The transcriptional repressor Blimp1 is expressed in rare luminal progenitors and is essential for mammary gland development

Mammary gland morphogenesis depends on a tight balance between cell proliferation, differentiation and apoptosis, to create a defined functional hierarchy within the epithelia. The limited availability of stem cell/progenitor markers has made it challenging to decipher lineage relationships. Here, we identify a rare subset of luminal progenitors that express the zinc finger transcriptional repressor Blimp1, and demonstrate that this subset of highly clonogenic luminal progenitors is required for mammary gland development. Conditional inactivation experiments using K14-Cre and WAPi-Cre deleter strains revealed essential functions at multiple developmental stages. Thus, Blimp1 regulates proliferation, apoptosis and alveolar cell maturation during puberty and pregnancy. Loss of Blimp1 disrupts epithelial architecture and lumen formation both in vivo and in three-dimensional (3D) primary cell cultures. Collectively, these results demonstrate that Blimp1 is required to maintain a highly proliferative luminal subset necessary for mammary gland development and homeostasis

Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease

INTRODUCTION: Immune system activation is involved in Huntington’s disease (HD) pathogenesis and biomarkers for this process could be relevant to study the disease and characterise the therapeutic response to specific interventions. We aimed to study inflammatory cytokines and microglial markers in the CSF of HD patients. METHODS: CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed. RESULTS: CSF TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriosidase (p = 0.015) and IL-6 (p = 0.041) than controls. YKL-40 significantly correlated with disease stage (p = 0.007), UHDRS total functional capacity score (r = -0.46, p = 0.016), and UHDRS total motor score (r = 0.59, p = 4.5*10−4) after adjustment for age. CONCLUSION: YKL-40 levels in CSF may, after further study, come to have a role as biomarkers for some aspects of HD. Further investigation is needed to support our exploratory findings

Optimal client recommendation for market makers in illiquid financial products

The process of liquidity provision in financial markets can result in prolonged exposure to illiquid instruments for market makers. In this case, where a proprietary position is not desired, pro-actively targeting the right client who is likely to be interested can be an effective means to offset this position, rather than relying on commensurate interest arising through natural demand. In this paper, we consider the inference of a client profile for the purpose of corporate bond recommendation, based on typical recorded information available to the market maker. Given a historical record of corporate bond transactions and bond meta-data, we use a topic-modelling analogy to develop a probabilistic technique for compiling a curated list of client recommendations for a particular bond that needs to be traded, ranked by probability of interest. We show that a model based on Latent Dirichlet Allocation offers promising performance to deliver relevant recommendations for sales traders.Comment: 12 pages, 3 figures, 1 tabl

Quantifying the robustness of the neutron reflectometry technique for structural characterization of polymer brushes

Neutron reflectometry is the foremost technique for in situ determination of the volume fraction profiles of polymer brushes at planar interfaces. However, the subtle features in the reflectometry data produced by these diffuse interfaces challenge data interpretation. Historically, data analyses have used least-squares approaches that do not adequately quantify the uncertainty of the modeled profile and ignore the possibility of other structures that also match the collected data (multimodality). Here, a Bayesian statistical approach is used that permits the structural uncertainty and multimodality to be quantified for polymer brush systems. A free-form model is used to describe the volume fraction profile, minimizing assumptions regarding brush structure, while only allowing physically reasonable profiles to be produced. The model allows the total volume of polymer and the profile monotonicity to be constrained. The rigor of the approach is demonstrated via a round-Trip analysis of a simulated system, before it is applied to real data examining the well characterized collapse of a thermoresponsive brush. It is shown that, while failure to constrain the interfacial volume and consider multimodality may result in erroneous structures being derived, carefully constraining the model allows for robust determination of polymer brush compositional profiles. This work highlights that an appropriate combination of flexibility and constraint must be used with polymer brush systems to ensure the veracity of the analysis. The code used in this analysis is provided, enabling the reproduction of the results and the application of the method to similar problems

