Frailty Trajectories and Social Determinants of Health of Older Adults in Rural and Urban Areas in the U.S.

Older adults, aged 65 years and older, develop and experience frailty at different rates. Yet, this heterogeneity is not well understood, nor are the factors, such as geographical residence, that influence different frailty trajectories and subsequent healthcare outcomes. We aim to identify factors that impact older adult frailty trajectories, skilled nursing facility (SNF) placement, and death.

Combining multiple high-resolution in-situ techniques to understand the metals mobilization at anoxic-oxic interfaces in flooded industrial soils.

Industrial sites in coastal cities experience fluctuating redox conditions driven by climate change, forming anoxic-oxic interfaces and influencing the availability of heavy metals (HMs). What remains elusive is how oxygen contents influence the formation of anoxic-oxic interfaces and HMs mobilization in industrial soils with varying physicochemical properties. Here we investigated the mobilization mechanisms of HMs (Fe, Mn, Cu, Ni, and Zn) at anoxic-oxic interfaces in different depths soils at a historical industrial site using high-resolution in-situ techniques, including planar optodes (PO) and diffusive gradients in thin-films (DGT).

Unraveling the Efficacy of AR Antagonists Bearing -(4-(Benzyloxy)phenyl)piperidine-1-sulfonamide Scaffold in Prostate Cancer Therapy by Targeting LBP Mutations.

Point mutations in the androgen receptor (AR) are significant drivers of resistance in prostate cancer (PCa), posing a great challenge to the development of effective treatment strategies. Building on our previous discovery of the suboptimal AR antagonist , we developed , which contains an -(4-(benzyloxy)phenyl)piperidine-1-sulfonamide scaffold through structural optimization and comprehensive screening against T878A-mutated AR. outperformed existing antiandrogens by fully antagonizing clinical AR mutations and effectively suppressing castration- and enzalutamide-resistant LNCaP cells proliferation .

Proteomic study of plasma and L1CAM-captured exosomal proteins in children with autism spectrum disorders.

Autism spectrum disorder (ASD) has become a neurodevelopmental disorder that seriously endangers the health of infants and children. In order to explore the pathogenesis of the disease and search for early diagnostic biomarkers. In this study, plasma exosomes (PEs) and neural cell adhesion molecule L1 (L1CAM)-captured exosomes (LCEs) of ASD and controls were extracted and lysed to obtain proteins.

Inherent fast inactivation particle of Nav channels as a new binding site for a neurotoxin.

Neurotoxins derived from animal venoms are indispensable tools for probing the structure and function of voltage-gated sodium (Nav) channels. Utilizing a novel centipede peptide toxin called rpTx1, we show that the "inherent inactivation particle" of Nav channels represents a binding site for a neurotoxin. The toxin comprises two functional domains: one for cell penetration and one for modulating Nav channel activity.

A discrete-time split-state framework for multi-state modeling with application to describing the course of heart disease.

In chronic disease epidemiology, the investigation of disease etiology has largely focused on an endpoint, while the course of chronic disease is understudied, representing a knowledge gap. Multi-state models can be used to describe the course of chronic disease, such as Markov models which assume that the future state depends only on the present state, and semi-Markov models which allow transition rates to depend on the duration in the current state. However, these models are unsuitable for chronic diseases that are largely non-memoryless.

Discovery of Novel Na1.7-Selective Inhibitors with the 1-Indole-3-Propionamide Scaffold for Effective Pain Relief.

Na1.7 is considered a promising target for developing next-generation analgesic drugs, given its critical role in human pain pathologies. Although most reported inhibitors with strong in vitro activity and high selectivity share the aryl sulfonamide scaffold, they failed to demonstrate marked clinical efficacy.

Migration and availability of Ni and Cd in industrial soils under different leaching conditions: Insights from DGT and DIFS models.

