Clinical and laboratory characteristics of asymptomatic and symptomatic neurosyphilis in HIV-infected patients: A retrospective study in China.

There are high rates of human immunodeficiency virus (HIV) and Treponema pallidum coinfection, HIV can increase the incidence and disability rate of neurosyphilis. However, there is a lack of data about the risk factors associated with the development of symptomatic neurosyphilis (SNS). We retrospectively reviewed the medical records of inpatients with concurrent syphilis and HIV infection who underwent a lumbar puncture and completed cerebrospinal fluid (CSF) examination. Sixty inpatients were consecutively enrolled from Beijing Ditan Hospital between January 2015 and March 2023. The clinical and laboratory features were evaluated between the SNS and asymptomatic neurosyphilis (ANS) groups. All patients were male, 25% (15/60) patients were diagnosed with ANS, and 75% (45/60) patients were diagnosed with SNS. Meningovascular neurosyphilis was the most prevalent clinical form in this study. Age, CD4 cell count, highly active antiretroviral therapy use, and serum HIV viral load showed no statistically significant differences between the 2 groups. The SNS group lacked early detection of syphilis (P < .001) and did not get previous adequate therapy for syphilis (P < .001) than the ANS group, as well as a higher initial serum toluidine red unheated serum test (TRUST) titer, current serum TRUST titer, CSF white blood cell count (WBC), protein concentration, and CSF TRUST titer (P = .014, P = .042, P = .01, P = .007, and P = .007, respectively). In multivariable logistic regression, high CSF WBC count (odds ratio = 1.08; P = .032) and previous treatment of syphilis (odds ratio = 0.01; P = .049) related to the SNS. Lack of antisyphilis treatment in the early stage of syphilis and a higher CSF WBC count are related risk factors for SNS in HIV-infected patients. Meningovascular neurosyphilis should get more attention in young patients with cryptogenic stroke.

Adsorption and C-C bond cleavage of benzene on hematite α-Fe2O3 surfaces: a DFT mechanistic study.

Reforming tar molecules into smaller gaseous molecules has been a critical challenge for biomass energy utilization. Hematite (α-Fe2O3) has been demonstrated as an effective catalyst for the catalytic reforming of tar, nevertheless, the detailed mechanism of α-Fe2O3 catalyzed tar reforming remains unclear. In this work, we apply the density functional theory method to investigate this problem. Specifically, we study both (0001) and (01[Formula: see text]2) surface structures of α-Fe2O3 and then use the structures to investigate the adsorption and C-C bond cleavage of benzene on these surfaces. Our results show that the dominant interactions between benzene and a single Fe-terminated (0001) surface are van der Waals forces, yet benzene could be chemisorbed on the Fe and O co-exposed (01[Formula: see text]2) surface via strong C-O interactions. As a result, the (0001) surface is not active towards benzene cleavage, whereas the (01[Formula: see text]2) surface can promote the aromatic C-C bond breaking. Furthermore, our calculations indicate that chain-like alkene species and carbonyl species are the two types of potential products that form after the C-C bond cleavage of benzene on the α-Fe2O3 (01[Formula: see text]2) surface, with the activation energy of 1.78 eV and 2.62 eV, respectively. In summary, we reveal the importance of co-adsorption on both Fe and O centers and oxidative addition on C-C bond cleavage of aromatic compounds on the α-Fe2O3 surface, which provides novel insights into the mechanisms of tar cracking on oxide catalysts.

Lumican promotes calcific aortic valve disease through H3 histone lactylation.

BACKGROUND AND AIMS: Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. METHODS: Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro, ex vivo, in vivo, and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. RESULTS: ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro, ex vivo, in vivo level, and ApoE-/-//LUM-/- double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. CONCLUSIONS: The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD.

Characteristic Profiling of Soluble Factors in the Cerebrospinal Fluid of Patients With Neurosyphilis.

