Extracellular regulation of BMP signaling: welcome to the matrix

Given its importance in development and homeostasis, bone morphogenetic protein (BMP) signaling is tightly regulated at the extra-and intracellular level. The extracellular matrix (ECM) was initially thought to act as a passive mechanical barrier that sequesters BMPs. However, a new understanding about how the ECM plays an instructive role in regulating BMP signaling is emerging. In this mini-review, we discuss various ways in which the biochemical and physical properties of the ECM regulate BMP signaling

Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells

Abstract BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients. Hyaluronic acid (HA), a pericellular matrix component, supports BMP7 signalling in murine chondrocytes through its receptor CD44. However, its role in regulating BMP signalling in melanoma is not clear. In this study we found that depletion of endogenously-produced HA by hyaluronidase treatment or by inhibition of HA synthesis by 4-methylumbelliferone (4-MU) resulted in reduced BMP4/7-dependent Id1/3 protein expression in mouse melanoma B16-F10 and Ret cells. Conversely, exogenous HA treatment increased BMP4/7-dependent Id1/3 protein expression. Knockdown of CD44 reduced BMP4/7-dependent Id1/3 protein expression, and attenuated the ability of exogenous HA to stimulate Id1 and Id3 expression in response to BMP. Co-IP experiments demonstrated that CD44 can physically associate with the BMP type II receptor (BMPR) ACVR2B. Importantly, we found that coordinate expression of Id1 or Id3 with HA synthases HAS2, HAS3, and CD44 is associated with reduced overall survival of cutaneous melanoma patients. Our results suggest that HA-CD44 interactions with BMPR promote BMP4/7-dependent Id1/3 protein expression in melanoma, contributing to reduced survival in melanoma patients

Extended surfaces modulate and can catalyze hydrophobic effects

Interfaces are a most common motif in complex systems. To understand how the presence of interfaces affect hydrophobic phenomena, we use molecular simulations and theory to study hydration of solutes at interfaces. The solutes range in size from sub-nanometer to a few nanometers. The interfaces are self-assembled monolayers with a range of chemistries, from hydrophilic to hydrophobic. We show that the driving force for assembly in the vicinity of a hydrophobic surface is weaker than that in bulk water, and decreases with increasing temperature, in contrast to that in the bulk. We explain these distinct features in terms of an interplay between interfacial fluctuations and excluded volume effects---the physics encoded in Lum-Chandler-Weeks theory [J. Phys. Chem. B 103, 4570--4577 (1999)]. Our results suggest a catalytic role for hydrophobic interfaces in the unfolding of proteins, for example, in the interior of chaperonins and in amyloid formation.Comment: 22 pages, 5 figure

A combined view on precipitation and temperature climatology and trends in the southern Andes of Peru

In the southern Peruvian Andes, communities are highly dependent on climatic conditions due to the mainly rain-fed agriculture and the importance of glaciers and snow melt as a freshwater resource. Longer-term trends and year-to-year variability of precipitation or temperature severely affect living conditions. This study evaluates seasonal precipitation and temperature climatologies and trends in the period 1965/66–2017/18 for the southern Peruvian Andes using quality-controlled and homogenized station data and new observational gridded data. In this region, precipitation exhibits a strong annual cycle with very dry winter months and most of the precipitation falling from spring to autumn. Spatially, a northeast–southwest gradient in austral spring is observed, related to an earlier start of the rainy season in the northeastern partof the study area. Seasonal variations of maximum temperature are weak withan annual maximum in austral spring, which is related to reduced cloud coverin austral spring compared to summer. On the contrary, minimum tempera-tures show larger seasonal variations, possibly enhanced through changes inlongwave incoming radiation following the precipitation cycle. Precipitationtrends since 1965 exhibit low spatial consistency except for austral summer,when in most of the study area increasing precipitation is observed, and in aus-tral spring, when stations in the central-western region of the study area regis-ter decreasing precipitation. All seasonal and annual trends in maximum temperature are larger than trends in minimum temperature. Maximum temperature exhibits strong trends in austral winter and spring, whereas minimum temperature trends are strongest in austral winter. We hypothesize, that these trends are related to precipitation changes, as decreasing (increasing) precipita-tion in spring (summer) may enhance maximum (minimum) temperature trends through changes in cloud cover. El Niño Southern Oscillation (ENSO), however, has modifying effects onto precipitation and temperature, and thereby leads to larger trends in maximum temperatures

Virtual patients design and its effect on clinical reasoning and student experience : a protocol for a randomised factorial multi-centre study

