Combined metagenomic and phenomic approaches identify a novel salt tolerance gene from the human gut microbiome

In the current study, a number of salt-tolerant clones previously isolated from a human gut metagenomic library were screened using Phenotype MicroArray (PM) technology to assess their functional capacity. One clone, SMG 9, was found to be positive for utilisation/transport of L-carnitine (a well-characterised osmoprotectant) in the presence of 6% w/v sodium chloride (NaCl). Subsequent experiments revealed a significant growth advantage in minimal media containing NaCl and L-carnitine. Fosmid sequencing revealed putative candidate genes responsible for the phenotype. Subsequent cloning of two genes did not replicate the L-carnitine-associated phenotype, although one of the genes, a σ54-dependent transcriptional regulator, did confer salt tolerance to Escherichia coli when expressed in isolation. The original clone, SMG 9, was subsequently found to have lost the original observed phenotype upon further investigation. Nevertheless, this study demonstrates the usefulness of a phenomic approach to assign a functional role to metagenome-derived clones

Are bullies more productive? Empirical study of affectiveness vs. issue fixing time

Human Affectiveness, i.e., The emotional state of a person, plays a crucial role in many domains where it can make or break a team's ability to produce successful products. Software development is a collaborative activity as well, yet there is little information on how affectiveness impacts software productivity. As a first measure of this impact, this paper analyzes the relation between sentiment, emotions and politeness of developers in more than 560K Jira comments with the time to fix a Jira issue. We found that the happier developers are (expressing emotions such as JOY and LOVE in their comments), the shorter the issue fixing time is likely to be. In contrast, negative emotions such as SADNESS, are linked with longer issue fixing time. Politeness plays a more complex role and we empirically analyze its impact on developers' productivity

Gut microbiota modulation of chemotherapy efficacy and toxicity

Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds

A conserved Polϵ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1

Defects during chromosome replication in eukaryotes activate a signaling pathway called the S-phase checkpoint, which produces a multifaceted response that preserves genome integrity at stalled DNA replication forks. Work with budding yeast showed that the ‘alternative clamp loader’ known as Ctf18-RFC acts by an unknown mechanism to activate the checkpoint kinase Rad53, which then mediates much of the checkpoint response. Here we show that budding yeast Ctf18-RFC associates with DNA polymerase epsilon, via an evolutionarily conserved ‘Pol ϵ binding module’ in Ctf18-RFC that is produced by interaction of the carboxyl terminus of Ctf18 with the Ctf8 and Dcc1 subunits. Mutations at the end of Ctf18 disrupt the integrity of the Pol ϵ binding module and block the S-phase checkpoint pathway, downstream of the Mec1 kinase that is the budding yeast orthologue of mammalian ATR. Similar defects in checkpoint activation are produced by mutations that displace Pol ϵ from the replisome. These findings indicate that the association of Ctf18-RFC with Pol ϵ at defective replication forks is a key step in activation of the S-phase checkpoint

Resolving the cosmic X-ray background with a next-generation high-energy X-ray observatory

The cosmic X-ray background (CXB), which peaks at an energy of ~30 keV, is produced primarily by emission from accreting supermassive black holes (SMBHs). The CXB therefore serves as a constraint on the integrated SMBH growth in the Universe and the accretion physics and obscuration in active galactic nuclei (AGNs). This paper gives an overview of recent progress in understanding the high-energy (>~10 keV) X-ray emission from AGNs and the synthesis of the CXB, with an emphasis on results from NASA's NuSTAR hard X-ray mission. We then discuss remaining challenges and open questions regarding the nature of AGN obscuration and AGN physics. Finally, we highlight the exciting opportunities for a next-generation, high-resolution hard X-ray mission to achieve the long-standing goal of resolving and characterizing the vast majority of the accreting SMBHs that produce the CXB.Comment: Science White paper submitted to Astro2020 Decadal Survey; 5 pages, 3 figures, plus references and cover pag

Impact of shortened crop rotation of oilseed rape on soil and rhizosphere microbial diversity in relation to yield decline

Oilseed rape (OSR) grown in monoculture shows a decline in yield relative to virgin OSR of up to 25%, but the mechanisms responsible are unknown. A long term field experiment of OSR grown in a range of rotations with wheat was used to determine whether shifts in fungal and bacterial populations of the rhizosphere and bulk soil were associated with the development of OSR yield decline. The communities of fungi and bacteria in the rhizosphere and bulk soil from the field experiment were profiled using terminal restriction fragment length polymorphism (TRFLP) and sequencing of cloned internal transcribed spacer regions and 16S rRNA genes, respectively. OSR cropping frequency had no effect on rhizosphere bacterial communities. However, the rhizosphere fungal communities from continuously grown OSR were significantly different to those from other rotations. This was due primarily to an increase in abundance of two fungi which showed 100% and 95% DNA identity to the plant pathogens Olpidium brassicae and Pyrenochaeta lycopersici, respectively. Real-time PCR confirmed that there was significantly more of these fungi in the continuously grown OSR than the other rotations. These two fungi were isolated from the field and used to inoculate OSR and Brassica oleracea grown under controlled conditions in a glasshouse to determine their effect on yield. At high doses, Olpidium brassicae reduced top growth and root biomass in seedlings and reduced branching and subsequent pod and seed production. Pyrenochaeta sp. formed lesions on the roots of seedlings, and at high doses delayed flowering and had a negative impact on seed quantity and quality

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Compton Thick AGN in the XMM-COSMOS survey

Heavily obscured, Compton Thick (CT, NH>10^24 cm^-2) AGN may represent an important phase in AGN/galaxy co-evolution and are expected to provide a significant contribution to the cosmic X-ray background (CXB). Through direct X-ray spectra analysis, we selected 39 heavily obscured AGN (NH>3x10^23 cm^-2) in the 2 deg^2 XMM-COSMOS survey. After selecting CT AGN based on the fit of a simple absorbed two power law model to the XMM data, the presence of CT AGN was confirmed in 80% of the sources using deeper Chandra data and more complex models. The final sample of CT AGN comprises 10 sources spanning a large range of redshift and luminosity. We collected the multi-wavelength information available for all these sources, in order to study the distribution of SMBH and host properties, such as BH mass (M_BH), Eddington ratio (\lambda_Edd), stellar mass (M*), specific star formation rate (sSFR) in comparison with a sample of unobscured AGN. We find that highly obscured sources tend to have significantly smaller M_BH and higher \lambda_edd with respect to unobscured ones, while a weaker evolution in M* is observed. The sSFR of highly obscured sources is consistent with the one observed in the main sequence of star forming galaxies, at all redshift. We also present optical spectra, spectral energy distribution (SED) and morphology for the sample of 10 CT AGN: all the available optical spectra are dominated by the stellar component of the host galaxy, and a highly obscured torus component is needed in the SED of the CT sources. Exploiting the high resolution Hubble-ACS images available, we conclude that these highly obscured sources have a significantly larger merger fraction with respect to other X-ray selected samples of AGN. Finally we discuss implications in the context of AGN/galaxy co-evolutionary models, and compare our results with the predictions of CXB synthesis models.Comment: Revised version after referee comments. Accepted for publication in Astronomy & Astrophysics on 25 November 2014. 23 pages, 2 tables, 16 figure