MicroRNA-330-5p as a putative modulator of neoadjuvant chemoradiotherapy sensitivity in oesophageal adenocarcinoma

Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC

A downward revision to the distance of the 1806-20 cluster and associated magnetar from Gemini near-Infrared spectroscopy

We present H- and K-band spectroscopy of OB and Wolf-Rayet (WR) members of the Milky Way cluster 1806-20 (G10.0-0.3), to obtain a revised cluster distance of relevance to the 2004 giant flare from the SGR 1806-20 magnetar. From GNIRS spectroscopy obtained with Gemini South, four candidate OB stars are confirmed as late O/early B supergiants, while we support previous mid WN and late WC classifications for two WR stars. Based upon an absolute Ks-band magnitude calibration for B supergiants and WR stars, and near-IR photometry from NIRI at Gemini North plus archival VLT/ISAAC datasets, we obtain a cluster distance modulus of 14.7+/-0.35 mag. The known stellar content of the 1806-20 cluster suggests an age of 3-5 Myr, from which theoretical isochrone fits infer a distance modulus of 14.7+/-0.7 mag. Together, our results favour a distance modulus of 14.7+/-0.4 mag (8.7^+1.8_-1.5 kpc) to the 1806-20 cluster, which is significantly lower than the nominal 15 kpc distance to the magnetar. For our preferred distance, the peak luminosity of the December 2004 giant flare is reduced by a factor of three to 7 X 10^46 erg/s, such that the contamination of BATSE short gamma ray bursts (GRB's) from giant flares of extragalactic magnetars is reduced to a few percent. We infer a magnetar progenitor mass of ~48^+20_-8 Msun, in close agreement with that obtained recently for the magnetar in Westerlund 1.Comment: 6 pages, 4 figures, accepted for MNRAS Letter

Shift in the microbial ecology of a hospital hot water system following the introduction of an on-site monochloramine disinfection system

Drinking water distribution systems, including premise plumbing, contain a diverse microbiological community that may include opportunistic pathogens. On-site supplemental disinfection systems have been proposed as a control method for opportunistic pathogens in premise plumbing. The majority of on-site disinfection systems to date have been installed in hospitals due to the high concentration of opportunistic pathogen susceptible occupants. The installation of on-site supplemental disinfection systems in hospitals allows for evaluation of the impact of on-site disinfection systems on drinking water system microbial ecology prior to widespread application. This study evaluated the impact of supplemental monochloramine on the microbial ecology of a hospital's hot water system. Samples were taken three months and immediately prior to monochloramine treatment and monthly for the first six months of treatment, and all samples were subjected to high throughput Illumina 16S rRNA region sequencing. The microbial community composition of monochloramine treated samples was dramatically different than the baseline months. There was an immediate shift towards decreased relative abundance of Betaproteobacteria, and increased relative abundance of Firmicutes, Alphaproteobacteria, Gammaproteobacteria, Cyanobacteria and Actinobacteria. Following treatment, microbial populations grouped by sampling location rather than sampling time. Over the course of treatment the relative abundance of certain genera containing opportunistic pathogens and genera containing denitrifying bacteria increased. The results demonstrate the driving influence of supplemental disinfection on premise plumbing microbial ecology and suggest the value of further investigation into the overall effects of premise plumbing disinfection strategies on microbial ecology and not solely specific target microorganisms. © 2014 Baron et al

'I would rather die': reasons given by 16-year-olds for not continuing their study of mathematics

Improving participation rates in specialist mathematics after the subject ceases to be compulsory at age 16 is part of government policy in England. This article provides independent and recent support for earlier findings concerning reasons for non- participation, based on free response and closed items in a questionnaire with a sample of over 1500 students in 17 schools, close to the moment of choice. The analysis supports findings that perceived difficulty and lack of confidence are important reasons for students not continuing with mathematics, and that perceived dislike and boredom, and lack of relevance, are also factors. There is a close relationship between reasons for non-participation and predicted grade, and a weaker relation to gender. An analysis of the effects of schools, demonstrates that enjoyment is the main factor differentiating schools with high and low participation indices. Building on discussion of these findings, ways of improving participation are briefly suggested

