Direct observation of small molecule activator binding to single PR65 protein.

The reactivation of heterotrimeric protein phosphatase 2A (PP2A) through small molecule activators is of interest to therapeutic intervention due to its dysregulation, which is linked to chronic conditions. This study focuses on the PP2A scaffold subunit PR65 and a small molecule activator, ATUX-8385, designed to bind directly to this subunit. Using a label-free single-molecule approach with nanoaperture optical tweezers (NOT), we quantify its binding, obtaining a dissociation constant of 13.

More micrometastases, more recurrence? The role of qPCR of PSA mRNA in lymph nodes during prostatectomy.

Background And Objectives: Radical prostatectomy is a standard treatment for prostate cancer, yet about 30% of patients experience rising biochemical markers within a decade post-surgery. Pelvic lymph node sampling during prostatectomy assesses potential lymph node metastases, but standard histological assessments, which typically examine only 2-3 tissue sections, often miss occult metastases. This study assesses the effectiveness of qPCR in detecting PSA coding KLK3 mRNA for identifying lymph node metastases post-prostatectomy and explores the correlation between PSA-mRNA and biochemical recurrence.

Introduction to Artificial Intelligence (AI) and Machine Learning (ML) in Pathology & Medicine: Generative & Non-Generative AI Basics.

This manuscript serves as an introduction to a comprehensive seven-part review article series on artificial intelligence (AI) and machine learning (ML) and their current and future influence within pathology and medicine. This introductory review provides a comprehensive grasp of this fast-expanding realm and its potential to transform medical diagnosis, workflow, research, and education. Fundamental terminology employed in AI-ML is covered using an extensive dictionary.

Global hinge sites of proteins as target sites for drug binding.

Hinge sites of proteins play a key role in mediating conformational mechanics. Among them, those involved in the most collective modes of motion, also called global hinges, are of particular interest, as they support cooperative rearrangements that are often functional. Yet, the utility of targeting global hinges for modulating function remains to be established.

Statistics of Generative Artificial Intelligence and Nongenerative Predictive Analytics Machine Learning in Medicine.

The rapidly evolving landscape of artificial intelligence (AI) and machine learning (ML) in medicine has prompted medical professionals to increasingly familiarize themselves with related topics. This also demands grasping the underlying statistical principles that govern their design, validation, and reproducibility. Uniquely, the practice of pathology and medicine produces vast amount of data that can be exploited by AI/ML.

A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.

The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons.

Clinical Significance of Mucor in Airway Culture of Immunocompetent Patients With Chronic Lung Disease.

Objectives: Mucor within the airways of immunocompromised patients often signifies an invasive life-threatening infection. However, its significance in immunocompetent patients with chronic lung diseases is less clear. We aimed to assess the clinical implication of mucor in airway-secretion cultures of these patients.

Influence of point mutations on PR65 conformational adaptability: Insights from molecular simulations and nanoaperture optical tweezers.

PR65 is the HEAT repeat scaffold subunit of the heterotrimeric protein phosphatase 2A (PP2A) and an archetypal tandem repeat protein. Its conformational mechanics plays a crucial role in PP2A function by opening/closing substrate binding/catalysis interface. Using in silico saturation mutagenesis, we identified PR65 "hinge" residues whose substitutions could alter its conformational adaptability and thereby PP2A function, and selected six mutations that were verified to be expressed and soluble.

Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

Background: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown.

Is the use of secukinumab after anti-TNF therapy greater than expected for the risk of developing inflammatory bowel disease?

Objective: In this study, our objective was to present real-life data on the incidence of inflammatory bowel disease (IBD) among patients receiving secukinumab treatment.

Methods: The study consisted of 209 patients who had prior exposure to anti-tumor necrosis factor (TNF) or were biologically naive. Patients with a pre-existing history of IBD were excluded from the study.

The mechanism and energetics of the dynein priming stroke.

