The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1

The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5 + malignant melanoma-initiating cells (ABCB5 + MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro

Topologically Protected Quantum State Transfer in a Chiral Spin Liquid

Topology plays a central role in ensuring the robustness of a wide variety of physical phenomena. Notable examples range from the robust current carrying edge states associated with the quantum Hall and the quantum spin Hall effects to proposals involving topologically protected quantum memory and quantum logic operations. Here, we propose and analyze a topologically protected channel for the transfer of quantum states between remote quantum nodes. In our approach, state transfer is mediated by the edge mode of a chiral spin liquid. We demonstrate that the proposed method is intrinsically robust to realistic imperfections associated with disorder and decoherence. Possible experimental implementations and applications to the detection and characterization of spin liquid phases are discussed.Comment: 14 pages, 7 figure

Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global data

Background: Men who have sex with men (MSM) are disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide. Previous reviews investigating the role of circumcision in preventing HIV and other STIs among MSM were inconclusive. Many new studies have emerged in the past decade. To inform global prevention strategies for HIV and other STIs among MSM, we reviewed all available evidence on the associations between circumcision and HIV and other STIs among MSM. Methods: In this systematic review and meta-analysis, we searched PubMed, Web of Science, BioMed Central, Scopus, ResearchGate, Cochrane Library, Embase, PsycINFO, Google Scholar, and websites of international HIV and STI conferences for studies published before March 8, 2018. Interventional or observational studies containing original quantitative data describing associations between circumcision and incident or prevalent infection of HIV and other STIs among MSM were included. Studies were excluded if MSM could not be distinguished from men who have sex with women only. We calculated pooled odds ratios (ORs) and their 95% CIs using random-effect models. We assessed risk of bias using the Newcastle-Ottawa scale. Findings: We identified 62 observational studies including 119 248 MSM. Circumcision was associated with 23% reduced odds of HIV infection among MSM overall (OR 0·77, 95% CI 0·67–0·89; number of estimates [k]=45; heterogeneity I 2 =77%). Circumcision was protective against HIV infection among MSM in countries of low and middle income (0·58, 0·41–0·83; k=23; I 2 =77%) but not among MSM in high-income countries (0·99, 0·90–1·09; k=20; I 2 =40%). Circumcision was associated with reduced odds of herpes simplex virus (HSV) infection among MSM overall (0·84, 0·75–0·95; k=5; I 2 =0%) and penile human papillomavirus (HPV) infection among HIV-infected MSM (0·71, 0·51–0·99; k=3; I 2 =0%). Interpretation: We found evidence that circumcision is likely to protect MSM from HIV infection, particularly in countries of low and middle income. Circumcision might also protect MSM from HSV and penile HPV infection. MSM should be included in campaigns promoting circumcision among men in countries of low and middle income. In view of the substantial proportion of MSM in countries of low and middle income who also have sex with women, well designed longitudinal studies differentiating MSM only and bisexual men are needed to clarify the effect of circumcision on male-to-male transmission of HIV and other STIs. Funding: National Natural Science Foundation of China, National Science and Technology Major Project of China, Australian National Health and Medical Research Council Early Career Fellowship, Sanming Project of Medicine in Shenzhen, National Institutes of Health, Mega Projects of National Science Research for the 13th Five-Year Plan, Doris Duke Charitable Foundation

The Formation and Evolution of the First Massive Black Holes

The first massive astrophysical black holes likely formed at high redshifts (z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations. These black holes grow by mergers and gas accretion, evolve into the population of bright quasars observed at lower redshifts, and eventually leave the supermassive black hole remnants that are ubiquitous at the centers of galaxies in the nearby universe. The astrophysical processes responsible for the formation of the earliest seed black holes are poorly understood. The purpose of this review is threefold: (1) to describe theoretical expectations for the formation and growth of the earliest black holes within the general paradigm of hierarchical cold dark matter cosmologies, (2) to summarize several relevant recent observations that have implications for the formation of the earliest black holes, and (3) to look into the future and assess the power of forthcoming observations to probe the physics of the first active galactic nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant Universe", Ed. A. J. Barger, Kluwer Academic Publisher

