The Luminosities of Protostars in the Spitzer c2d and Gould Belt Legacy Clouds

Motivated by the long-standing "luminosity problem" in low-mass star formation whereby protostars are underluminous compared to theoretical expectations, we identify 230 protostars in 18 molecular clouds observed by two Spitzer Space Telescope Legacy surveys of nearby star-forming regions. We compile complete spectral energy distributions, calculate Lbol for each source, and study the protostellar luminosity distribution. This distribution extends over three orders of magnitude, from 0.01 Lsun - 69 Lsun, and has a mean and median of 4.3 Lsun and 1.3 Lsun, respectively. The distributions are very similar for Class 0 and Class I sources except for an excess of low luminosity (Lbol < 0.5 Lsun) Class I sources compared to Class 0. 100 out of the 230 protostars (43%) lack any available data in the far-infrared and submillimeter (70 um < wavelength < 850 um) and have Lbol underestimated by factors of 2.5 on average, and up to factors of 8-10 in extreme cases. Correcting these underestimates for each source individually once additional data becomes available will likely increase both the mean and median of the sample by 35% - 40%. We discuss and compare our results to several recent theoretical studies of protostellar luminosities and show that our new results do not invalidate the conclusions of any of these studies. As these studies demonstrate that there is more than one plausible accretion scenario that can match observations, future attention is clearly needed. The better statistics provided by our increased dataset should aid such future work.Comment: Accepted for publication in AJ. 21 pages, 10 figures, 4 table

Infectious Necrotizing Enteritis and Mortality Caused by \u3cem\u3eVibrio carachariae\u3c/em\u3e in Summer Flounder \u3cem\u3eParalichthys dentatus\u3c/em\u3e During Intensive Culture

An epizootic causing mortality among cultured summer flounder Paralichthys dentatus occurred in summer of 1998 at a land-based facility on Narragansett Bay, Rhode Island, USA. The disease, flounder infectious necrotizing enteritis (FINE), was characterized by reddening around the anal area, distended abdomens filled with opaque serosanguineous fluid, enteritis and necrosis of the posterior intestine. In extreme cases of the disease, the posterior intestine was detached from the anus and was observed coming out the vent. The intestine of individuals that recovered from the dsease ended in a blind-sac; the abdomens of these fish were distended, due to food and water inside the intestinal blind-sac. A bacterium was isolated from ascites fluid and kidney of moribund flounder and identified as the causative agent in challenge experiments. The pathogen was identified as Vibno carchariae by morphological and biochemical characteristics and sequence of the 16S rRNA. The LD50 estimate was 5 x 105 colony-forming units injected intraperitoneally into 100 to 200 g summer flounder

Longitudinal identification of clinically distinct neurophenotypes in young children with fragile X syndrome

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability. The cognitive, behavioral, and neurological phenotypes observed in affected individuals can vary considerably, making it difficult to predict outcomes and determine the need for interventions. We sought to examine early structural brain growth as a potential marker for identification of clinically meaningful subgroups. Participants included 42 very young boys with FXS who completed a T1-weighted anatomical MRI and cognitive/behavioral assessment at two longitudinal time points, with mean ages of 2.89 y and 4.91 y. Topological data analysis (TDA), an unsupervised approach to multivariate pattern analysis, was applied to the longitudinal anatomical data to identify coherent but heretofore unknown subgroups. TDA revealed two large subgroups within the study population based solely on longitudinal MRI data. Post hoc comparisons of cognition, adaptive functioning, and autism severity scores between these groups demonstrated that one group was consistently higher functioning on all measures at both time points, with pronounced and significant unidirectional differences (P < 0.05 for time point 1 and/or time point 2 for each measure). These results support the existence of two longitudinally defined, neuroanatomically distinct, and clinically relevant phenotypes among boys with FXS. If confirmed by additional analyses, such information may be used to predict outcomes and guide design of targeted therapies. Furthermore, TDA of longitudinal anatomical MRI data may represent a useful method for reliably and objectively defining subtypes within other neuropsychiatric disorders

Characterization of polyoxometalate I as an inhibitor of RNA-dependent RNA polymerase of Foot and Mouth Disease virus [abstract]

