Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass

Meeting the support and information needs of women with advanced breast cancer: a randomised controlled trial

Addressing psychosocial and quality of life needs is central to provision of excellent care for people with advanced cancer. This study tested a brief nurse-delivered intervention to address the needs of urban women with advanced breast cancer. This study was conducted at four large urban hospitals in Australia. One hundred and five women with advanced breast cancer were recruited and randomised to receive the intervention or usual care, then asked to complete the European Organisation of Research and Treatment of Quality of life Q-C30 version (2.0) (EORTC Q-C30) (version 2) and Supportive Care Needs Survey (SCNS) at 1 month and 3 months postrecruitment. No significant differences were detected between intervention and usual care groups in the SCNS or the EORTC Q-C30 subscale scores. However, when the groups were divided into high needs (score of above 50) and low baseline needs (score of 50 or below) for each SCNS subscale, a significant difference between intervention and usual care groups was found in the psychological/emotional subscale among women with high baseline needs. In conclusions, this study demonstrated that a face-to-face session and follow-up phone call with a breast care nurse significantly reduced the psychological and emotional needs of those with high initial needs. There was no evidence of the intervention influencing the quality of life; or perceived needs of women with low initial psychological/emotional needs or perceived needs in other domains. Possibly, the intervention was not sufficiently intense to achieve an effect

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2017. Supplementary information accompanies this paper at doi:10.1038/s41598-017-01971-2.The question of how cell division orientation is determined is fundamentally important for understanding tissue and organ shape in both healthy or disease conditions. Here we provide evidence for cell contact-dependent orientation of planar cell division in the mammalian embryonic skin. We propose a model where the core planar polarity proteins Celsr1 and Frizzled-6 (Fz6) communicate the long axis orientation of interphase basal cells to neighbouring basal mitoses so that they align their horizontal division plane along the same axis. The underlying mechanism requires a direct, cell surface, planar polarised cue, which we posit depends upon variant post-translational forms of Celsr1 protein coupled to Fz6. Our hypothesis has parallels with contact-mediated division orientation in early C. elegans embryos suggesting functional conservation between the adhesion-GPCRs Celsr1 and Latrophilin-1. We propose that linking planar cell division plane with interphase neighbour long axis geometry reinforces axial bias in skin spreading around the mouse embryo body.Peer reviewe

First Dinosaur Tracks from the Arabian Peninsula

Background: The evolutionary history of Mesozoic terrestrial vertebrates from the Arabian Peninsula is virtually unknown. Despite vast exposures of rocky outcrops, only a handful of fossils have yet been described from the region. Here we report a multi-taxon dinosaur track assemblage near Madar village, 47 km north of Sana’a, Republic of Yemen. This represents the first dinosaur tracksite from the Arabian Peninsula, and the only multi-taxon dinosaur ichnosite in the Middle East. Methodology/Findings: Measurements were taken directly from trackway impressions, following standard ichnological conventions. The presence of bipedal trackmakers is evidenced by a long series of pes imprints preserving smoothly rounded posterior margins, no evidence of a hallux, bluntly rounded digit tips and digital divarication angles characteristic of ornithopod dinosaurs. Nearby, eleven parallel quadrupedal trackways document a sauropod herd that included large and small individuals traveling together. Based on the morphology of manus impressions along with a narrow-gauged stance, the quadrupedal trackways were made by non-titanosauriform neosauropods. Additional isolated tracks and trackways of sauropod and ornithopod dinosaurs are preserved nearby. Conclusions/Significance: Taken together, these discoveries present the most evocative window to date into the evolutionary history of dinosaurs of the Arabian Peninsula. Given the limited Mesozoic terrestrial record from the region, this discovery is of both temporal and geographic significance, and massive exposures of similarly-aged outcrops nearby offe

The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19

"You've got a friend in me": can social networks mediate the relationship between mood and MCI?

