Endothelin receptor Aa regulates proliferation and differentiation of Erb-dependent pigment progenitors in zebrafish.

Skin pigment patterns are important, being under strong selection for multiple roles including camouflage and UV protection. Pigment cells underlying these patterns form from adult pigment stem cells (APSCs). In zebrafish, APSCs derive from embryonic neural crest cells, but sit dormant until activated to produce pigment cells during metamorphosis.

Human health in relation to exposure to solar ultraviolet radiation under changing stratospheric ozone and climate.

The Montreal Protocol has limited increases in the UV-B (280-315 nm) radiation reaching the Earth's surface as a result of depletion of stratospheric ozone. Nevertheless, the incidence of skin cancers continues to increase in most light-skinned populations, probably due mainly to risky sun exposure behaviour. In locations with strong sun protection programs of long duration, incidence is now reducing in younger age groups.

Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline.

An evidence-based clinical guideline for the diagnosis and management of Paget's disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget's Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed.

Correction to: Comparison of whole-genome bisulfite sequencing library preparation strategies identifies sources of biases affecting DNA methylation data.

Following publication of the original article [1], it was reported that the incorrect "Additional file 3" was published. The correct additional file is given below.

Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of Docetaxel in mouse models of breast cancer.

IκB kinase subunit epsilon (IKKε), a key component of NFκB and interferon signalling, has been identified as a breast cancer oncogene. Here we report that the IKKε/TBK1 axis plays a role in the initiation and progression of breast cancer osteolytic metastasis. Cancer-specific knockdown of IKKε in the human MDA-MB-231-BT cells and treatment with the verified IKKε/TBK1 inhibitor Amlexanox reduced skeletal tumour growth and osteolysis in mice.

Negotiating jurisdictional boundaries in response to new genetic possibilities in breast cancer care: The creation of an 'oncogenetic taskscape'.

Changes in the nature and structure of healthcare pathways have implications for healthcare professionals' jurisdictional boundaries. The introduction of treatment focused BRCA1 and 2 genetic testing (TFGT) for newly diagnosed patients with breast cancer offers a contemporary example of pathway change brought about by technological advancements in gene testing and clinical evidence, and reflects the cultural shift towards genomics. Forming part of an ethnographically informed study of patient and practitioner experiences of TFGT at a UK teaching hospital, this paper focuses on the impact of a proposal to pilot a mainstreamed TFGT pathway on healthcare professionals' negotiations of professional jurisdiction.

Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer.

Ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors (especially HER1/EGFR and HER2/ERBB2) are involved in disease progression; hence, strategies to inhibit their action could prove advantageous in ovarian cancer patients, especially in patients resistant to first line therapy. Monoclonal antibodies and tyrosine kinase inhibitors are two classes of drugs that act on these receptors.

Rare Inherited forms of Paget's Disease and Related Syndromes.

Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the receptor activator of nuclear factor kappa B (RANK), cause severe PDB-like disorders including familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia.

Raman spectroscopy as a predictive tool for monitoring osteoporosis therapy in a rat model of postmenopausal osteoporosis.

Pharmacological therapy of osteoporosis reduces bone loss and risk of fracture in patients. Modulation of bone mineral density cannot explain all effects. Other aspects of bone quality affecting fragility and ways to monitor them need to be better understood.

A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.

Cyclophilins (Cyps) are a major family of drug targets that are challenging to prosecute with small molecules because the shallow nature and high degree of conservation of the active site across human isoforms offers limited opportunities for potent and selective inhibition. Herein a computational approach based on molecular dynamics simulations and free energy calculations was combined with biophysical assays and X-ray crystallography to explore a flip in the binding mode of a reported urea-based Cyp inhibitor. This approach enabled access to a distal pocket that is poorly conserved among key Cyp isoforms, and led to the discovery of a new family of sub-micromolar cell-active inhibitors that offer unprecedented opportunities for the development of next-generation drug therapies based on Cyp inhibition.

