This paper describes the current update on macromolecular model validation services that are provided at the MolProbity website, emphasizing changes and additions since the previous review in 2010. ...There have been many infrastructure improvements, including rewrite of previous Java utilities to now use existing or newly written Python utilities in the open‐source CCTBX portion of the Phenix software system. This improves long‐term maintainability and enhances the thorough integration of MolProbity‐style validation within Phenix. There is now a complete MolProbity mirror site at http://molprobity.manchester.ac.uk. GitHub serves our open‐source code, reference datasets, and the resulting multi‐dimensional distributions that define most validation criteria. Coordinate output after Asn/Gln/His “flip” correction is now more idealized, since the post‐refinement step has apparently often been skipped in the past. Two distinct sets of heavy‐atom‐to‐hydrogen distances and accompanying van der Waals radii have been researched and improved in accuracy, one for the electron‐cloud‐center positions suitable for X‐ray crystallography and one for nuclear positions. New validations include messages at input about problem‐causing format irregularities, updates of Ramachandran and rotamer criteria from the million quality‐filtered residues in a new reference dataset, the CaBLAM Cα‐CO virtual‐angle analysis of backbone and secondary structure for cryoEM or low‐resolution X‐ray, and flagging of the very rare cis‐nonProline and twisted peptides which have recently been greatly overused. Due to wide application of MolProbity validation and corrections by the research community, in Phenix, and at the worldwide Protein Data Bank, newly deposited structures have continued to improve greatly as measured by MolProbity's unique all‐atom clashscore.
Social presence, the ability to perceive others in an online environment, has been shown to impact student motivation and participation, actual and perceived learning, course and instructor ...satisfaction, and retention in online courses; yet very few researchers have attempted to look across contexts, disciplinary areas, or measures of social presence. This meta-analysis allowed us to look across these variables of the primary studies and identify the pattern of student outcomes (e.g., perceived learning and satisfaction) in relation to social presence through scrutiny of differences between the studies. The results showed a moderately large positive average correlation between social presence and satisfaction (r = 0.56, k = 26) and social presence and perceived learning (r = 0.51, k = 26). Large variation among correlations (86.7% for satisfaction and 92.8% for perceived learning, respectively) also indicated systematic differences among these correlations due to online course settings. We found that (a) the strength of the relationship between social presence and satisfaction was moderated by the course length, discipline area, and scale used to measure social presence; and (b) the relationship between social presence and perceived learning was moderated by the course length, discipline area, and target audience of the course. Implications and future research are discussed.
•This meta-analysis examined the relationship between Social Presence (SP) and students' satisfaction and perceived learning.•Strong positive relationship between SP and satisfaction.•Strong positive relationship between SP and perceived learning.•Course length, discipline, and SP scale significant moderators for satisfaction.•Course length, discipline, and audience significant moderators for perceived learning.
Diffraction (X‐ray, neutron and electron) and electron cryo‐microscopy are powerful methods to determine three‐dimensional macromolecular structures, which are required to understand biological ...processes and to develop new therapeutics against diseases. The overall structure‐solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data‐quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time‐consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command‐line features of Phenix and streamlines the transition between programs, project tracking and re‐running of previous tasks.
Recent developments in the Phenix software package are described in the context of macromolecular structure determination using X‐rays, neutrons and electrons.
More than 40 nanomedicines are already in routine clinical use with a growing number following in preclinical and clinical development. The therapeutic objectives are often enhanced disease-specific ...targeting (with simultaneously reduced access to sites of toxicity) and, especially in the case of macromolecular biotech drugs, improving access to intracellular pharmacological target receptors. Successful navigation of the endocytic pathways is usually a prerequisite to achieve these goals. Thus a comprehensive understanding of endocytosis and intracellular trafficking pathways in both the target and bystander normal cell type(s) is essential to enable optimal nanomedicine design. It is becoming evident that endocytic pathways can become disregulated in disease and this, together with the potential changes induced during exposure to the nanocarrier itself, has the potential to significantly impact nanomedicine performance in terms of safety and efficacy. Here we overview the endomembrane trafficking pathways, discuss the methods used to determine and quantitate the intracellular fate of nanomedicines, and review the current status of lysosomotropic and endosomotropic delivery. Based on the lessons learned during more than 3 decades of clinical development, the need to use endocytosis-relevant clinical biomarkers to better select those patients most likely to benefit from nanomedicine therapy is also discussed.
Extracellular vesicles (EVs) are nano-sized vesicles containing nucleic acid and protein cargo that are released from a multitude of cell types and have gained significant interest as potential ...diagnostic biomarkers. Human serum is a rich source of readily accessible EVs; however, the separation of EVs from serum proteins and non-EV lipid particles represents a considerable challenge. In this study, we compared the most commonly used isolation techniques, either alone or in combination, for the isolation of EVs from 200 µl of human serum and their separation from non-EV protein and lipid particles present in serum. The size and yield of particles isolated by each method was determined by nanoparticle tracking analysis, with the variation in particle size distribution being used to determine the relative impact of lipoproteins and protein aggregates on the isolated EV population. Purification of EVs from soluble protein was determined by calculating the ratio of EV particle count to protein concentration. Finally, lipoprotein particles co-isolated with EVs was determined by Western blot analysis of lipoprotein markers APOB and APOE. Overall, this study reveals that the choice of EV isolation procedure significantly impacts EV yield from human serum, together with the presence of lipoprotein and protein contaminants.
