α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model.

The cellular prion protein, PrPC, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson's disease. Previously, we generated the "Salt (S)" and "No Salt (NS)" strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrPC facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrPC.

Social prescribing needs and priorities of older adults in Canada: a qualitative analysis.

Introduction: Social prescribing (SP) is a holistic and collaborative approach to help individuals access community-based supports and services for their nonmedical social needs. The aim of this study was to assess the needs and priorities of Canadian older adults (aged 55 years and older), with a focus on optimizing SP programs for those who are systemically disadvantaged and socially marginalized.

Methods: Semistructured focus groups (N = 10 groups, 43 participants) were conducted online via Zoom with participants from across Canada.

Negative and Positive Experiences During the COVID-19 Pandemic in Canadians With Developmental Disabilities: A One-Year Ontario-Based Survey.

Purpose: Understanding the experiences of people with developmental disabilities during the initial period of COVID-19 pandemic.

Methods: Individuals with developmental disabilities and their caregivers completed baseline and up to five follow-up online surveys using the CRISIS-AFAR measures, between July 2020 and September 2021. We used qualitative (thematic analysis) and quantitative (MANOVA) analytic methods.

PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in , encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287.

High SARS-CoV-2 seroincidence but low excess COVID mortality in Sierra Leone in 2020-2022.

While SARS-CoV-2 infection appears to have spread widely throughout Africa, documentation of associated mortality is limited. We implemented a representative serosurvey in one city of Sierra Leone in Western Africa, paired with nationally representative mortality and selected death registration data. Cumulative seroincidence using high quality SARS-CoV-2 serological assays was 69% by July 2021, rising to 84% by April 2022, mostly preceding SARS-CoV-2 vaccination.

Identification of an embryonic differentiation stage marked by Sox1 and FoxA2 co-expression using combined cell tracking and high dimensional protein imaging.

Pluripotent mouse embryonic stem cells (ESCs) can differentiate to all germ layers and serve as an in vitro model of embryonic development. To better understand the differentiation paths traversed by ESCs committing to different lineages, we track individual differentiating ESCs by timelapse imaging followed by multiplexed high-dimensional Imaging Mass Cytometry (IMC) protein quantification. This links continuous live single-cell molecular NANOG and cellular dynamics quantification over 5-6 generations to protein expression of 37 different molecular regulators in the same single cells at the observation endpoints.

Paraspeckle-independent co-transcriptional regulation of nuclear microRNA biogenesis by SFPQ.

MicroRNAs (miRNAs) play crucial roles in physiological functions and disease, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, reveals its proximity to splicing factor proline- and glutamine (Q)-rich (SFPQ), a multifunctional RNA-binding protein (RBP) involved in forming paraspeckle nuclear condensates. SFPQ depletion impacts both primary and mature miRNA expression, while other paraspeckle proteins (PSPs) or the paraspeckle scaffolding RNA NEAT1 do not, indicating a paraspeckle-independent role.

The Feasibility for Screening for Ovarian Cancer.

Introduction: The majority of the high-grade serous ovarian cancer (HGSOC) cases are diagnosed late, preventing effective treatment and therapy. We examine the feasibility of using EVA (Early oVArian cancer), a new molecular test for early HGSOC detection.

Methods: Comparison of the advantages and disadvantages of EVA with previously reported ovarian cancer tests, including CA125, was made, and the positive and negative predictive values of the tests were calculated as a measure of usefulness in the clinic.

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls.

Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders.

Psychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are characterized by altered cognition and mood, brain functions that depend on information processing by cortical microcircuits. We hypothesized that psychiatric disorders would display cell type-specific transcriptional alterations in neuronal subpopulations that make up cortical microcircuits: excitatory pyramidal (PYR) neurons and vasoactive intestinal peptide- (VIP), somatostatin- (SST), and parvalbumin- (PVALB) expressing inhibitory interneurons. Using laser capture microdissection followed by RNA sequencing (LCM-seq), we performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control.

Women's and Partners' Experiences With a Closed-loop Insulin Delivery System to Manage Type 1 Diabetes in the Postpartum Period.

