Network theory approach for data evaluation in the dynamic force spectroscopy of biomolecular interactions

Investigations of molecular bonds between single molecules and molecular complexes by the dynamic force spectroscopy are subject to large fluctuations at nanoscale and possible other aspecific binding, which mask the experimental output. Big efforts are devoted to develop methods for effective selection of the relevant experimental data, before taking the quantitative analysis of bond parameters. Here we present a methodology which is based on the application of graph theory. The force-distance curves corresponding to repeated pulling events are mapped onto their correlation network (mathematical graph). On these graphs the groups of similar curves appear as topological modules, which are identified using the spectral analysis of graphs. We demonstrate the approach by analyzing a large ensemble of the force-distance curves measured on: ssDNA-ssDNA, peptide-RNA (system from HIV1), and peptide-Au surface. Within our data sets the methodology systematically separates subgroups of curves which are related to different intermolecular interactions and to spatial arrangements in which the molecules are brought together and/or pulling speeds. This demonstrates the sensitivity of the method to the spatial degrees of freedom, suggesting potential applications in the case of large molecular complexes and situations with multiple binding sites

Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS)

.Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA-like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties

Internal and external cooling methods and their effect on body temperature, thermal perception and dexterity

© 2018 The Authors. Published by PLOS. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1371/journal.pone.0191416© 2018 Maley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective The present study aimed to compare a range of cooling methods possibly utilised by occupational workers, focusing on their effect on body temperature, perception and manual dexterity. Methods Ten male participants completed eight trials involving 30 min of seated rest followed by 30 min of cooling or control of no cooling (CON) (34C, 58% relative humidity). The cooling methods utilised were: ice cooling vest (CV0), phase change cooling vest melting at 14C (CV14), evaporative cooling vest (CVEV), arm immersion in 10C water (AI), portable water-perfused suit (WPS), heliox inhalation (HE) and ice slushy ingestion (SL). Immediately before and after cooling, participants were assessed for fine (Purdue pegboard task) and gross (grip and pinch strength) manual dexterity. Rectal and skin temperature, as well as thermal sensation and comfort, were monitored throughout. Results Compared with CON, SL was the only method to reduce rectal temperature (P = 0.012). All externally applied cooling methods reduced skin temperature (P0.05). Conclusion The present study observed that ice ingestion or ice applied to the skin produced the greatest effect on rectal and skin temperature, respectively. AI should not be utilised if workers require subsequent fine manual dexterity. These results will help inform future studies investigating appropriate pre-cooling methods for the occupational worker.This project is financially supported by the US Government through the Technical Support Working Group within the Combating Terrorism Technical Support Office.Published versio

Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors

PURPOSE: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0 mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose. RESULTS: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients. CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor

Overlap Statistics of Cumuliform Boundary-Layer Cloud Fields in Large-Eddy Simulations

Overlap statistics of cumuliform boundary-layer clouds are studied using large-eddy simulations at high resolutions. The cloud overlap is found to be highly inefficient, due to the typical irregularity of cumuliform clouds over a wide range of scales. The detection of such inefficient overlap is enabled in this study by i) applying fine enough discretizations and ii) by limiting the analysis to exclusively cumuliform boundary-layer cloud fields. It is argued that these two factors explain the differences with some previous studies on cloud overlap. In contrast, good agreement exists with previously reported observations of cloud overlap as derived from lidar measurements of liquid water clouds at small cloud covers. Various candidate functional forms are fitted to the results, suggesting that an inverse linear function is most successful in reproducing the observed behavior. The sensitivity of cloud overlap to various aspects is assessed, reporting a minimal or non-systematic dependence on discretization and vertical wind-shear, as opposed to a strong case-dependence, the latter probably reflecting differences in the cloud size distribution. Finally, calculations with an offline radiation scheme suggest that accounting for the inefficient overlap in cumuliform cloud fields in a general circulation model can change the top-of-atmosphere short-wave cloud radiative forcing by −20 to −40 W m−2, depending on vertical discretization. This corresponds to about 50 to 100% of the typical values in areas of persistent shallow cumulus, respectively

PIN71 QUALITY OF LIFE (QOL) AND OTHER ENDPOINTS COMPARISON IN THE TREATMENT OF FACIAL LIPOATROPHY WITH INJECTION OF POLY-L-LACTIC ACID

