On-chip topological beamformer for multi-link terahertz 6G to XG wireless.

Terahertz (THz) wireless communication holds immense potential to revolutionize future 6G to XG networks with high capacity, low latency and extensive connectivity. Efficient THz beamformers are essential for energy-efficient connections, compensating path loss, optimizing resource usage and enhancing spectral efficiency. However, current beamformers face several challenges, including notable loss, limited bandwidth, constrained spatial coverage and poor integration with on-chip THz circuits. Here we present an on-chip broadband THz topological beamformer using valley vortices for waveguiding, splitting and perfect isolation in waveguide phased arrays, featuring 184 densely packed valley-locked waveguides, 54 power splitters and 136 sharp bends. Leveraging neural-network-assisted inverse design, the beamformer achieves complete 360° azimuthal beamforming with gains of up to 20 dBi, radiating THz signals into free space with customizable user-defined beams. Photoexciting the all-silicon beamformer enables reconfigurable control of THz beams. The low-loss and broadband beamformer enables a 72-Gbps chip-to-chip wireless link over 300 mm and eight simultaneous 40-Gbps wireless links. Using four of these links, we demonstrate point-to-4-point real-time HD video streaming. Our work provides a complementary metal-oxide-semiconductor-compatible THz topological photonic integrated circuit for efficient large-scale beamforming, enabling massive single-input multiple-output and multiple-input and multiple-output systems for terabit-per-second 6G to XG wireless communications.

Mnemonic But Not Contextual Feedback Signals Defy Dedifferentiation in the Aging Early Visual Cortex.

Perception is an intricate interplay between feedforward visual input and internally generated feedback signals that comprise concurrent contextual and time-distant mnemonic (episodic and semantic) information. Yet, an unresolved question is how the composition of feedback signals changes across the lifespan and to what extent feedback signals undergo age-related dedifferentiation, that is, a decline in neural specificity. Previous research on this topic has focused on feedforward perceptual representation and episodic memory reinstatement, suggesting reduced fidelity of neural representations at the item and category levels. In this fMRI study, we combined an occlusion paradigm that filters feedforward input to the visual cortex and multivariate analysis techniques to investigate the information content in cortical feedback, focusing on age-related differences in its composition. We further asked to what extent differentiation in feedback signals (in the occluded region) is correlated to differentiation in feedforward signals. Comparing younger (18-30 years) and older female and male adults (65-75 years), we found that contextual but not mnemonic feedback was prone to age-related dedifferentiation. Semantic feedback signals were even better differentiated in older adults, highlighting the growing importance of generalized knowledge across ages. We also found that differentiation in feedforward signals was correlated with differentiation in episodic but not semantic feedback signals. Our results provide evidence for age-related adjustments in the composition of feedback signals and underscore the importance of examining dedifferentiation in aging for both feedforward and feedback processing.

(2S,4S)-5-Fluoroleucine, (2S,4R)-5-Fluoroleucine, and 5,5'-Difluoroleucine in Escherichia coli PpiB: Protein Production, 19F NMR, and Ligand Sensing Enhanced by the γ-Gauche Effect.

Global substitution of leucine for analogues containing CH2F instead of methyl groups delivers proteins with multiple sites for monitoring by 19F nuclear magnetic resonance (NMR) spectroscopy. The 19 kDa Escherichia coli peptidyl-prolyl cis-trans isomerase B (PpiB) was prepared with uniform high-level substitution of leucine by (2S,4S)-5-fluoroleucine, (2S,4R)-5-fluoroleucine, or 5,5'-difluoroleucine. The stability of the samples toward thermal denaturation was little altered compared to the wild-type protein. 19F nuclear magnetic resonance (NMR) spectra showed large chemical shift dispersions between 6 and 17 ppm. The 19F chemical shifts correlate with the three-bond 1H-19F couplings (3JHF), providing the first experimental verification of the γ-gauche effect predicted by [Feeney, J. J. Am. Chem. Soc. 1996, 118, 8700-8706] and establishing the effect as the predominant determinant of the 19F chemical shifts of CH2F groups. Individual CH2F groups can be confined to single rotameric states by the protein environment, but most CH2F groups exchange between different rotamers at a rate that is fast on the NMR chemical shift scale. Interactions between fluorine atoms in 5,5'-difluoroleucine bias the CH2F rotamers in agreement with results obtained previously for 1,3-difluoropropane. The sensitivity of the 19F chemical shift to the rotameric state of the CH2F groups potentially renders them particularly sensitive for detecting allosteric effects.