A spectroscopic census of the M82 stellar cluster population

We present a spectroscopic study of the stellar cluster population of M82, the archetype starburst galaxy, based primarily on new Gemini-North multi-object spectroscopy of 49 star clusters. These observations constitute the largest to date spectroscopic dataset of extragalactic young clusters, giving virtually continuous coverage across the galaxy; we use these data to deduce information about the clusters as well as the M82 post-starburst disk and nuclear starburst environments. Spectroscopic age-dating places clusters in the nucleus and disk between (7, 15) and (30, 270) Myr, with distribution peaks at ~10 and ~140 Myr respectively. We find cluster radial velocities in the range (-160, 220) km/s (wrt the galaxy centre) and line of sight Na I D interstellar absorption line velocities in (-75, 200) km/s, in many cases entirely decoupled from the clusters. As the disk cluster radial velocities lie on the flat part of the galaxy rotation curve, we conclude that they comprise a regularly orbiting system. Our observations suggest that the largest part of the population was created as a result of the close encounter with M81 ~220 Myr ago. Clusters in the nucleus are found in solid body rotation on the bar. The possible detection of WR features in their spectra indicates that cluster formation continues in the central starburst zone. We also report the potential discovery of two old populous clusters in the halo of M82, aged >8 Gyr. Using these measurements and simple dynamical considerations, we derive a toy model for the invisible physical structure of the galaxy, and confirm the existence of two dominant spiral arms.Comment: Accepted for publication in the Astrophysical Journa

Effect of magnetic state on the γ−α\gamma -\alpha transition in iron: First-principle calculations of the Bain transformation path

Energetics of the fcc ($\gamma$) - bcc ($\alpha$) lattice transformation by the Bain tetragonal deformation is calculated for both magnetically ordered and paramagnetic (disordered local moment) states of iron. The first-principle computational results manifest a relevance of the magnetic order in a scenario of the $\gamma$ - $\alpha$ transition and reveal a special role of the Curie temperature of $\alpha$-Fe, $T_C$, where a character of the transformation is changed. At a cooling down to the temperatures $T < T_C$ one can expect that the transformation is developed as a lattice instability whereas for $T > T_C$ it follows a standard mechanism of creation and growth of an embryo of the new phase. It explains a closeness of $T_C$ to the temperature of start of the martensitic transformation, $M_s$.Comment: 4 pages, 3 figures, submitted in Phys. Rev. Letter

Multi-color Molecular Visualization of Signaling Proteins Reveals How C-Terminal Src Kinase Nanoclusters Regulate T Cell Receptor Activation

Elucidating the mechanisms that controlled T cell activation requires visualization of the spatial organization of multiple proteins on the submicron scale. Here, we use stoichiometrically accurate, multiplexed, singlemolecule super-resolution microscopy (DNA-PAINT) to image the nanoscale spatial architecture of the primary inhibitor of the T cell signaling pathway, Csk, and two binding partners implicated in its membrane association, PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we find that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and are re-recruited at later time points. Unexpectedly, these clusters do not co-localize with PAG at the membrane but instead provide a ready pool of monomers to downregulate signaling. By generating CRISPR-Cas9 knockout T cells, our data also identify that a major risk factor for autoimmune diseases, the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus, is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population

Evidence for polyploidy in the globally important diazotroph Trichodesmium

Polyploidy is a well-described trait in some prokaryotic organisms; however, it is unusual in marine microbes from oligotrophic environments, which typically display a tendency towards genome streamlining. The biogeochemically significant diazotrophic cyanobacterium Trichodesmium is a potential exception. With a relatively large genome and a comparatively high proportion of non-protein-coding DNA, Trichodesmium appears to allocate relatively more resources to genetic material than closely related organisms and microbes within the same environment. Through simultaneous analysis of gene abundance and direct cell counts, we show for the first time that Trichodesmium spp. can also be highly polyploid, containing as many as 100 genome copies per cell in field-collected samples and >600 copies per cell in laboratory cultures. These findings have implications for the widespread use of the abundance of the nifH gene (encoding a subunit of the N2-fixing enzyme nitrogenase) as an approach for quantifying the abundance and distribution of marine diazotrophs. Moreover, polyploidy may combine with the unusual genomic characteristics of this genus both in reflecting evolutionary dynamics and influencing phenotypic plasticity and ecological resilience