engagement is beneficial to both mental health and cognition, and represents a potentially modifiable factor. Consequently this study explored this association and assessed whether the relationship between mild cognitive impairment (MCI) and mood problems was mediated by social networks. Methods: This study includes an analysis of data from the Cognitive Function and Ageing Study Wales (CFAS Wales). CFAS Wales Phase 1 data were collected from 2010-2013 by conducting structured interviews with older people aged over 65 years of age living in urban and rural areas of Wales, and included questions that assessed cognitive functioning, mood, and social networks. Regression analyses were used to investigate the associations between individual variables and the mediating role of social networks. Results: Having richer social networks was beneficial to both mood and cognition. Participants in the MCI category had weaker social networks than participants without cognitive impairment, whereas stronger social networks were associated with a decrease in the odds of experiencing mood problems, suggesting that they may offer a protective effect against anxiety and depression. Regression analyses revealed that social networks are a significant mediator of the relationship between MCI and mood problems. Conclusions: These findings are important, as mood problems are a risk factor for progression from MCI to dementia, so interventions that increase and strengthen social networks may have beneficial effects on slowing the progression of cognitive decline

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

BACKGROUND: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. METHODS: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. RESULTS: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. CONCLUSIONS: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study

Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

The number of patients diagnosed with chronic bile duct disease is increasing and in most cases these diseases result in chronic ductular scarring, necessitating liver transplantation. The formation of ductular scaring affects liver function; however, scar-generating portal fibroblasts also provide important instructive signals to promote the proliferation and differentiation of biliary epithelial cells. Therefore, understanding whether we can reduce scar formation while maintaining a pro-regenerative microenvironment will be essential in developing treatments for biliary disease. Here, we describe how regenerating biliary epithelial cells express Wnt-Planar Cell Polarity signalling components following bile duct injury and promote the formation of ductular scars by upregulating pro-fibrogenic cytokines and positively regulating collagen-deposition. Inhibiting the production of Wnt-ligands reduces the amount of scar formed around the bile duct, without reducing the development of the pro-regenerative microenvironment required for ductular regeneration, demonstrating that scarring and regeneration can be uncoupled in adult biliary disease and regeneration

First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting

This review summarizes phase I trial results of 11 drugs presented at the American Society of Clinical Oncology meeting held in Chicago IL from May 30 to June 3rd 2008: BMS-663513, CT-322, CVX-045, GDC-0449, GRN163L, LY2181308, PF-00562271, RAV12, RTA 402, XL765, and the survivin vaccine

Canonical wnt signaling activity in early stages of chick lung development

Wnt signaling pathway is an essential player during vertebrate embryonic development which has been associated with several developmental processes such as gastrulation, body axis formation and morphogenesis of numerous organs, namely the lung. Wnt proteins act through specific transmembrane receptors, which activate intracellular pathways that regulate cellular processes such as cell proliferation, differentiation and death. Morphogenesis of the fetal lung depends on epithelial-mesenchymal interactions that are governed by several growth and transcription factors that regulate cell proliferation, fate, migration and differentiation. This process is controlled by different signaling pathways such as FGF, Shh and Wnt among others. Wnt signaling is recognized as a key molecular player in mammalian pulmonary development but little is known about its function in avian lung development. The present work characterizes, for the first time, the expression pattern of several Wnt signaling members, such as wnt-1, wnt-2b, wnt-3a, wnt-5a, wnt-7b, wnt-8b, wnt-9a, lrp5, lrp6, sfrp1, dkk1, β-catenin and axin2 at early stages of chick lung development. In general, their expression is similar to their mammalian counterparts. By assessing protein expression levels of active/total β-catenin and phospho-LRP6/LRP6 it is revealed that canonical Wnt signaling is active in this embryonic tissue. In vitro inhibition studies were performed in order to evaluate the function of Wnt signaling pathway in lung branching. Lung explants treated with canonical Wnt signaling inhibitors (FH535 and PK115-584) presented an impairment of secondary branch formation after 48 h of culture along with a decrease in axin2 expression levels. Branching analysis confirmed this inhibition. Wnt-FGF crosstalk assessment revealed that this interaction is preserved in the chick lung. This study demonstrates that Wnt signaling is crucial for precise chick lung branching and further supports the avian lung as a good model for branching studies since it recapitulates early mammalian pulmonary development.Rute S. Moura was supported by a grant of ON.2 SR&TD Integrated Program (N-01-01-0124-01-07), ref: UMINHO/BPD/31/2013. The funders had no role in study design, data collection and analysis