Investigating stellar-mass black hole kicks

We investigate whether stellar-mass black holes have to receive natal kicks in order to explain the observed distribution of low-mass X-ray binaries containing black holes within our Galaxy. Such binaries are the product of binary evolution, where the massive primary has exploded forming a stellar-mass black hole, probably after a common envelope phase where the system contracted down to separations of order 10-30 Rsun. We perform population synthesis calculations of these binaries, applying both kicks due to supernova mass-loss and natal kicks to the newly-formed black hole. We then integrate the trajectories of the binary systems within the Galactic potential. We find that natal kicks are in fact necessary to reach the large distances above the Galactic plane achieved by some binaries. Further, we find that the distribution of natal kicks would seem to be similar to that of neutron stars, rather than one where the kick velocities are reduced by the ratio of black hole to neutron-star mass (i.e. where the kicks have the same momentum). This result is somewhat surprising; in many pictures of stellar-mass black-hole formation, one might have expected black holes to receive kicks having the same momentum (rather than the same speed) as those given to neutron stars.Comment: 13 pages, 8 figures, 4 tables. Accepted for publication in MNRA

Holistic cancer genome profiling for every patient.

Technological advances in the ability to read the human genome have accelerated the speed of sequencing, such that today we can perform whole genome sequencing (WGS) in one day. Until recently, genomic studies have largely been limited to seeking novel scientific discoveries. The application of new insights gained through cancer WGS into the clinical domain, have been relatively limited. Looking ahead, a vast amount of data can be generated by genomic studies. Of note, excellent organisation of genomic and clinical data permits the application of machine-learning methods which can lead to the development of clinical algorithms that could assist future clinicians and genomicists in the analysis and interpretation of individual cancer genomes. Here, we describe what can be gleaned from holistic whole cancer genome profiling and argue that we must build the infrastructure and educational frameworks to support the modern clinical genomicist to prepare for a future where WGS will be the norm

Ozone impacts on vegetation in a nitrogen enriched and changing climate

This paper provides a process-oriented perspective on the combined effects of ozone (O3), climate change and/or nitrogen (N) on vegetation. Whereas increasing CO2 in controlled environments or opentop chambers often ameliorates effects of O3 on leaf physiology, growth and C allocation, this is less likely in the field. Combined responses to elevated temperature and O3 have rarely been studied even though some critical growth stages such as seed initiation are sensitive to both. Under O3 exposure, many species have smaller roots, thereby enhancing drought sensitivity. Of the 68 species assessed for stomatal responses to ozone, 22.5% were unaffected, 33.5% had sluggish or increased opening and 44% stomatal closure. The beneficial effect of N on root development was lost at higher O3 treatments whilst the effects of increasing O3 on root biomass became more pronounced as N increased. Both responses to gradual changes in pollutants and climate and those under extreme weather events require further study

Short inverted repeats contribute to localized mutability in human somatic cells.

Selected repetitive sequences termed short inverted repeats (SIRs) have the propensity to form secondary DNA structures called hairpins. SIRs comprise palindromic arm sequences separated by short spacer sequences that form the hairpin stem and loop respectively. Here, we show that SIRs confer an increase in localized mutability in breast cancer, which is domain-dependent with the greatest mutability observed within spacer sequences (∼1.35-fold above background). Mutability is influenced by factors that increase the likelihood of formation of hairpins such as loop lengths (of 4-5 bp) and stem lengths (of 7-15 bp). Increased mutability is an intrinsic property of SIRs as evidenced by how almost all mutational processes demonstrate a higher rate of mutagenesis of spacer sequences. We further identified 88 spacer sequences showing enrichment from 1.8- to 90-fold of local mutability distributed across 283 sites in the genome that intriguingly, can be used to inform the biological status of a tumor

Determinants of the Acceptance of Sustainable Production Strategies in Conventional and Organic Dairying in Europe: An Empirical Analysis

An extended version of the Technology Acceptance Model (TAM) was applied by means of Structural Equation Modelling to testing various hypotheses on attitudes and intentions of dairy farmers towards three novel sustainable production strategies, as well as the influence of organic practices and collaborative behaviours, such as information sharing with supply-chain partners. Data on the acceptance of three sustainable production strategies, namely Agro-forestry, Alternative protein source, and Prolonged maternal feeding were collected by a survey of dairy farmers in six European Union (EU) countries (Austria, Belgium, Denmark, Finland, Italy, United Kingdom). We found that perceived usefulness is the key determinant of acceptance, while the intention to adopt a sustainable production strategy may derive from the influence of opinions (and behaviours) of relevant others (e.g., leading dairy farmers, family members, advisors) showing the role of interactions among farmers and other stakeholders in the adoption of innovations. Finally, the perceived usefulness of all of the investigated strategies is higher for organic farmers, while collaborative patterns reduce the impact of subjective norm on usefulness and overall acceptance. Our findings should encourage policy makers to consider the important role of supply chain management practices, including collaboration, to enhance the sustainability of dairy farming systems

Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome

Abstract: Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis

CMV-specific T-cell responses at older ages: broad responses with a large central memory component may be key to long-term survival

