Single-Cell Study Unveils Lead Lifespan in Blood Cell Populations Follows a Universal Lognormal Distribution with Individual Skewness.

Lead is a widespread environmental hazard that can adversely affect multiple biological functions. Blood cells are the initial targets that face lead exposure. However, a systematic assessment of lead dynamics in blood cells at single-cell resolution is still absent. Herein, C57BL/6 mice were fed with lead-contaminated food. Peripheral blood was harvested at different days. Extracted red blood cells and leukocytes were stained with 19 metal-conjugated antibodies and analyzed by mass cytometry. We quantified the time-lapse lead levels in 12 major blood cell subpopulations and established the distribution of lead heterogeneity. Our results show that the lead levels in all major blood cell subtypes follow lognormal distributions but with distinctively individual skewness. The lognormal distribution suggests a multiplicative accumulation of lead with stochastic turnover of cells, which allows us to estimate the lead lifespan of different blood cell populations by calculating the distribution skewness. These findings suggest that lead accumulation by single blood cells follows a stochastic multiplicative process.

Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1.

Increasing evidence has demonstrated that glutaminase (GLS) as a key mitochondrial enzyme plays a pivotal role in glutaminolysis, which widely participates in glutamine metabolism serving as main energy sources and building blocks for tumor growth. However, the roles and molecular mechanisms of GLS in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we found that GLS was highly expressed in ESCC tissues and cells. GLS inhibitor CB-839 significantly suppressed cell proliferation, colony formation, migration and invasion of ESCC cells, whereas GLS overexpression displayed the opposite effects. In addition, CB-839 markedly suppressed glucose consumption and lactate production, coupled with the downregulation of glycolysis-related proteins HK2, PFKM, PKM2 and LDHA, whereas GLS overexpression exhibited the adverse results. In vivo animal experiment revealed that CB-839 dramatically suppressed tumor growth, whereas GLS overexpression promoted tumor growth in ESCC cells xenografted nude mice. Mechanistically, GLS was localized in mitochondria of ESCC cells, which interacted with PDK1 protein. CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.

Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

Comparison of rehabilitation outcomes between robot-assisted and freehand screw placement in treatment of femoral neck fractures: a systematic review and meta-analysis.

PURPOSE: To compare the postoperative rehabilitation of femoral neck fractures treated with robot-assisted nailing and freehand nailing. METHODS: We systematically searched the PubMed, EMBASE, Cochrane, China National Knowledge Infrastructure(CNKI), WanFang database, China Science and Technology Journal Database (VIP) and Web of Science databases to identify potentially eligible articles. Indispensable data such as the year of publication, country, study type, robot type, age, number of patients, sex distribution, study design, and outcome indicators were extracted. The outcome indicators of interest included healing rate, length of healing time, Harris score, operation time, frequency of X-ray fluoroscopy, frequency of guide pin insertion, and intraoperative blood loss. RevMan 5.4.1 was used for the meta-analysis. RESULTS: Fourteen studies with 908 participants were included in this meta-analysis. The results showed that in terms of healing rate (SMD = 2.75, 95% CI, 1.03 to 7.32, P = 0.04) and Harris score (SMD = 2.27, 95% CI, 0.79 to 3.75, P = 0.003), robot-assisted screw placement technique scores were higher than the traditional freehand technique. Additionally, operative time (SMD = -12.72, 95% CI, -19.74 to -5.70, P = 0.0004), healing time (SMD = -13.63, 95% CI, -20.18 to -7.08, P < 0.0001), frequency of X-ray fluoroscopy (SMD = - 13.64, 95% CI, - 18.32 to - 8.95, P < 0.00001), frequency of guide pin insertion (SMD = - 7.95, 95% CI, - 10.13 to - 5.76, P < 0.00001), and intraoperative blood loss (SMD = - 17.33, 95% CI, - 23.66 to - 11.00, P < 0.00001) were lower for patients who underwent robotic-assisted screw placement than those for patients who underwent the conventional freehand technique. CONCLUSION: Compared to the freehand nailing technique, robot-assisted nailing helps improve postoperative healing rates in patients with femoral neck fractures; shortens healing times; better restores hip function; reduces the number of intraoperative fluoroscopies, guides pin placements; reduces intraoperative bleeding; and increases perioperative safety.