BACKGROUND: Soluble inflammatory factors in the cerebrospinal fluid (CSF) of patients with neurosyphilis have been investigated with low-throughput technology. This study aimed to illustrate the characteristics of soluble factor profiles in CSF of patients with neurosyphilis. METHODS: We measured the concentrations of 45 cytokines, chemokines, and growth factors in CSF from 112 untreated syphilis cases, including latent syphilis (LS), asymptomatic neurosyphilis (ANS), meningeal neurosyphilis (MNS), meningovascular neurosyphilis (MVNS), paralytic dementia (PD), and ocular syphilis (OS). RESULTS: Thirty-three differentially expressed soluble factors (DeSFs) were categorized into 3 clusters. DeSF scores of clusters 1 and 2 (DeSFS1 and DeSFS2) were positively correlated with elevated neopterin and neurofilament light subunit (NF-L) concentration, respectively. DeSF scores of cluster 3 were positively correlated with white blood cells, protein, NF-L, and neopterin. Patients with LS, ANS, and OS exhibited an overall lower abundance of DeSFs. Patients with PD exhibited significantly increased levels of clusters 1 and 3, and the highest total DeSF score, whereas patients with MNS and MVNS showed enhanced levels of cluster 2. Receiver operating characteristic analysis revealed that DeSFS1 effectively discriminated PD, and DeSFS2 discriminated MNS/MVNS with high accuracy. CONCLUSIONS: Patients with neurosyphilis at different stages have distinctive patterns of soluble factors in CSF, which are correlated with immune status and neuronal damage.

Multiple Parameter Replica Exchange Gaussian Accelerated Molecular Dynamics for Enhanced Sampling and Free Energy Calculation of Biomolecular Systems.

This study introduces a novel method named multiple parameter replica exchange Gaussian accelerated molecular dynamics (MP-Rex-GaMD), building on the Gaussian accelerated molecular dynamics (GaMD) algorithm. GaMD enhances sampling and retrieves free energy information for biomolecular systems by adding a harmonic boost potential to smooth the potential energy surface without the need for predefined reaction coordinates. Our innovative approach advances the acceleration power and energetic reweighting accuracy of GaMD by incorporating a replica exchange algorithm that enables the exchange of multiple parameters, including the GaMD boost parameters of force constant and energy threshold, as well as temperature. Applying MP-Rex-GaMD to the three model systems of dialanine, chignolin, and HIV protease, we demonstrate its superior capability over conventional molecular dynamics and GaMD simulations in exploring protein conformations and effectively navigating various biomolecular states across energy barriers. MP-Rex-GaMD allows users to accurately map free energy landscapes through energetic reweighting, capturing the ensemble of biomolecular states from low-energy conformations to rare high-energy transitions within practical computational time scales.

Socioeconomic support, quality of life, and prognosis of frailty among the older adults.

Background: Although socioeconomic support is recommended for frailty management, its association with the prognosis of frailty is unclear. Methods: Using data from participants aged ≥65 years in the Chinese Longitudinal Healthy Longevity Survey (2008-2018), the associations between socioeconomic support (source of income, medical insurance, community support, living status), onset of prefrailty/frailty, and worsening of prefrailty, were analyzed using multinominal logistic regression models. The associations between self-reported low quality of life (QoL) and reversion of prefrailty/frailty were analyzed using multivariate logistic regression models. Associations with mortality risk were analyzed using Cox proportional hazard regression models. Results: A total of 13,859 participants (mean age: 85.8 ± 11.1 years) containing 2056 centenarians were included. Financial dependence was a risk factor for low QoL among prefrail/frail individuals, but not among robust individuals. Having commercial or other insurance, and receiving social support from the community were protective factors for low QoL among prefrail/frail individuals and for the worsening of prefrailty. Continuing to work was a risk factor for low QoL, but a protective factor for worsening of prefrailty. A negative association between continuing to work and mortality existed in prefrail individuals aged <85 years and ≥85 years. Living alone was a risk factor for low QoL, but was not significantly associated with frailty prognosis. Conclusions: Prefrail and frail individuals were vulnerable to changes in socioeconomic support and more sensitive to it compared with robust individuals. Preferential policies regarding financial support, social support, and medical insurance should be developed for individuals with frailty.

Utilizing Industrial Sludge Ash in Brick Manufacturing and Quality Improvement.

This research demonstrates changes in the behaviors and characteristics of sintered bricks while using industrial sludge ash (ISA) and waste glass (WG) as a replacement for clay in the brick manufacturing procedure. Owing to the limited amount of available land in Taiwan, it is becoming increasingly difficult to locate suitable sites for sanitary landfills, which is a common final disposal method for ash that is produced during thermal treatment in sludge factories. To meet the urgent need for land, the final waste disposal must convert this waste into a new resource. This research investigated the feasibility of using general industrial sludge ash waste, due to its abundance and high potential as a raw material in producing bricks. The result of this study shows that the bricks made from ISA and WG under a certain mixture proportion (ISA50%/WG40%/Clay10%) had excellent industrial potentials, such as compressive strength and water absorption rate. However, owing to the wide variety of components from different sources of ISA, the mixture proportion might vary accordingly. This study also analyzed the incineration index, proportion design, and process improvement, as well as investigating the possibility of increasing the total use of sludge ash as a resource. This study shows the potentials of utilizing wastes as raw materials in industrial manufacturing procedures. Therefore, more wastes can be tested and turned into resources in the future.