Abstract only availableFoot and Mouth Disease (FMD) is a highly contagious disease that affects a variety of domesticated cloven-hoofed animals including cattle, swine, sheep and goats, as well as several wild animal species. FMD outbreaks are currently controlled with mass-extermination of livestock. The financial cost of potential outbreaks would be immense. This disease is caused by foot-and-mouth disease virus (FMDV), a non-enveloped, single-stranded, positive-sense RNA virus. The purpose of our investigation is to identify chemicals that interfere with the replication of FMDV. As part of this effort we have identified a polyoxometalate inhibitor (polyoxometalate I). We have cloned, expressed and purified FMDV RdRp. We use steady-state kinetic experiments and polymerization assays to characterize the inhibitory activity of the polyoxometalate I, determining the precise inhibitory potential and the mechanism of inhibition. Preliminary results show that polyoxometalate I inhibits the FMDV RdRp surprisingly efficiently with an IC50 of 0.5uM. Current experiments are focusing on a detailed kinetic characterization of the mechanism of action for this inhibitor. This research may provide insights that lead to new treatment options to prevent the further spread of FMD to unaffected animals.USD

The Spitzer Survey of Interstellar Clouds in the Gould Belt. VI. The Auriga-California Molecular Cloud observed with IRAC and MIPS

We present observations of the Auriga-California Molecular Cloud (AMC) at 3.6, 4.5, 5.8, 8.0, 24, 70 and 160 micron observed with the IRAC and MIPS detectors as part of the Spitzer Gould Belt Legacy Survey. The total mapped areas are 2.5 sq-deg with IRAC and 10.47 sq-deg with MIPS. This giant molecular cloud is one of two in the nearby Gould Belt of star-forming regions, the other being the Orion A Molecular Cloud (OMC). We compare source counts, colors and magnitudes in our observed region to a subset of the SWIRE data that was processed through our pipeline. Using color-magnitude and color-color diagrams, we find evidence for a substantial population of 166 young stellar objects (YSOs) in the cloud, many of which were previously unknown. Most of this population is concentrated around the LkHalpha 101 cluster and the filament extending from it. We present a quantitative description of the degree of clustering and discuss the fraction of YSOs in the region with disks relative to an estimate of the diskless YSO population. Although the AMC is similar in mass, size and distance to the OMC, it is forming about 15 - 20 times fewer stars.Comment: (30 pages, 17 figures (2 multipage figures), accepted for publication in ApJ

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.

A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.This study was supported by the Swiss National Science Foundation (SNSF professorship PP00P2_123536 and PP00P2_146321 to M.L.), the BBSRC (G.L., BB/G01227X/1 and BB/M00015X/1), an MRC Doctoral Training Partnership (I.W. MR/J003964/1), and the EPSRC (A.K., EP/G500045/1).This is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/acs.jmedchem.5b0140

Blocking Nupr1 Protein, A Successful Approach for Pancreatic Adenocarcinoma Treatment

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancy. Nuclear protein 1 (NUPR1) is a recognized protein, over-expressed and involved in PDAC development. NUPR1 belongs to the special class of intrinsically disordered proteins (IDPs) and it is implicated in cell signaling and regulatory functions. The multifunctional nature of NUPR1 renders it as an attractive target for drug design and development. Aim: Identify a small molecule inhibiting protein-protein interactions in NUPR1 and able to interfere with any of NUPR1 key oncogenic activities, thus, constituting a new chemotherapy strategy against PDAC. Methods: Ligand-induced stabilization against thermal denaturation (thermal-shift assay) was employed for identifying potential NUPR1-interacting compounds. An in vitro molecular screening based on thermal denaturation of NUPR1 in the presence of a variety of potential ligands was performed using a collection of 1120 compounds. All compounds are FDA-approved drugs for different therapeutic indications, exhibiting high chemical and pharmacological diversity, as well as good bioavailability and safety parameters in humans. Direct interaction of selected compounds with NUPR1 was assessed experimentally (calorimetry, fluorescence spectroscopy, nuclear magnetic resonance, and proximity ligation assay) and computationally (molecular dynamics simulations). Compound efficacy was determined in PDAC-derived cell-based assays and in vivo assays on xenografted PDACderived cells in mice. Comparisons of treatment outcome were tested for statistical significance by using the t-test, and statistical significance was assumed at a p-value lower than 0.05. Results: Fifteen candidates were selected, and their interactions with NUPR1 were characterized. In vitro experiments with MiaPaCa-2 cells treated using 10 µM of compounds for 6 days showed that two of the compounds (C13 and C15) were very efficient in diminishing cell viability (10 ± 3% and 26 ± 7%, respectively; assays in triplicates (n = ) p= 0.01). These values were similar to those obtained with oxaliplatin (10 ± 2%; p= 0.01). Also, they reduced cell migration (from 10-20% wound-healing ability compared to 50% in control assays; p= 0.05) and colony formation (completely suppressed in the presence of both compounds; p= 0.01). In addition, the most promising compound, C15, interfered with the interaction of NUPR1 with MSL1, one of the NUPR1 binding partners (Figure 1). The administration of a 10 mg/Kg dose of C15 promoted complete arrest of tumor development on xenografted PDAC-derived cells in mice (Figure 2). Conclusion: We report the discovery of a compound specifically active against PDAC and interfering with NUPR1. In addition, we demonstrate that it is possible to identify small molecules able to modulate the function of complex targets such as IDPs

