, with strong PAH features, show steeper CO vs. mid-IR slopes than the $22\mu$m and $24\mu$m, consistent with PAH emission arising not just from CO-bright gas but also from atomic or CO-dark gas. The CO-to-mid-IR ratio correlates with global galaxy stellar mass ($M_\star$) and anti-correlates with SFR/$M_\star$. At $\sim 1$ kpc resolution, the first four PHANGS-JWST targets show CO to mid-IR relationships that are quantitatively similar to our larger literature sample, including showing the steep CO-to-mid-IR slopes for the JWST PAH-tracing bands, although we caution that these initial data have a small sample size and span a limited range of intensities.Comment: 29 pages, 13 figures, key quantitative results in Table 3, Accepted as part of a PHANGS-JWST Focus Issue to appear in Ap

Measurement of patients' knowledge of their medication in community pharmacies in Portugal

El objetivo do artículo es determinar el conocimiento de los pacientes sobre sus medicamentos. Estudio observacional descriptivo transversal. El conocimiento se midió mediante un cuestionario válido y fiable (CPM-PT-PT), a los pacientes que acudieron a las farmacias comunitarias participantes en el estudio solicitando uno o varios medicamentos en el Área Metropolitana de Lisboa. Se determinó el conocimiento en sus cuatro dimensiones: objetivo terapéutico, proceso de uso, seguridad y conservación de los medicamentos que el paciente utiliza. Participaron 35 farmacias, obteniéndose 633 pacientes válidos. El 82.5% (IC95%: 79,3%-85,3%) no conocen el medicamento que utilizan. En todos los ítems, hubo un alto porcentaje de pacientes con conocimiento incorrecto, destacando especialmente las precauciones (44,7%). La dimensión que menos conocen los pacientes fue la "seguridad del medicamento" (1,9%). 8 de cada 10 pacientes de la población no conocen el medicamento que utilizan. La mayor carencia de información correcta corresponde a la "seguridad" del medicamento.The scope of this article is to determine patients' knowledge about the medication they take. For this purpose, a cross-sectional, observational and descriptive study was conducted. Knowledge was measured by a valid and reliable questionnaire (CPM-PT-PT), given to the patients attending community pharmacies participating in the study, who had prescriptions for one or more drugs in the Lisbon Metropolitan Area. Knowledge was assessed in four dimensions: therapeutic objective, process of use, safety and maintenance of the medications that the patient takes. Thirty-five pharmacies participated, and 633 valid patients were obtained. Fully 82.5% (95% CI: 79.3% -85.3%) were uninformed about the nature of the drug they use. In all items, there was a high percentage of patients with incorrect knowledge, with emphasis on precautions (44.7%). The dimension that the patients were least aware of was "drug safety" (1.9%). Eight out of 10 patients in the population do not know what drug they use. The highest lack of correct information was with respect to the "safety" of the medication

A clinical pathway for community-acquired pneumonia: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>Six hospitals instituted a voluntary, system-wide, pathway for community acquired pneumonia (CAP). We proposed this study to determine the impact of pathway antibiotics on patient survival, hospital length of stay (LOS), and total hospital cost.</p> <p>Methods</p> <p>Data were collected for adults from six U.S. hospitals with a principal CAP discharge diagnosis code, a chest infiltrate, and medical notes indicative of CAP from 2005-2007. Pathway and non-pathway cohorts were assigned according to antibiotics received within 48 hours of admission. Pathway antibiotics included levofloxacin 750 mg monotherapy or ceftriaxone 1000 mg plus azithromycin 500 mg daily. Multivariable regression models assessed 90-day mortality, hospital LOS, total hospital cost, and total pharmacy cost.</p> <p>Results</p> <p>Overall, 792 patients met study criteria. Of these, 505 (64%) received pathway antibiotics and 287 (36%) received non-pathway antibiotics. Adjusted means and p-values were derived from Least Squares regression models that included Pneumonia Severity Index risk class, patient age, heart failure, chronic obstructive pulmonary disease, and admitting hospital as covariates. After adjustment, patients who received pathway antibiotics experienced lower adjusted 90-day mortality (<it>p </it>= 0.02), shorter mean hospital LOS (3.9 vs. 5.0 days, <it>p </it>< 0.01), lower mean hospital costs ($2,485 vs.$3,281, <it>p </it>= 0.02), and similar mean pharmacy costs ($356 vs.$442, <it>p </it>= 0.11).</p> <p>Conclusions</p> <p>Pathway antibiotics were associated with improved patient survival, hospital LOS, and total hospital cost for patients admitted to the hospital with CAP.</p

Pre-microRNA and Mature microRNA in Human Mitochondria

Chantier qualité GAInternational audienceBACKGROUND: Because of the central functions of the mitochondria in providing metabolic energy and initiating apoptosis on one hand and the role that microRNA (miRNA) play in gene expression, we hypothesized that some miRNA could be present in the mitochondria for post-transcriptomic regulation by RNA interference. We intend to identify miRNA localized in the mitochondria isolated from human skeletal primary muscular cells. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the potential origin of mitochondrial miRNA, we in-silico searched for microRNA candidates in the mtDNA. Twenty five human pre-miRNA and 33 miRNA aligments (E-value35) for the smallest RNA input concentration and 204 miRNA for the maximum RNA input concentration. In silico analysis predicted 80 putative miRNA target sites in the mitochondrial genome (E-value<0.05). CONCLUSIONS/SIGNIFICANCE: The present study experimentally demonstrated for the first time the presence of pre-miRNA and miRNA in the human mitochondria isolated from skeletal muscular cells. A set of miRNA were significantly detected in mitochondria fraction. The origin of these pre-miRNA and miRNA should be further investigate to determine if they are imported from the cytosol and/or if they are partially processed in the mitochondria

Interpreting Cancer Genomes Using Systematic Host Perturbations by Tumour Virus Proteins

Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations associated with cancer predisposition and large numbers of somatic genomic alterations. However, it remains challenging to distinguish between background, or “passenger” and causal, or “driver” cancer mutations in these datasets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. To test the hypothesis that genomic variations and tumour viruses may cause cancer via related mechanisms, we systematically examined host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways that go awry in cancer, such as Notch signalling and apoptosis. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches result in increased specificity for cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate prioritization of cancer-causing driver genes so as to advance understanding of the genetic basis of human cancer

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively;P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci