Molecular dynamics simulations of the intrinsically disordered protein amelogenin

Amelogenin refers to a class of intrinsically disordered proteins that are the major constituents of enamel matrix derivative (EMD), an extract of porcine fetal teeth used in regenerative periodontal therapy. Modifications in molecular conformation induced by external stresses, such as changes in temperature or pH, are known to reduce the effectiveness of EMD. However, detailed descriptions of the conformational behavior of native amelogenin are lacking in the open literature. In the present work, a molecular model for the secondary and tertiary structure of the full-length major porcine amelogenin P173 was constructed from its primary sequence by replica exchange molecular dynamics (REMD) simulations. The REMD results for isolated amelogenin molecules at different temperatures were shown to be consistent with the available spectroscopic data. They therefore represent an important first step toward the simulation of the intra- and intermolecular interactions that mediate self-organization in amelogenin and its behavior in the presence of other EMD components under conditions representative of its therapeutic application

Thermal and dynamic mechanical properties of blends of bitumen with metallocene catalyzed polyolefins

A high penetration grade bitumen has been blended with up to 50 wt% of two different grades of metallocene catalyzed linear low density polyethylene (m-LLDPE) in order to investigate the potential of these and similar copolymers as a substitute for styrene butadiene styrene triblock copolymers in polymer-modified bitumens (PMB). A continuous polymer-rich phase was observed at m-LLDPE contents as low as 5-10 wt%, along with a significant decrease in the effective glass transition temperature of the PMBs with increasing polymer concentration, suggesting benefits for low temperature flexibility. The m-LLDPE-based PMBs also showed relatively low dynamic shear viscosities up to high polymer contents in the range of temperature and shear rate corresponding to typical PMB processing conditions. However, the presence of bitumen in the m-LLDPE-rich phase led to a significant reduction in the melting points of the m-LLDPE, and softening of the PMBs at temperatures as low as 40-50 degrees C, depending on the composition and the melting point of the pure polymer. PMBs based on the m-LLDPE with the higher melting point remained fully elastic in this temperature range, but at the expense of increased crystallinity and a higher glass transition temperature, which limit improvements in low temperature flexibility. On the other hand, the potentially broad composition and property windows associated with m-LLDPEs suggest considerable scope for the fine tuning of PMB properties by using combinations of different m-LLDPEs and/or other polyolefins as a means to optimize performance

Semiaromatic polyamides with enhanced charge carrier mobility

The control of local order in polymer semiconductors using non-covalent interactions may be used to engineer materials with interesting combinations of mechanical and optoelectronic properties. To investigate the possibility of preparing n-type polymer semiconductors in which hydrogen bonding plays an important role in structural order and stability, we have used solution-phase polycondensation to incorporate dicyanoperylene bisimide repeat units into an aliphatic polyamide chain backbone. The morphology and thermomechanical characteristics of the resulting polyamides, in which the aliphatic spacer length was varied systematically, were comparable with those of existing semiaromatic engineering polyamides. At the same time, the charge carrier mobility as determined by pulse-radiolysis time-resolved microwave conductivity measurements was found to be about 10-2 cm2 V-1 s-1, which is similar to that reported for low molecular weight perylene bisimides. Our results hence demonstrate that it is possible to use hydrogen bonding interactions as a means to introduce promising optoelectronic properties into high-performance engineering polymers.Peer ReviewedPostprint (author's final draft

Biodegradable polylactide/hydroxyapatite nanocomposite foam scaffolds for bone tissue engineering applications

Supercritical carbon dioxide processing of poly--lactide (PLLA)/hydroxyapatite (nHA) nanocomposites was investigated as a means to prepare foams suitable as scaffolds in bone tissue engineering applications. For given foaming parameters, addition of nHA to the PLLA gave reduced cell sizes and improved homogeneity in the size distribution, but did not significantly affect the degree of crystallinity, which remained of the order of 50 wt% in all the foams. The compressive modulus and strength were primarily influenced by the porosity and there was no significant reinforcement of the matrix by the nHA. The mechanical properties of the foams were nevertheless comparable with those of trabecular bone, and by adjusting the saturation pressure and depressurization rate it was possible to generate porosities of about 85 %, an interconnected morphology and cell diameters in the range 200-400 mu m from PLLA containing 4.17 vol% nHA, satisfying established geometrical requirements for bone replacement scaffolds

Morphological investigation of polylactide/microfibrillated cellulose composites

Optical microscopy and transmission electron microscopy have been used to investigate the morphology of polylactide (PLA)/microfibrillated cellulose (MFC) composites prepared by: compression molding of wet-comingled MFC and PLA latex or powder, twin-screw extrusion of the wet-comingled compounds, and solvent mixing of PLA with MFC or acetylated MFC. Compression molding of wet-comingled MFC and PLA latex or powder compounds resulted in a cellular MFC network, whereas solvent-cast films showed a more uniform dispersion of MFC fibers. Somewhat lower aggregate diameters observed in the acetylated MFC were assumed to be due to decreased MFC hydrophilicity and improved chemical affinity with the PLA matrix. The MFC networks in the commingled compounds were severely disrupted after twin-screw extrusion. This confirmed the limited deformability of the networks inferred from the extensive syneresis during the initial compression molding step, and accounted for substantial losses in stiffness reinforcement by the MFC after extrusion

