Diverse functions of clusterin promote and protect against the development of pulmonary fibrosis.

Pulmonary fibrosis is a progressive scarring disorder of the lung with dismal prognosis and no curative therapy. Clusterin, an extracellular chaperone and regulator of cell functions, is reduced in bronchoalveolar lavage fluid of patients with pulmonary fibrosis. However, its distribution and role in normal and fibrotic human lung are incompletely characterized. Immunohistochemical localization of clusterin revealed strong staining associated with fibroblasts in control lung and morphologically normal areas of fibrotic lung but weak or undetectable staining in fibrotic regions and particularly fibroblastic foci. Clusterin also co-localized with elastin in vessel walls and additionally with amorphous elastin deposits in fibrotic lung. Analysis of primary lung fibroblast isolates in vitro confirmed the down-regulation of clusterin expression in fibrotic compared with control lung fibroblasts and further demonstrated that TGF-β1 is capable of down-regulating fibroblast clusterin expression. shRNA-mediated down-regulation of clusterin did not affect TGF-β1-induced fibroblast-myofibroblast differentiation but inhibited fibroblast proliferative responses and sensitized to apoptosis. Down-regulation of clusterin in fibrotic lung fibroblasts at least partly due to increased TGF-β1 may therefore represent an appropriate but insufficient response to limit fibroproliferation. Reduced expression of clusterin in the lung may also limit its extracellular chaperoning activity contributing to dysregulated deposition of extracellular matrix proteins

USP7 controls NGN3 stability and pancreatic endocrine lineage development

AbstractUnderstanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited.</jats:p

VLT FORS2 comparative transmission spectroscopy: Detection of Na in the atmosphere of WASP-39b from the ground

We present transmission spectroscopy of the warm Saturn-mass exoplanet WASP-39b made with the Very Large Telescope FOcal Reducer and Spectrograph (FORS2) across the wavelength range 411–810 nm. The transit depth is measured with a typical precision of 240 parts per million (ppm) in wavelength bins of 10 nm on a V = 12.1 mag star. We detect the sodium absorption feature (3.2σ) and find evidence of potassium. The ground-based transmission spectrum is consistent with Hubble Space Telescope (HST) optical spectroscopy, supporting the interpretation that WASP-39b has a largely clear atmosphere. Our results demonstrate the great potential of the recently upgraded FORS2 spectrograph for optical transmission spectroscopy, with which we obtained HST-quality light curves from the ground

Academic achievement at ages 11 and 16 in children born with congenital anomalies in England: A multi-registry linked cohort study

\ua9 2024 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley &amp; Sons Ltd. Background: Children born with major congenital anomalies (CAs) have lower academic achievement compared with their peers, but the existing evidence is restricted to a number of specific CAs. Objectives: To investigate academic outcomes at ages 11 and 16 in children with major isolated structural CAs and children with Down or Turner syndromes. Methods: This population-based cohort study linked data on approximately 11,000 school-aged children born with major CAs in 1994–2004 registered by four regional CA registries in England with education data from the National Pupil Database (NPD). The comparison group was a random sample of children without major CAs from the background population recorded in the NPD that were frequency matched (5:1) to children with CAs by birth year, sex and geographical area. Results: Overall, 71.9%, 73.0% and 80.9% of children with isolated structural CAs achieved the expected attainment level at age 11 compared to 78.3%, 80.6% and 86.7% of the comparison group in English language, Mathematics and Science, respectively. Children with nervous system CAs as a whole had the lowest proportion who achieved the expected attainment at age 11. At age 16, 46.9% of children with CAs achieved the expected level compared to 52.5% of their peers. Major CAs were associated with being up to 9% (95% confidence interval [CI] 8%, 11%) and 12% (95% CI 9%, 14%) less likely to achieve expected levels at ages 11 and 16, respectively, after adjustment for socioeconomic deprivation. Conclusions: Although many children with isolated CAs achieved the expected academic level at ages 11 and 16, they were at higher risk of underachievement compared to their peers. These stark yet cautiously encouraging results are important for counselling parents of children with specific CAs and also highlight the possible need for special education support to reduce potential academic difficulties

A life less lonely: the state of the art in interventions to reduce loneliness in people with mental health problems

