NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells

Activating PIK3CA mutations are known “drivers” of human cancer and developmental overgrowth syndromes. We recently demonstrated that the "hotspot" PIK3CAH1047R variant exerts unexpected allele dose-dependent effects on stemness in human pluripotent stem cells (hPSCs). In the present study, we combine high-depth transcriptomics, total proteomics and reverse-phase protein arrays to reveal potentially disease-related alterations in heterozygous cells, and to assess the contribution of activated TGFβ signalling to the stemness phenotype of homozygous PIK3CAH1047R cells. We demonstrate signalling rewiring as a function of oncogenic PI3K signalling strength, and provide experimental evidence that self-sustained stemness is causally related to enhanced autocrine NODAL/TGFβ signalling. A significant transcriptomic signature of TGFβ pathway activation in heterozygous PIK3CAH1047R was observed but was modest and was not associated with the stemness phenotype seen in homozygous mutants. Notably, the stemness gene expression in homozygous PIK3CAH1047R iPSCs was reversed by pharmacological inhibition of NODAL/TGFβ signalling, but not by pharmacological PI3Kα pathway inhibition. Altogether, this provides the first in-depth analysis of PI3K signalling in human pluripotent stem cells and directly links strong PI3K activation to developmental NODAL/TGFβ signalling. This work illustrates the importance of allele dosage and expression when artificial systems are used to model human genetic disease caused by activating PIK3CA mutations

Climate Change and invasibility of the Antarctic benthos

Benthic communities living in shallow-shelf habitats in Antarctica (<100-m depth) are archaic in their structure and function. Modern predators, including fast-moving, durophagous (skeleton-crushing) bony fish, sharks, and crabs, are rare or absent; slow-moving invertebrates are the top predators; and epifaunal suspension feeders dominate many soft substratum communities. Cooling temperatures beginning in the late Eocene excluded durophagous predators, ultimately resulting in the endemic living fauna and its unique food-web structure. Although the Southern Ocean is oceanographically isolated, the barriers to biological invasion are primarily physiological rather than geographic. Cold temperatures impose limits to performance that exclude modern predators. Global warming is now removing those physiological barriers, and crabs are reinvading Antarctica. As sea temperatures continue to rise, the invasion of durophagous predators will modernize the shelf benthos and erode the indigenous character of marine life in Antarctica

Rhodopsin Mutant P23H Destabilizes Rod Photoreceptor Disk Membranes

Mutations in rhodopsin cause retinitis pigmentosa in humans and retinal degeneration in a multitude of other animals. We utilized high-resolution live imaging of the large rod photoreceptors from transgenic frogs (Xenopus) to compare the properties of fluorescently tagged rhodopsin, Rho-EGFP, and RhoP23H-EGFP. The mutant was abnormally distributed both in the inner and outer segments (OS), accumulating in the OS to a concentration of ∼0.1% compared to endogenous opsin. RhoP23H-EGFP formed dense fluorescent foci, with concentrations of mutant protein up to ten times higher than other regions. Wild-type transgenic Rho-EGFP did not concentrate in OS foci when co-expressed in the same rod with RhoP23H-EGFP. Outer segment regions containing fluorescent foci were refractory to fluorescence recovery after photobleaching, while foci in the inner segment exhibited recovery kinetics similar to OS regions without foci and Rho-EGFP. The RhoP23H-EGFP foci were often in older, more distal OS disks. Electron micrographs of OS revealed abnormal disk membranes, with the regular disk bilayers broken into vesiculotubular structures. Furthermore, we observed similar OS disturbances in transgenic mice expressing RhoP23H, suggesting such structures are a general consequence of mutant expression. Together these results show that mutant opsin disrupts OS disks, destabilizing the outer segment possibly via the formation of aggregates. This may render rods susceptible to mechanical injury or compromise OS function, contributing to photoreceptor loss

Psychological Determinants of Consumer Acceptance of Personalised Nutrition in 9 European Countries

YesObjective: To develop a model of the psychological factors which predict people’s intention to adopt personalised nutrition. Potential determinants of adoption included perceived risk and benefit, perceived self-efficacy, internal locus of control and health commitment. Methods: A questionnaire, developed from exploratory study data and the existing theoretical literature, and including validated psychological scales was administered to N = 9381 participants from 9 European countries (Germany, Greece, Ireland, Poland, Portugal, Spain, the Netherlands, the UK, and Norway). Results: Structural equation modelling indicated that the greater participants’ perceived benefits to be associated with personalised nutrition, the more positive their attitudes were towards personalised nutrition, and the greater their intention to adopt it. Higher levels of nutrition self-efficacy were related to more positive attitudes towards, and a greater expressed intention to adopt, personalised nutrition. Other constructs positively impacting attitudes towards personalised nutrition included more positive perceptions of the efficacy of regulatory control to protect consumers (e.g. in relation to personal data protection), higher self-reported internal health locus of control, and health commitment. Although higher perceived risk had a negative relationship with attitude and an inverse relationship with perceived benefit, its effects on attitude and intention to adopt personalised nutrition was less influential than perceived benefit. The model was stable across the different European countries, suggesting that psychological factors determining adoption of personalised nutrition have generic applicability across different European countries. Conclusion: The results suggest that transparent provision of information about potential benefits, and protection of consumers’ personal data is important for adoption, delivery of public health benefits, and commercialisation of personalised nutrition.This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n u 265494 (http://cordis.europa.eu/fp7/home_en.html). Food4Me is the acronym of the project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges’’ (http://www.food4me.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Home-based chlamydia testing of young people attending a music festival - who will pee and post?