Conformational Preferences of the Non-Canonical Amino Acids (2S,4S)-5-Fluoroleucine, (2S,4R)-5-Fluoroleucine, and 5,5'-Difluoroleucine in a Protein.

Proteins produced with leucine analogues, where CH2F groups substitute specific methyl groups, can readily be probed by 19F NMR spectroscopy. As CF and CH groups are similar in hydrophobicity and size, fluorinated leucines are expected to cause minimal structural perturbation, but the impact of fluorine on the rotational freedom of CH2F groups is unclear. We present high-resolution crystal structures of Escherichia coli peptidyl-prolyl cis-trans isomerase B (PpiB) prepared with uniform high-level substitution of leucine by (2S,4S)-5-fluoroleucine, (2S,4R)-5-fluoroleucine, or 5,5'-difluoroleucine. Apart from the fluorinated leucine residues, the structures show complete structural conservation of the protein backbone and the amino acid side chains except for a single isoleucine side chain located next to a fluorine atom in the hydrophobic core of the protein. The carbon skeletons of the fluorinated leucine side chains are also mostly conserved. The CH2F groups show a strong preference for staggered rotamers and often appear locked into single rotamers. Substitution of leucine CH3 groups for CH2F groups is thus readily tolerated in the three-dimensional (3D) structure of a protein, and the rotation of CH2F groups can be halted at cryogenic temperatures.

Proinflammatory CD14highCD16low monocytes/macrophages prevail in Treponema phagedenis-associated bovine digital dermatitis.

Digital dermatitis (DD) is a skin disease in cattle characterized by painful inflammatory ulcerative lesions in the feet, mostly associated with local colonization by Treponema spp., including Treponema phagedenis. The reason why most DD lesions remain actively inflamed and progress to chronic conditions despite antibiotic treatment remains unknown. Herein, we show an abundant infiltration of proinflammatory (CD14highCD16low) monocytes/macrophages in active DD lesions, a skin response that was not mitigated by topical treatment with oxytetracycline. The associated bacterium, T. phagedenis, isolated from DD lesions in cattle, when injected subcutaneously into mice, induced abscesses with a local recruitment of Ly6G+ neutrophils and proinflammatory (Ly6ChighCCR2+) monocytes/macrophages, which appeared at infection onset (4 days post challenge) and persisted for at least 7 days post challenge. When exploring the ability of macrophages to regulate inflammation, we showed that bovine blood-derived macrophages challenged with live T. phagedenis or its structural components secreted IL-1ß via a mechanism dependent on the NLRP3 inflammasome. This study shows that proinflammatory characteristics of monocytes/macrophages and neutrophils dominate active non-healing ulcerative lesions in active DD, thus likely impeding wound healing after antibiotic treatment.

Proteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles.

The evolving use of covalent ligands as chemical probes and therapeutic agents could greatly benefit from an expanded array of cysteine-reactive electrophiles for efficient and versatile proteome profiling. Herein, to expand the current repertoire of cysteine-reactive electrophiles, we developed a new class of strain-enabled electrophiles based on cyclopropanes. Proteome profiling has unveiled that C163 of lactate dehydrogenase A (LDHA) and C88 of adhesion regulating molecule 1 (ADRM1) are ligandable residues to modulate the protein functions. Moreover, fragment-based ligand discovery (FBLD) has revealed that one fragment (Y-35) shows strong reactivity toward C66 of thioredoxin domain-containing protein 12 (TXD12), and its covalent binding has been demonstrated to impact its downstream signal pathways. TXD12 plays a pivotal role in enabling Y-35 to exhibit its antisurvival and antiproliferative effects. Finally, dicarbonitrile-cyclopropane has been demonstrated to be an electrophilic warhead in the development of GSTO1-involved dual covalent inhibitors, which is promising to alleviate drug resistance.

