Nf2/Merlin controls spinal cord neural progenitor function in a Rac1/ErbB2-dependent manner

Objective: Individuals with the neurofibromatosis type 2 (NF2) cancer predisposition syndrome develop spinal cord glial tumors (ependymomas) that likely originate from neural progenitor cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural progenitor cells (NPCs). Methods: To identify potential therapeutic targets for these tumors, we leveraged primary mouse Nf2-deficient spinal cord neural progenitor cells. Results: We demonstrate that the Nf2 protein, merlin, negatively regulates spinal neural progenitor cell survival and glial differentiation in an ErbB2-dependent manner, and that NF2-associated spinal ependymomas exhibit increased ErbB2 activation. Moreover, we show that Nf2-deficient SC NPC ErbB2 activation results from Rac1-mediated ErbB2 retention at the plasma membrane. Significance: Collectively, these findings establish ErbB2 as a potential rational therapeutic target for NF2-associated spinal ependymoma

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Understanding and predicting animal movements and distributions in the Anthropocene

\ua9 2025 The Author(s). Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society. Predicting animal movements and spatial distributions is crucial for our comprehension of ecological processes and provides key evidence for conserving and managing populations, species and ecosystems. Notwithstanding considerable progress in movement ecology in recent decades, developing robust predictions for rapidly changing environments remains challenging. To accurately predict the effects of anthropogenic change, it is important to first identify the defining features of human-modified environments and their consequences on the drivers of animal movement. We review and discuss these features within the movement ecology framework, describing relationships between external environment, internal state, navigation and motion capacity. Developing robust predictions under novel situations requires models moving beyond purely correlative approaches to a dynamical systems perspective. This requires increased mechanistic modelling, using functional parameters derived from first principles of animal movement and decision-making. Theory and empirical observations should be better integrated by using experimental approaches. Models should be fitted to new and historic data gathered across a wide range of contrasting environmental conditions. We need therefore a targeted and supervised approach to data collection, increasing the range of studied taxa and carefully considering issues of scale and bias, and mechanistic modelling. Thus, we caution against the indiscriminate non-supervised use of citizen science data, AI and machine learning models. We highlight the challenges and opportunities of incorporating movement predictions into management actions and policy. Rewilding and translocation schemes offer exciting opportunities to collect data from novel environments, enabling tests of model predictions across varied contexts and scales. Adaptive management frameworks in particular, based on a stepwise iterative process, including predictions and refinements, provide exciting opportunities of mutual benefit to movement ecology and conservation. In conclusion, movement ecology is on the verge of transforming from a descriptive to a predictive science. This is a timely progression, given that robust predictions under rapidly changing environmental conditions are now more urgently needed than ever for evidence-based management and policy decisions. Our key aim now is not to describe the existing data as well as possible, but rather to understand the underlying mechanisms and develop models with reliable predictive ability in novel situations

Morphology and photoluminescence study of titania nanoparticles

Titania nanoparticles are prepared by sol–gel chemistry with a poly(ethylene oxide) methyl ether methacrylate-block-poly(dimethylsiloxane)-block-poly(ethylene oxide) methyl ether methacrylate triblock copolymer acting as the templating agent. The sol–gel components—hydrochloric acid, titanium tetraisopropoxide, and triblock copolymer—are varied to investigate their effect on the resulting titania morphology. An increased titania precursor or polymer content yields smaller primary titania structures. Microbeam grazing incidence small-angle X-ray scattering measurements, which are analyzed with a unified fit model, reveal information about the titania structure sizes. These small structures could not be observed via the used microscopy techniques. The interplay among the sol–gel components via our triblock copolymer results in different sized titania nanoparticles with higher packing densities. Smaller sized titania particles, (∼13–20 nm in diameter) in the range of exciton diffusion length, are formed by 2% by weight polymer and show good crystallinity with less surface defects and high oxygen vacancies

Simple and efficient expression of Agaricus meleagris pyranose dehydrogenase in Pichia pastoris

Pyranose dehydrogenase (PDH) is a fungal flavin-dependent sugar oxidoreductase that is highly interesting for applications in organic synthesis or electrochemistry. The low expression levels of the filamentous fungus Agaricus meleagris as well as the demand for engineered PDH make heterologous expression necessary. Recently, Aspergillus species were described to efficiently secrete recombinant PDH. Here, we evaluate recombinant protein production with expression hosts more suitable for genetic engineering. Expression in Escherichia coli resulted in no soluble or active PDH. Heterologous expression in the methylotrophic yeast Pichia pastoris was investigated using two different signal sequences as well as a codon-optimized sequence. A 96-well plate activity screening for transformants of all constructs was established and the best expressing clone was used for large-scale production in 50-L scale, which gave a volumetric yield of 223 mg L−1 PDH or 1,330 U L−1 d−1 in space–time yield. Purification yielded 13.4 g of pure enzyme representing 95.8% of the initial activity. The hyperglycosylated recombinant enzyme had a 20% lower specific activity than the native enzyme; however, the kinetic properties were essentially identical. This study demonstrates the successful expression of PDH in the eukaryotic host organism P. pastoris paving the way for protein engineering. Additionally, the feasibility of large-scale production of the enzyme with this expression system together with a simplified purification scheme for easy high-yield purification is shown

Prediction of Promiscuous P-Glycoprotein Inhibition Using a Novel Machine Learning Scheme

