On the Importance of Including Cohesive Zone Models in Modelling Mixed-Mode Aneurysm Rupture.

Introduction: The precise mechanism of rupture in abdominal aortic aneurysms (AAAs) has not yet been uncovered. The phenomenological failure criterion of the coefficient of proportionality between von Mises stress and tissue strength does not account for any mechanistic foundation of tissue fracture. Experimental studies have shown that arterial failure is a stepwise process of fibrous delamination (mode II) and kinking (mode I) between layers.

Enhancing the Small-Scale Screenable Biological Space beyond Known Chemogenomics Libraries with Gray Chemical Matter─Compounds with Novel Mechanisms from High-Throughput Screening Profiles.

Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries.

Optimizing the Cell Painting assay for image-based profiling.

In image-based profiling, software extracts thousands of morphological features of cells from multi-channel fluorescence microscopy images, yielding single-cell profiles that can be used for basic research and drug discovery. Powerful applications have been proven, including clustering chemical and genetic perturbations on the basis of their similar morphological impact, identifying disease phenotypes by observing differences in profiles between healthy and diseased cells and predicting assay outcomes by using machine learning, among many others. Here, we provide an updated protocol for the most popular assay for image-based profiling, Cell Painting.

Is Myofascial Decompression Effective at Increasing Hamstring Flexibility in the Athletic Population? A Critically Appraised Topic.

Clinical Scenario: There are a variety of therapeutic modalities used to treat flexibility issues in athletes, which can be the main cause of hamstring injuries. Myofascial decompression is one modality used to treat these patients.

Focused Clinical Question: Is myofascial decompression effective at increasing hamstring flexibility in the athletic population? Summary of Search, "Best Evidence" Appraised, and Key Findings: The literature was searched for studies of level 2 evidence or higher that investigated the use of myofascial decompression to increase hamstring flexibility, that were published in the last 5 years.

Endovascular versus conventional open surgical repair for thoracoabdominal aortic aneurysms.

Background: Thoracoabdominal aortic aneurysms (TAAAs) are a life-threatening condition which remain difficult to treat. Endovascular and open surgical repair (OSR) provide treatment options for patients, however, due to the lack of clinical trials comparing these, the optimum treatment option is unknown.

Objectives: To assess the effectiveness and safety of endovascular repair versus conventional OSR for the treatment of TAAAs.

Influence of shape-memory stent grafts on local aortic compliance.

The effect of repair techniques on the biomechanics of the aorta is poorly understood, resulting in significant levels of postoperative complications for patients worldwide. This study presents a computational analysis of the influence of Nitinol-based devices on the biomechanical performance of a healthy patient-specific human aorta. Simulations reveal that Nitinol stent-grafts stretch the artery wall so that collagen is stretched to a straightened high-stiffness configuration.

Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.

While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints-mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size.

Development of an FEA framework for analysis of subject-specific aortic compliance based on 4D flow MRI.

This paper presents a subject-specific in-silico framework in which we uncover the relationship between the spatially varying constituents of the aorta and the non-linear compliance of the vessel during the cardiac cycle uncovered through our MRI investigations. A microstructurally motivated constitutive model is developed, and simulations reveal that internal vessel contractility, due to pre-stretched elastin and actively generated smooth muscle cell stress, must be incorporated, along with collagen strain stiffening, in order to accurately predict the non-linear pressure-area relationship observed in-vivo. Modelling of elastin and smooth muscle cell contractility allows for the identification of the reference vessel configuration at zero-lumen pressure, in addition to accurately predicting high- and low-compliance regimes under a physiological range of pressures.

A Dual-VENC Four-Dimensional Flow MRI Framework for Analysis of Subject-Specific Heterogeneous Nonlinear Vessel Deformation.

Advancement of subject-specific in silico medicine requires new imaging protocols tailored to specific anatomical features, paired with new constitutive model development based on structure/function relationships. In this study, we develop a new dual-velocity encoding coefficient (VENC) 4D flow MRI protocol that provides unprecedented spatial and temporal resolution of in vivo aortic deformation. All previous dual-VENC 4D flow MRI studies in the literature focus on an isolated segment of the aorta, which fail to capture the full spectrum of aortic heterogeneity that exists along the vessel length.

Advancements in Assay Technologies and Strategies to Enable Drug Discovery.

Assays drive drug discovery from the exploratory phases to the clinical testing of drug candidates. As such, numerous assay technologies and methodologies have arisen to support drug discovery efforts. Robust identification and characterization of tractable chemical matter requires biochemical, biophysical, and cellular approaches and often benefits from high-throughput methods.

Quantification of the regional bioarchitecture in the human aorta.

Regional variance in human aortic bioarchitecture responsible for the elasticity of the vessel is poorly understood. The current study quantifies the elements responsible for aortic compliance, namely, elastin, collagen and smooth muscle cells, using histological and stereological techniques on human tissue with a focus on regional heterogeneity. Using donated cadaveric tissue, a series of samples were excised between the proximal ascending aorta and the distal abdominal aorta, for five cadavers, each of which underwent various staining procedures to enhance specific constituents of the wall.