Calcium buffering in the heart in health and disease

Changes of intracellular Ca2+ concentration regulate many aspects of cardiac myocyte function. About 99% of the cytoplasmic calcium in cardiac myocytes is bound to buffers, and their properties will therefore have a major influence on Ca2+ signaling. This article considers the fundamental properties and identities of the buffers and how to measure them. It reviews the effects of buffering on the systolic Ca2+ transient and how this may change physiologically, and in heart failure and both atrial and ventricular arrhythmias, as well. It is concluded that the consequences of this strong buffering may be more significant than currently appreciated, and a fuller understanding is needed for proper understanding of cardiac calcium cycling and contractility

Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming

Epiblast cells in the early post-implantation stage mammalian embryo undergo a transition described as lineage priming before cell fate allocation, but signaling pathways acting upstream remain ill defined. Genetic studies demonstrate that Smad2/3 double-mutant mouse embryos die shortly after implantation. To learn more about the molecular disturbances underlying this abrupt failure, here we characterized Smad2/3-deficient embryonic stem cells (ESCs). We found that Smad2/3 double-knockout ESCs induced to form epiblast-like cells (EpiLCs) display changes in naive and primed pluripotency marker gene expression, associated with the disruption of Oct4-bound distal regulatory elements. In the absence of Smad2/3, we observed enhanced Bmp target gene expression and de-repression of extra-embryonic gene expression. Cell fate allocation into all three embryonic germ layers is disrupted. Collectively, these experiments demonstrate that combinatorial Smad2/3 functional activities are required to maintain distinct embryonic and/or extra-embryonic cell identity during lineage priming in the epiblast before gastrulation. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved

The relationship between sensory sensitivity and autistic traits in the general population.

Individuals with Autism Spectrum Disorders (ASDs) tend to have sensory processing difficulties (Baranek et al. in J Child Psychol Psychiatry 47:591–601, 2006). These difficulties include over- and under-responsiveness to sensory stimuli, and problems modulating sensory input (Ben-Sasson et al. in J Autism Dev Disorders 39:1–11, 2009). As those with ASD exist at the extreme end of a continuum of autistic traits that is also evident in the general population, we investigated the link between ASD and sensory sensitivity in the general population by administering two questionnaires online to 212 adult participants. Results showed a highly significant positive correlation (r = .775, p < .001) between number of autistic traits and the frequency of sensory processing problems. These data suggest a strong link between sensory processing and autistic traits in the general population, which in turn potentially implicates sensory processing problems in social interaction difficulties

A preliminary study of the effect of closed incision management with negative pressure wound therapy over high-risk incisions

Background Certain postoperative wounds are recognised to be associated with more complications than others and may be termed high-risk. Wound healing can be particularly challenging following high-energy trauma where wound necrosis and infection rates are high. Surgical incision for joint arthrodesis can also be considered high-risk as it requires extensive and invasive surgery and postoperative distal limb swelling and wound dehiscence are common. Recent human literature has investigated the use of negative pressure wound therapy (NPWT) over high-risk closed surgical incisions and beneficial effects have been noted including decreased drainage, decreased dehiscence and decreased infection rates. In a randomised, controlled study twenty cases undergoing distal limb high-energy fracture stabilisation or arthrodesis were randomised to NPWT or control groups. All cases had a modified Robert-Jones dressing applied for 72 h postoperatively and NPWT was applied for 24 h in the NPWT group. Morphometric assessment of limb circumference was performed at six sites preoperatively, 24 and 72 h postoperatively. Wound discharge was assessed at 24 and 72 h. Postoperative analgesia protocol was standardised and a Glasgow Composite Measure Pain Score (GCPS) carried out at 24, 48 and 72 h. Complications were noted and differences between groups were assessed. Results Percentage change in limb circumference between preoperative and 24 and 72 h postoperative measurements was significantly less at all sites for the NPWT group with exception of the joint proximal to the surgical site and the centre of the operated bone at 72 h. Median discharge score was lower in the NPWT group than the control group at 24 h. No significant differences in GCPS or complication rates were noted. Conclusions Digital swelling and wound discharge were reduced when NPWT was employed for closed incision management. Larger studies are required to evaluate whether this will result in reduced discomfort and complication rates postoperatively

Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale '99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ANCOVA. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p<0.05. Seventy-six participants were included in this cross-sectional multicentre international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p=0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r=-0.29, p=0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r=0.32, p=0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased comparing with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. This article is protected by copyright. All rights reserved