Rainfall runoff can mobilize heavy metals in industrial soils, posing environmental risks. The mobility and distribution of heavy metals in different industrial soil layers are often overlooked. This study employed dynamic leaching experiments in layered soil columns with DGT (the diffusive gradients in thin films) measurements and DIFS (DGT-induced fluxes in soils and sediments) model to describe the migration, availability, and resupply ability of metals at different depths in surface and deep soil columns of industrial soils.

Effects of nZVI on the migration and availability of Cr(VI) in soils under simulated acid rain leaching conditions.

Hexavalent chromium, Cr(VI), is a ubiquitous toxic metal that can be reduced to Cr(III) by nano-zero-valent iron (nZVI). Finding out effects of continuous rainfall leaching on the Cr(VI) release and availability remains a problem, needing to be addressed. Whether the Cr(VI) reduction by nZVI and continuous rainfall leaching lead to localized heterogeneity in soil is unclear.

A Multi-state Non-Markov Framework to Estimate Progression of Chronic Disease.

In chronic disease epidemiology, investigation of disease etiology has largely focused on one single endpoint, and progression of chronic disease as a multi-state process is understudied, representing a knowledge gap. Most of existing multi-state regression models require Markov assumption and are unsuitable to estimate progression of chronic diseases that is largely non-memoryless. We propose a new non-Markov framework that allows past states to affect transition rates of current states.

Discovery of Novel Anti-Resistance AR Antagonists Guided by Funnel Metadynamics Simulation.

Androgen receptor (AR) antagonists are widely used for the treatment of prostate cancer (PCa), but their therapeutic efficacy is usually compromised by the rapid emergence of drug resistance. However, the lack of the detailed interaction between AR and its antagonists poses a major obstacle to the design of novel AR antagonists. Here, funnel metadynamics is employed to elucidate the inherent regulation mechanisms of three AR antagonists (hydroxyflutamide, enzalutamide, and darolutamide) on AR.

On the Dynamic Mechanism of Long-Flexible Fatty Acid Binding to Fatty Acid Binding Protein: Resolving the Long-Standing Debate.

Fatty acids (FAs) are one of the essential energy sources for physiological processes, and they play a vital role in regulating immune and inflammatory responses, promoting cell differentiation and apoptosis, and inhibiting tumor growth. These functions are carried out by FA binding proteins (FABPs) that recognize and transport FAs. Although the crystal structure of the FA-FABPs complex has long been characterized, the mechanism behind FA binding and dissociation from FABP remains unclear.

Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model.

Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2.

A Novel In Situ Method for Simultaneously and Selectively Measuring As, Sb, and Se in Freshwater and Soils.

Anthropogenic and climatic perturbations redistribute arsenic (As), antimony (Sb), and selenium (Se) within the environment. The speciation characteristics of these elements determine their behavior and biogeochemical cycling, but these redox-sensitive species are challenging to capture, with few methods able to harmonize measurements across the whole plant-soil-ecosystem continuum. In this study, we developed a novel diffusive gradient in thin films (DGT) method based on aminopropyl and mercaptopropyl bi-functionalized mesoporous silica spheres (AMBS) to achieve in-situ, simultaneous, and selective quantification of As, Sb, and Se, three typical/toxic but difficult to measure inorganic species.

Validation and Assessment of Diffusive Gradients in Thin-Films (DGT) Technique for Measuring Nutrients in Taihu Lake Water with Algae Bloom.

DGT (diffusive gradients in thin films) technique has been developed for measuring nitrogen in freshwaters and applied to assess the bioavailability of phosphorus in soils/sediments. These two elements are the main nutrients causing algae bloom, but DGT has never been used in the field water conditions with algae bloom. In our study, a pair of DGT devices were used in comparison with grab sampling to characterize the performance of this technique to measure labile NO-N, NH-N, and PO-P concentrations in algae-cultivated Taihu Lake water.

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis.

Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function-2 through the residues Phe737 and Gln738.