Cytomegalovirus (CMV) infection sometimes causes large expansions of CMV-specific T-cells, particularly in older people. This is believed to undermine immunity to other pathogens and to accelerate immunosenescence. While multiple different CMV proteins are recognized, most publications on age-related T-cell expansions have focused on dominant target proteins, UL83 or UL123, and the T-cell activation marker, IFN-γ. We were concerned that this narrow approach might have skewed our understanding of CMV-specific immunity at older ages. We have, therefore, widened the scope of analysis to include in vitro-induced T-cell responses to 19 frequently recognized CMV proteins in young and older healthy volunteers and a group of oldest old, long-term survivors (>85 years of age). Polychromatic flow-cytometry was used to analyze T-cell activation markers (CD107, CD154, IL-2, TNF, IFN-γ) and memory phenotype (CD27, CD45RA). The older had on average larger T-cell responses than the young, but, interestingly, response size differences were relatively smaller when all activation markers were considered rather than IFN-γ or TNF alone. The oldest old recognized more proteins on average than the other groups and had even bigger T-cell responses than the older with a significantly larger central memory CD4 T-cell component

Functional diversity of CMV-specific T-cells is maintained in older people and significantly associated with protein specificity and response size

Background: Parallel up-regulation of several T-cell effector functions (‘polyfunctionality’) is believed to be critical for the protection against viruses but thought to decrease in large T-cell expansions, in particular at older ages. The factors determining T-cell polyfunctionality are incompletely understood. Here we revisit the question of CMV-specific T-cell polyfunctionality, including a wide range of T-cell target proteins, response sizes, and participant ages. Methods: Polychromatic flow-cytometry was used to analyze the functional diversity (CD107, CD154, IL-2, TNF, IFN-) of CD4 and CD8 T-cell responses to 19 CMV proteins in a large group of young and older UK participants. A group of oldest old people (>85years) was included to explore these parameters in exceptional ‘survivors’. Polyfunctionality was assessed for each proteinspecific response subset by subset and in aggregate across all proteins using the novel polyfunctionality index (PI). Results: Polyfunctionality was not reduced in healthy older compared to young people. However, it was significantly related to target protein specificity. For each protein it increased with response size. In the oldest old overall T-cell polyfunctionality was significantly lower. Discussion: Our results give a new perspective on T-cell polyfunctionality and raise the question if maintaining polyfunctionality of CMV-specific T-cells at older ages is necessarily beneficial

A living biobank of canine mammary tumor organoids as a comparative model for human breast cancer.

Mammary tumors in dogs hold great potential as naturally occurring breast cancer models in translational oncology, as they share the same environmental risk factors, key histological features, hormone receptor expression patterns, prognostic factors, and genetic characteristics as their human counterparts. We aimed to develop in vitro tools that allow functional analysis of canine mammary tumors (CMT), as we have a poor understanding of the underlying biology that drives the growth of these heterogeneous tumors. We established the long-term culture of 24 organoid lines from 16 dogs, including organoids derived from normal mammary epithelium or benign lesions. CMT organoids recapitulated key morphological and immunohistological features of the primary tissue from which they were derived, including hormone receptor status. Furthermore, genetic characteristics (driver gene mutations, DNA copy number variations, and single-nucleotide variants) were conserved within tumor-organoid pairs. We show how CMT organoids are a suitable model for in vitro drug assays and can be used to investigate whether specific mutations predict therapy outcomes. Specifically, certain CMT subtypes, such as PIK3CA mutated, estrogen receptor-positive simple carcinomas, can be valuable in setting up a preclinical model highly relevant to human breast cancer research. In addition, we could genetically modify the CMT organoids and use them to perform pooled CRISPR/Cas9 screening, where library representation was accurately maintained. In summary, we present a robust 3D in vitro preclinical model that can be used in translational research, where organoids from normal, benign as well as malignant mammary tissues can be propagated from the same animal to study tumorigenesis

Early and efficient detection of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures.

Early, efficient and inexpensive methods for the detection of pulmonary tuberculosis are urgently needed for effective patient management as well as to interrupt transmission. These methods to detect M. tuberculosis in a timely and affordable way are not yet widely available in resource-limited settings. In a developing-country setting, we prospectively evaluated two methods for culturing and detecting M. tuberculosis in sputum. Sputum samples were cultured in liquid assay (micro broth culture) in microplate wells and growth was detected by microscopic observation, or in Löwenstein-Jensen (LJ) solid media where growth was detected by visual inspection for colonies. Sputum samples were collected from 321 tuberculosis (TB) suspects attending Bugando Medical Centre, in Mwanza, Tanzania, and were cultured in parallel. Pulmonary tuberculosis cases were diagnosed using the American Thoracic Society diagnostic standards. There were a total of 200 (62.3%) pulmonary tuberculosis cases. Liquid assay with microscopic detection detected a significantly higher proportion of cases than LJ solid culture: 89.0% (95% confidence interval [CI], 84.7% to 93.3%) versus 77.0% (95% CI, 71.2% to 82.8%) (p = 0.0007). The median turn around time to diagnose tuberculosis was significantly shorter for micro broth culture than for the LJ solid culture, 9 days (interquartile range [IQR] 7-13), versus 21 days (IQR 14-28) (p<0.0001). The cost for micro broth culture (labor inclusive) in our study was US $4.56 per sample, versus US$11.35 per sample for the LJ solid culture. The liquid assay (micro broth culture) is an early, feasible, and inexpensive method for detection of pulmonary tuberculosis in resource limited settings