Integral field spectroscopy of massive young stellar objects in the N113 H II region in the Large Magellanic Cloud

The Spitzer Surveying the Agents of Galaxy Evolution (SAGE) survey has allowed the identification and analysis of significant samples of Young Stellar Object (YSO) candidates in the Large Magellanic Cloud (LMC). However, the angular resolution of Spitzer is relatively poor meaning that at the distance of the LMC, it is likely that many of the Spitzer YSO candidates in fact contain multiple components. We present high-resolution K-band integral field spectroscopic observations of the three most prominent massive YSO candidates in the N113 H II region using Very Large Telescope/Spectrograph for INtegral Field Observations in the Near Infrared (VLT/SINFONI). We have identified six K-band continuum sources within the three Spitzer sources and we have mapped the morphology and velocity fields of extended line emission around these sources. Br γ, He I and H2 emission is found at the position of all six K-band sources; we discuss whether the emission is associated with the continuum sources or whether it is ambient emission. H2 emission appears to be mostly ambient emission and no evidence of CO emission arising in the discs of YSOs has been found. We have mapped the centroid velocities of extended Br γ emission and He I emission and found evidence of two expanding compact H II regions. One source shows compact and strong H2 emission suggestive of a molecular outflow. The diversity of spectroscopic properties observed is interpreted in the context of a range of evolutionary stages associated with massive star formation

Hybrid metabolic flux analysis: combining stoichiometric and statistical constraints to model the formation of complex recombinant products

<p>Abstract</p> <p>Background</p> <p>Stoichiometric models constitute the basic framework for fluxome quantification in the realm of metabolic engineering. A recurrent bottleneck, however, is the establishment of consistent stoichiometric models for the synthesis of recombinant proteins or viruses. Although optimization algorithms for <it>in silico </it>metabolic redesign have been developed in the context of genome-scale stoichiometric models for small molecule production, still rudimentary knowledge of how different cellular levels are regulated and phenotypically expressed prevents their full applicability for complex product optimization.</p> <p>Results</p> <p>A hybrid framework is presented combining classical metabolic flux analysis with projection to latent structures to further link estimated metabolic fluxes with measured productivities. We first explore the functional metabolic decomposition of a baculovirus-producing insect cell line from experimental data, highlighting the TCA cycle and mitochondrial respiration as pathways strongly associated with viral replication. To reduce uncertainty in metabolic target identification, a Monte Carlo sampling method was used to select meaningful associations with the target, from which 66% of the estimated fluxome had to be screened out due to weak correlations and/or high estimation errors. The proposed hybrid model was then validated using a subset of preliminary experiments to pinpoint the same determinant pathways, while predicting the productivity of independent cultures.</p> <p>Conclusions</p> <p>Overall, the results indicate our hybrid metabolic flux analysis framework is an advantageous tool for metabolic identification and quantification in incomplete or ill-defined metabolic networks. As experimental and computational solutions for constructing comprehensive global cellular models are in development, the contribution of hybrid metabolic flux analysis should constitute a valuable complement to current computational platforms in bridging the metabolic state with improved cell culture performance.</p

The VMC survey – XXXIX: Mapping metallicity trends in the Small Magellanic Cloud using near-infrared passbands

We have derived high spatial resolution metallicity maps covering ∼42 deg2 across the Small Magellanic Cloud (SMC) in an attempt to understand its metallicity distribution and gradients up to a radius of ∼ 4○. Using the near-infrared VISTA Survey of the Magellanic Clouds, our data cover a thrice larger area compared with previous studies. We identify red giant branch (RGB) stars in spatially distinct Y, (Y − Ks) colour–magnitude diagrams. In any of our selected subregions, the RGB slope is used as an indicator of the average metallicity, based on calibration to metallicity using spectroscopic data. The metallicity distribution across the SMC is unimodal and can be fitted by a Gaussian distribution with a peak at [Fe/H] = −0.97 dex (σ[Fe/H] = 0.05 dex). We find evidence of a shallow gradient in metallicity (−0.031 ± 0.005 dex deg−1) from the galactic centre to radii of 2○–2.5○, followed by a flat metallicity trend from ∼ 3.5○ to 4○. We find that the SMCâs metallicity gradient is radially asymmetric. It is flatter towards the East than to the West, hinting at mixing and/or distortion of the spatial metallicity distribution (within the inner 3○), presumably caused by tidal interactions between the Magellanic Clouds