PURPOSE: There is growing evidence of significant harmful effects of loneliness. Relatively little work has focused on how best to reduce loneliness in people with mental health problems. We aim to present an overview of the current state of the art in loneliness interventions in people with mental health problems, identify relevant challenges, and highlight priorities for future research and implementation. METHODS: A scoping review of the published and grey literature was conducted, as well as discussions with relevant experts, to propose a broad classification system for types of interventions targeting loneliness. RESULTS: We categorised interventions as ‘direct’, targeting loneliness and related concepts in social relationships, and ‘indirect’ broader approaches to well-being that may impact on loneliness. We describe four broad groups of direct interventions: changing cognitions; social skills training and psychoeducation; supported socialisation or having a ‘socially-focused supporter’; and ‘wider community approaches’. The most promising emerging evidence appears to be in ‘changing cognitions’, but, as yet, no approaches have a robust evidence base. Challenges include who is best placed to offer the intervention, how to test such complex interventions, and the stigma surrounding loneliness. CONCLUSIONS: Development of clearly defined loneliness interventions, high-quality trials of effectiveness, and identifying which approaches work best for whom is required. Promising future approaches may include wider community initiatives and social prescribing. It is important to place loneliness and social relationships high on the wider public mental health and research agenda

Metabonomics and Intensive Care

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance.

BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies

VLT/FORS2 comparative transmission spectroscopy II: Confirmation of a cloud deck and Rayleigh scattering in WASP-31b, but no potassium?

We present transmission spectroscopy of the hot-Jupiter WASP-31b using the FOcal Reducer and low dispersion Spectrograph 2 (FORS2) on the Very Large Telescope during two primary transits. The observations cover a wavelength range of ≈400–840 nm. The light curves are corrupted by significant systematics, but these were to first-order invariant with wavelength and could be removed using a common-mode correction derived from the white light curves. We reach a precision in the transit depth of ≈140 ppm in 15 nm bins, although the precision varies significantly over the wavelength range. Our FORS2 observations confirm the cloud deck previously inferred using Hubble Space Telescope (HST)/Space Telescope Imaging Spectrograph (STIS). We also re-analyse the HST/STIS data using a Gaussian process model, finding excellent agreement with earlier measurements. We reproduce the Rayleigh scattering signature at short wavelengths (5300 Å) and the cloud deck at longer wavelengths. However, our FORS2 observations appear to rule out the large potassium feature previously detected using STIS, yet it is recovered from the HST/STIS data, although with reduced amplitude and significance (≈2.5σ ). The discrepancy between our results and the earlier STIS detection of potassium (≈4.3σ ) is either a result of telluric contamination of the ground-based observations, or an underestimate of the uncertainties for narrow-band features in HST/STIS when using linear basis models to account for the systematics. Our results further demonstrate the use of ground-based multi-object spectrographs for the study of exoplanet atmospheres, and highlight the need for caution in our interpretation of narrow-band features in low-resolution spectra of hot Jupiters

Ground-Based Transmission Spectroscopy with FORS2: A featureless optical transmission spectrum and detection of H2O for the ultra-hot Jupiter WASP-103b

We report ground-based transmission spectroscopy of the highly irradiated and ultra-short period hot-Jupiter WASP-103b covering the wavelength range ≈ 400 – 600 nm using the FORS2 instrument on the Very Large Telescope. The light curves show significant time-correlated noise which is mainly invariant in wavelength and which we model using a Gaussian process. The precision of our transmission spectrum is improved by applying a common-mode correction derived from the white light curve, reaching typical uncertainties in transit depth of ≈ 2 × 10−4 in wavelength bins of 15 nm. After correction for flux contamination from a blended companion star, our observations reveal a featureless spectrum across the full range of the FORS2 observations and we are unable to confirm the Na absorption previously inferred using Gemini/GMOS or the strong Rayleigh scattering observed using broad-band light curves. We performed a Bayesian atmospheric retrieval on the full optical-infrared transmission spectrum using the additional data from Gemini/GMOS, HST/WFC3 and Spitzer observations and recover evidence for H2O absorption at the 4.0 σ level. However, our observations are not able to completely rule out the presence of Na, which is found at 2.0 σ in our retrievals. This may in part be explained by patchy/inhomogeneous clouds or hazes damping any absorption features in our FORS2 spectrum, but an inherently small scale height also makes this feature challenging to probe from the ground. Our results nonetheless demonstrate the continuing potential of ground-based observations for investigating exoplanet atmospheres and emphasise the need for the application of consistent and robust statistical techniques to low-resolution spectra in the presence of instrumental systematics