The Formation of the First Massive Black Holes

Supermassive black holes (SMBHs) are common in local galactic nuclei, and SMBHs as massive as several billion solar masses already exist at redshift z=6. These earliest SMBHs may grow by the combination of radiation-pressure-limited accretion and mergers of stellar-mass seed BHs, left behind by the first generation of metal-free stars, or may be formed by more rapid direct collapse of gas in rare special environments where dense gas can accumulate without first fragmenting into stars. This chapter offers a review of these two competing scenarios, as well as some more exotic alternative ideas. It also briefly discusses how the different models may be distinguished in the future by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First Galaxies - Theoretical Predictions and Observational Clues", Springer Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B. Mobasher, in pres

Early star-forming galaxies and the reionization of the Universe

Star forming galaxies represent a valuable tracer of cosmic history. Recent observational progress with Hubble Space Telescope has led to the discovery and study of the earliest-known galaxies corresponding to a period when the Universe was only ~800 million years old. Intense ultraviolet radiation from these early galaxies probably induced a major event in cosmic history: the reionization of intergalactic hydrogen. New techniques are being developed to understand the properties of these most distant galaxies and determine their influence on the evolution of the universe.Comment: Review article appearing in Nature. This posting reflects a submitted version of the review formatted by the authors, in accordance with Nature publication policies. For the official, published version of the review, please see http://www.nature.com/nature/archive/index.htm

Conformal algebra: R-matrix and star-triangle relation

The main purpose of this paper is the construction of the R-operator which acts in the tensor product of two infinite-dimensional representations of the conformal algebra and solves Yang-Baxter equation. We build the R-operator as a product of more elementary operators S_1, S_2 and S_3. Operators S_1 and S_3 are identified with intertwining operators of two irreducible representations of the conformal algebra and the operator S_2 is obtained from the intertwining operators S_1 and S_3 by a certain duality transformation. There are star-triangle relations for the basic building blocks S_1, S_2 and S_3 which produce all other relations for the general R-operators. In the case of the conformal algebra of n-dimensional Euclidean space we construct the R-operator for the scalar (spin part is equal to zero) representations and prove that the star-triangle relation is a well known star-triangle relation for propagators of scalar fields. In the special case of the conformal algebra of the 4-dimensional Euclidean space, the R-operator is obtained for more general class of infinite-dimensional (differential) representations with nontrivial spin parts. As a result, for the case of the 4-dimensional Euclidean space, we generalize the scalar star-triangle relation to the most general star-triangle relation for the propagators of particles with arbitrary spins.Comment: Added references and corrected typo

Systematic literature review of determinants of sedentary behaviour in older adults:a DEDIPAC study

BACKGROUND: Older adults are the most sedentary segment of society and high sedentary time is associated with poor health and wellbeing outcomes in this population. Identifying determinants of sedentary behaviour is a necessary step to develop interventions to reduce sedentary time. METHODS: A systematic literature review was conducted to identify factors associated with sedentary behaviour in older adults. Pubmed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between 2000 and May 2014. The search strategy was based on four key elements: (a) sedentary behaviour and its synonyms; (b) determinants and its synonyms (e.g. correlates, factors); (c) types of sedentary behaviour (e.g. TV viewing, sitting, gaming) and (d) types of determinants (e.g. environmental, behavioural). Articles were included in the review if specific information about sedentary behaviour in older adults was reported. Studies on samples identified by disease were excluded. Study quality was rated by means of QUALSYST. The full review protocol is available from PROSPERO (PROSPERO 2014: CRD42014009823). The analysis was guided by the socio-ecological model framework. RESULTS: Twenty-two original studies were identified out of 4472 returned by the systematic search. These included 19 cross-sectional, 2 longitudinal and 1 qualitative studies, all published after 2011. Half of the studies were European. The study quality was generally high with a median of 82 % (IQR 69-96 %) using Qualsyst tool. Personal factors were the most frequently investigated with consistent positive association for age, negative for retirement, obesity and health status. Only four studies considered environmental determinants suggesting possible association with mode of transport, type of housing, cultural opportunities and neighbourhood safety and availability of places to rest. Only two studies investigated mediating factors. Very limited information was available on contexts and sub-domains of sedentary behaviours. CONCLUSION: Few studies have investigated determinants of sedentary behaviour in older adults and these have to date mostly focussed on personal factors, and qualitative studies were mostly lacking. More longitudinal studies are needed as well as inclusion of a broader range of personal and contextual potential determinants towards a systems-based approach, and future studies should be more informed by qualitative work