Highly Crystalline Iridium-Nickel Nanocages with Subnanopores for Acidic Bifunctional Water Splitting Electrolysis.

Developing efficient bifunctional materials is highly desirable for overall proton membrane water splitting. However, the design of iridium materials with high overall acidic water splitting activity and durability, as well as an in-depth understanding of the catalytic mechanism, is challenging. Herein, we successfully developed subnanoporous Ir3Ni ultrathin nanocages with high crystallinity as bifunctional materials for acidic water splitting. The subnanoporous shell enables Ir3Ni NCs optimized exposure of active sites. Importantly, the nickel incorporation contributes to the favorable thermodynamics of the electrocatalysis of the OER after surface reconstruction and optimized hydrogen adsorption free energy in HER electrocatalysis, which induce enhanced intrinsic activity of the acidic oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Together, the Ir3Ni nanocages achieve 3.72 A/mgIr(η=350 mV) and 4.47 A/mgIr(η=40 mV) OER and HER mass activity, which are 18.8 times and 3.3 times higher than that of commercial IrO2 and Pt, respectively. In addition, their highly crystalline identity ensures a robust nanostructure, enabling good catalytic durability during the oxygen evolution reaction after surface oxidation. This work provides a new revenue toward the structural design and insightful understanding of metal alloy catalytic mechanisms for the bifunctional acidic water splitting electrocatalysis.

MXene-Derived Na+ -Pillared Vanadate Cathodes for Dendrite-Free Potassium Metal Batteries.

Cation-intercalated vanadates, which have considerable promise as the cathode for high-performance potassium metal batteries (PMBs), suffer from structural collapse upon K+ insertion and desertion. Exotic cations in the vanadate cathode may ease the collapse, yet their effect on the intrinsic cation remains speculative. Herein, a stable and dendrite-free PMB, composed of a Na+ and K+ co-intercalated vanadate (NKVO) cathode and a liquid NaK alloy anode, is presented. A series of NKVO with tuneable Na/K ratios are facilely prepared using MXene precursors, in which Na+ is testified to be immobilized upon cycling, functioning as a structural pillar. Due to stronger ionic bonding and lower Fermi level of Na+ compared to K+ , moderate Na+ intercalation could reduce K+ binding to the solvation sheath and favor K+ diffusion kinetics. As a result, the MXene-derived Na+ -pillared NKVO exhibits markedly improved specific capacities, rate performance, and cycle stability than the Na+ -free counterpart. Moreover, thermally-treated carbon paper, which imitates the microscopic structure of Chinese Xuan paper, allows high surface tension liquid NaK alloy to adhere readily, enabling dendrite-free metal anodes. By clarifying the role of foreign intercalating cations, this study may lead to a more rational design of stable and high-performance electrode materials.

Influence of Sex on Respiratory Syncytial Virus Genotype Infection Frequency and Nasopharyngeal Microbiome.

Respiratory syncytial virus (RSV) has a significant health burden in children, older adults, and the immunocompromised. However, limited effort has been made to identify emergence of new RSV genotypes' frequency of infection and how the combination of nasopharyngeal microbiome and viral genotypes impact RSV disease outcomes. In an observational cohort designed to capture the first infant RSV infection, we employed multi-omics approaches to sequence 349 RSV complete genomes and matched nasopharyngeal microbiomes, during which the 2012/2013 season was dominated by RSV-A, whereas 2013 and 2014 was dominated by RSV-B. We found non-G-72nt-duplicated RSV-A strains were more frequent in male infants (P = 0.02), whereas G-72nt-duplicated genotypes (which is ON1 lineage) were seen equally in both males and females. DESeq2 testing of the nasal microbiome showed Haemophilus was significantly more abundant in infants with RSV-A infection compared to infants with RSV-B infection (adjusted P = 0.002). In addition, the broad microbial clustering of the abundant genera was significantly associated with infant sex (P = 0.03). Overall, we show sex differences in infection by RSV genotype and host nasopharyngeal microbiome, suggesting an interaction between host genetics, virus genotype, and associated nasopharyngeal microbiome. IMPORTANCE Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infections in young children and is responsible for high hospitalization rates and morbidity in infants and the elderly. To understand how the emergence of RSV viral genotypes and viral-respiratory microbiome interactions contribute to infection frequency and severity, we utilized an observational cohort designed to capture the first infant RSV infection we employed multi-omics approaches to sequence 349 RSV complete genomes and matched nasopharyngeal microbiomes. We found non-G-72nt-duplicated RSV-A genotypes were more frequent in male infants, whereas G-72nt-duplicated RSV-A strains (ON1 lineage) were seen equally in both males and females. Microbiome analysis show Haemophilus was significantly more abundant in infants with RSV-A compared to infants with RSV-B infection and the microbial clustering of the abundant genera was associated with infant sex. Overall, we show sex differences in RSV genotype-nasopharyngeal microbiome, suggesting an interaction host genetics-virus-microbiome interaction.

Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.

BACKGROUND: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations. OBJECTIVES: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients. METHODS: Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients. RESULTS: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN. CONCLUSIONS: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.

Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial. METHODS: Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated. RESULTS: APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice. CONCLUSION: Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

Direct and Indirect Mapping of AQoL-6D onto EQ-5D-5L Utilities Using Data from a Multi-centre, Cross-Sectional Study of Malaysians with Chronic Heart Failure.

OBJECTIVE: The AQoL-6D, a generic preference-based measure, is an appealing alternative to EQ-5D-5L for assessing health status in patients with chronic heart failure (HF), given its expanded scope. However, without a Malaysian value set, the AQoL-6D cannot generate health state utility values (HSUVs) to support local economic evaluations. This study intended to develop algorithms for predicting EQ-5D-5L HSUVs from AQoL-6D in an HF population. METHODS: Cross-sectional data from a multi-centre cohort of 419 HF outpatients were used. Both direct and indirect mapping approaches were attempted using five sets of explanatory variables and 8 models (ordinary least squares, Tobit, censored least absolute deviations, generalised linear model, two-part model [TPM], beta regression-based model, adjusted limited dependent variable mixture model, and multinomial ordinal regression [MLOGIT]). The models' predictive performance was assessed through ten-fold cross-validated mean absolute error [MAE] and root mean squared error [RMSE]). Potential prediction bias was also examined graphically. The best-performing models, with the lowest RMSE and no bias, were then identified. RESULTS: Among the models evaluated, TPM, which included age, sex, and five AQoL-6D dimension scores as predictors, appears to be the best-performing model for directly predicting EQ-5D-5L HSUVs from AQoL-6D. TPM yielded the lowest MAE (0.0802) and RMSE (0.1116), and demonstrated predictive accuracy for HSUVs >0.2 without significant bias. A MLOGIT model developed for response mapping had suboptimal predictive accuracy. CONCLUSION: This study developed potentially useful mapping algorithms for generating Malaysian EQ-5D-5L HSUVs from AQoL-6D responses among patients with HF when direct EQ-5D-5L data is unavailable.

Cinnamic Acid: A Low-Toxicity Natural Bidentate Ligand for Uranium Decorporation.

Uranium accumulation in the kidneys and bones following internal contamination results in severe damage, emphasizing the pressing need for the discovery of actinide decorporation agents with efficient removal of uranium and low toxicity. In this work, cinnamic acid (3-phenyl-2-propenoic acid, CD), a natural aromatic carboxylic acid, is investigated as a potential uranium decorporation ligand. CD demonstrates markedly lower cytotoxicity than that of diethylenetriaminepentaacetic acid (DTPA), an actinide decorporation agent approved by the FDA, and effectively removes approximately 44.5% of uranyl from NRK-52E cells. More importantly, the results of the prompt administration of the CD solution remove 48.2 and 27.3% of uranyl from the kidneys and femurs of mice, respectively. Assessments of serum renal function reveal the potential of CD to ameliorate uranyl-induced renal injury. Furthermore, the single crystal of CD and uranyl compound (C9H7O2)2·UO2 (denoted as UO2-CD) reveals the formation of uranyl dimers as secondary building units. Thermodynamic analysis of the solution shows that CD coordinates with uranyl to form a 2:1 molar ratio complex at a physiological pH of 7.4. Density functional theory (DFT) calculations further show that CD exhibits a significant 7-fold heightened affinity for uranyl binding in comparison to DTPA.