Edar is a downstream target of beta-catenin and drives collagen accumulation in the mouse prostate.

Beta-catenin (CTNNB1) directs ectodermal appendage spacing by activating ectodysplasin A receptor (EDAR) transcription, but whether CTNNB1 acts by a similar mechanism in the prostate, an endoderm-derived tissue, is unclear. Here we examined the expression, function, and CTNNB1 dependence of the EDAR pathway during prostate development. hybridization studies reveal EDAR pathway components including in the developing prostate and localize these factors to prostatic bud epithelium where CTNNB1 target genes are co-expressed.

Modeling double strand break susceptibility to interrogate structural variation in cancer.

Background: Structural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood. Many SVs are thought to emerge from errors in the repair processes following DNA double strand breaks (DSBs).

Results: We used experimentally quantified DSB frequencies in cell lines with matched chromatin and sequence features to derive the first quantitative genome-wide models of DSB susceptibility.

Disentangling the genetics of lean mass.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups.

Author Correction: Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism.

In the version of this article initially published, in Table 2, the descriptions of pathways and definitions in the first and last columns did not correctly correspond to the values in the other columns. The error has been corrected in the HTML and PDF versions of the article.

Evaluation of Machine Learning Classifiers to Predict Compound Mechanism of Action When Transferred across Distinct Cell Lines.

Multiparametric high-content imaging assays have become established to classify cell phenotypes from functional genomic and small-molecule library screening assays. Several groups have implemented machine learning classifiers to predict the mechanism of action of phenotypic hit compounds by comparing the similarity of their high-content phenotypic profiles with a reference library of well-annotated compounds. However, the majority of such examples are restricted to a single cell type often selected because of its suitability for simple image analysis and intuitive segmentation of morphological features.

Linked Mutations at Adjacent Nucleotides Have Shaped Human Population Differentiation and Protein Evolution.

Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human evolution, there are still large gaps in our understanding of the forces that shape their distribution across the genome. SNPs have been shown to not be distributed evenly, with directly adjacent SNPs found unusually frequently. Why this is the case is unclear.

Moving into the mainstream: healthcare professionals' views of implementing treatment focussed genetic testing in breast cancer care.

A proportion of breast cancers are attributable to BRCA1 or BRCA2 mutations. Technological advances has meant that mutation testing in newly diagnosed cancer patients can be used to inform treatment plans. Although oncologists increasingly deliver treatment-focused genetic testing (TFGT) as part of mainstream ovarian cancer care, we know little about non-genetics specialists' views about offering genetic testing to newly diagnosed breast cancer patients.

Sex-specific moderation by lifestyle and psychosocial factors on the genetic contributions to adiposity in 112,151 individuals from UK Biobank.

Evidence suggests that lifestyle factors, e.g. physical activity, moderate the manifestation of genetic susceptibility to obesity.

An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning.

Male germ cells of all placental mammals express an ancient nuclear RNA binding protein of unknown function called RBMXL2. Here we find that deletion of the retrogene encoding RBMXL2 blocks spermatogenesis. Transcriptome analyses of age-matched deletion mice show that RBMXL2 controls splicing patterns during meiosis.

HER2 regulates HIF-2α and drives an increased hypoxic response in breast cancer.

Background: Tumour hypoxia is a driver of breast cancer progression associated with worse prognosis and more aggressive disease. The cellular response to hypoxia is mediated by the hypoxia-inducible transcription factors HIF-1 and HIF-2, whose transcriptional activity is canonically regulated through their oxygen-labile HIF-α subunits. These are constitutively degraded in the presence of oxygen; however, HIF-1α can be stabilised, even at high oxygen concentrations, through the activation of HER receptor signalling.

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV.

A validation of the diathesis-stress model for depression in Generation Scotland.

Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al.

Self-Awareness: Nucleic Acid-Driven Inflammation and the Type I Interferonopathies.

Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon-mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e.