Improved Particle Filter Algorithm for Multi-Target Detection and Tracking.

In modern radar detection systems, the particle filter technique has become one of the core algorithms for real-time target detection and tracking due to its good nonlinear and non-Gaussian system state estimation capability. However, when dealing with complex dynamic scenes, the traditional particle filter algorithm exposes obvious deficiencies. The main expression is that the sample degradation is serious, which leads to a decrease in estimation accuracy. In multi-target states, the algorithm is difficult to effectively distinguish and stably track each target, which increases the difficulty of state estimation. These problems limit the application potential of particle filter technology in multi-target complex environments, and there is an urgent need to develop a more advanced algorithmic framework to enhance its robustness and accuracy in complex scenes. Therefore, this paper proposes an improved particle filter algorithm for multi-target detection and tracking. Firstly, the particles are divided into tracking particles and searching particles. The tracking particles are used to maintain and update the trajectory information of the target, and the searching particles are used to identify and screen out multiple potential targets in the environment, to sufficiently improve the diversity of the particles. Secondly, the density-based spatial clustering of applications with noise is integrated into the resampling phase to improve the efficiency and accuracy of particle replication, so that the algorithm can effectively track multiple targets. Experimental result shows that the proposed algorithm can effectively improve the detection probability, and it has a lower root mean square error (RMSE) and a stronger adaptability to multi-target situation.

A novel seasonal grey prediction model with fractional order accumulation for energy forecasting.

To accurately predict sequence data with seasonal characteristics, we combine data restart technology and fractional order accumulation into a novel seasonal grey model (FSGM (1,1, α)). The particle swarm optimization (PSO) algorithm is used to solve the fractional order and background value coefficients of the model, and the effectiveness of FSGM (1,1, α) is verified using three cases. Finally, we use FSGM (1,1, α) to predict quarterly electricity generation in Beijing and Henan Province and quarterly petroleum coke production in China from 2023 to 2027. The research results indicate that, first, FSGM (1,1, α) is reasonable and effective and has the ability to accurately capture the dynamic trend of seasonal data. Second, compared with the grey model (GM (1,1)), seasonal grey model (SGM (1,1)), data grouping grey model (DGGM (1,1)), data grouping seasonal model (DGSM (1,1)), and data grouping seasonal time model (DGSTM (1,1)), which have seasonal characteristics, FSGM (1,1, α) can better fit the original data, achieve higher prediction accuracy, and perform better. Third, from 2023 to 2027, it is predicted that there will be no significant change in Beijing's electricity generation, and the current stable trend will be maintained. Both the power generation in Henan Province and the petroleum coke production in China will steadily increase to a certain extent, with obvious seasonal cyclical fluctuations. Notably, the power generation and petroleum coke production in Henan Province in the fourth quarter of 2027 will increase by 11.50 % and 10.93 %, respectively, compared to those in the fourth quarter of 2023.

Efficacy of e-health interventions for smoking cessation management in smokers: a systematic review and meta-analysis.