FOXO1 regulates RUNX2 ubiquitination through SMURF2 in calcific aortic valve disease.

The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.

Promoting oxygen vacancies utility for tetracycline degradation via peroxymonosulfate activation by reduced Mg-doped Co3O4: Kinetics and key role of electron transfer pathway.

Developing cobalt-based catalysts with a high abundance of oxygen vacancies (Vo) and exceptional Vo utility efficiency for the prompt removal of stubborn contaminants through peroxymonosulfate (PMS) activation poses a significant challenge. Herein, we reported the synthesis of the reduced Mg-doped Co3O4 nanosheets, i.e. Mg-doped Co3O4-r, via Mg doping and followed by NaBH4 reduction, aiming to degrade tetracycline (TC). Various characterization results illustrated that NaBH4 reduction imparted higher Vo utility efficiency to Mg-doped Co3O4-r, along with an ample presence of reduced Co2+ species and an increased surface area, thereby substantially elevating PMS activation capability. Notably, Mg-doped Co3O4-r achieved more than 97.9% degradation of 20 mg/L TC within 10 min, showing an over 8-fold increase in reaction rate relative to the Mg-doped Co3O4 (kobs: 0.3285 min-1 vs 0.0399 min-1). The high removal efficiency of TC was sustained across a broad pH range of 3-11, even in the presence of common anions and humic acid. Radical quenching trials, EPR outcomes, and electrochemical analysis indicated that neither radicals nor 1O2 were the primary active species. Instead, electron transfer pathway played a dominant role in TC degradation. The Mg-doped Co3O4-r displayed excellent recyclability and versatility. Even after the fifth cycle, it maintained an impressive 83.0% removal of TC. Furthermore, it exhibited rapid degradation capabilities for various pollutants, including levofloxacin, pefloxacin, ciprofloxacin, malachite green, and rhodamine B. The TC degradation pathway was proposed based on LC-MS determination of its degradation intermediates. This study showcases an innovative strategy for the rational design of an efficient cobalt-based activator, leveraging electron transfer pathways through PMS activation to degrade antibiotics effectively.

A new ChatGPT-empowered, easy-to-use machine learning paradigm for environmental science.

The quantity and complexity of environmental data show exponential growth in recent years. High-quality big data analysis is critical for performing a sophisticated characterization of the complex network of environmental pollution. Machine learning (ML) has been employed as a powerful tool for decoupling the complexities of environmental big data based on its remarkable fitting ability. Yet, due to the knowledge gap across different subjects, ML concepts and algorithms have not been well-popularized among researchers in environmental sustainability. In this context, we introduce a new research paradigm-"ChatGPT + ML + Environment", providing an unprecedented chance for environmental researchers to reduce the difficulty of using ML models. For instance, each step involved in applying ML models to environmental sustainability, including data preparation, model selection and construction, model training and evaluation, and hyper-parameter optimization, can be easily performed with guidance from ChatGPT. We also discuss the challenges and limitations of using this research paradigm in the field of environmental sustainability. Furthermore, we highlight the importance of "secondary training" for future application of "ChatGPT + ML + Environment".

Mechanistic insights into ligand dissociation from the SARS-CoV-2 spike glycoprotein.

The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. The spike glycoprotein of the SARS-CoV-2 is crucial for infiltrating host cells, rendering it a key candidate for drug development. By interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor, the spike initiates the infection of SARS-CoV-2. Linoleate is known to bind the spike glycoprotein, subsequently reducing its interaction with ACE2. However, the detailed mechanisms underlying the protein-ligand interaction remain unclear. In this study, we characterized the pathways of ligand dissociation and the conformational changes associated with the spike glycoprotein by using ligand Gaussian accelerated molecular dynamics (LiGaMD). Our simulations resulted in eight complete ligand dissociation trajectories, unveiling two distinct ligand unbinding pathways. The preference between these two pathways depends on the gate distance between two α-helices in the receptor binding domain (RBD) and the position of the N-linked glycan at N343. Our study also highlights the essential contributions of K417, N121 glycan, and N165 glycan in ligand unbinding, which are equally crucial in enhancing spike-ACE2 binding. We suggest that the presence of the ligand influences the motions of these residues and glycans, consequently reducing accessibility for spike-ACE2 binding. These findings enhance our understanding of ligand dissociation from the spike glycoprotein and offer significant implications for drug design strategies in the battle against COVID-19.

