Cryo-EM in drug discovery: achievements, limitations and prospects.

Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances - including the development of direct electron detectors and more effective computational image analysis techniques - are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies.

High-Throughput Quantitation of Neonicotinoids in Lyophilized Surface Water by LC-APCI-MS/MS.

: Neonicotinoids are among the most widely used insecticides. Recently, there has been concern associated with unintended adverse effects on honeybees and aquatic invertebrates at low parts-per-trillion levels. : There is a need for LC-MS/MS methods that are capable of high-throughput measurements of the most widely used neonicotinoids at environmentally relevant concentrations in surface water.

Saline-push improves rubidium-82 PET image quality.

Introduction: Rubidium-82 (Rb) PET is used widely for myocardial perfusion imaging. The purpose of this study was to investigate if an additional saline-push following the Rb elution improves PET image quality.

Methods: Rb PET scans were acquired with and without 26 mL saline-push in six patients as part of a clinical quality improvement program.

Iron-Catalyzed Chemoselective Reduction of α,β-Unsaturated Ketones.

An iron-catalyzed chemo- and diastereoselective reduction of α,β-unsaturated ketones into the corresponding saturated ketones in mild reaction conditions is reported herein. DFT calculations and experimental work underline that transfer hydride reduction is a more facile process than hydrogenation, unveiling the fundamental role of the base.

Impact of a Student-Driven, Virtual Patient Application on Objective Structured Clinical Examination Performance: Observational Study.

Background: Peer-assisted learning (PAL) refers to a learning activity whereby students of similar academic level teach and learn from one another. Groupe de perfectionnement des habiletés cliniques (Clinical Skills Improvement Group), a student organization at Université Laval, Canada, propelled PAL into the digital era by creating a collaborative virtual patient platform. Medical interviews can be completed in pairs (a student-patient and a student-doctor) through an interactive Web-based application, which generates a score (weighted for key questions) and automated feedback.

Repeatable and reproducible measurements of myocardial oxidative metabolism, blood flow and external efficiency using C-acetate PET.

Background: Non-invasive approaches to investigate myocardial efficiency can help track the progression of heart failure (HF). This study evaluates the repeatability and reproducibility of C-acetate positron emission tomography (PET) imaging of oxidative metabolism.

Methods And Results: Dynamic C-acetate PET scans were performed at baseline and followup (47 ± 22 days apart) in 20 patients with stable HF with reduced ejection fraction.

Life-History Traits Evolved Jointly with Climatic Niche and Disturbance Regime in the Genus Leucadendron (Proteaceae).

Organisms have evolved a diversity of life-history strategies to cope with variation in their environment. Persistence as adults and/or seeds across recruitment events allows species to dampen the effects of environmental fluctuations. The evolution of life cycles with overlapping generations should thus permit the colonization of environments with uncertain recruitment.

Childhood trajectories of peer victimization and prediction of mental health outcomes in midadolescence: a longitudinal population-based study.

Background: Exposure to peer victimization is relatively common. However, little is known about its developmental course and its effect on impairment associated with mental illnesses. We aimed to identify groups of children following differential trajectories of peer victimization from ages 6 to 13 years and to examine predictive associations of these trajectories with mental health in adolescence.

Twelve Lessons Learned for Effective Research Partnerships Between Patients, Caregivers, Clinicians, Academic Researchers, and Other Stakeholders.

Research increasingly means that patients, caregivers, health professionals, other stakeholders, and academic investigators work in partnership. This requires effective collaboration rooted in mutual respect, involvement of all participants, and good communication. Having conducted such partnered research over multiple projects, and having recently completed a project together funded by the Patient-Centered Outcomes Research Institute, we collaboratively developed a list of 12 lessons we have learned about how to ensure effective research partnerships.

Detecting rater bias using a person-fit statistic: a Monte Carlo simulation study.

Introduction: With the Standards voicing concern for the appropriateness of response processes, we need to explore strategies that would allow us to identify inappropriate rater response processes. Although certain statistics can be used to help detect rater bias, their use is complicated by either a lack of data about their actual power to detect rater bias or the difficulty related to their application in the context of health professions education. This exploratory study aimed to establish the worthiness of pursuing the use of l to detect rater bias.

Alternative formulations and improved bounds for the multi-depot fleet size and mix vehicle routing problem.

In this paper, we compare different formulations of the multi-depot fleet size and mix vehicle routing problem (MDFSMVRP). This problem extends the multi-depot vehicle routing problem and the fleet size and mix vehicle routing problem, two logistics problems that have been extensively studied for many decades. This difficult vehicle routing problem combines complex assignment and routing decisions under the objective of minimizing fixed vehicle costs and variable routing costs.

Riders in the sky (islands): using a mega-phylogenetic approach to understand plant species distribution and coexistence at the altitudinal limits of angiosperm plant life.

Aim: Plants occurring on high-alpine summits are generally expected to persist due to adaptations to extreme selective forces caused by the harshest climates where angiosperm life is known to thrive. We assessed the relative effects of this strong environmental filter and of other historical and stochastic factors driving plant community structure in very high-alpine conditions (up to 4,000m).

Location: European Alps, Écrins National Park, France.

Aflatoxin exposure in Nigerian children with severe acute malnutrition.

Aflatoxin exposure is an important public health concern in sub-Saharan Africa as well as parts of Latin America and Asia. In addition to hepatocellular carcinoma, chronic aflatoxin exposure is believed to play a role in childhood growth impairment. The most reliable biomarker of chronic aflatoxin exposure is the aflatoxin-albumin adduct, as measured by ELISA or isotope dilution mass spectrometry (IDMS).