Background: Smoking is one of the major risk factors for shortened lifespan and disability, while smoking cessation is currently the only guaranteed method to reduce the harm caused by smoking. E-health is a field that utilizes information and communication technology to support the health status of its users. The emergence of this digital health approach has provided a new way of smoking cessation support for smokers seeking help, and an increasing number of researchers are attempting to use e-health for a wide range of effective smoking cessation interventions. We conducted a systematic review and meta-analysis of studies that used e-health as a smoking cessation support tool. Methods: This systematic review and meta-analysis searched the PubMed, Embase, and Cochrane Library databases until December 2022. The included studies were randomized controlled trials (RCTs) comparing the use of e-health interventions and traditional offline smoking cessation care interventions. The primary outcome of the studies was the point smoking cessation rate (7-day and 30-day), and the secondary outcome was sustained smoking cessation rates. Studies were excluded if there was no clear e-health intervention described or if standard-compliant cessation outcomes were not clearly reported. Fixed-effects meta-analysis and meta-regression analyses were performed on the included study data to evaluate the effectiveness of the interventions. The meta-analysis outcome was the risk ratio (RR) and a 95% confidence interval. The study was registered with PROSPERO, CRD42023388667. Findings: We collectively screened 2408 articles, and ultimately included 39 articles with a total of 17,351 eligible participants, of which 44 studies were included in the meta-analysis. The meta-analysis revealed that compared to traditional smoking cessation interventions, e-health interventions can increase point quit rates (RR 1.86, 95% CI 1.69-2.04) as well as sustained quit rates in the long-term (RR 1.79, 95% CI 1.60-2.00) among smokers. Subgroup analysis showed that text and telephone interventions in e-health significantly improved short-term quit rates for up to 7 days (RR 2.10, 95% CI 1.77-2.48). Website and app interventions also had a positive impact on improving short-term quit rates for up to 7 days (RR 1.74, 95% CI 1.56-1.94). The heterogeneity of the study results was low, demonstrating the significant smoking cessation advantages of e-health interventions. Interpretation: We have found that personalized e-health interventions can effectively help smokers quit smoking. The diverse remote intervention methods of e-health can provide more convenient options for further customization. Additionally, further follow-up research is needed to evaluate the sustained effectiveness of interventions on smokers' continuous abstinence over a longer period (greater than one year). In the future, e-health can further optimize smoking cessation strategies. Funding: No funding.

Cyclization Engineering of Electron-Deficient Maleimide Unit for Nonfused Ring Electron Acceptors Enables Efficient Organic Solar Cells.

Nonfused ring electron acceptors (NFREAs) have emerged as promising materials for commercial applications in organic solar cells due to their straightforward synthesis process and cost-effectiveness. The rational design of their structural frameworks is crucial for enhancing device efficiency. In this study, we explore the use of maleimide and thiophene as key building blocks, employing cyclization engineering techniques. Additionally, cyclopentanedithiophene was chosen as the bridging unit, coupled with fluorinated terminals, to fabricate NFREAs, namely, PI-DTS and DPI-DTS. DPI-DTS demonstrated superior molecular planarity and an upshifted lowest unoccupied molecular orbital energy level. Moreover, DPI-DTS-based blend films display enhanced π-π interactions and crystallinity, alongside a predominantly face-on orientation. Consequently, DPI-DTS-based devices displayed enhanced and more balanced carrier mobility, reduced bimolecular recombination, and trap-assisted recombination, leading to improved charge transfer efficiency. Ultimately, this led to an excellent efficiency of 10.48%, with an open-circuit voltage as high as 0.914 V. These findings highlight the significant promise of aromatic imides in constructing NFREAs, and the established structure-performance relationship provides a theoretical basis for the design of high performance NFREAs.

A new equation for estimating low-density lipoprotein cholesterol concentration based on machine learning.

Low-density lipoprotein cholesterol (LDL-C) is a crucial marker of cardiovascular system damage. In the Chinese population, the estimation of LDL-C concentration by Friedewald, Martin-Hopkins or Sampson equations is not accurate. The aim of this study was to develop a group of new equations for calculating LDL-C concentration using machine learning techniques and to evaluate their efficacy. A total of 182,901 patient samples were collected with standard lipid panel measurements. These samples were collated and randomly divided into a training set and a test set. In the training set, a new equation was constructed using polynomial ridge-regression and compared to the Friedewald, Martin/Hopkins and extended Martin/Hopkins, or Sampson equations in the test set. Subsequently, an additional set of 17,285 patient samples were collected to evaluate the performance of the new equation in clinical practice. The new equation, a ternary cubic equation, was accurate and easy to use, with a goodness-of-fit R2 of 0.9815 and an uncertainty MSE of 37.4250 on the testing set. The difference between the calculated value by the new equation and the measured value of LDL-C was small (0.0424 ±â€…5.1161 vs Friedewald equation: -13.3647 ±â€…17.9198, vs Martin/Hopkins and extended Martin/Hopkins equation: -6.4737 ±â€…8.1036, vs Sampson equation: -8.9252 ±â€…12.6522, P < .001). It could accurately calculate LDL-C concentration even at high triglyceride and low LDL-C. Furthermore, the new equation could also precisely calculate LDL-C concentration in actual clinical use (R2 = 0.9780, MSE = 24.8482). The new equation developed in this study can accurately calculate LDL-C concentration within the full concentration range of triglyceride and LDL-C, and can serve as a supplement to the direct determination of LDL-C concentration for the prevention, treatment, evaluation, and monitoring of atherosclerotic diseases, compared to the Friedewald, Martin/Hopkins and extended Martin/Hopkins, or Sampson equations.