Dyneins are an AAA+ motor responsible for motility and force generation toward the minus end of microtubules. Dynein motility is powered by nucleotide-dependent transitions of its linker domain, which transitions between straight (post-powerstroke) and bent (pre-powerstroke) conformations. To understand the dynamics and energetics of the linker, we performed all-atom molecular dynamics simulations of human dynein-2 primed for its power stroke.

Pulmonary functions, nasal symptoms, and quality of life in patients with primary ciliary dyskinesia (PCD).

Background: Several factors may influence quality of life (QOL) for patients with primary ciliary dyskinesia (PCD). We aimed to evaluate the association between pulmonary functions, nasal symptoms and QOL in PCD patients.

Methods: A prospective single center study.

There is a fundamental, unbridgeable gap between DNNs and the visual cortex.

Deep neural networks (DNNs) are not just inadequate models of the visual system but are so different in their structure and functionality that they are not even on the same playing field. DNN units have almost nothing in common with neurons, and, unlike visual neurons, they are often fully connected. At best, DNNs can label inputs, while our object perception is both holistic and detail preserving.

Influence of Point Mutations on PR65 Conformational Adaptability: Insights from Nanoaperture Optical Tweezer Experiments and Molecular Simulations.

PR65 is the HEAT-repeat scaffold subunit of the heterotrimeric protein phosphatase 2A (PP2A) and an archetypal tandem-repeat protein, forming a spring-like architecture. PR65 conformational mechanics play a crucial role in PP2A function by opening/closing the substrate-binding/catalysis interface. Using saturation mutagenesis we identified "hinge" residues of PR65, whose substitutions are predicted to restrict its conformational adaptability and thereby disrupt PP2A function.

The new face of cystic fibrosis in the era of population genetic carrier screening.

Background: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features.

Methods: This was a retrospective national study.

An expanded CRISPR-Cas9-assisted recombineering toolkit for engineering genetically intractable Pseudomonas aeruginosa isolates.

Much of our current understanding of microbiology is based on the application of genetic engineering procedures. Since their inception (more than 30 years ago), methods based largely on allelic exchange and two-step selection processes have become a cornerstone of contemporary bacterial genetics. While these tools are established for adapted laboratory strains, they have limited applicability in clinical or environmental isolates displaying a large and unknown genetic repertoire that are recalcitrant to genetic modifications.

Pediatric negative pressure pulmonary edema: Case series and review of the literature.

Introduction: Negative pressure pulmonary edema (NPPE) is a potentially life-threatening complication that develops rapidly following acute upper airway obstruction. The condition is rare, dramatic but resolves quickly. Prompt recognition and appropriate supportive treatment may prevent unnecessary investigations and iatrogenic complications.

Effects of acute aerobic exercise on brain-derived neurotrophic factor level in rheumatoid arthritis patients.

Objectives: The study aimed to investigate the variation of brain-derived neurotrophic factor (BDNF) levels following acute exercise in patients with rheumatoid arthritis (RA).

Patients And Methods: This cross-sectional study was conducted with 88 participants (25 males, 63 females; mean age: 45.1±8.

The effect of inspiratory muscle training in PCD and CF patients: A pilot study.

Background: Effective work of breathing and bronchial hygiene requires synergy of inspiratory and expiratory muscles. Inspiratory muscle training (IMT) is a part of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD). There is some evidence of its efficacy in cystic fibrosis (CF) and, recently, in long COVID-19.

Clinical characteristics and short-term outcomes of adult patients with urolithiasis: first report from Somalia.

Objective: This study aimed to investigate the data of adult patients admitted to the only tertiary care center in Somalia with the diagnosis of urolithiasis and to present the first report from this Sub-Saharan African country.

Patients And Methods: This study was designed as a retrospective single-center study conducted in Somalia Turkiye Training and Research Hospital. Adult patients who received the diagnosis of urolithiasis and who were admitted to the urology department constituted the target population.