Low-intensity cognitive-behaviour therapy interventions for obsessive-compulsive disorder compared to waiting list for therapist-led cognitive-behaviour therapy: 3-arm randomised controlled trial of clinical effectiveness

Background Obsessive-compulsive disorder (OCD) is prevalent and without adequate treatment usually follows a chronic course. “High-intensity” cognitive-behaviour therapy (CBT) from a specialist therapist is current “best practice.” However, access is difficult because of limited numbers of therapists and because of the disabling effects of OCD symptoms. There is a potential role for “low-intensity” interventions as part of a stepped care model. Low-intensity interventions (written or web-based materials with limited therapist support) can be provided remotely, which has the potential to increase access. However, current evidence concerning low-intensity interventions is insufficient. We aimed to determine the clinical effectiveness of 2 forms of low-intensity CBT prior to high-intensity CBT, in adults meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for OCD. Methods and findings This study was approved by the National Research Ethics Service Committee North West–Lancaster (reference number 11/NW/0276). All participants provided informed consent to take part in the trial. We conducted a 3-arm, multicentre randomised controlled trial in primary- and secondary-care United Kingdom mental health services. All patients were on a waiting list for therapist-led CBT (treatment as usual). Four hundred and seventy-three eligible patients were recruited and randomised. Patients had a median age of 33 years, and 60% were female. The majority were experiencing severe OCD. Patients received 1 of 2 low-intensity interventions: computerised CBT (cCBT; web-based CBT materials and limited telephone support) through “OCFighter” or guided self-help (written CBT materials with limited telephone or face-to-face support). Primary comparisons concerned OCD symptoms, measured using the Yale-Brown Obsessive Compulsive Scale–Observer-Rated (Y-BOCS-OR) at 3, 6, and 12 months. Secondary outcomes included health-related quality of life, depression, anxiety, and functioning. At 3 months, guided self-help demonstrated modest benefits over the waiting list in reducing OCD symptoms (adjusted mean difference = −1.91, 95% CI −3.27 to −0.55). These effects did not reach a prespecified level of “clinically significant benefit.” cCBT did not demonstrate significant benefit (adjusted mean difference = −0.71, 95% CI −2.12 to 0.70). At 12 months, neither guided self-help nor cCBT led to differences in OCD symptoms. Early access to low-intensity interventions led to significant reductions in uptake of high-intensity CBT over 12 months; 86% of the patients allocated to the waiting list for high-intensity CBT started treatment by the end of the trial, compared to 62% in supported cCBT and 57% in guided self-help. These reductions did not compromise longer-term patient outcomes. Data suggested small differences in satisfaction at 3 months, with patients more satisfied with guided self-help than supported cCBT. A significant issue in the interpretation of the results concerns the level of access to high-intensity CBT before the primary outcome assessment. Conclusions We have demonstrated that providing low-intensity interventions does not lead to clinically significant benefits but may reduce uptake of therapist-led CBT

Connecting Land–Atmosphere Interactions to Surface Heterogeneity in CHEESEHEAD19

The Chequamegon Heterogeneous Ecosystem Energy-Balance Study Enabled by a High-Density Extensive Array of Detectors 2019 (CHEESEHEAD19) is an ongoing National Science Foundation project based on an intensive field campaign that occurred from June to October 2019. The purpose of the study is to examine how the atmospheric boundary layer (ABL) responds to spatial heterogeneity in surface energy fluxes. One of the main objectives is to test whether lack of energy balance closure measured by eddy covariance (EC) towers is related to mesoscale atmospheric processes. Finally, the project evaluates data-driven methods for scaling surface energy fluxes, with the aim to improve model–data comparison and integration. To address these questions, an extensive suite of ground, tower, profiling, and airborne instrumentation was deployed over a 10 km × 10 km domain of a heterogeneous forest ecosystem in the Chequamegon–Nicolet National Forest in northern Wisconsin, United States, centered on an existing 447-m tower that anchors an AmeriFlux/NOAA supersite (US-PFa/WLEF). The project deployed one of the world’s highest-density networks of above-canopy EC measurements of surface energy fluxes. This tower EC network was coupled with spatial measurements of EC fluxes from aircraft; maps of leaf and canopy properties derived from airborne spectroscopy, ground-based measurements of plant productivity, phenology, and physiology; and atmospheric profiles of wind, water vapor, and temperature using radar, sodar, lidar, microwave radiometers, infrared interferometers, and radiosondes. These observations are being used with large-eddy simulation and scaling experiments to better understand submesoscale processes and improve formulations of subgrid-scale processes in numerical weather and climate models

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin

A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human–nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570