Help or hindrance : young people's experiences of predictive testing for Huntington's disease

Funded by Scottish GovernmentPeer reviewedPublisher PD

Vitamin D in polycystic ovary syndrome: Relationship to obesity and insulin resistance

Scope: Polycystic ovary syndrome (PCOS) is underpinned by insulin resistance (IR). In PCOS, the relationships between vitamin D, adiposity, and IR are unclear. We aim to explore these relationships in lean and overweight women with PCOS. Methods and results: This is a cross-sectional study conducted in a tertiary medical center. Participants included 42 women with PCOS and 34 controls without PCOS. Vitamin D and metabolic markers were measured. Detailed body composition and gold standard hyperinsulinemic euglycemic clamps were performed. The main outcome measures were plasma levels of vitamin D, adiposity measures, and glucose infusion rate. Vitamin D levels were lower in overweight women with PCOS compared with overweight controls (31.6 and 46.1 nmol/L, respectively, p = 0.01). Vitamin D was not associated with IR after adjustment for confounders; however, there was a significant interaction between PCOS and percentage body fat. Further analysis by PCOS status revealed that vitamin D was associated with IR in the PCOS group (β coefficient 2.1, 95% CI 0.2–4.0, p = 0.03), but not in the non-PCOS group. Conclusion: Vitamin D is associated with IR in women with PCOS, but not in controls. Large intervention studies are needed to determine if vitamin D supplementation can improve IR in PCOS.Anju E. Joham, Helena J. Teede, Samantha Cassar, Nigel K. Stepto, Boyd J. Strauss, Cheryce L. Harrison, Jacqueline Boyle and Barbora de Courte

Molecular Gas in the Host Galaxy of a Quasar at Redshift z=6.42

Observations of the molecular gas phase in quasar host galaxies provide fundamental constraints on galaxy evolution at the highest redshifts. Molecular gas is the material out of which stars form; it can be traced by spectral line emission of carbon--monoxide (CO). To date, CO emission has been detected in more than a dozen quasar host galaxies with redshifts (z) larger 2, the record holder being at z=4.69. At these distances the CO lines are shifted to longer wavelengths, enabling their observation with sensitive radio and millimetre interferometers. Here we present the discovery of CO emission toward the quasar SDSS J114816.64+525150.3 (hereafter J1148+5251) at a redshift of z=6.42, when the universe was only 1/16 of its present age. This is the first detection of molecular gas at the end of cosmic reionization. The presence of large amounts of molecular gas (M(H_2)=2.2e10 M_sun) in an object at this time demonstrates that heavy element enriched molecular gas can be generated rapidly in the earliest galaxies.Comment: 12 pages, 2 figures. To appear in Nature, July, 200

Tumor-resident dendritic cells and macrophages modulate the accumulation of TCR-engineered T cells in melanoma

Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c+ cells in CD11c.diphtheria toxin receptor (DTR) mice, we analyzed the interaction between tumor-resident cDCs and engineered T cells expressing the melanoma-specific TRP-2 TCR. We found that depletion of CD11c+ cells triggered the recruitment of cross-presenting cDC1 into the tumor and enhanced the accumulation of TCR-engineered T cells. We show that the recruited tumor cDCs present melanoma tumor antigen, leading to enhanced activation of TCR-engineered T cells. In addition, detailed analysis of the tumor myeloid compartment revealed that the depletion of a population of DT-sensitive macrophages can contribute to the accumulation of tumor-infiltrating T cells. Together, these data suggest that the relative frequency of tumor-resident cDCs and macrophages may impact the therapeutic efficacy of TCR gene therapy in solid tumors

Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis

OBJECTIVE:Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill-defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor β (TGFβ) regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. METHODS:A secondary analysis from a cross-sectional study was undertaken in women with (n=30) or without (n=29) PCOS across lean and overweight BMIs. A subset of participants with (n=8) or without (n=8) PCOS who were overweight completed 12-weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre- and post-training. RESULTS:We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFβ signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. CONCLUSIONS:We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin-signalling defects were isolated to mTOR, while gene expression implicated TGFβ ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance

Fake people, real effects : the presence of virtual onlookers can impair performance and learning

Can effects of social influence be elicited in virtual contexts, and if so, under which conditions can they be observed? Answering these questions has theoretical merit, as the answers can help broaden our understanding of the interaction mechanisms described by social psychology. The increasing popularity of immersive media in training applications, however, has made these questions of practical significance. Virtual reality (VR), in particular, is a weapon of choice in designing training and education simulations, as it can be used to generate highly realistic characters and environments. As a consequence, it is key to understand under which circumstances virtual ‘others’ can facilitate or impede performance and – especially – learning. In this study, we investigated the impact of virtual onlookers on an adapted Serial Reaction Time (SRT) task that was presented in VR. In each trial, participants responded to a series of spherical stimuli by tapping them with handheld controllers when they lit up. Depending on the experiment block, the sequence order was either the permutation of a fixed order (and therefore predictable given the first stimulus), or fully random (and therefore unpredictable). Participants were divided into three groups (audience variable), depending on the environment in which the task was set: a group without onlookers (none condition), a group with a computer-generated audience (CGI condition), and a group being watched by a prerecorded audience (filmed condition). Results showed that the presence of a virtual audience can hamper both overall performance and learning, particularly when the audience appears more realistic. This study further reinforces the notion that the effects of social influence transcend the physical presence of others, but rather extend to virtual audiences

An overview of conservative treatment options for diabetic Charcot foot neuroarthropathy

Conservative management of Charcot foot neuroarthropathy remains efficacious for certain clinical scenarios. Treatment of the patient should take into account the stage of the Charcot neuroarthopathy, site(s) of involvement, presence or absence of ulceration, presence or absence of infection, overall medical status, and level of compliance. The authors present an overview of evidence-based non-operative treatment for diabetic Charcot neuroarthropathy with an emphasis on the most recent developments in therapy

Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus

Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses