RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.     

A collision in 2009 as the origin of the debris trail of asteroid P/2010 A2

The peculiar object P/2010?A2 was discovered in January 2010 and given a cometary designation because of the presence of a trail of material, although there was no central condensation or coma. The appearance of this object, in an asteroidal orbit (small eccentricity and inclination) in the inner main asteroid belt attracted attention as a potential new member of the recently recognized class of main-belt comets. If confirmed, this new object would expand the range in heliocentric distance over which main-belt comets are found. Here we report observations of P/2010?A2 by the Rosetta spacecraft. We conclude that the trail arose from a single event, rather than a period of cometary activity, in agreement with independent results. The trail is made up of relatively large particles of millimetre to centimetre size that remain close to the parent asteroid. The shape of the trail can be explained by an initial impact ejecting large clumps of debris that disintegrated and dispersed almost immediately. We determine that this was an asteroid collision that occurred around 10 February 2009.     

TRIM24 links a non-canonical histone signature to breast cancer

Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.     

The complete genome of an individual by massively parallel DNA sequencing

The association of genetic variation with disease and drug response, and improvements in nucleic acid technologies, have given great optimism for the impact of 'genomic medicine'. However, the formidable size of the diploid human genome, approximately 6 gigabases, has prevented the routine application of sequencing methods to deciphering complete individual human genomes. To realize the full potential of genomics for human health, this limitation must be overcome. Here we report the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing in picolitre-size reaction vessels. This sequence was completed in two months at approximately one-hundredth of the cost of traditional capillary electrophoresis methods. Comparison of the sequence to the reference genome led to the identification of 3.3 million single nucleotide polymorphisms, of which 10,654 cause amino-acid substitution within the coding sequence. In addition, we accurately identified small-scale (2-40,000 base pair (bp)) insertion and deletion polymorphism as well as copy number variation resulting in the large-scale gain and loss of chromosomal segments ranging from 26,000 to 1.5 million base pairs. Overall, these results agree well with recent results of sequencing of a single individual by traditional methods. However, in addition to being faster and significantly less expensive, this sequencing technology avoids the arbitrary loss of genomic sequences inherent in random shotgun sequencing by bacterial cloning because it amplifies DNA in a cell-free system. As a result, we further demonstrate the acquisition of novel human sequence, including novel genes not previously identified by traditional genomic sequencing. This is the first genome sequenced by next-generation technologies. Therefore it is a pilot for the future challenges of 'personalized genome sequencing'.     

Abundance and diversity of microbial life in ocean crust

Oceanic lithosphere exposed at the sea floor undergoes seawater-rock alteration reactions involving the oxidation and hydration of glassy basalt. Basalt alteration reactions are theoretically capable of supplying sufficient energy for chemolithoautotrophic growth. Such reactions have been shown to generate microbial biomass in the laboratory, but field-based support for the existence of microbes that are supported by basalt alteration is lacking. Here, using quantitative polymerase chain reaction, in situ hybridization and microscopy, we demonstrate that prokaryotic cell abundances on seafloor-exposed basalts are 3-4 orders of magnitude greater than in overlying deep sea water. Phylogenetic analyses of basaltic lavas from the East Pacific Rise (9 degrees N) and around Hawaii reveal that the basalt-hosted biosphere harbours high bacterial community richness and that community membership is shared between these sites. We hypothesize that alteration reactions fuel chemolithoautotrophic microorganisms, which constitute a trophic base of the basalt habitat, with important implications for deep-sea carbon cycling and chemical exchange between basalt and sea water.     

Production of multiple plant hormones from a single polyprotein precursor.

Some animal and yeast hormone genes produce prohormone polypeptides that are proteolytically processed to produce multiple copies of hormones with the same or different functions. In plants, four polypeptides have been identified that can be classed as hormones (intercellular chemical messengers) but none are known to be produced as multiple copies from a single precursor. Here we describe a polyprotein hormone precursor, present in tobacco plants, that gives rise to two polypeptide hormones, as often found in animals and yeast. The tobacco polypeptides activate the synthesis of defensive proteinase-inhibitor proteins in a manner similar to that of systemin, an 18-amino-acid polypeptide found in tomato plants. The two tobacco polypeptides are derived from each end of a 165-amino-acid precursor that bears no homology to tomato prosystemin. The data show that structurally diverse polypeptide hormones in different plant species can serve similar signalling roles, a condition not found in animals or yeast.     

Multi‐model Forecasts of the West Texas Intermediate Crude Oil Spot Price

We measure the performance of multi‐model inference (MMI) forecasts compared to predictions made from a single model for crude oil prices. We forecast the West Texas Intermediate (WTI) crude oil spot prices using total OECD petroleum inventory levels, surplus production capacity, the Chicago Board Options Exchange Volatility Index and an implementation of a subset autoregression with exogenous variables (SARX). Coefficient and standard error estimates obtained from SARX determined by conditioning on a single ‘best model’ ignore model uncertainty and result in underestimated standard errors and overestimated coefficients. We find that the MMI forecast outperforms a single‐model forecast for both in‐ and out‐of‐sample datasets over a variety of statistical performance measures, and further find that weighting models according to the Bayesian information criterion generally yields superior results both in and out of sample when compared to the Akaike information criterion. Copyright © 2016 John Wiley & Sons, Ltd.     

A Systemic Model for Managing and Evaluating Conflicts in Organizational Change

Change or innovation diffusion is a key issue for most business organizations but is yet difficult to implement as the change management process is often complex as it relies on an organized methodology to complement an organization’s commitment and participation. An ambiguous environment surrounding change mechanism tends to develop unintended attitudes, resulting in resistance and conflict. The study proposes a model for the management of such conflicts among change participants (involved and affected) in the context of organizational change. The authors consider organizational change process as an innovation project that treats change and conflicts holistically with the Ulrich’s notion of boundary considerations (boundary critique). A social network setting of multiple stakeholders is considered to effectively help in resolving problematic situations that hinder organizational learning and change. The proposed model provides a theoretical foundation based on concepts governing Critical Systems Heuristics (CSH), change theory, stakeholder theory and conflict management.     

Complete genome sequence of Salmonella enterica serovar Typhimurium LT2.

Salmonella enterica subspecies I, serovar Typhimurium (S. typhimurium), is a leading cause of human gastroenteritis, and is used as a mouse model of human typhoid fever. The incidence of non-typhoid salmonellosis is increasing worldwide, causing millions of infections and many deaths in the human population each year. Here we sequenced the 4,857-kilobase (kb) chromosome and 94-kb virulence plasmid of S. typhimurium strain LT2. The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A (S. paratyphi A) and Klebsiella pneumoniae, and hybridization of three unsequenced genomes to a microarray of S. typhimurium LT2 genes. Lateral transfer of genes is frequent, with 11% of the S. typhimurium LT2 genes missing from S. enterica serovar Typhi (S. typhi), and 29% missing from Escherichia coli K12. The 352 gene homologues of S. typhimurium LT2 confined to subspecies I of S. enterica-containing most mammalian and bird pathogens-are useful for studies of epidemiology, host specificity and pathogenesis. Most of these homologues were previously unknown, and 50 may be exported to the periplasm or outer membrane, rendering them accessible as therapeutic or vaccine targets.