Thyroid Hormones within the Normal Range and Cardiac Function in the General Population: The EPIPorto Study

Background: Hypothyroidism and hyperthyroidism are associated with marked changes in cardiac structure and function. However, the association of thyroid function within the normal range with cardiac structure and function in the general population remains uncertain. Methods: Eight hundred thirty-five subjects aged ≥45 years from the EPIPorto cohort (evaluation between 2006 and 2008) were cross-sectionally analyzed. We excluded participants with TSH, free T4 (FT4), or free T3 (FT3) outside of the reference range or with self-reported cardiovascular or thyroid disease. Cardiac structure and function were evaluated by echocardiography. We used linear regression models unadjusted and adjusted for sex and age (model 1), and sex, age, BMI, diabetes, hypertension, and smoking (model 2). Nonlinear associations were assessed using restricted cubic splines. Results: The mean age was 61.5 years (SD 10.5); 61.1% of the patients were women. In the adjusted model 2, heart rate was positively associated with FT3; diastolic blood pressure was positively associated with TSH; LV end-diastolic and end-systolic volumes were inversely associated with TSH, and ejection fraction was nonlinearly associated with FT3, with higher ejection fractions near the limits of the reference range. Left ventricle (LV) posterior wall thickness was nonlinearly associated with FT4 in the adjusted model 1, with a greater thickness near the limits of the reference range. Regarding diastolic function, no significant associations were observed in adjusted models. Conclusions: Thyroid function within the reference range was associated with heart rate, blood pressure, cardiac structure, and function. Increasing thyroid function (lower TSH, higher FT4, or higher FT3) was associated with a higher heart rate, a lower diastolic blood pressure, and larger LV volumes. LV wall thickness and ejection fraction had a U-shaped association with thyroid hormones.This work was supported by the DOCnet project (NORTE-01-0145-FEDER-000003), supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and the NETDIAMOND project (POCI-01-0145-FEDER-016385), supported by European Structural and Investment Funds, Lisbon’s Regional Operational Program 2020, and national funds from the Portuguese Foundation for Science and Technology – both projects through the Cardiovascular Research Center (UnIC, FCT 51/94) – and by the Portuguese Foundation for Science and Technology (grant POCI/SAU-ESP/61492/2004) and the Unidade de Investigação em Epidemiologia – Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (POCI-01-0145-FEDER-006862, ref. info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/DTP/04750/2013/PT)

A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role

Cell functional enviromics: Unravelling the function of environmental factors

<p>Abstract</p> <p>Background</p> <p>While functional genomics, focused on gene functions and gene-gene interactions, has become a very active field of research in molecular biology, equivalent methodologies embracing the environment and gene-environment interactions are relatively less developed. Understanding the function of environmental factors is, however, of paramount importance given the complex, interactive nature of environmental and genetic factors across multiple time scales.</p> <p>Results</p> <p>Here, we propose a systems biology framework, where the function of environmental factors is set at its core. We set forth a "reverse" functional analysis approach, whereby cellular functions are reconstructed from the analysis of dynamic envirome data. Our results show these data sets can be mapped to less than 20 core cellular functions in a typical mammalian cell culture, while explaining over 90% of flux data variance. A functional enviromics map can be created, which provides a template for manipulating the environmental factors to induce a desired phenotypic trait.</p> <p>Conclusion</p> <p>Our results support the feasibility of cellular function reconstruction guided by the analysis and manipulation of dynamic envirome data.</p