<p>Abstract</p> <p>Background</p> <p>Chlamydia is most common among young people, but only a small proportion of Australian young people are tested annually. Home-based chlamydia testing has been piloted in several countries to increase testing rates, but uptake has been low. We aimed to identify predictors of uptake of home-based chlamydia testing to inform future testing programs.</p> <p>Methods</p> <p>We offered home-based chlamydia testing kits to participants in a sexual behaviour cross-sectional survey conducted at a music festival in Melbourne, Australia. Those who consented received a testing kit and were asked to return their urine or vaginal swab sample via post.</p> <p>Results</p> <p>Nine hundred and two sexually active music festival attendees aged 16-29 completed the survey; 313 (35%) opted to receive chlamydia testing kits, and 67 of 313 (21%) returned a specimen for testing. One participant was infected with chlamydia (1% prevalence). Independent predictors of consenting to receive a testing kit included older age, knowing that chlamydia can make women infertile, reporting more than three lifetime sexual partners and inconsistent condom use. Independent predictors of returning a sample to the laboratory included knowing that chlamydia can be asymptomatic, not having had an STI test in the past six months and not living with parents.</p> <p>Conclusions</p> <p>A low proportion of participants returned their chlamydia test, suggesting that this model is not ideal for reaching young people. Home-based chlamydia testing is most attractive to those who report engaging in sexual risk behaviours and are aware of the often asymptomatic nature and potential sequelae of chlamydia infection.</p

Exercise and Physical Therapy Interventions for Children with Ataxia: a systematic review

The effectiveness of exercise and physical therapy for children with ataxia is poorly understood. The aim of this systematic review was to critically evaluate the range, scope and methodological quality of studies investigating the effectiveness of exercise and physical therapy interventions for children with ataxia. The following databases were searched: AMED, CENTRAL, CDSR, CINAHL, ClinicalTrials.gov, EMBASE, Ovid MEDLINE, PEDro and Web of Science. No limits were placed on language, type of study or year of publication. Two reviewers independently determined whether the studies met the inclusion criteria, extracted all relevant outcomes, and conducted methodological quality assessments. A total of 1988 studies were identified, and 124 full texts were screened. Twenty studies were included in the review. A total of 40 children (aged 5-18 years) with ataxia as a primary impairment participated in the included studies. Data were able to be extracted from eleven studies with a total of 21 children (aged 5-18 years), with a range of cerebellar pathology. The studies reported promising results but were of low methodological quality (no RCTs), used small sample sizes and were heterogeneous in terms of interventions, participants and outcomes. No firm conclusions can be made about the effectiveness of exercise and physical therapy for children with ataxia. There is a need for further high-quality child-centred research

Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro

Inappropriate signalling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognised as being causally linked to a variety of cancers. Consequently, monoclonal antibodies specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a critical role in cancer progression and resistance to therapy. We hypothesised that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single-chain Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumour-associated antigen (TAA). In addition, we hypothesised that targeting this important heterodimer could induce a therapeutic effect. Here, we describe the construction and evaluation of the A5-linker-ML3.9 bs-scFv (ALM), an anti-ErbB3/ErbB2 bs-scFv. The A5-linker-ML3.9 bs-scFv exhibits selective targeting of tumour cells in vitro and in vivo that co-express the two target antigens over tumour cells that express only one target antigen or normal cells that express low levels of both antigens. The A5-linker-ML3.9 bs-scFv also exhibits significantly greater in vivo targeting of ErbB2‘+'/ErbB3‘+' tumours than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2‘+'/ErbB3‘+' cells mediates inhibition of tumour cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics

HDNetDB: A Molecular Interaction Database for Network-Oriented Investigations into Huntington’s Disease

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although HD is monogenic, its molecular manifestation appears highly complex and involves multiple cellular processes. The recent application of high throughput platforms such as microarrays and mass-spectrometry has indicated multiple pathogenic routes. The massive data generated by these techniques together with the complexity of the pathogenesis, however, pose considerable challenges to researchers. Network-based methods can provide valuable tools to consolidate newly generated data with existing knowledge, and to decipher the interwoven molecular mechanisms underlying HD. To facilitate research on HD in a network-oriented manner, we have developed HDNetDB, a database that integrates molecular interactions with many HD-relevant datasets. It allows users to obtain, visualize and prioritize molecular interaction networks using HD-relevant gene expression, phenotypic and other types of data obtained from human samples or model organisms. We illustrated several HDNetDB functionalities through a case study and identified proteins that constitute potential cross-talk between HD and the unfolded protein response (UPR). HDNetDB is publicly accessible at http://hdnetdb.sysbiolab.eu.CHDI Foundation [A-2666]; Portuguese Fundacao para a Ciencia e a Tecnologia [SFRH/BPD/70718/2010, SFRH/BPD/96890/2013, IF/00881/2013, UID/BIM/04773/2013 - CBMR, UID/Multi/04326/2013 - CCMAR]info:eu-repo/semantics/publishedVersio