Context: Longitudinal data on bone mineral density(BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMAD(LS)) in children with PWS. Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. Intervention: The children received GH treatment, 1 mg/m(2)/day (congruent to 0.035 mg/kg/d). Main Outcome Measures: BMDTB, BMDLS, and BMAD(LS) was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMAD(LS)SDS remained stable. During adolescence, BMDTBSDS and BMAD(LS)SDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lowerBMAD(LS)SDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMAD(LS) remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty

Continuous Single-Column Model Evaluation at a Permanent Meteorological Supersite

Uncertainties in numerical predictions of weather and climate are often linked to the representation of unresolved processes that act relatively quickly compared to the resolved general circulation. These processes include turbulence, convection, clouds, and radiation. Single-column model (SCM) simulation of idealized cases and the subsequent evaluation against large-eddy simulation (LES) results has become an often used and relied on method to obtain insight at process level into the behavior of such parameterization schemes; benefits of SCM simulation are the enhanced model transparency and the high computational efficiency. Although this approach has achieved demonstrable success, some shortcomings have been identified; among these, i) the statistical significance and relevance of single idealized case studies might be questioned and ii) the use of observational datasets has been relatively limited. A recently initiated project named the Royal Netherlands Meteorological Institute (KNMI) Parameterization Testbed (KPT) is part of a general move toward a more statistically significant process-level evaluation, with the purpose of optimizing the identification of problems in general circulation models that are related to parameterization schemes. The main strategy of KPT is to apply continuous long-term SCM simulation and LES at various permanent meteorological sites, in combination with comprehensive evaluation against observations at multiple time scales. We argue that this strategy enables the reproduction of typical long-term mean behavior of fast physics in large-scale models, but it still preserves the benefits of single-case studies (such as model transparency). This facilitates the tracing and understanding of errors in parameterization schemes, which should eventually lead to a reduction of related uncertainties in numerical predictions of weather and climate

Overlap Statistics of Cumuliform Boundary-Layer Cloud Fields in Large-Eddy Simulations

Overlap statistics of cumuliform boundary-layer clouds are studied using large-eddy simulations at high resolutions. The cloud overlap is found to be highly inefficient, due to the typical irregularity of cumuliform clouds over a wide range of scales. The detection of such inefficient overlap is enabled in this study by i) applying fine enough discretizations and ii) by limiting the analysis to exclusively cumuliform boundary-layer cloud fields. It is argued that these two factors explain the differences with some previous studies on cloud overlap. In contrast, good agreement exists with previously reported observations of cloud overlap as derived from lidar measurements of liquid water clouds at small cloud covers. Various candidate functional forms are fitted to the results, suggesting that an inverse linear function is most successful in reproducing the observed behavior. The sensitivity of cloud overlap to various aspects is assessed, reporting a minimal or non-systematic dependence on discretization and vertical wind-shear, as opposed to a strong case-dependence, the latter probably reflecting differences in the cloud size distribution. Finally, calculations with an offline radiation scheme suggest that accounting for the inefficient overlap in cumuliform cloud fields in a general circulation model can change the top-of-atmosphere short-wave cloud radiative forcing by −20 to −40 W m−2, depending on vertical discretization. This corresponds to about 50 to 100% of the typical values in areas of persistent shallow cumulus, respectively

Power-Law Scaling in the Internal Variability of Cumulus Cloud Size Distributions due to Subsampling and Spatial Organization

In this study, the spatial structure of cumulus cloud populations is investigated using three-dimensional snapshots from large-domain LES experiments. The aim is to understand and quantify the internal variability in cloud size distributions due to subsampling effects and spatial organization. A set of idealized shallow cumulus cases is selected with varying degrees of spatial organization, including a slowly organizing marine precipitating case and five more quickly organizing diurnal cases over land. A subdomain analysis is applied, yielding cloud number distributions at sample sizes ranging from severely undersampled to nearly complete. A strong power-law scaling is found in the relation between cloud number variability and subdomain size, reflecting an inverse linear relation. Scaling subdomain size by cloud size yields a data collapse across time points and cases, highlighting the role played by cloud spacing in controlling the stochastic variability. Spatial organization acts on top of this baseline model by increasing the maximum cloud size and by enhancing the variability in the number of smallest clouds. This reflects that the smaller clouds start to live on top of larger-scale thermodynamic structures, such as cold pools, which favor or inhibit their formation. Compositing all continental cumulus cases suggests the existence of a prototype diurnal time dependence in the spatial organization. A simple stochastic expression for cloud number variability is proposed that is formulated in terms of two dimensionless groups, which allows objective estimation of the degree of spatial organization in simulated and observed cumulus cloud populations