Intrinsic Peroxidase-like Activity of Polystyrene Nanoplastics Mediates Oxidative Stress.

Nanoplastics represent a global environmental concern due to their ubiquitous presence and potential adverse impacts on public and environmental health. There is a growing need to advance the mechanistic understanding of their reactivity as they interact with biological and environmental systems. Herein, for the first time, we report that polystyrene nanoplastics (PSNPs) have intrinsic peroxidase-like activity and are able to mediate oxidative stress. The peroxidase-like activity is dependent on temperature and pH, with a maximum at pH 4.5 and 40 °C. The catalytic activity exhibits saturation kinetics, as described by the Michaelis-Menten model. The peroxidase-like activity of PSNPs is attributed to their ability to mediate electron transfer from peroxidase substrates to H2O2. Ozone-induced PSNP aging can introduce oxygen-containing groups and disrupt aromatic structures on the nanoplastic surface. While ozonation initially enhances peroxidase-like activity by increasing oxygen-containing groups without degrading many aromatic structures, extended ozonation destroys aromatic structures, significantly reducing this activity. The peroxidase-like activity of PSNPs can mediate oxidative stress, which is generally positively correlated with their aromatic structures, as suggested by the ascorbic acid assay. These results help explain the reported oxidative stress exerted by nanoplastics and provide novel insights into their environmental and public health implications.

Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia.

Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 µM, respectively.

Chemokines and Their Receptors: Predictors of Therapeutic Potential in Tumor Microenvironment on Esophageal Cancer.

Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.

Examining health-related quality of life in ambulatory adult patients with chronic heart failure: insights from Malaysia using EQ-5D-5L.

PURPOSE: Health-related quality-of-life (HRQoL) data for the chronic heart failure (HF) population in Malaysia are lacking. Using EQ-5D-5L, this study intended to describe their HRQoL, identify predictors of worse HRQoL, and derive EQ-5D-5L index scores for use in economic evaluations. METHODS: A cross-sectional survey was conducted between April and September 2023 to collect EQ-5D-5L, sociodemographic, and clinical data from outpatients with HF across seven public specialist hospitals in Malaysia. Multivariable logistic and linear regression models were used to identify independent predictors of reported problems in the EQ-5D-5L dimensions, and predictors of index scores and EQ-VAS, respectively. RESULTS: EQ-5D-5L data from 424 outpatients of multi-ethnic background (mean age: 57.1 years, 23.8% female, mean left ventricular ejection fraction: 35.7%, 89.7% NYHA class I-II) were collected using either Malay, English, or Chinese, achieving a 99.8% completion rate. Nearly half of the respondents reported issues in the Mobility, Usual Activities, and Pain/Discomfort dimensions. Mean EQ-5D-5L index was 0.820, lower than the general population, and significantly lower with NYHA class III-IV (0.747) versus NYHA class I (0.846) and NYHA class II (0.805). Besides NYHA class, independent predictors of worse HRQoL included Indian ethnicity, living alone, lower education, unemployment due to ill-health, and proxy-reported HRQoL, largely aligning with existing literature. CONCLUSION: Community-dwelling Malaysians with HF reported poorer HRQoL compared to the general population. The observed disparities in HRQoL among HF patients may be linked to specific patient characteristics, suggesting potential areas for targeted interventions. HRQoL assessment using EQ-5D-5L proves feasible and should be considered for routine implementation in local clinics.

Young osteocyte-derived extracellular vesicles facilitate osteogenesis by transferring tropomyosin-1.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. RESULTS: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. CONCLUSIONS: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis.

MUC4 O-GlcNAcylation Regulates the Epithelial Phenotype in Conjunctival Epithelial Cells.