Characterization and Function Analysis of miRNA Editing during Fat Deposition in Chinese Indigenous Ningxiang Pigs.

This study aimed to identify active miRNA editing sites during adipose development in Ningxiang pigs and analyze their characteristics and functions. Based on small RNA-seq data from the subcutaneous adipose tissues of Ningxiang pigs at four stages-30 days (piglet), 90 days (nursery), 150 days (early fattening), and 210 days (late fattening)-we constructed a developmental map of miRNA editing in the adipose tissues of Ningxiang pigs. A total of 505 miRNA editing sites were identified using the revised pipeline, with C-to-U editing types being the most prevalent, followed by U-to-C, A-to-G, and G-to-U. Importantly, these four types of miRNA editing exhibited base preferences. The number of editing sites showed obvious differences among age groups, with the highest occurrence of miRNA editing events observed at 90 days of age and the lowest at 150 days of age. A total of nine miRNA editing sites were identified in the miRNA seed region, with significant differences in editing levels (p < 0.05) located in ssc-miR-23a, ssc-miR-27a, ssc-miR-30b-5p, ssc-miR-15a, ssc-miR-497, ssc-miR-15b, and ssc-miR-425-5p, respectively. Target gene prediction and KEGG enrichment analyses indicated that the editing of miR-497 might potentially regulate fat deposition by inhibiting adipose synthesis via influencing target binding. These results provide new insights into the regulatory mechanism of pig fat deposition.

Metagenomic evidence for antibiotic-associated actinomycetes in the Karamay Gobi region.

Due to the misuse of antibiotics, there is an increasing emergence and spread of multidrug-resistant (MDR) bacteria, leading to a human health crisis. To address clinical antibiotic resistance and prevent/control pathogenic microorganisms, the development of novel antibiotics is essential. This also offers a new approach to discovering valuable actinobacterial flora capable of producing natural bioactive products. In this study, we employed bioinformatics and macro-genome sequencing to collect 15 soil samples from three different locations in the Karamay Gobi region. First, we assessed the diversity of microorganisms in soil samples from different locations, analyzing the content of bacteria, archaea, actinomycetes, and fungi. The biodiversity of soil samples from outside the Gobi was found to be higher than that of soil samples from within and in the center of the Gobi. Second, through microbial interaction network analysis, we identified actinomycetes as the dominant group in the system. We have identified the top four antibiotic genes, such as Ecol_fabG_TRC, Efac_liaR_DAP, tetA (58), and macB, by CARD. These genes are associated with peptide antibiotics, disinfecting agents and antiseptics, tetracycline antibiotics, and macrolide antibiotics. In addition, we also obtained 40 other antibiotic-related genes through CARD alignment. Through in-depth analysis of desert soil samples, we identified several unstudied microbial species belonging to different families, including Erythrobacteriaceae, Solirubrobacterales, Thermoleophilaceae, Gaiellaceae, Nocardioidaceae, Actinomycetia, Egibacteraceae, and Acidimicrobiales. These species have the capability to produce peptide antibiotics, macrolide antibiotics, and tetracycline antibiotics, as well as disinfectants and preservatives. This study provides valuable theoretical support for future in-depth research.

SpiDe-Sr: blind super-resolution network for precise cell segmentation and clustering in spatial proteomics imaging.

