Effects of All-Atom and Coarse-Grained Molecular Mechanics Force Fields on Amyloid Peptide Assembly: The Case of a Tau K18 Monomer.

To propose new mechanism-based therapeutics for Alzheimer's disease (AD), it is crucial to study the kinetics and oligomerization/aggregation mechanisms of the hallmark tau proteins, which have various isoforms and are intrinsically disordered. In this study, multiple all-atom (AA) and coarse-grained (CG) force fields (FFs) have been benchmarked on molecular dynamics (MD) simulations of K18 tau (M243-E372), which is a truncated form (130 residues) of full-length tau (441 residues). FF19SB is first excluded because the dynamics are too slow, and the conformations are too stable.

Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.

Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5 intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages.

Stability and cavitation of nanobubble: Insights from large-scale atomistic molecular dynamics simulations.

We perform large-scale atomistic simulations of a system containing 12 × 106 atoms, comprising an oxygen gas-filled bubble immersed in water, to understand the stability and cavitation induced by ultrasound. First, we propose a method to construct a bubble/water system. For a given bubble radius, the pressure inside the bubble is estimated using the Young-Laplace equation.

Oral Candida-biome and Early Childhood Caries: A Systematic Review and Meta-Analysis.

Objective: Candida is a common fungal pathogen in the oral cavity, with Candida albicans being the most prevalent species. Some studies report a correlation between Candida prevalence and dental caries experience in preschoolers, while others report no such association. This systematic review and meta-analysis aimed to evaluate the association of Candida-biome with Early Childhood Caries (ECC) in preschool children.

Expanding the genetic landscape of Usher syndrome type IV caused by pathogenic ARSG variants.

Usher syndrome (USH) is the most common cause of deafblindness. USH is autosomal recessively inherited and characterized by rod-cone dystrophy or retinitis pigmentosa (RP), often accompanied by sensorineural hearing loss. Variants in >15 genes have been identified as causative for clinically and genetically distinct subtypes.

The Prevalence of and in Preschool Children with Severe Early Childhood Caries: A Case-Control Study.

This cross-sectional study aimed to identify the prevalence of and in children with severe early childhood caries and caries-free children in Hong Kong. This study first recruited a total of 80 children aged between 48 and 72 months old, 40 children with severe early childhood caries, and 40 caries-free children. The children were then further divided into four groups, with 20 children in each group: Group 1: Severe early childhood caries-, Group 2: Severe early childhood caries-, Group 3: Caries-free- and Group 4: Caries-free-.

Ophthalmological and Neurological Findings in Patients with Idiopathic Uveitis Associated with Retinal Vasculitis and the Relation with the HLA DR15 Allele.

Purpose: In 15 patients with idiopathic uveitis associated with retinal vasculitis, HLA DRB1 gene testing was performed to detect a possible association. 11 patients tested positive and 4 negative for the HLA DRB1 × 15 allele. The presence of the HLA DRB1 × 15 haplotype might be associated with a higher susceptibility to develop Multiple Sclerosis (MS).

Comparison of clinical characteristics between ACOSOG Z0011-eligible cohort and sentinel lymph node-positive breast cancer patients in Hong Kong.

Introduction: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial resulted in de-escalation of axillary surgery among early-stage breast cancer patients with low-volume sentinel lymph node (SLN) disease undergoing breast-conserving surgery and radiation therapy. Nevertheless, the mastectomy rate in the Chinese population remains high. This study compared the clinical characteristics of the ACOSOG Z0011-eligible cohort with SLN-positive breast cancer patients in Hong Kong.

Diagnostic accuracy of contrast-enhanced CT versus PET/CT for advanced ovarian cancer staging: a comparative systematic review and meta-analysis.

Purpose: Accurate staging of ovarian cancer is critical to guide optimal management pathways. North American guidelines recommend contrast-enhanced CT as the primary work-up for staging ovarian cancer. This meta-analysis aims to compare the diagnostic accuracy of contrast-enhanced CT alone to PET/CT for detecting abdominal metastases in patients with a new or suspected diagnosis of ovarian cancer.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization.

Pregnancy-related breast cancer: 14-year experience in a tertiary institution in Hong Kong.

Background: The incidence of pregnancy-associated breast cancer (PABC) is increasing. Its tumor characteristics and overall survival compared with those in nonpregnant patients remain controversial. While there have been suggestions that PABC patients have a 40 % increase in the risk of death compared to non-pregnant patients, other studies suggested similar disease outcomes.

Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology.

Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid-liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue.

Comparison and summary of in silico prediction tools for CYP450-mediated drug metabolism.

The cytochrome P450 (CYP450) enzyme system is responsible for the metabolism of more than two-thirds of xenobiotics. This review summarizes reports of a series of in silico tools for CYP450 enzyme-drug interaction predictions, including the prediction of sites of metabolism (SOM) of a drug and the identification of inhibitor/substrates for CYP subtypes. We also evaluated four prediction tools to identify CYP inhibitors utilizing 52 of the most frequently prescribed drugs.

Knowledge, attitudes and intention on fertility preservation among breast cancer patients.

Breast cancer is the most common cancer in reproductive age women. The aim of this study is to assess the knowledge, attitude and intention on fertility preservation among women diagnosed to have breast cancer. This is a multi-centre cross-sectional questionnaire study.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time.

