A pheromone receptor in cichlid fish mediates attraction to females but inhibits male parental care.

Reproductive behaviors differ across species, but the mechanisms that control variation in mating and parental care systems remain unclear. In many animal species, pheromones guide mating and parental care. However, it is not well understood how vertebrate pheromone signaling evolution can lead to new reproductive behavior strategies. In fishes, prostaglandin F2α (PGF2α) drives mating and reproductive pheromone signaling in fertile females, but this pheromonal activity appears restricted to specific lineages, and it remains unknown how a female fertility pheromone is sensed for most fish species. Here, we utilize single-cell transcriptomics and CRISPR gene editing in a cichlid fish model to identify and test the roles of key genes involved in olfactory sensing of reproductive cues. We find that a pheromone receptor, Or113a, detects fertile cichlid females and thereby promotes male attraction and mating behavior, sensing a ligand other than PGF2α. Furthermore, while cichlid fishes exhibit extensive parental care, for most species, care is provided solely by females. We find that males initiate mouthbrooding parental care if they have disrupted signaling in ciliated sensory neurons due to cnga2b mutation or if or113a is inactivated. Together, these results show that distinct mechanisms of pheromonal signaling drive reproductive behaviors across taxa. Additionally, these findings indicate that a single pheromone receptor has gained a novel role in behavior regulation, driving avoidance of paternal care among haplochromine cichlid fishes. Lastly, a sexually dimorphic, evolutionarily derived parental behavior is controlled by central circuits present in both sexes, while olfactory signals gate this behavior in a sex-specific manner.

In-situ activation of biomimetic single-site bioorthogonal nanozyme for tumor-specific combination therapy.

Copper-catalyzed click chemistry offers creative strategies for activation of therapeutics without disrupting biological processes. Despite tremendous efforts, current copper catalysts face fundamental challenges in achieving high efficiency, atom economy, and tissue-specific selectivity. Herein, we develop a facile "mix-and-match synthetic strategy" to fabricate a biomimetic single-site copper-bipyridine-based cerium metal-organic framework (Cu/Ce-MOF@M) for efficient and tumor cell-specific bioorthogonal catalysis. This elegant methodology achieves isolated single-Cu-site within the MOF architecture, resulting in exceptionally high catalytic performance. Cu/Ce-MOF@M favors a 32.1-fold higher catalytic activity than the widely used MOF-supported copper nanoparticles at single-particle level, as first evidenced by single-molecule fluorescence microscopy. Furthermore, with cancer cell-membrane camouflage, Cu/Ce-MOF@M demonstrates preferential tropism for its parent cells. Simultaneously, the single-site CuII species within Cu/Ce-MOF@M are reduced by upregulated glutathione in cancerous cells to CuI for catalyzing the click reaction, enabling homotypic cancer cell-activated in situ drug synthesis. Additionally, Cu/Ce-MOF@M exhibits oxidase and peroxidase mimicking activities, further enhancing catalytic cancer therapy. This study guides the reasonable design of highly active heterogeneous transition-metal catalysts for targeted bioorthogonal reactions.

The efficacy and acceptability of anti-inflammatory omega-3 polyunsaturated fatty acid supplements in sepsis management: a network meta-analysis of randomized controlled trials.

Sepsis is a critical medical condition associated with high mortality for patients. Current pharmacological strategies for sepsis management or prevention had not achieved satisfactory results. The omega-3 fatty acids, with anti-inflammatory benefits, are considered to be promising agents for sepsis management/prevention. The aim of this network meta-analysis (NMA) is to compare the efficacy of various dosages and formulations of fish oil supplements for sepsis management and sepsis prevention. The current NMA consisted of two parts: (1) sepsis management and (2) sepsis prevention. The PubMed, ClinicalKey, Embase, ProQuest, Cochrane CENTRAL, ScienceDirect, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of February 22nd, 2024 for relevant randomized controlled trials (RCTs). RCTs were eligible for inclusion if they enrolled participants with a diagnosis of sepsis or who with high risk for sepsis. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed are (1) mortality rate in sepsis treatment or (2) incidence of sepsis in sepsis prevention. Our NMA, based on 28 RCTs and 1718 participants (mean age=51.6 years, mean female proportion=35.6 %), showed that (1) high dose parenteral fish oil supplement yield the lowest mortality rate in sepsis management in adult patients, and (2) high dose enteral fish oil supplement yield the lowest incidence of sepsis in pediatric patients. This study provides compelling evidence that high-dose fish oil supplements provide beneficial effects for both sepsis management and sepsis prevention. Our findings provide a preliminary rationale for future large-scale RCTs to investigate the role of fish oil supplementation in sepsis management or prevention.

[Evidence mapping of clinical studies on 23 commonly used Chinese patent medicines for treating insomnia].

