Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments.

Rational drug design focuses on the explanation and prediction of complex formation between therapeutic targets and small-molecule ligands. As a third and often overlooked interacting partner, water molecules play a critical role in the thermodynamics of protein-ligand binding, impacting both the entropy and enthalpy components of the binding free energy and by extension, on-target affinity and bioactivity. The community has realized the importance of binding site waters, as evidenced by the number of computational tools to predict the structure and thermodynamics of their networks.

Artificial Intelligence and Machine Learning in Ocular Oncology, Retinoblastoma (ArMOR): Experience with a Multiracial Cohort.

The color variation in fundus images from differences in melanin concentrations across races can affect the accuracy of artificial intelligence and machine learning (AI/ML) models. Hence, we studied the performance of our AI model (with proven efficacy in an Asian-Indian cohort) in a multiracial cohort for detecting and classifying intraocular RB (iRB). Retrospective observational study.

Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential.

The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations of allosteric modulation, and yet few drugs target them. This gap highlights the need for a deeper understanding of allosteric modulation in GPCR drug discovery. The current work introduces a systematic annotation scheme to structurally classify GPCR binding sites based on receptor class, transmembrane helix contacts, and, for membrane-facing sites, membrane sublocation.

Mica Lattice Orientation of Epitaxially Grown Amyloid β25-35 Fibrils.

β-amyloid (Aβ) peptides form self-organizing fibrils in Alzheimer's disease. The biologically active, toxic Aβ25-35 fragment of the full-length Aβ-peptide forms a stable, oriented filament network on the mica surface with an epitaxial mechanism at the timescale of seconds. While many of the structural and dynamic features of the oriented Aβ25-35 fibrils have been investigated before, the β-strand arrangement of the fibrils and their exact orientation with respect to the mica lattice remained unknown.

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas.

Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions.

Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents.

Penicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations.

Machine learning for prediction of concurrent endometrial carcinoma in patients diagnosed with endometrial intraepithelial neoplasia.

Objective: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning.

Methods: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC.

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones.

Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines.

Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.

Background And Objectives: The 9-valent human papillomavirus (9vHPV) vaccine Phase III immunogenicity study in 9- to 15-year-old boys and girls was extended to assess immunogenicity and effectiveness through 10 years after the last vaccine dose (NCT00943722).

Methods: Boys (n = 301) and girls (n = 971) who received three 9vHPV vaccine doses in the base study (day 1, months 2 and 6) enrolled in the extension. Serum was collected through month 126 for antibody assessments by competitive Luminex immunoassay and immunoglobulin G-Luminex immunoassay.

Efficacy, tolerability, and endometrial safety of ospemifene compared with current therapies for the treatment of vulvovaginal atrophy: a systematic literature review and network meta-analysis.

Importance: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA).

Objective: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe.

Evidence Review: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Safety of the Trauma Quality Improvement Program Guideline for Venous Thromboembolism Prophylaxis in Traumatic Brain Injury.

Background: The American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP) provides a guideline for when to initiate pharmacologic venous thromboembolism (VTE) prophylaxis in traumatic brain injury (TBI) patients. We hypothesized that implementation of the guideline would not result in progression in intracranial hemorrhage.

Methods: The TBI TQIP guideline was implemented at a Level I Trauma Center.

Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors.

Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.

Genotyping and Cytology Triage of High-Risk HPV DNA Positive Women for Detection of Cervical High-Grade Lesions.

Objective: A demonstration project of primary human papillomavirus (HPV) testing was initiated in 2011 among more than 23,000 women attending routine cervical cancer screening. We examined the additional diagnostic performance of HPV genotyping for detecting disease in women with abnormal cytology.

Methods: Women aged 30 to 65 years were originally screened for HPV using Hybrid Capture II test.

Traumatic Gallbladder Rupture in a Pediatric Patient Misdiagnosed as Acute Appendicitis.

We present an 8-year-old male with a history liver surgery as a neonate who presented to the emergency department with a chief complaint of abdominal pain. A computed tomography scan (CT) showed ascites with dilated loops of small bowel and the appendix was not visualized. The pediatric surgery team was consulted for possible perforated appendicitis.

Molybdenum(IV) dithiocarboxylates as single-source precursors for AACVD of MoS thin films.

Tetrakis(dithiocarboxylato)molybdenum(IV) complexes of the type Mo(SCR) (R = Me, Et, Pr, Ph) were synthesized, characterized, and prescreened as precursors for aerosol assisted chemical vapor deposition (AACVD) of MoS thin films. The thermal behavior of the complexes as determined by TGA and GC-MS was appropriate for AACVD, although the complexes were not sufficiently volatile for conventional CVD bubbler systems. Thin films of MoS were grown by AACVD at 500 °C from solutions of Mo(SCMe) in toluene.

Effectiveness, immunogenicity, and safety of the quadrivalent HPV vaccine in women and men aged 27-45 years.

Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up.

Total Obliteration and Subsequent Recanalization of Esophagus via Endoscopic Rendezvous Procedure in a Pediatric Patient.

Esophageal strictures are well-known to the pediatric gastroenterology and surgery communities. Such strictures can arise from congenital malformations, inflammatory disorders, gastro-esophageal reflux disease (GERD), or even caustic substance ingestion. Rarely, in the instances of caustic ingestion, GERD, or inflammatory disorders, total obliteration of the esophageal lumen has been described.

Contribution of hydrophobic interactions to protein mechanical stability.

The role of hydrophobic and polar interactions in providing thermodynamic stability to folded proteins has been intensively studied, but the relative contribution of these interactions to the mechanical stability is less explored. We used steered molecular dynamics simulations with constant-velocity pulling to generate force-extension curves of selected protein domains and monitor hydrophobic surface unravelling upon extension. Hydrophobic contribution was found to vary between one fifth and one third of the total force while the rest of the contribution is attributed primarily to hydrogen bonds.

Correlation of D-dimer and Outcomes in COVID-19 Patients.

Background: The coronavirus disease 2019 (COVID-19) global pandemic has impacted daily life and medical practices around the world. Hospitals are continually making observations about this unique population as it relates to laboratory data and outcomes. Plasma D-dimer levels have been shown to be promising as a prognostic factor for outcomes in COVID-19 patients.

Speech perception in noise in children with learning difficulties: A scoping review.

Background: Children with learning difficulties (LD) face multiple challenges in classrooms settings while having to meet various auditory demands, such as understanding verbal instructions in the presence of background noise. These challenges pose a risk for academic failure, underachievement, and underemployment. Well-developed skills regarding speech perception in noise promote learning, communication, and academic success.

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads.

Constitutive- and immunoproteasomes are part of the ubiquitin-proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse.

Efficacy, immunogenicity, and safety of a quadrivalent HPV vaccine in men: results of an open-label, long-term extension of a randomised, placebo-controlled, phase 3 trial.

Background: The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16-26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up.

Methods: The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries.