Single Synonymous Mutations in KRAS Cause Transformed Phenotypes in NIH3T3 Cells

Synonymous mutations in the KRAS gene are clustered at G12, G13, and G60 in human cancers. We constructed 9 stable NIH3T3 cell lines expressing KRAS, each with one of these synonymous mutations. Compared to the negative control cell line expressing the wild type human KRAS gene, all the synonymous mutant lines expressed more KRAS protein, grew more rapidly and to higher densities, and were more invasive in multiple assays. Three of the cell lines showed dramatic loss of contact inhibition, were more refractile under phase contrast, and their refractility was greatly reduced by treatment with trametinib. Codon usage at these glycines is highly conserved in KRAS compared to HRAS, indicating selective pressure. These transformed phenotypes suggest that synonymous mutations found in driver genes such as KRAS may play a role in human cancers

Belimumab : a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis

Objectives: To undertake a systematic review and meta-analysis to investigate clinical effectiveness of belimumab for patients with systemic lupus erythematosus (SLE) and antinuclear and/or anti-double-stranded DNA (dsDNA) autoantibodies. Methods: We searched eight electronic databases and reference lists for randomised controlled trials (RCTs) of belimumab against placebo or best supportive care. Quality assessment and random effects meta-analysis were undertaken. Design: A meta-analysis of RCTs. Participants: 2133 SLE patients. Primary and secondary outcome measures: SLE Responder Index (SRI) at week 52. Results: Three double-blind placebo-controlled RCTs (L02, BLISS-52 BLISS-76) investigated 2133 SLE patients. BLISS-52 and BLISS-76 trials recruited patients with antinuclear and/or anti-dsDNA autoantibodies and demonstrated belimumab effectiveness for the SRI at week 52. Ethnicity and geographical location of participants varied considerably between BLISS trials. Although tests for statistical heterogeneity were negative, BLISS-52 results were systematically more favourable for all measured outcomes. Meta-analysis of pooled 52-week SRI BLISS results showed benefit for belimumab (OR 1.63, 95% CI 1.27 to 2.09). By week 76, the primary SRI outcome in BLISS-76 was not statistically significant (OR 1.31, 95% CI 0.919 to 1.855)

The mass evolution of the first galaxies: stellar mass functions and star formation rates at 4<z<74 < z < 7 in the CANDELS GOODS-South field

We measure new estimates for the galaxy stellar mass function and star formation rates for samples of galaxies at $z \sim 4,~5,~6~\&~7$ using data in the CANDELS GOODS South field. The deep near-infrared observations allow us to construct the stellar mass function at $z \geq 6$ directly for the first time. We estimate stellar masses for our sample by fitting the observed spectral energy distributions with synthetic stellar populations, including nebular line and continuum emission. The observed UV luminosity functions for the samples are consistent with previous observations, however we find that the observed $M_{UV}$ - M$_{*}$ relation has a shallow slope more consistent with a constant mass to light ratio and a normalisation which evolves with redshift. Our stellar mass functions have steep low-mass slopes ($\alpha \approx -1.9$), steeper than previously observed at these redshifts and closer to that of the UV luminosity function. Integrating our new mass functions, we find the observed stellar mass density evolves from $\log_{10} \rho_{*} = 6.64^{+0.58}_{-0.89}$ at $z \sim 7$ to $7.36\pm0.06$ $\text{M}_{\odot} \text{Mpc}^{-3}$ at $z \sim 4$. Finally, combining the measured UV continuum slopes ($\beta$) with their rest-frame UV luminosities, we calculate dust corrected star-formation rates (SFR) for our sample. We find the specific star-formation rate for a fixed stellar mass increases with redshift whilst the global SFR density falls rapidly over this period. Our new SFR density estimates are higher than previously observed at this redshift.Comment: 28 pages, 23 figures, 2 appendices. Accepted for publication in MNRAS, August 7 201

The First Quiescent Galaxies in TNG300

We identify the first quiescent galaxies in TNG300, the largest volume of the IllustrisTNG cosmological simulation suite, and explore their quenching processes and time evolution to z=0. We find that the first quiescent galaxies with stellar masses M_* > 3 x 10^{10} M_sun and specific star formation rates sSFR < 10^{-11} yr^{-1} emerge at z~4.2 in TNG300. Suppression of star formation in these galaxies begins with a thermal mode of AGN feedback at z~6, and a kinetic feedback mode acts in each galaxy by z~4.7 to complete the quenching process, which occurs on a time-scale of ~0.35 Gyr. Surprisingly, we find that the majority of these galaxies are not the main progenitors of their z=0 descendants; instead, four of the five galaxies fall into more massive galaxies in subsequent mergers at a range of redshifts 2.5 < z < 0.2. By z=0, these descendants are the centres of galaxy clusters with average stellar masses of 8 x 10^{11} M_sun. We make predictions for the first quenched galaxies to be located by the James Webb Space Telescope (JWST).Comment: 6 pages, 4 figure