Unpolarized laser method for infrared spectrum calculation of amide I CO bonds in proteins using molecular dynamics simulation.

The investigation of the strong infrared (IR)-active amide I modes of peptides and proteins has received considerable attention because a wealth of detailed information on hydrogen bonding, dipole-dipole interactions, and the conformations of the peptide backbone can be derived from the amide I bands. The interpretation of experimental spectra typically requires substantial theoretical support, such as direct ab-initio molecular dynamics simulation or mixed quantum-classical description. However, considering the difficulties associated with these theoretical methods and their applications are limited in small peptides, it is highly desirable to develop a simple yet efficient approach for simulating the amide I modes of any large proteins in solution.

Use of Superparamagnetic Iron Oxide (SPIO) Versus Conventional Technique in Sentinel Lymph Node Detection for Breast Cancer: A Randomised Controlled Trial.

Background: The objective of this study is to compare the efficacy of the superparamagnetic iron oxide (SPIO)-guided and standard techniques for sentinel lymph node (SLN) detection in early breast cancer. Multiple inferiority trials have concluded the non-inferiority of SPIO to the conventional radioisotope technique, with or without blue dye, in detecting SLNs.

Patients And Methods: From July 2018 to August 2022, patients clinically diagnosed with node-negative invasive breast cancer were randomised into the study group (SPIO) and control group (radioisotope and blue dye).

Development and test of highly accurate endpoint free energy methods. 2: Prediction of logarithm of n-octanol-water partition coefficient (logP) for druglike molecules using MM-PBSA method.

The logarithm of n-octanol-water partition coefficient (logP) is frequently used as an indicator of lipophilicity in drug discovery, which has substantial impacts on the absorption, distribution, metabolism, excretion, and toxicity of a drug candidate. Considering that the experimental measurement of the property is costly and time-consuming, it is of great importance to develop reliable prediction models for logP. In this study, we developed a transfer free energy-based logP prediction model-FElogP.

Development and test of highly accurate endpoint free energy methods. 1: Evaluation of ABCG2 charge model on solvation free energy prediction and optimization of atom radii suitable for more accurate solvation free energy prediction by the PBSA method.

Accurate estimation of solvation free energy (SFE) lays the foundation for accurate prediction of binding free energy. The Poisson-Boltzmann (PB) or generalized Born (GB) combined with surface area (SA) continuum solvation method (PBSA and GBSA) have been widely used in SFE calculations because they can achieve good balance between accuracy and efficiency. However, the accuracy of these methods can be affected by several factors such as the charge models, polar and nonpolar SFE calculation methods and the atom radii used in the calculation.

Phosphorylation at Ser289 Enhances the Oligomerization of Tau Repeat R2.

In tauopathies such as Alzheimer's disease (AD), aberrant phosphorylation causes the dissociation of tau proteins from microtubules. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments and insoluble neurofibrillary tangles (NFTs). NFTs is a hallmark of AD, while oligomers are found to be the most toxic form of the tau aggregates.

Delayed Sentinel Lymph Node Dissection in Patients with a Preoperative Diagnosis of Ductal Cancer In Situ by Preoperative Injection with Superparamagnetic Iron Oxide (SPIO) Nanoparticles: The SentiNot Study.

Background: Difficulty in preoperatively assessing the risk for occult invasion or surgery that precludes future accurate axillary mapping in patients with ductal cancer in situ (DCIS) account for overutilization of SLND.

Methods: Prospective, multicenter, cohort study, including women with any DCIS planned for mastectomy or DCIS grade 2 and > 20 mm, any DCIS grade 3, any mass-forming DCIS and any planned surgery. Patients received an interstitial SPIO injection during breast surgery, but no upfront SLND was performed.

Phosphorylation of Tau R2 Repeat Destabilizes Its Binding to Microtubules: A Molecular Dynamics Simulation Study.

Phosphorylation, the most popular post-translational modification of tau protein, plays an important role in regulating tau physiological functions. However, aberrant phosphorylation attenuates the binding affinity of tau to a microtubule (MT), resulting in MT destabilization followed by accumulation of neurofibrillary tangles in the brain. There are in total 85 potential phosphorylation sites in a full-length tau protein, and about half of them are abnormal as they occur in tau of Alzheimer's disease (AD) brain only.

Investigation of the Structure of Full-Length Tau Proteins with Coarse-Grained and All-Atom Molecular Dynamics Simulations.

Tau proteins not only have many important biological functions but also are associated with several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease (AD). However, it is still a challenge to identify the atomic structure of full-length tau proteins due to their lengthy and disordered characteristics and the factor that there are no crystal structures of full-length tau proteins available. We performed multi- and large-scale molecular dynamics simulations of the full-length tau monomer (the 2N4R isoform and 441 residues) in aqueous solution under biological conditions with coarse-grained and all-atom force fields.

Molecular dynamics simulation of cancer cell membrane perforated by shockwave induced bubble collapse.

It has been widely accepted that cancer cells are softer than their normal counterparts. This motivates us to propose, as a proof-of-concept, a method for the efficient delivery of therapeutic agents into cancer cells, while normal cells are less affected. The basic idea of this method is to use a water jet generated by the collapse of the bubble under shockwaves to perforate pores in the cell membrane.