In the present study, our aim was to explore the role of MUC4 in IL-4-stimulated conjunctival epithelial cells and the underlying mechanisms. Human recombinant IL-4 was employed in human conjunctival epithelial cells (HConEpic) cells, and MUC4 shRNA (sh-MUC4) was constructed to explore the functional role of MUC4. The protein level of MUC4, O-GlcNAc transferase (OGT), O-GlcNAc hydrolase (OGA), zonula occludens 1 (ZO-1), gap junction protein beta 2 (GJB2), claudin-8 (CLDN8), and E-cadherin were detected by Western blot in HConEpic cells, the interaction between MUC4 and OGT/OGA was assessed by co-immunoprecipitation (IP) and Western blot in 293T cells. Our results showed that IL-4 significantly up-regulated MUC4 and OGT protein levels in HConEpic cells, while down-regulated OGA protein level. Also, IL-4 down-regulated ZO-1, GJB2, CLDN8, and E-cadherin protein levels in HConEpic cells, while which was markedly reversed by sh-MUC4. Additionally, OGT inhibitor significantly reduced MUC4 protein level, and elevated ZO-1, GJB2, CLDN8, and E-cadherin protein levels in HConEpic cells, while OGA inhibitor resulted in the opposite results. Furthermore, in addition to the interaction between OGT/OGA and MUC4, Co-IP and Western blot also revealed the alteration of MUC4 O-GlcNAcylation in 293T cells treated with OGT/OGA inhibitor. Above findings suggested that OGT/OGA inhibitor regulated MUC4 protein level by affecting MUC4 O-GlcNAcylation to regulate ZO-1, GJB2, CLDN8, and E-cadherin protein levels in HConEpic cells, which was achieved via inhibiting the interaction between OGT/OGA and MUC4. This study may provide a better understanding of the pathogenesis of allergic conjunctivitis (AC).

Mechanism through which the hsa-circ_0000992- hsa- miR- 936-AKT3 regulatory network promotes the PM2.5-induced inflammatory response in human bronchial epithelial cells.

BACKGROUND: Studies have shown that fine particulate matter (PM2.5) remains a significant problem in developing countries and plays a critical role in the onset and progression of respiratory illnesses. Circular RNAs (circRNAs) are involved in many pathophysiological processes,but their relationship to PM2.5 pollution is largely unexplored. OBJECTIVES: To elucidate the functional role of hsa_circ_0000992 in PM2.5-induced inflammation in a human bronchial epithelial cell line (16HBE) and to clarify whether the competing endogenous RNA (ceRNA) mechanism is involved in the interrelationships between hsa_circ_0000992 and hsa-miR-936 and the inflammatory signaling pathways. METHODS: Detection of inflammatory factors in 16HBE cells exposed to PM2.5 by RT-qPCR and ELISA.High throughput sequencing and bioinformatics analysis methods were used to screen circRNA.The bioinformatics analysis method western blotting and dual-luciferase reporter gene system were used to verify mechanisms associated with circRNA. RESULTS: PM2.5 cause inflammation in the 16HBE cells. High throughput sequencing and RT-qPCR result revealed that the expression of hsa_circ_0000992 was markedly up-regulated in 16HBE exposed to PM2.5. The binding sites between hsa_circ_0000992 and hsa-miR-936 was confirmed by dual-luciferase reporter gene system.Western blotting and RT-qPCR showed that hsa_circ_0000992 can interact with hsa-miR-936 to regulate AKT serine/threonine kinase 3(AKT3),thereby activating the PI3K/AKT pathway and ultimately promoting the expression of interleukin (IL)- 1ß and IL-8. CONCLUSION: PM2.5 can induce the inflammatory response in 16HBE cells by activating the PI3K/AKT pathway. The expression of hsa_circ_0000992 increased when PM2.5 stimulated 16HBE cells,and the circRNA could then regulate the inflammatory response.Hsa_circ_0000992 regulates the hsa-miR-936/AKT3 axis through the ceRNA mechanism,thereby activating the PI3K/AKT signaling pathway,increasing the expression of cellular inflammatory factors,and promoting PM2.5-induced respiratory inflammation.