Spatial proteomics elucidates cellular biochemical changes with unprecedented topological level. Imaging mass cytometry (IMC) is a high-dimensional single-cell resolution platform for targeted spatial proteomics. However, the precision of subsequent clinical analysis is constrained by imaging noise and resolution. Here, we propose SpiDe-Sr, a super-resolution network embedded with a denoising module for IMC spatial resolution enhancement. SpiDe-Sr effectively resists noise and improves resolution by 4 times. We demonstrate SpiDe-Sr respectively with cells, mouse and human tissues, resulting 18.95%/27.27%/21.16% increase in peak signal-to-noise ratio and 15.95%/31.63%/15.52% increase in cell extraction accuracy. We further apply SpiDe-Sr to study the tumor microenvironment of a 20-patient clinical breast cancer cohort with 269,556 single cells, and discover the invasion of Gram-negative bacteria is positively correlated with carcinogenesis markers and negatively correlated with immunological markers. Additionally, SpiDe-Sr is also compatible with fluorescence microscopy imaging, suggesting SpiDe-Sr an alternative tool for microscopy image super-resolution.

Elevating Thermoelectric Performance by Compositing Dibromo-Substituted Thienoacene with SWCNTs.

Composites of organic small molecules (OSMs) and single-walled carbon nanotubes (SWCNTs) have drawn great attention as flexible thermoelectric (TE) materials in recent years. Here, we synthesized thieno[2',3':4,5]thieno[3,2-b]thieno[2,3-d]thiophene (TTA) and 2,6-dibromothieno[2',3':4,5]thieno[3,2-b]thieno[2,3-d]thiophene (TTA-2Br) and compounded them with SWCNTs, obtaining thermoelectric TTA/SWCNT and TTA-2Br/SWCNT composites. The introduction of the electron-withdrawing Br group was found to decrease the highest molecular orbital energy level and bandgap (Eg) of TTA-2Br. As a result, the Seebeck coefficient (S) and power factor (PF) of the OSM/SWCNT composite films were significantly improved. Moreover, suitable energy barrier between TTA-2Br and SWCNTs facilitates the energy filtering effect, which further enhances thermoelectric properties of the 40 wt % TTA-2Br/SWCNT composite film with optimum thermoelectric properties (PF = 242.59 ± 9.42 µW m-1 K-2 at room temperature), good thermal stability, and mechanical flexibility. In addition, the thermoelectric generator (TEG) prepared using 40 wt % TTA-2Br/SWCNT composite films and n-type SWCNT films can generate an output power of 102.8 ± 7.4 nW at a temperature difference of 20 °C. This work provides new insights into the preparation of OSM/SWCNT composites with significantly enhanced thermoelectric properties.

Oxygen tracer diffusion in amorphous hafnia films for resistive memory.

The oxygen diffusion rate in hafnia (HfO2)-based resistive memory plays a pivotal role in enabling nonvolatile data retention. However, the information retention times obtained in HfO2 resistive memory devices are many times higher than the expected values obtained from oxygen diffusion measurements in HfO2 materials. In this study, we resolve this discrepancy by conducting oxygen isotope tracer diffusion measurements in amorphous hafnia (a-HfO2) thin films. Our results show that the oxygen tracer diffusion in amorphous HfO2 films is orders of magnitude lower than that of previous measurements on monoclinic hafnia (m-HfO2) pellets. Moreover, oxygen tracer diffusion is much lower in denser a-HfO2 films deposited by atomic layer deposition (ALD) than in less dense a-HfO2 films deposited by sputtering. The ALD films yield similar oxygen diffusion times as experimentally measured device retention times, reconciling this discrepancy between oxygen diffusion and retention time measurements. More broadly, our work shows how processing conditions can be used to control oxygen transport characteristics in amorphous materials without long-range crystal order.

Optimal Planting Density Increases the Seed Yield by Improving Biomass Accumulation and Regulating the Canopy Structure in Rapeseed.