Advancing Glucose Sensing Through Auto-Fluorescent Polymer Brushes: From Surface Design to Nano-Arrays.

Designing smart (bio)interfaces with the capability to sense and react to changes in local environments offers intriguing possibilities for new surface-based sensing devices and technologies. Polymer brushes make ideal materials to design such adaptive and responsive interfaces given their large variety of functional and structural possibilities as well as their outstanding abilities to respond to physical, chemical, and biological stimuli. Herein, a practical sensory interface for glucose detection based on auto-fluorescent polymer brushes decorated with phenylboronic acid (PBA) receptors is presented. The glucose-responsive luminescent surfaces, which are capable of translating conformational transitions triggered by pH variations and binding events into fluorescent readouts without the need for fluorescent dyes, are grown from both nanopatterned and non-patterned substrates. Two-photon laser scanning confocal microscopy and atomic force microscopy (AFM) analyses reveal the relationship between the brush conformation and glucose concentration and confirm that the phenylboronic acid functionalized brushes can bind glucose over a range of physiologically relevant concentrations in a reversible manner. The combination of auto-fluorescent polymer brushes with synthetic receptors presents a promising avenue for designing innovative and robust sensing systems, which are essential for various biomedical applications, among other uses.

Exploring additives beyond phthalates: Release from plastic mulching films, biodegradation and occurrence in agricultural soils.

It is widely recognized that applications of plastic films result in plastic pollution in agroecosystems. However, there is limited knowledge on the release and occurrence of additives beyond phthalates in agricultural soil. In this study, the rates of release and biodegradation of various additives, including phthalates, bisphenols, organophosphate esters, phenolic antioxidants, and ultraviolet absorbents from mulching films in soil were quantified by laboratory incubation. The rates of release and biodegradation ranged from 0.069 d-1 to 5.893 d-1 and from 1.43 × 10-3 d-1 to 0.600 d-1, respectively. Both of these rates were affected by temperature, flooding, and the properties of additives, films, and soils. An estimated 4000 metric tons of these additives were released into soil annually in China exclusively. The total concentrations of these additives in 80 agricultural soils varied between 228 and 3455 µg kg-1, with phenolic antioxidants, phthalates, and bisphenols accounting for 54.1%, 25.2%, and 17.9% of the total concentrations, respectively. A preliminary risk assessment suggested that the current levels of these additives could potentially present moderate hazards to the soil ecosystem.

Cationic regulation of specificity and activity of defective MCo2O4 nanozyme (M=Fe, Co, Ni, Cu) for colorimetric detection of caffeic acid.

Spinel oxide has great promise in constructing highly active nanozymes due to its tunable crystal structure. However, it still faces the problems of poor specificity and insufficient enzyme activity, which limits its application in the field of analysis. Herein, a series of transition metal spinel oxides were synthesized by cation regulation strategy, and their enzymatic activity and catalytic mechanism were analyzed. Interestingly, FeCo2O4, Co3O4 and NiCo2O4 had oxidase-like activity and peroxidase-like activity, while CuCo2O4 had specific and high oxidase-like activity. Their oxidase-like activities follow the order of FeCo2O4 < Co3O4 < NiCo2O4 < CuCo2O4, which is consistent with their cation radius. The smaller the cation radius of tetrahedral site, the more beneficial it is to increase the oxidase-like activity. The high oxidase-like activity of CuCo2O4 may be attributed to the production of 1O2, •O2- and •OH. EPR results showed the presence of abundant oxygen vacancies in CuCo2O4. Upon the introduction of EDTA, TMB color reaction fades because of oxygen vacancies elimination by EDTA, indicating that oxygen vacancies played an important role in the reaction. Based on the inhibition effect of caffeic acid on the high oxidase-like activity of CuCo2O4, a simple and sensitive caffeic acid colorimetric sensing platform was developed. The linear range for the detection of caffeic acid is 0.02-15 µM, with a detection limit as low as 13 nM. The constructed sensor enables the detection of caffeic acid in caffeic acid tablets and actual water samples, providing a new strategy for the detection of caffeic acid and drug quality control.

Elucidating the impact of oxygen functional groups on the catalytic activity of M-N4-C catalysts for the oxygen reduction reaction: a density functional theory and machine learning approach.