The RAD51 and DMC1 homoeologous genes of bread wheat: cloning, molecular characterization and expression analysis

<p>Abstract</p> <p>Background</p> <p>Meiotic recombination in eukaryotes requires two homologues of the <it>E. coli </it>RecA proteins: Rad51 and Dmc1. Both proteins play important roles in the binding of single stranded DNA, homology search, strand invasion and strand exchange. Meiotic recombination has been well studied in Arabidopsis, rice, maize and the orthologues of <it>RAD51 </it>and <it>DMC1 </it>have been characterized. However genetic analysis of the <it>RAD51 </it>and <it>DMC1 </it>genes in bread wheat has been hampered due to the absence of complete sequence information and because of the existence of multiple copies of each gene in the hexaploid wheat genome.</p> <p>Findings</p> <p>In this study we have identified that <it>TaRAD51 </it>and <it>TaDMC1 </it>homoeologues are located on group 7 and group 5 chromosomes of hexaploid wheat, respectively. Comparative sequence analysis of cDNA derived from the <it>TaRAD51 </it>and <it>TaDMC1 </it>homoeologues revealed limited sequence divergence at both the nucleotide and the amino acid level. Indeed, comparisons between the predicted amino acid sequences of <it>TaRAD51 </it>and <it>TaDMC1 </it>and those of other eukaryotes reveal a high degree of evolutionary conservation. Despite the high degree of sequence conservation at the nucleotide level, genome-specific primers for cDNAs of <it>TaRAD51 </it>and <it>TaDMC1 </it>were developed to evaluate expression patterns of individual homoeologues during meiosis. QRT-PCR analysis showed that expression of the <it>TaRAD51 </it>and <it>TaDMC1 </it>cDNA homoeologues was largely restricted to meiotic tissue, with elevated levels observed during the stages of prophase I when meiotic recombination occurs. All three homoeologues of both strand-exchange proteins (<it>TaRAD51 </it>and <it>TaDMC1</it>) are expressed in wheat.</p> <p>Conclusions</p> <p>Bread wheat contains three expressed copies of each of the <it>TaRAD51 </it>and <it>TaDMC1 </it>homoeologues. While differences were detected between the three cDNA homoeologues of <it>TaRAD51 </it>as well as the three homoeologues of <it>TaDMC1</it>, it is unlikely that the predicted amino acid substitutions would have an effect on the protein structure, based on our three-dimensional structure prediction analyses. There are differences in the levels of expression of the three homoeologues of <it>TaRAD51 </it>and <it>TaDMC1 </it>as determined by QRT-PCR and if these differences are reflected at the protein level, bread wheat may be more dependent upon a particular homoeologue to achieve full fertility than all three equally.</p

Formation of Supermassive Black Holes

Evidence shows that massive black holes reside in most local galaxies. Studies have also established a number of relations between the MBH mass and properties of the host galaxy such as bulge mass and velocity dispersion. These results suggest that central MBHs, while much less massive than the host (~ 0.1%), are linked to the evolution of galactic structure. In hierarchical cosmologies, a single big galaxy today can be traced back to the stage when it was split up in hundreds of smaller components. Did MBH seeds form with the same efficiency in small proto-galaxies, or did their formation had to await the buildup of substantial galaxies with deeper potential wells? I briefly review here some of the physical processes that are conducive to the evolution of the massive black hole population. I will discuss black hole formation processes for `seed' black holes that are likely to place at early cosmic epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final publication is available at http://www.springerlink.co