Objectives: Closed-loop insulin delivery has the potential to offer women with type 1 diabetes a break from intense diabetes self-care efforts postpartum. Our aim in this study was to explore the views and opinions of hybrid closed-loop users and their partners in the first 24 weeks postpartum.

Methods: This qualitative study was embedded in a controlled study of women with type 1 diabetes randomized to closed-loop insulin delivery (MiniMed 670G or 770G; Medtronic, Minneapolis, Minnesota, United States) or sensor-augmented pump use for 1 to 11 weeks 6 days postpartum, with all on closed-loop delivery from 12 to 24 weeks postpartum.

Healthy First-Degree Relatives From Multiplex Families vs Simplex Families Have Higher Subclinical Intestinal Inflammation, a Distinct Fecal Microbial Signature, and Harbor a Higher Risk of Developing Crohn's Disease.

Background & Aims: Unaffected first-degree relatives (FDRs) from families with ≥2 affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex vs simplex families and investigate the risk of future CD onset accounting for potential confounders.

Methods: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy FDRs of patients with CD.

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.

Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively.

Impact of targeted neonatal echocardiography consultations for critically sick preterm neonates.

Rationale: Preterm neonates needing rescue treatments with inotropes and/or inhaled nitric oxide (iNO) (acute critical illnesses, ACIs) in neonatal intensive care units (NICUs) are at high risk of mortality. While targeted neonatal echocardiography consultations (TNE) are increasingly used to guide management, its clinical impact need evaluation.

Objectives: To investigate clinical outcomes in relation to TNE utilisation during episodes of ACIs among preterm neonates.

The Integrated Care World is a Stage: Applying Goffman's Theory of Dramaturgy to the Activities of Integrated Care.

Among the challenges in delivering integrated health and social care services is the need to attend to the coordination of tasks, roles, activities, and operations, while considering how these efforts are experienced by patients, carers and communities. The literature has noted an important disconnect between how providers and leaders view their efforts to coordinate service delivery, and how patients perceive these efforts on the receiving end. Our team has provided guidance to integrated care efforts in Ontario, Canada by drawing on Goffman's theory of Dramaturgy to help classify the actions of integrated care delivery as linked to the roles individuals play in the delivery of care.

The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice.

Objective: The development of glucagon-like peptide-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has been accompanied by evidence for anti-inflammatory and cytoprotective actions in the heart, blood vessels, kidney, and brain. Whether GLP-1R agonists might be useful clinically for attenuating deterioration of cognitive dysfunction and reducing the progression of Alzheimer's disease remains uncertain.

Methods: Here we evaluated the actions of semaglutide and tirzepatide, clinically distinct GLP-1 medicines, in two mouse models of neurodegeneration.

FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation.

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2).

The impact of time-restricted eating on beta-cell function in adults with type 2 diabetes: a randomized cross-over trial.

Objective: Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM.

Research Design And Methods: In a randomized cross-over trial, 39 participants [mean 2.

Testing a Nanoparticle Reagent for Imaging Mass Cytometry.

Mass cytometry (MC), a powerful single-cell analysis technique, has limitations in detecting low-abundance biomarkers. Nanoparticle (NP) reagents offer the potential for enhancing sensitivity by carrying large numbers of heavy metal isotopes. Here, we report NP reporters for imaging mass cytometry (IMC) based on NaYF:Yb/Er NPs.

Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities.

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSC) that persist after therapy and seed treatment-refractory recurrent tumors. GBM tumors display a high degree of intra- and intertumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on a gradient between two transcriptional states or subtypes termed developmental and injury response.

Pregnancy-Related Factors and Breast Cancer Risk for Women Across a Range of Familial Risk.

Importance: Few studies have investigated whether the associations between pregnancy-related factors and breast cancer (BC) risk differ by underlying BC susceptibility. Evidence regarding variation in BC risk is critical to understanding BC causes and for developing effective risk-based screening guidelines.

Objective: To examine the association between pregnancy-related factors and BC risk, including modification by a of BC where scores are based on age and BC family history.