Patients who had a positive laboratory test for influenza were six times as likely to be hospitalized for acute myocardial infarction during the 7 days after specimen collection (the “risk interval”) ...as during the year before and the year after the risk interval.
MolProbity is a general-purpose web service offering quality validation for three-dimensional (3D) structures of proteins, nucleic acids and complexes. It provides detailed all-atom contact analysis ...of any steric problems within the molecules and can calculate and display the H-bond and van der Waals contacts in the interfaces between components. An integral step in the process is the addition and full optimization of all hydrogen atoms, both polar and nonpolar. The results are reported in multiple forms: as overall numeric scores, as lists, as downloadable PDB and graphics files, and most notably as informative, manipulable 3D kinemage graphics shown on-line in the KiNG viewer. This service is available free to all users at http://kinemage.biochem.duke.edu.
Abstract Background Use of Extracorporeal Membrane Oxygenation during cardiopulmonary resuscitation (ECPR) is increasingly being deployed as an adjunct to conventional CPR. It is unknown if this has ...been associated with improved outcomes. Aims To describe trends in survival and patient demographics for ECPR patients in the international Extracorporeal Life Support Organisation (ELSO) database over the past 12 years and identify factors associated with changes in survival. Methods Patients greater than 16 years of age who received ECPR between January 2003 and December 2014 were extracted from the ELSO registry and were divided into three 4-year cohorts (Cohort 1: 2003–2006, Cohort 2: 2007–2010, Cohort 3: 2011–2014). Univariable analysis was performed to compare demographics and outcomes of patients across the three cohorts. Univariable and multivariable analyses were then performed to identify factors independently associated with survival. Results 1796 patients treated with ECPR were extracted from the registry, aged 50 (±18.5) years. Annual ECPR episodes increased over 10-fold, from 35 to over 400 per year. Survival to hospital discharge was 29% overall (27% cohort 1, 28% cohort 2, 30% cohort 3 (p = 0.71)). Age, body weight and documented comorbidities increased over time. There was a reduction in complications associated with ECMO usage. After adjusting for confounders there was no change in the odds of survival over the time period examined. Interpretation Over the period 2003–2014, survival to hospital discharge was 29% for patients who require ECPR. Despite advances in provision of ECMO care and increasing co-morbidities of patients, there has been no change in risk-adjusted survival over time.
Background
The American Cancer Society, the Centers for Disease Control and Prevention, the National Cancer Institute, and the North American Association of Central Cancer Registries collaborate to ...provide annual updates on cancer occurrence and trends in the United States.
Methods
Data on new cancer diagnoses during 2001 through 2016 were obtained from the Centers for Disease Control and Prevention‐funded and National Cancer Institute‐funded population‐based cancer registry programs and compiled by the North American Association of Central Cancer Registries. Data on cancer deaths during 2001 through 2017 were obtained from the National Center for Health Statistics' National Vital Statistics System. Trends in incidence and death rates for all cancers combined and for the leading cancer types by sex, racial/ethnic group, and age were estimated by joinpoint analysis and characterized by the average annual percent change during the most recent 5 years (2012‐2016 for incidence and 2013‐2017 for mortality).
Results
Overall, cancer incidence rates decreased 0.6% on average per year during 2012 through 2016, but trends differed by sex, racial/ethnic group, and cancer type. Among males, cancer incidence rates were stable overall and among non‐Hispanic white males but decreased in other racial/ethnic groups; rates increased for 5 of the 17 most common cancers, were stable for 7 cancers (including prostate), and decreased for 5 cancers (including lung and bronchus lung and colorectal). Among females, cancer incidence rates increased during 2012 to 2016 in all racial/ethnic groups, increasing on average 0.2% per year; rates increased for 8 of the 18 most common cancers (including breast), were stable for 6 cancers (including colorectal), and decreased for 4 cancers (including lung). Overall, cancer death rates decreased 1.5% on average per year during 2013 to 2017, decreasing 1.8% per year among males and 1.4% per year among females. During 2013 to 2017, cancer death rates decreased for all cancers combined among both males and females in each racial/ethnic group, for 11 of the 19 most common cancers among males (including lung and colorectal), and for 14 of the 20 most common cancers among females (including lung, colorectal, and breast). The largest declines in death rates were observed for melanoma of the skin (decreasing 6.1% per year among males and 6.3% among females) and lung (decreasing 4.8% per year among males and 3.7% among females). Among children younger than 15 years, cancer incidence rates increased an average of 0.8% per year during 2012 to 2016, and cancer death rates decreased an average of 1.4% per year during 2013 to 2017. Among adolescents and young adults aged 15 to 39 years, cancer incidence rates increased an average of 0.9% per year during 2012 to 2016, and cancer death rates decreased an average of 1.0% per year during 2013 to 2017.
Conclusions
Although overall cancer death rates continue to decline, incidence rates are leveling off among males and are increasing slightly among females. These trends reflect population changes in cancer risk factors, screening test use, diagnostic practices, and treatment advances. Many cancers can be prevented or treated effectively if they are found early. Population‐based cancer incidence and mortality data can be used to inform efforts to decrease the cancer burden in the United States and regularly monitor progress toward goals.
The Centers for Disease Control and Prevention, the American Cancer Society, the National Cancer Institute, and the North American Association of Central Cancer Registries collaborate to provide annual updates on cancer occurrence and trends in the United States and to address a special topic of interest. Part I of this report focuses on national cancer statistics, and part II characterizes progress in achieving select Healthy People 2020 objectives related to 4 common cancers.
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