Efforts to enhance the efficiency of electrocatalysts for the oxygen reduction reaction (ORR) in energy conversion and storage devices present formidable challenges. In this endeavor, M-N4-C single-atom catalysts (MN4) have emerged as promising candidates due to their precise atomic structure and adaptable electronic properties. However, MN4 catalysts inherently introduce oxygen functional groups (OGs), intricately influencing the catalytic process and complicating the identification of active sites. This study employs advanced density functional theory (DFT) calculations to investigate the profound influence of OGs on ORR catalysis within MN4 catalysts (referred to as OGs@MN4, where M represents Fe or Co). We established the following activity order for the 2eORR: for OGs@CoN4: OH@CoN4 > CoN4 > CHO@CoN4 > C-O-C@CoN4 > COC@CoN4 > COOH@CoN4 > CO@CoN4; for OGs@FeN4: COC@FeN4 > CO@FeN4 > OH@FeN4 > FeN4 > COOH@FeN4 > CHO@FeN4 > C-O-C@FeN4. Multiple oxygen combinations were constructed and found to be the true origin of MN4 activity (for instance, the overpotential of 2OH@CoN4 as low as 0.07 V). Furthermore, we explored the performance of the OGs@MN4 system through charge and d-band center analysis, revealing the limitations of previous electron-withdrawing/donating strategies. Machine learning analysis, including GBR, GPR, and LINER models, effectively guides the prediction of catalyst performance (with an R2 value of 0.93 for predicting ΔG*OOH_vac in the GBR model). The Eg descriptor was identified as the primary factor characterizing ΔG*OOH_vac (accounting for 62.8%; OGs@CoN4: R2 = 0.9077, OGs@FeN4: R2 = 0.7781). This study unveils the significant impact of OGs on MN4 catalysts and pioneers design and synthesis criteria rooted in Eg. These innovative findings provide valuable insights into understanding the origins of catalytic activity and guiding the design of carbon-based single-atom catalysts, appealing to a broad audience interested in energy conversion technologies and materials science.

Pain behavior and phenotype in a modified anterior lumbar disc puncture mouse model.

Background: An experimental study was performed to improve the anterior approach model of intervertebral disc degeneration (IVDD). Objective: The aims of this study were to investigate the anterior approach model of IVDD for the cause of death, phenotypes, and underlying mechanisms of low back pain in mice. Method: In this study, we conducted an anterior puncture procedure on a cohort of 300 C57BL/6J mice that were 8 weeks old. Our investigation focused on exploring the causes of death in the study population (n = 300) and assessing the time-course changes in various parameters, including radiographical, histological, immunofluorescence, and immunohistochemistry analyses (n = 10). Additionally, we conducted behavioral assessments on a subset of the animals (n = 30). Results: Transverse vertebral artery rupture is a major factor in surgical death. Radiographical analyses showed that the hydration of the nucleus pulposus began to decrease at 2 weeks after puncture and obviously disappeared over 4 weeks. 3D-CT showed that disc height was significantly decreased at 4 weeks. Osteophyte at the anterior vertebral rims was observed at 2 weeks after the puncture. As the time course increased, histological analyses showed progressive disruption of the destruction of the extracellular matrix and increased secretion of inflammatory cytokines and apoptosis. Behavioral signs of low back pain were increased between the puncture and sham groups at 4 weeks. Conclusion: The improvement of anterior intervertebral disc approach model in mice will be useful to investigate underlying mechanisms and potential therapeutic strategies for behavior and phenotypes. Furthermore, the application of vibrational pre-treatment can be used to increase the sensitivity of axial back pain in the model, thereby providing researchers with a reliable method for measuring this critical phenotype.

Serglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration.

Intervertebral disc degeneration is a natural process during aging and a leading cause of lower back pain. Here, we generate a comprehensive atlas of nucleus pulposus cells using single-cell RNA-seq analysis of human nucleus pulposus tissues (three males and four females, age 41.14 ± 18.01 years). We identify fibrotic late-stage nucleus pulposus cells characterized by upregulation of serglycin expression which facilitate the local inflammatory response by promoting the infiltration of inflammatory cytokines and macrophages. Finally, we discover that daphnetin, a potential serglycin ligand, substantially mitigates the local inflammatory response by downregulating serglycin expression in an in vivo mouse model, thus alleviating intervertebral disc degeneration. Taken together, we identify late-stage nucleus pulposus cells and confirm the potential mechanism by which serglycin regulates intervertebral disc degeneration. Our findings indicate that serglycin is a latent biomarker of intervertebral disc degeneration and may contribute to development of diagnostic and therapeutic strategies.