Planting density is an important factor affecting plant growth and yield formation in rapeseed. However, the understanding of the mechanism underlying the impact of planting density on biomass, canopy, and ultimate seed yield remains limited. A field experiment was conducted to investigate the effect of planting density on seed yield, yield components, biomass accumulation and partitioning, and canopy structure. Five planting density levels were set as D1 (2.4 × 105 plants ha-1), D2 (3.6 × 105 plants ha-1), D3 (5.4 × 105 plants ha-1), D4 (6.0 × 105 plants ha-1), and D5 (7.2 × 105 plants ha-1). The results showed that with planting density increasing from D1 to D3, the seed yield, number of pods in population, and 1000-seed weight increased, while seedling survival rate, yield per plant, number of pods per plant, and number of seeds per plant decreased. When planting density increased to D4 and D5, seed yield dramatically decreased due to a decreased number of seeds per pod and 1000-seed weight. Increasing planting density from D1 to D3 increased biomass accumulation in all organs. D3 produced the highest biomass partitioning in seeds. In addition, D2 and D3 treatments had a high level of pod area index (5.3-5.8), which caused an approximately 93% of the light to be intercepted. The distribution of light in D2 and D3 was more evenly spread, with the upper and lower parts of the canopy displaying a distribution ratio of roughly 7:3. Therefore, D2 and D3 produced the highest seed yields. In conclusion, D2 and D3 are recommended in rapeseed production due to their role in improving biomass accumulation and partitioning and canopy structure.

High-performance flexible resistive random-access memory based on SnS2 quantum dots with a charge trapping/de-trapping effect.

The application of resistive random-access memory (RRAM) in storage and neuromorphic computing has attracted widespread attention. Benefitting from the quantum effect, transition metal dichalcogenides (TMD) quantum dots (QDs) exhibit distinctive optical and electronic properties, which make them promising candidates for emerging RRAM. Here, we show a high-performance forming-free flexible RRAM based on high-quality tin disulfide (SnS2) QDs prepared by a facile liquid phase method. The RRAM device demonstrates high flexibility with a large on/off ratio of ∼106 and a long retention time of over 3 × 104 s. The excellent switching behavior of the memristor is elucidated by a charge trapping/de-trapping mechanism where the SnS2 QDs act as charge trapping centers. This study is of significance for the understanding and development of TMD QD-based flexible memristors.

Polymyxin B-targeted liposomal photosensitizer cures MDR A. baumannii burn infections and accelerates wound healing via M1/M2 macrophage polarization.

Multidrug-resistant (MDR) Acinetobacter baumannii infections pose a significant challenge in burn wound management, necessitating the development of innovative therapeutic strategies. In this work, we introduced a novel polymyxin B (PMB)-targeted liposomal photosensitizer, HMME@Lipo-PMB, for precise and potent antimicrobial photodynamic therapy (aPDT) against burn infections induced by MDR A. baumanni. HMME@Lipo-PMB-mediated aPDT exhibited enhanced antibacterial efficacy by specifically targeting and disrupting bacterial cell membranes, and generating increased intracellular ROS. Remarkably, even at low concentrations, this targeted approach significantly reduced bacterial viability in vitro and completely eradicated burn infections induced by MDR A. baumannii in vivo. Additionally, HMME@Lipo-PMB-mediated aPDT facilitated burn infection wound healing by modulating M1/M2 macrophage polarization. It also effectively promoted acute inflammation in the early stage, while attenuated chronic inflammation in the later stage of wound healing. This dynamic modulation promoted the formation of granulation tissue, angiogenesis, and collagen regeneration. These findings demonstrate the tremendous potential of HMME@Lipo-PMB-mediated aPDT as a promising alternative for the treatment of burn infections caused by MDR A. baumannii.

TRPV1 Regulates Proinflammatory Properties of M1 Macrophages in Periodontitis Via NRF2.