Protein kinase A activation inhibits gene expression in myotubes from patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent of the adult-onset muscular dystrophies. FSHD causes a loss of muscle mass and function, resulting in severe debilitation and reduction in quality of life. Currently, only the symptoms of FSHD can be treated, and such treatments have minimal benefit.

Data-analysis strategies for image-based cell profiling.

Image-based cell profiling is a high-throughput strategy for the quantification of phenotypic differences among a variety of cell populations. It paves the way to studying biological systems on a large scale by using chemical and genetic perturbations. The general workflow for this technology involves image acquisition with high-throughput microscopy systems and subsequent image processing and analysis.

Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation.

Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC.

Development of a Fluorescent Quenching Based High Throughput Assay to Screen for Calcineurin Inhibitors.

Currently there is no effective treatment available for major neurodegenerative disorders associated to protein misfolding, including Alzheimer's and Parkinson's disease. One of most promising therapeutic approaches under development focuses on inhibiting the misfolding and aggregation pathway. However, it is likely that by the time clinical symptoms appear, there is a large accumulation of misfolded aggregates and a very substantial damage to the brain.

Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors.

PERK is serine/threonine kinase localized to the endoplasmic reticulum (ER) membrane. PERK is activated and contributes to cell survival in response to a variety of physiological stresses that affect protein quality control in the ER, such as hypoxia, glucose depravation, increased lipid biosynthesis, and increased protein translation. Pro-survival functions of PERK are triggered by such stresses, suggesting that development of small-molecule inhibitors of PERK may be efficacious in a variety of disease scenarios.

A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity.

TDP-43 is an RNA binding protein found to accumulate in the cytoplasm of brain and spinal cord from patients affected with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nuclear TDP-43 protein regulates transcription through several mechanisms, and under stressed conditions, it forms cytoplasmic aggregates that co-localize with stress granule (SG) proteins in cell culture. These granules are also found in the brain and spinal cord of patients affected with ALS and FTLD.

Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-β precursor protein dimerization.

The amyloid β precursor protein (APP) is a single-pass transmembrane glycoprotein that is ubiquitously expressed in many cell types, including neurons. Amyloidogenic processing of APP by β- and γ-secretases leads to the production of amyloid-β (Aβ) peptides that can oligomerize and aggregate into amyloid plaques, a characteristic hallmark of Alzheimer's disease (AD) brains. Multiple reports suggest that dimerization of APP may play a role in Aβ production; however, it is not yet clear whether APP dimers increase or decrease Aβ and the mechanism is not fully understood.

Arsenic exposure disrupts neurite growth and complexity in vitro.

Arsenic has neurotoxic effects on both central and peripheral components of the mature nervous system. There is increasing evidence that exposure to arsenic is also toxic to the developing nervous system and can result in decreased cell division and increased apoptosis in cultured developing neurons. However, the effects of arsenic on subsequent neuron growth and morphology remain unclear.

Perinatal exposure to low levels of the environmental antiandrogen vinclozolin alters sex-differentiated social play and sexual behaviors in the rat.

In this study we examined the effects of exposure to the antiandrogenic fungicide vinclozolin (Vz) on the development of two sex-differentiated behaviors that are organized by the perinatal actions of androgens. Pregnant Long-Evans rats were administered a daily oral dose of 0, 1.5, 3, 6, or 12 mg/kg Vz from the 14th day of gestation through postnatal day (PND)3.

Adjuvant specific active lung cancer immunotherapy trials. Tumor-associated antigens.

The 10-year cumulative experiences of five year survivals of patients entered into a successful phase II specific active tumor-associated antigen (TAA) immunotherapy trial, a successful phase III specific active immunotherapy trial A and of patients from centers with acceptable protocol violation levels of an unsuccessful specific active immunotherapy trial B are evaluated. Here the authors report the efficacy of specific active TAA immunotherapy when the protocol is adhered to strictly, where the induction of cell-mediated immunity to TAA indicated a successful adherence to the protocol rather than the strategic result when centers from the third trial with major violations are included. The authors repeat here a summary of each of the three separate trials, each of the three trials having been reported elsewhere in their entirety, so that these total results may be compared to the present analysis.

Stability of aqueous solutions of amoxicillin sodium in the frozen and liquid states.

The stability of aqueous admixtures of amoxicillin sodium in both the liquid and frozen (solid) states was studied. Admixtures of amoxicillin sodium were prepared in sterile water for injection to a theoretical concentration of 10 mg/mL. For each experimental run, 2-mL aliquots of the admixture were placed in stoppered glass volumetric flasks and stored at temperatures ranging from 19.

Length of the distal esophageal sphincter and competency of the cardia.

Pressure and abdominal length of the distal esophageal sphincter are important factors in maintaining competency of the cardia against challenges of intraabdominal pressure. Some patients with normal distal esophageal sphincter pressure and position may have reflux which could be due to the inability of the cardia to overcome challenges of intragastric pressure. Three experimental studies and one clinical study were designed to evaluate this problem.