Blood pressure in the longevous population with different status of hypertension and frailty.

Blood pressure(BP) of the longevous population with hypertension and/or frailty was under-investigated. To investigate the association between age, BP, variation of BP, and survival among the old adults with different status of hypertension and frailty, the present study included adults ≥65 years in the Chinese Longitudinal Healthy Longevity Survey (2008-2018), defined frailty using the Fried criteria, and identified hypertension by self-report or SBP/DBP ≥ 140/90 mm Hg. The association between age and BP were investigated using linear regression models. Variation of BP was defined if annual change of BP lower than quartile 1(sharp decrease) or higher than quartile 3(sharp increase). The association between age and BP variation were investigated using multinominal logistic regression models. The association between BP and survival was analyzed using Cox regression models. Among 13,447 adults (centenarian: 1965[14.6%]), age was positively associated with SBP in robust hypertensive elderly but negatively associated with it in frail hypertensive elderly. Annual change of BP was more likely to be increment among the normotensive elderly, but be decrement among the hypertensive elderly, especially among those with frailty. SBP < 120 mmHg was the risk factor of mortality among the frail oldest-old (≥85 years) while SBP ≥ 150 mmHg was that among the robust young-old (65-84 years). DBP ≥ 90 mmHg was the risk factor of mortality both in the robust young-old and the frail oldest old. In conclusion, age and frailty might be the criteria to predict the change of BP to guide the BP management of the longevous population.

Acetylshikonin promoting PI3K/Akt pathway and inhibiting SOX4 expression to delay intervertebral disc degeneration and low back pain.

This study investigated the molecular mechanism by which acetylshikonin inhibits SOX4 expression via the PI3K/Akt pathway to delay intervertebral disc degeneration (IVDD) and low back pain (LBP). Bulk RNA-seq, RT-qPCR, Western blot analysis, immunohistochemical staining, small interfering RNA (siSOX4), lentivirus (lentiv-SOX4hi ), and imaging techniques were used to assess SOX4 expression and validate its upstream regulatory pathway. Acetylshikonin and siSOX4 were injected into the IVD to measure IVDD. SOX4 expression significantly increased in degenerated IVD tissues. TNF-α increased SOX4 expression and apoptosis-related proteins in nucleus pulposus cells (NPCs). siSOX4 reduced TNF-α-induced NPCs apoptosis, while Lentiv-SOX4hi increased it. The PI3K/Akt pathway was significantly correlated with SOX4, and acetylshikonin upregulated PI3K/Akt pathway while inhibiting SOX4 expression. In the anterior puncture IVDD mouse model, SOX4 expression was upregulated, and acetylshikonin and siSOX4 delayed IVDD-induced LBP. Acetylshikonin delays IVDD-induced LBP by inhibiting SOX4 expression through the PI3K/Akt pathway. These findings offer potential therapeutic targets for future treatments.

Natural product fargesin interferes with H3 histone lactylation via targeting PKM2 to inhibit non-small cell lung cancer tumorigenesis.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. There is an urgent need to find more effective drugs that inhibit NSCLC. Fargesin (FGS) has demonstrated anti-tumor effects; however, its efficacy and the molecular mechanism of inhibiting NSCLC are unclear. Herein, we investigated FGS' inhibitory effects on NSCLC by CCK8 and EdU assays and cell cycle analysis of A549 cells in vitro and in a nude mouse tumor transplantation model in vivo. FGS (10-50 µM) significantly inhibited cell proliferation and down-regulated expression levels of CDK1 and CCND1. Transcriptomic analysis showed that FGS regulated the cell metabolic process pathway. Differential metabolites with FGS treatment were enriched in glycolysis and pyruvate pathways. Cell metabolism assay were used to evaluate the oxygen consumption rate (OCR), Extracellular acidification rate (ECAR) in A549 cells. FGS also inhibited the production of cellular lactate and the expression of LDHA, LDHB, PKM2, and SLC2A1. These genes were identified as important oncogenes in lung cancer, and their binding to FGS was confirmed by molecular docking simulation. Notably, the over-expression and gene silencing experiments signified PKM2 as the molecular target of FGS for anti-tumorigenesis. Moreover, the H3 histone lactylation, were correlated with tumorigenesis, were inhibited with FGS treatment. Conclusively, FGS inhibited the aerobic glycolytic and H3 histone lactylation signaling pathways in A549 NSCLC cells by targeting PKM2. These findings provide evidence of the therapeutic potential of FGS in NSCLC.