Empathic accuracy in adolescent girls with Turner Syndrome

Objective: Girls and women with Turner Syndrome (TS) demonstrate social challenges and difficulties identifying negative emotions, specifically fear. Previous studies suggest that social deficits in TS could be associated with theory of mind (TOM) difficulties or visual-spatial processing abnormalities. To further examine the potential mechanisms underlying social deficits in TS, we administered the empathic accuracy task, a naturalistic social cognition task. Method: The performance of 14 girls with TS was compared to 12 age-matched typically developing girls (ages 12 to 17) on an empathic accuracy task and a (control) visual-motor line-tracking task. Empathic accuracy was compared across positive and negative emotionally valanced videos. Results: We found that girls with TS differ from typically developing girls on empathic accuracy ratings for negative videos; no differences were detected for the positive videos. No between group differences were found on the control line tracking task. Conclusion: Our findings expand upon the previously detected affect recognition problems in TS to also include impaired detection of negatively valanced empathic interactions. Such difficulties for girls with TS could contribute to their social deficits and anxiety. Results from this study provide important information about gene-body-brain interactions and their influence on emotion processing and empathic accuracy during adolescence

Soil properties explain tree growth and mortality, but not biomass, across phosphorus-depleted tropical forests

We observed strong positive relationships between soil properties and forest dynamics of growth and mortality across twelve primary lowland tropical forests in a phosphorus-poor region of the Guiana Shield. Average tree growth (diameter at breast height) increased from 0.81 to 2.1 mm yr-1 along a soil texture gradient from 0 to 67% clay, and increasing metal-oxide content. Soil organic carbon stocks in the top 30 cm ranged from 30 to 118 tons C ha-1, phosphorus content ranged from 7 to 600 mg kg-1 soil, and the relative abundance of arbuscular mycorrhizal fungi ranged from 0 to 50%, all positively correlating with soil clay, and iron and aluminum oxide and hydroxide content. In contrast, already low extractable phosphorus (Bray P) content decreased from 4.4 to <0.02 mg kg-1 in soil with increasing clay content. A greater prevalence of arbuscular mycorrhizal fungi in more clayey forests that had higher tree growth and mortality, but not biomass, indicates that despite the greater investment in nutrient uptake required, soils with higher clay content may actually serve to sustain high tree growth in tropical forests by avoiding phosphorus losses from the ecosystem. Our study demonstrates how variation in soil properties that retain carbon and nutrients can help to explain variation in tropical forest growth and mortality, but not biomass, by requiring niche specialization and contributing to biogeochemical diversification across this region

Knowledge practices in design: The role of visual representations as 'epistemic objects'

We use a detailed study of the knowledge work around visual representations to draw attention to the multidimensional nature of `objects'. Objects are variously described in the literatures as relatively stable or in flux; as abstract or concrete; and as used within or across practices. We clarify these dimensions, drawing on and extending the literature on boundary objects, and connecting it with work on epistemic and technical objects. In particular, we highlight the epistemic role of objects, using our observations of knowledge work on an architectural design project to show how, in this setting, visual representations are characterized by a `lack' or incompleteness that precipitates unfolding. The conceptual design of a building involves a wide range of technical, social and aesthetic forms of knowledge that need to be developed and aligned. We explore how visual representations are used, and how these are meaningful to different stakeholders, eliciting their distinct contributions. As the project evolves and the drawings change, new issues and needs for knowledge work arise. These objects have an `unfolding ontology' and are constantly in flux, rather than fully formed. We discuss the implications for wider understandings of objects in organizations and for how knowledge work is achieved in practice