Behavioral and neurophysiological effects of electrical stunning on zebrafish larvae.

Two methods dominate the way that zebrafish larvae are euthanized after experimental procedures: anesthetic overdose and rapid cooling. Although MS-222 is easy to apply, this anesthetic takes about a minute to act and fish show aversive reactions and interindividual differences, limiting its reliability. Rapid cooling kills larvae after several hours and is not listed as an approved method in the relevant European Union directive.

Randomized controlled trial comparing the immunogenicity of experimental Salmonella Dublin siderophore receptor vaccines in calves.

Objective: To describe immune responses following administration of experimental Salmonella Dublin siderophore receptor protein (SRP) vaccines in Holstein heifer calves with adequate passive antibody transfer.

Methods: Calves were randomly assigned to receive placebo, vaccination with S Dublin SRP in adjuvant A, or vaccination with S Dublin SRP in adjuvant B at 7 ± 3 days of age and 3 weeks later. Before each vaccination, 4 and 8 days after the second vaccination (postvaccination), and 61 to 91 days postvaccination, S Dublin antibody titers were measured.

How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities.

The cell is arguably the most fundamental unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells.

Streamlining quantitative joint-wide medial femoro-tibial histopathological scoring of mouse post-traumatic knee osteoarthritis models.

Objectives: Histological scoring remains the gold-standard for quantifying post-traumatic osteoarthritis (ptOA) in animal models, allowing concurrent evaluation of numerous joint tissues. Available systems require scoring multiple sections/joint making analysis laborious and expensive. We investigated if a single section allowed equivalent quantitation of pathology in different joint tissues and disease stages, in three ptOA models.

Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor-induced diabetes.

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induced diabetes rapidly.

Inpatient Perioperative Euglycemic Diabetic Ketoacidosis Due to Sodium-Glucose Cotransporter-2 Inhibitors - Lessons From a Case Series and Strategies to Decrease Incidence.

Objective: To identify clinical characteristics and factors associated with the development of euglycemic diabetic ketoacidosis (eDKA), and develop suitable strategies to reduce such events.

Methods: Electronic health record (EHR) data were extracted to identify all patients between December 1, 2013, and March 30, 2021, who underwent surgical procedures and had been prescribed a sodium-glucose cotransporter 2 inhibitor (SGLT2i) before these procedures. The resulting list was streamlined to a subset of patients who either had diabetic ketoacidosis (DKA) listed as a hospital diagnosis, postoperative serum bicarbonate ≤ 16 mmol/L, or postoperative serum pH ≤ 7.

Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning.

Abstract: Phenotypic plasticity describes the ability of cancer cells to undergo dynamic, nongenetic cell state changes that amplify cancer heterogeneity to promote metastasis and therapy evasion. Thus, cancer cells occupy a continuous spectrum of phenotypic states connected by trajectories defining dynamic transitions upon a cancer cell state landscape. With technologies proliferating to systematically record molecular mechanisms at single-cell resolution, we illuminate manifold learning techniques as emerging computational tools to effectively model cell state dynamics in a way that mimics our understanding of the cell state landscape.

Multiscale PHATE identifies multimodal signatures of COVID-19.

As the biomedical community produces datasets that are increasingly complex and high dimensional, there is a need for more sophisticated computational tools to extract biological insights. We present Multiscale PHATE, a method that sweeps through all levels of data granularity to learn abstracted biological features directly predictive of disease outcome. Built on a coarse-graining process called diffusion condensation, Multiscale PHATE learns a data topology that can be analyzed at coarse resolutions for high-level summarizations of data and at fine resolutions for detailed representations of subsets.

1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development.

Identification of physiological modulators of nuclear hormone receptor (NHR) activity is paramount for understanding the link between metabolism and transcriptional networks that orchestrate development and cellular physiology. Using libraries of metabolic enzymes alongside their substrates and products, we identify 1-deoxysphingosines as modulators of the activity of NR2F1 and 2 (COUP-TFs), which are orphan NHRs that are critical for development of the nervous system, heart, veins, and lymphatic vessels. We show that these non-canonical alanine-based sphingolipids bind to the NR2F1/2 ligand-binding domains (LBDs) and modulate their transcriptional activity in cell-based assays at physiological concentrations.

Generating hard-to-obtain information from easy-to-obtain information: Applications in drug discovery and clinical inference.

Often when biological entities are measured in multiple ways, there are distinct categories of information: some information is easy-to-obtain information (EI) and can be gathered on virtually every subject of interest, while other information is hard-to-obtain information (HI) and can only be gathered on some. We propose building a model to make probabilistic predictions of HI using EI. Our feature mapping GAN (FMGAN), based on the conditional GAN framework, uses an embedding network to process conditions as part of the conditional GAN training to create manifold structure when it is not readily present in the conditions.

Quantifying the effect of experimental perturbations at single-cell resolution.

Current methods for comparing single-cell RNA sequencing datasets collected in multiple conditions focus on discrete regions of the transcriptional state space, such as clusters of cells. Here we quantify the effects of perturbations at the single-cell level using a continuous measure of the effect of a perturbation across the transcriptomic space. We describe this space as a manifold and develop a relative likelihood estimate of observing each cell in each of the experimental conditions using graph signal processing.

Competition-Based Success Factors During the Talent Pathway of Elite Male Swimmers.

Marginal differences in race results between top swimmers have evoked the interest in competition-based success factors of long-term athlete development. To identify novel factors for the multi-dimensional model of talent development, the aim of the study was to investigate annual variation in competition performance (ACV), number of races per year, and age. Therefore, 45,398 race results of all male participants ( = 353) competing in individual events, i.

Long-Term Outcomes of Left Atrial Appendage Electrical Isolation in Patients With Nonparoxysmal Atrial Fibrillation: A Propensity Score-Matched Analysis.

Background: Left atrial appendage electrical isolation (LAAEI) has been proposed for the treatment of nonparoxysmal atrial fibrillation (AF). The long-term clinical outcomes of this approach remain unclear. The objective of our study was to investigate the incremental benefit and safety of LAAEI in patients undergoing catheter ablation for nonparoxysmal AF.

Epicardial Ablation Complications.

The percutaneous epicardial approach has become an adjunctive tool for electrophysiologists to treat disparate cardiac arrhythmias, including accessory pathways, atrial tachycardia, and particularly ventricular tachycardia. This novel technique prompted a strong impulse to perform epicardial access as an alternative strategy for pacing and defibrillation, left atrial appendage exclusion, heart failure with preserved ejection fraction, and genetically engineered tissue delivery. However, because of the incremental risk of major complications compared with stand-alone endocardial ablation, it is still practiced in a limited number of highly experienced centers across the world.

Is transesophageal echocardiography necessary in patients undergoing ablation of atrial fibrillation on an uninterrupted direct oral anticoagulant regimen? Results from a prospective multicenter registry.

Background: Thromboembolic stroke is a rare but devastating consequence of atrial fibrillation (AF) ablation. Transesophageal echocardiography (TEE) is recommended to rule out left atrial appendage thrombus; however, its use is variable.

Objective: The purpose of this study was to assess whether TEE is mandatory in patients undergoing AF ablation on uninterrupted direct oral anticoagulants (DOACs).