Antipseudomonal activity enhancement of luminescent iridium(iii) dipyridylamine complexes under visible blue light.

Cyclometallated iridium(iii) dipyridylamine complexes present antibacterial activity against P. aeruginosa, a highly resistant pathogenic bacterium. This activity is increased when the complex is conjugated to biotin, a bacterial nutrient, and a MIC of 4 μM (4 μg mL) has been observed.

Aerrow: A probe-format graphite calorimeter for absolute dosimetry of high-energy photon beams in the clinical environment.

Purpose: In this work, the design, operation, initial experimental evaluation, and characterization of a small-scale graphite calorimeter probe - herein referred to as the Aerrow - developed for routine use in the clinical environment, are described. Similar in size and shape to a Farmer type cylindrical ionization chamber, the Aerrow represents the first translation of calorimetry intended for direct use by clinical physicists in the radiotherapy clinic.

Methods: Based on a numerically optimized design obtained in previous work, a functioning Aerrow prototype capable of two independent modes of operation (quasi-adiabatic and isothermal) was constructed in-house.

Validation of the 5-item doctor-patient communication competency instrument for medical students (DPCC-MS) using two years of assessment data.

Background: Medical students on clinical rotations have to be assessed on several competencies at the end of each clinical rotation, pointing to the need for short, reliable, and valid assessment instruments of each competency. Doctor patient communication is a central competency targeted by medical schools however, there are no published short (i.e.

Prevalence and Correlates of Autism Spectrum Disorders in Quebec: Prévalence et corrélats des troubles du spectre de l'autisme au Québec.

Objective: To estimate the prevalence, comorbidities, and service use of people with autism spectrum disorders (ASDs) based on data from Quebec Integrated Chronic Diseases Surveillance System (QICDSS).

Methods: We included all residents up to age 24 eligible for health plan coverage who were in Quebec for at least 1 day from January 1, 1996, to March 31, 2015. To be considered as having an ASD, an individual had to have had at least 1 physician claim or hospital discharge abstract from 2000 to 2015 indicating one of the following ASD diagnosis codes: ICD-9 codes 299.

Large irradiation doses can improve the fast neutron/gamma discriminating capability of plastic scintillators.

When new materials appear as potential alternatives for radiation detection, several criteria have to be fulfilled. The one presented herein is the response variation to large irradiation doses of neutron/gamma discriminating plastic scintillators. Thus, several samples were exposed to high gamma doses reaching 10 kGy.

Formation of oxidative and non-oxidative dimers in metallothioneins: Implications for charge-state analysis for structural determination.

Rationale: Metallothioneins (MTs) are a class of dynamic proteins that have been investigated extensively using mass spectrometric methods due to their amenability to ionization. Here we detect the formation of oxidative and non-oxidative MT dimers using high-resolution mass spectrometry (HRMS) which has previously been overlooked with lower-resolution techniques.

Methods: Recombinant human MT1a and its isolated domain fragments were analyzed by high-resolution Thermo Q-Exactive and Bruker time-of-flight (TOF) mass spectrometers.

Cytosolic acetyl-CoA promotes histone acetylation predominantly at H3K27 in Arabidopsis.

Acetyl-coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27).

NbEXPA1, an α-expansin, is plasmodesmata-specific and a novel host factor for potyviral infection.

Plasmodesmata (PD), unique to the plant kingdom, are structurally complex microchannels that cross the cell wall to establish symplastic communication between neighbouring cells. Viral intercellular movement occurs through PD. To better understand the involvement of PD in viral infection, we conducted a quantitative proteomic study on the PD-enriched fraction from Nicotiana benthamiana leaves in response to infection by Turnip mosaic virus (TuMV).

Plant growth regulator-mediated anti-herbivore responses of cabbage (Brassica oleracea) against cabbage looper Trichoplusia ni Hübner (Lepidoptera: Noctuidae).

Plant elicitors can be biological or chemical-derived stimulators of jasmonic acid (JA) or salicylic acid (SA) pathways shown to prime the defenses in many crops. Examples of chemical elicitors of the JA and SA pathways include methyl-jasmonate and 1,2,3-benzothiadiazole-7-carbothioate (BTH or the commercial plant activator Actigard 50WG, respectively). The use of specific elicitors has been observed to affect the normal interaction between JA and SA pathways causing one to be upregulated and the other to be suppressed, often, but not always, at the expense of the plant's herbivore or pathogen defenses.

Role of the Bridging Group in Bis-Pyridyl Ligands: Enhancing Both the Photo- and Electroluminescent Features of Cationic (IPr)Cu Complexes.

We report on the benefits of changing the bridging group X of bis-pyridyl ligands, that is, Py-X-Py where X is NH, CH , C(CH ) , or PPh, on the photo- and electroluminescent properties of a new family of luminescent cationic H-heterocyclic carbene (NHC) copper(I) complexes. A joint experimental and theoretical study demonstrates that the bridging group affects the molecular conformation from a planar-like structure (X is NH and CH ) to a boat-like structure (X is C(CH ) and PPh), leading to i) four-fold enhancement of the photoluminescence quantum yield (ϕ ) without affecting the thermally activated delayed fluorescence mechanism, and ii) one order of magnitude reduction of the ionic conductivity (σ) of thin films. This leads to an overall enhancement of the device efficacy and luminance owing to the increased ϕ and the use of low applied driving currents.