Periodontitis, characterized by progressive alveolar bone destruction, leads to the loss of attachment and stability of the affected teeth. Macrophages, especially the proinflammatory M1 subtype, are key in periodontitis pathogenesis, driving the disease's inflammatory and destructive processes. Despite existing insight into their involvement, comprehensive understanding of the underlying molecular mechanisms remains limited. TRPV1 is a non-selective cation channel protein and is known to regulate cellular function and homeostasis in macrophages. Our research objective was to investigate the impact of TRPV1 on the proinflammatory attributes of M1 macrophages in periodontal tissues, exploring potential mechanistic pathways. A mouse model of periodontitis was established using Porphyromonas gingivalis inoculation and ligature application around the maxillary second molar. Immunohistological analysis showed a significant reduction in macrophage TRPV1 expression in periodontitis-induced mice. Treatment with capsaicin, a TRPV1 agonist, was observed to effectively elevate TRPV1 expression in these macrophages. Furthermore, micro-computed tomography analysis revealed a marked decrease in alveolar bone resorption in the capsaicin -treated group, compared with vehicle and healthy control groups. Our in vitro findings show that capsaicin treatment successfully attenuated LPS-induced TNF-α and IL-6 production in macrophages, mediated through NRF2 activation, consequently reducing intracellular ROS levels. These findings suggest that TRPV1 agonists, through modulating M1 macrophage activity and up-regulating TRPV1, could be a novel therapeutic approach in periodontal disease management.

Site-Directed Mutagenesis of VvCYP76F14 (Cytochrome P450) Unveils Its Potential for Selection in Wine Grape Varieties Linked to the Development of Wine Bouquet.

Bouquet is a fascinating wine characteristic that serves as an indicator of wine quality, developing during the aging process. The multifunctional monoterpenol oxidase VvCYP76F14 in wine grapes sequentially catalyzes three reactions to produce (E)-8-carboxylinalool, a crucial precursor for wine bouquet. Previous studies indicated that the activity of VvCYP76F14 derived from different wine grape varieties did not correlate with the amino acid sequence differences. In this study, 54 wine grape varieties were categorized into neutral, aromatic, and full-bodied types based on the sequence differences of VvCYP76F14, closely correlated with the content of wine lactone precursors. Computer modeling and molecular docking analysis of the full-bodied CYP76F14 revealed 17, 19, and 18 amino acid residues in the VvCYP76F14-linalool, VvCYP76F14-(E)-8-hydroxylinalool, and VvCYP76F14-(E)-8-oxolinalool complexes, respectively. Site-directed mutagenesis and in vitro enzyme activity analysis confirmed the substitutions of the key amino acid residues in neutral and aromatic varieties. Notably, the D299 mutation of VvCYP76F14 resulted in the complete loss of (E)-8-oxolinalool and (E)-8-carboxylinalool activities, aligning with the undetectable levels of (E)-8-oxolinalool and (E)-8-carboxylinalool in "Yantai 2-3-37", which harbors the D299T substitution. Favorably, VvCYP76F14 could serve as a cost-effective fingerprint marker for screening superior hybrid offspring with the desired levels of wine lactone precursors.

Lipid safety of tenofovir alafenamide during 96-week treatment in treatment-naive chronic hepatitis B patients.

Background: This study was aimed at investigating the dynamics of lipids and the effect of TAF on the lipid profile of patients including fatty liver disease in CHB patients. Methods: The data of TC, LDL-c, HDL-c, TG, and TC/HDL ratio were collected at baseline, 24 weeks, 48 weeks, 72 weeks, and 96 weeks. CHB patients with fatty liver at baseline were further analyzed in a subgroup. Results: A total of 137 CHB patients treated with TAF were enrolled in this study. During 96 weeks of TAF treatment, there was no significant change in TC, LDL-c, HDL-c, and TG level (P > 0.05). The TC/HDL-c ratio was increased with no significant change (+0.24, P > 0.05). In CHB patients with fatty liver (n = 48), TC, LDL-c, and TC/HDL-c ratio increased gradually during TAF treatment, TG levels increased to 146.63 mg/dL at 48 weeks (P = 0.057) and then decreased, but there was still no significant change compared with the baseline level by 96 weeks (P > 0.05). Conclusion: TAF treatment had a low effect on the lipid profile of CHB patients over the course of 96 weeks, and it was safe even in patients with fatty liver. Clinical trial registration: [https://www.chictr.org.cn/showproj.html?proj=65123], identifier [ChiCTR2000041005].