Molecular View on the Dissociation Pathways and Transactivation Regulation Mechanism of Nonsteroidal GR Ligands.

As a major drug target for anti-inflammatory therapy, the glucocorticoid receptor (GR) regulates a wide range of physiological processes through transactivation (TA) or transrepression. GR TA is involved in many adverse effects of GR-targeting drugs, and therefore, the discovery of novel GR ligands with lower TA activity and longer residence time is quite urgent. Undoubtedly, understanding the ligand dissociation mechanisms and the structural basis of the TA regulation is crucial for the development of novel GR-targeting drugs.

Pterostilbene inhibits hepatocellular carcinoma proliferation and HBV replication by targeting ribonucleotide reductase M2 protein.

Hepatocellular carcinoma (HCC), one of the most deadly diseases all around the world. HBV infection is a causative factor of HCC and closely associated with HCC development. Ribonucleotide reductase (RR) is a key enzyme for cellular DNA synthesis and RR small subunit M2 (RRM2) is highly upregulated in HCC with poor survival rates.

Regulation Mechanism for the Binding between the SARS-CoV-2 Spike Protein and Host Angiotensin-Converting Enzyme II.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is mainly mediated through the interaction between the spike protein (S-pro) of the virus and the host angiotensin-converting enzyme II (ACE2). The attachment of heparan sulfate (HS) to S-pro is necessary for its binding to ACE2. In this study, the binding process of the receptor-binding domain (RBD) of S-pro to ACE2 was explored by enhanced sampling simulations.

The MCR-3 inside linker appears as a facilitator of colistin resistance.

An evolving family of mobile colistin resistance (MCR) enzymes is threatening public health. However, the molecular mechanism by which the MCR enzyme as a rare member of lipid A-phosphoethanolamine (PEA) transferases gains the ability to confer phenotypic colistin resistance remains enigmatic. Here, we report an unusual example that genetic duplication and amplification produce a functional variant (Ah762) of MCR-3 in certain Aeromonas species.

Assessing the potential availability of selenium in the soil-plant system with manure application using diffusive gradients in thin-films technique (DGT) and DOM-Se fractions extracted by selective extractions.

Knowledge of the Se fractionation and the role of dissolved organic matter (DOM) in soil is the key to understanding Se mobility and its bioavailability in the soil-plant system. In this study, single extractions using phosphate-buffer (PBS), sequential extraction procedures (SEP), and diffusive gradients in thin-films (DGT) were used to measure Se bioavailability in soil supplemented with selenite and organic amendment (cow and chicken manures). Selenium fraction was isolated into DOM-Se fractions, such as hydrophilic acid-bound Se (HY-Se), fulvic acid-bound Se (FA-Se), humic acid-bound Se (HA-Se), and hydrophobic organic neutral-bound Se (HON-Se), by a rapid batch technique using XAD-8 resin (AMBERLITE XAD™, USA).

The inflammatory cytokine IL-6 induces FRA1 deacetylation promoting colorectal cancer stem-like properties.

Colorectal cancer (CRC) has long been known for its tight association with chronic inflammation, thought to play a key role in tumor onset and malignant progression through the modulation of cancer stemness. However, the underlying molecular and cellular mechanisms are still largely elusive. Here we show that the IL-6/STAT3 inflammatory signaling axis induces the deacetylation of FRA1 at the Lys-116 residue located within its DNA-binding domain.

Reliability of Docking-Based Virtual Screening for GPCR Ligands with Homology Modeled Structures: A Case Study of the Angiotensin II Type I Receptor.

The number of solved G-protein-coupled receptor (GPCR) crystal structures has expanded rapidly, but most GPCR structures remain unsolved. Therefore, computational techniques, such as homology modeling, have been widely used to produce the theoretical structures of various GPCRs for structure-based drug design (SBDD). Due to the low sequence similarity shared by the transmembrane domains of GPCRs, accurate prediction of GPCR structures by homology modeling is quite challenging.