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies

Researchers rely largely on antibodies to measure the abundance, activity, and localization of a protein, information that provides critical insight into both normal and pathological cellular functions. However, antibodies are not always reliable or universally valid for the methods in which they are used; in particular, the reliability of commercial antibodies against RAS is highly variable. Waters et al . rigorously assessed 22 commercially available RAS antibodies for their utility to detect the distinct RAS isoforms in various cell types and for their use in specific analytical methods. Their findings show how reliably one can interpret the data acquired from each reagent

Conducting robust ecological analyses with climate data

Although the number of studies discerning the impact of climate change on ecological systems continues to increase, there has been relatively little sharing of the lessons learnt when accumulating this evidence. At a recent workshop entitled ‘Using climate data in ecological research’ held at the UK Met Office, ecologists and climate scientists came together to discuss the robust analysis of climate data in ecology. The discussions identified three common pitfalls encountered by ecologists: 1) selection of inappropriate spatial resolutions for analysis; 2) improper use of publically available data or code; and 3) insufficient representation of the uncertainties behind the adopted approach. Here, we discuss how these pitfalls can be avoided, before suggesting ways that both ecology and climate science can move forward. Our main recommendation is that ecologists and climate scientists collaborate more closely, on grant proposals and scientific publications, and informally through online media and workshops. More sharing of data and code (e.g. via online repositories), lessons and guidance would help to reconcile differing approaches to the robust handling of data. We call on ecologists to think critically about which aspects of the climate are relevant to their study system, and to acknowledge and actively explore uncertainty in all types of climate data. And we call on climate scientists to make simple estimates of uncertainty available to the wider research community. Through steps such as these, we will improve our ability to robustly attribute observed ecological changes to climate or other factors, while providing the sort of influential, comprehensive analyses that efforts to mitigate and adapt to climate change so urgently require

Galaxies Going Bananas: Inferring the 3D Geometry of High-Redshift Galaxies with JWST-CEERS

The 3D geometry of high-redshift galaxies remains poorly understood. We build a differentiable Bayesian model and use Hamiltonian Monte Carlo to efficiently and robustly infer the 3D shapes of star-forming galaxies in JWST-CEERS observations with $\log M_*/M_{\odot}=9.0-10.5$ at $z=0.5-8.0$. We reproduce previous results from HST-CANDELS in a fraction of the computing time and constrain the mean ellipticity, triaxiality, size and covariances with samples as small as $\sim50$ galaxies. We find high 3D ellipticities for all mass-redshift bins suggesting oblate (disky) or prolate (elongated) geometries. We break that degeneracy by constraining the mean triaxiality to be $\sim1$ for $\log M_*/M_{\odot}=9.0-9.5$ dwarfs at $z>1$ (favoring the prolate scenario), with significantly lower triaxialities for higher masses and lower redshifts indicating the emergence of disks. The prolate population traces out a ``banana'' in the projected $b/a-\log a$ diagram with an excess of low $b/a$, large $\log a$ galaxies. The dwarf prolate fraction rises from $\sim25\%$ at $z=0.5-1.0$ to $\sim50-80\%$ at $z=3-8$. If these are disks, they cannot be axisymmetric but instead must be unusually oval (triaxial) unlike local circular disks. We simultaneously constrain the 3D size-mass relation and its dependence on 3D geometry. High-probability prolate and oblate candidates show remarkably similar S\'ersic indices ($n\sim1$), non-parametric morphological properties and specific star formation rates. Both tend to be visually classified as disks or irregular but edge-on oblate candidates show more dust attenuation. We discuss selection effects, follow-up prospects and theoretical implications.Comment: Submitted to ApJ, main body is 35 pages of which ~half are full-page figures, comments welcom

Comparing the effects of sun exposure and vitamin D supplementation on vitamin D insufficiency, and immune and cardio-metabolic function: The Sun Exposure and Vitamin D Supplementation (SEDS) Study

Background: Adults living in the sunny Australian climate are at high risk of skin cancer, but vitamin D deficiency (defined here as a serum 25-hydroxyvitamin D (25(OH)D) concentration of less than 50 nmol/L) is also common. Vitamin D deficiency may be a risk factor for a range of diseases. However, the optimal strategies to achieve and maintain vitamin D adequacy (sun exposure, vitamin D supplementation or both), and whether sun exposure itself has benefits over and above initiating synthesis of vitamin D, remain unclear. The Sun Exposure and Vitamin D Supplementation (SEDS) Study aims to compare the effectiveness of sun exposure and vitamin D supplementation for the management of vitamin D insufficiency, and to test whether these management strategies differentially affect markers of immune and cardio-metabolic function. Methods/Design: The SEDS Study is a multi-centre, randomised controlled trial of two different daily doses of vitamin D supplementation, and placebo, in conjunction with guidance on two different patterns of sun exposure. Participants recruited from across Australia are aged 18-64 years and have a recent vitamin D test result showing a serum 25(OH)D level of 40-60 nmol/L. Discussion: This paper discusses the rationale behind the study design, and considers the challenges but necessity of data collection within a non-institutionalised adult population, in order to address the study aims. We also discuss the challenges of participant recruitment and retention, ongoing engagement of referring medical practitioners and address issues of compliance and participant retention. Trial registration: Australia New Zealand Clinical Trials Registry: ACTRN12613000290796 Registered 14 March 2013