Background Virtual Patients (VPs) are web-based representations of realistic clinical cases. They are proposed as being an optimal method for teaching clinical reasoning skills. International standards exist which define precisely what constitutes a VP. There are multiple design possibilities for VPs, however there is little formal evidence to support individual design features. The purpose of this trial is to explore the effect of two different potentially important design features on clinical reasoning skills and the student experience. These are the branching case pathways (present or absent) and structured clinical reasoning feedback (present or absent). Methods/Design This is a multi-centre randomised 2x2 factorial design study evaluating two independent variables of VP design, branching (present or absent), and structured clinical reasoning feedback (present or absent).The study will be carried out in medical student volunteers in one year group from three university medical schools in the United Kingdom, Warwick, Keele and Birmingham. There are four core musculoskeletal topics. Each case can be designed in four different ways, equating to 16 VPs required for the research. Students will be randomised to four groups, completing the four VP topics in the same order, but with each group exposed to a different VP design sequentially. All students will be exposed to the four designs. Primary outcomes are performance for each case design in a standardized fifteen item clinical reasoning assessment, integrated into each VP, which is identical for each topic. Additionally a 15-item self-reported evaluation is completed for each VP, based on a widely used EViP tool. Student patterns of use of the VPs will be recorded. In one centre, formative clinical and examination performance will be recorded, along with a self reported pre and post-intervention reasoning score, the DTI. Our power calculations indicate a sample size of 112 is required for both primary outcomes

Explaining computation of predictive values: 2 × 2 table versus frequency tree. A randomized controlled trial [ISRCTN74278823]

BACKGROUND: Involving patients in decision making on diagnostic procedures requires a basic level of statistical thinking. However, innumeracy is prevalent even among physicians. In medical teaching the 2 × 2 table is widely used as a visual help for computations whereas in psychology the frequency tree is favoured. We assumed that the 2 × 2 table is more suitable to support computations of predictive values. METHODS: 184 students without prior statistical training were randomised either to a step-by-step self-learning tutorial using the 2 × 2 table (n = 94) or the frequency tree (n = 90). During the training session students were instructed by two sample tasks and a total of five positive predictive values had to be computed. During a follow-up session 4 weeks later participants had to compute 5 different tasks of comparable degree of difficulty without having the tutorial instructions at their disposal. The primary outcome was the correct solution of the tasks. RESULTS: There were no statistically significant differences between the two groups. About 58% achieved correct solutions in 4–5 tasks following the training session and 26% in the follow-up examination. CONCLUSIONS: These findings do not support the hypothesis that the 2 × 2 table is more valuable to facilitate the calculation of positive predictive values than the frequency tree

Validation of the modified Fresno Test: assessing physical therapists' evidence based practice knowledge and skills

<p>Abstract</p> <p>Background</p> <p>Health care educators need valid and reliable tools to assess evidence based practice (EBP) knowledge and skills. Such instruments have yet to be developed for use among physical therapists. The Fresno Test (FT) has been validated only among general practitioners and occupational therapists and does not assess integration of research evidence with patient perspectives and clinical expertise. The purpose of this study was to develop and validate a modified FT to assess EBP knowledge and skills relevant to physical therapist (PT) practice.</p> <p>Methods</p> <p>The FT was modified to include PT-specific content and two new questions to assess integration of patient perspectives and clinical expertise with research evidence. An expert panel reviewed the test for content validity. A cross-sectional cohort representing three training levels (EBP-novice students, EBP-trained students, EBP-expert faculty) completed the test. Two blinded raters, not involved in test development, independently scored each test. Construct validity was assessed through analysis of variance for linear trends among known groups. Inter and intra-rater reliability, internal consistency, item discrimination index, item total correlation, and difficulty were analyzed.</p> <p>Results</p> <p>Among 108 participants (31 EBP-novice students, 50 EBP-trained students, and 27 EBP-expert faculty), there was a statistically significant (p < 0.0001) difference in total score corresponding to training level. Total score reliability and psychometric properties of items modified for discipline-specific content were excellent [inter-rater (ICC (2,1)] = 0.91); intra-rater (ICC (2,1)] = 0.95, 0.96)]. Cronbach's α was 0.78. Of the two new items, only one had strong psychometric properties.</p> <p>Conclusions</p> <p>The 13-item modified FT presented here is a valid, reliable assessment of physical therapists' EBP knowledge and skills. One new item assesses integration of patient perspective as part of the EBP model. Educators and researchers may use the 13-item modified FT to evaluate PT EBP curricula and physical therapists' EBP knowledge and skills.</p