BACKGROUND: P-glycoprotein (P-gp) is an ATP-dependent membrane transporter that plays a pivotal role in eliminating xenobiotics by active extrusion of xenobiotics from the cell. Multidrug resistance (MDR) is highly associated with the over-expression of P-gp by cells, resulting in increased efflux of chemotherapeutical agents and reduction of intracellular drug accumulation. It is of clinical importance to develop a P-gp inhibition predictive model in the process of drug discovery and development. METHODOLOGY/PRINCIPAL FINDINGS: An in silico model was derived to predict the inhibition of P-gp using the newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme based on the data compiled from the literature. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those structurally diverse molecules in the training set (n = 31, r(2) = 0.89, q(2) = 0.86, RMSE = 0.40, s = 0.28), the test set (n = 88, r(2) = 0.87, RMSE = 0.39, s = 0.25) and the outlier set (n = 11, r(2) = 0.96, RMSE = 0.10, s = 0.05). The generated PhE/SVM model also showed high accuracy when subjected to those validation criteria generally adopted to gauge the predictivity of a theoretical model. CONCLUSIONS/SIGNIFICANCE: This accurate, fast and robust PhE/SVM model that can take into account the promiscuous nature of P-gp can be applied to predict the P-gp inhibition of structurally diverse compounds that otherwise cannot be done by any other methods in a high-throughput fashion to facilitate drug discovery and development by designing drug candidates with better metabolism profile

Structural genomics target selection for the New York consortium on membrane protein structure

The New York Consortium on Membrane Protein Structure (NYCOMPS), a part of the Protein Structure Initiative (PSI) in the USA, has as its mission to establish a high-throughput pipeline for determination of novel integral membrane protein structures. Here we describe our current target selection protocol, which applies structural genomics approaches informed by the collective experience of our team of investigators. We first extract all annotated proteins from our reagent genomes, i.e. the 96 fully sequenced prokaryotic genomes from which we clone DNA. We filter this initial pool of sequences and obtain a list of valid targets. NYCOMPS defines valid targets as those that, among other features, have at least two predicted transmembrane helices, no predicted long disordered regions and, except for community nominated targets, no significant sequence similarity in the predicted transmembrane region to any known protein structure. Proteins that feed our experimental pipeline are selected by defining a protein seed and searching the set of all valid targets for proteins that are likely to have a transmembrane region structurally similar to that of the seed. We require sequence similarity aligning at least half of the predicted transmembrane region of seed and target. Seeds are selected according to their feasibility and/or biological interest, and they include both centrally selected targets and community nominated targets. As of December 2008, over 6,000 targets have been selected and are currently being processed by the experimental pipeline. We discuss how our target list may impact structural coverage of the membrane protein space

Uptake of health services for common mental disorders by first-generation Turkish and Moroccan migrants in the Netherlands

Abstract Background Migration and ethnic minority status have been associated with higher occurrence of common mental disorders (CMD), while mental health care utilisation by non-Western migrants has been reported to be low compared to the general population in Western host countries. Still, the evidence-base for this is poor. This study evaluates uptake of mental health services for CMD and psychological distress among first-generation non-Western migrants in Amsterdam, the Netherlands. Methods A population-based survey. First generation non-Western migrants and ethnic Dutch respondents (N = 580) participated in structured interviews in their own languages. The interview included the Composite International Diagnostic Interview (CIDI) and the Kessler psychological distress scale (K10). Uptake of services was measured by self-report. Data were analysed using weighting techniques and multivariate logistic regression. Results Of subjects with a CMD during six months preceding the interview, 50.9% reported care for mental problems in that period; 35.0% contacted specialised services. In relation to CMD, ethnic groups were equally likely to access specialised mental health services. In relation to psychological distress, however, Moroccan migrants reported less uptake of primary care services (OR = 0.37; 95% CI = 0.15 to 0.88). Conclusion About half of the ethnic Dutch, Turkish and Moroccan population in Amsterdam with CMD contact mental health services. Since the primary purpose of specialised mental health services is to treat "cases", this study provides strong indications for equal access to specialised care for these ethnic groups. The purpose of primary care services is however to treat psychological distress, so that access appears to be lower among Moroccan migrants

Gas7-Deficient Mouse Reveals Roles in Motor Function and Muscle Fiber Composition during Aging

Background: Growth arrest-specific gene 7 (Gas7) has previously been shown to be involved in neurite outgrowth in vitro; however, its actual role has yet to be determined. To investigate the physiological function of Gas7 in vivo, here we generated a Gas7-deficient mouse strain with a labile Gas7 mutant protein whose functions are similar to wild-type Gas7. Methodology/Principal Findings: Our data show that aged Gas7-deficient mice have motor activity defects due to decreases in the number of spinal motor neurons and in muscle strength, of which the latter may be caused by changes in muscle fiber composition as shown in the soleus. In cross sections of the soleus of Gas7-deficient mice, gross morphological features and levels of myosin heavy chain I (MHC I) and MHC II markers revealed significantly fewer fast fibers. In addition, we found that nerve terminal sprouting, which may be associated with slow and fast muscle fiber composition, was considerably reduced at neuromuscular junctions (NMJ) during aging. Conclusions/Significance: These findings indicate that Gas7 is involved in motor neuron function associated with muscle strength maintenance