Evidence mapping was performed to systematically search and review the clinical studies about the treatment of insomnia with Chinese patent medicines. The evidence distribution in this field was analyzed and the problems of the studies were summarized. Chinese-and English-language articles of the studies involving the Chinese patent medicines specified in three national drug catalogs for the treatment of insomnia were searched against the databases with the time interval from inception to August 2023. Figures and tables were established to present the results. Finally, 23 Chinese patent medicines were screened out, which were mentioned in 299 articles involving 236 randomized controlled trials(RCTs), 35 non-randomized controlled trials(non-RCTs), 7 retrospective studies, 17 systematic reviews/Meta-analysis, and 4 guidelines/expert recommendations or consensus. Bailemian Capsules, Wuling Capsules, and Yangxue Qingnao Granules were mentioned in a large proportion of articles. The outcome indicators included sleep rating scale, clinical response rate, safety indicators, and anxiety and depression scores. The results showed that the studies about the treatment of insomnia with Chinese patent medicines were growing. However, there was a scarcity of research evidence, and the available studies were single-center with small sample sizes and short periods. These studies spanned broad clinical scopes with inadequately emphasized advantages of TCM and insufficient outcome indicators about quality of life, follow-up, and recurrence rate. RCT exhibited a high risk of bias, and the systematic reviews/Meta-analysis demonstrated low overall quality. The retrospective studies received suboptimal scores, and the non-RCT failed to mention follow-up time, loss rate to follow-up, and sample size estimations, which compromised result reliability. It is recommended that the research protocol for Chinese patent medicines in treating insomnia should adhere to the clinical research standards of TCM. The TCM syndrome score can serves as a crucial outcome measure, and emphasis should be placed on patients' quality of life, follow-up, and recurrence prevention. Measures should be taken to enhance the accessibility and affordability of Chinese patent medicines and strengthen the connection between medical insurance policies and the policies pertaining to Chinese patent medicines. Furthermore, it is advisable to reasonably increase the inclusion of Chinese patent medicines with well-established efficacy and safety evidence in the category A list of medical insurance.

Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Reconstruction of single-cell lineage trajectories and identification of diversity in fates during the epithelial-to-mesenchymal transition.

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta-induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories.

Impacts of parental genomic divergence in non-syntenic regions on cotton heterosis.

INTRODUCTION: Heterosis has revolutionized crop breeding, enhancing global agricultural production. However, the mechanisms underlying heterosis remain obscure. Xiangzamian 2# (XZM2), a super hybrid upland cotton (Gossypium hirsutum L.) characterized by high-yield heterosis, has been developed and extensively planted in China. OBJECTIVES: We conducted a systematic analysis of CRI12 and J8891, two parents of XZM2. We aimed to reveal the precise genetic information and the role of non-syntenic divergence in shaping heterosis, laying a foundation for advancing understanding of heterosis. METHODS: We de novo assembled high-quality genomes of CRI12 and J8891, and further uncovered abundant genetic variations and non-syntenic regions between the parents. Whole-genome comparison, association analysis, transcriptomic analysis and relative identity-by-descent (rIBD) estimation were conducted to identify structural variations (SVs) and introgressions within non-syntenic blocks and to analyze their impacts on promoting heterosis. RESULTS: Parental genetic divergence increased in non-syntenic regions. Furthermore, these regions, accounting for only 16.71% of the total genome, contained more loci with significantly higher heterotic effects, far exceeding the syntenic background. SVs covered 97.26% of non-syntenic sequences and caused widespread gene expression differences in these regions, driving dynamic complementation of gene expression in the hybrid. A set of SVs were responsible for trait improvement and had positive effects on heterosis, contributing larger heritability than short variations. We characterized numerous parental-specific introgressions from G. barbadense. Specifically, a functional introgression segment within non-syntenic blocks introduced an elite haplotype, which significantly increased lint yield and enhanced heterosis. CONCLUSION: Our study clarified non-syntenic regions to harbor more loci with higher heterotic effects, revealed their importance in promoting heterosis and supported the crucial role of genetic complementation in heterosis. SVs and introgressions were identified as key factors responsible for non-syntenic divergence between the parents. They had important effects on gene expression and trait improvement, positively contributing to heterosis.

Gender differences in 381 patients undergoing isolated mitral regurgitation repair.

Objectives To compare the gender differences in isolated mitral regurgitation (MR) repair. Methods Of 381 adults aged 54.8±12.3 years undergoing mitral valve repair (MVP) for isolated MR from 01/2019-12/2022, the baseline and operative data, and outcomes were compared between 161 women (42.3%) and 220 men (57.7%). Results Women tended to be non-smoker (98.1% vs 45%, P<0.001), and have more cerebrovascular accidents (38.5% vs 24.1%, P=0.004), lower creatinine (70.0±19.5 vs 86.3±19.9 µmol/dL, P<0.001), smaller LVEDD (54.4±6.7 vs 57.8±6.6 mm, P<0.001) and isolated annular dilatation (19.3% vs 9.1%, P=0.010). One female died of stroke at 2 days (0.3%). Another female (0.3%) underwent MV replacement for failed repair. Stroke occurred in 4 (1.0%). Two underwent re-exploration for bleeding (0.5%). Women were more likely to have less 24-hour drainage (290±143 vs 385±196 mL, P<0.001). Over a mean follow-up of 2.1±1.1 years (100% complete), one woman died, one man underwent a reoperation; 28 had moderate MR, and 9 had severe MR. Neither did early and late mortality and reoperation, nor freedom from late moderate/severe MR (71.6% vs 71.4% at 5 years; P=0.992) differ significantly between two genders. Predictors for late moderate/severe MR were anterior leaflet prolapse (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.18-16.72; P=0.027) and isolated annular dilation (HR 5.47, 95% CI 1.29-23.25; P=0.021). Conclusions Despite significant differences in smoking, cerebrovascular accidents, creatinine, LVEDD, and isolated annular dilatation at baseline, and 24-hour drainage, women and men did not show significant difference in early and late survival, reoperation and freedom from late moderate/severe MR.

Artificial Polymerizations in Living Organisms for Biomedical Applications.

Within living organisms, numerous nanomachines are constantly involved in complex polymerization processes, generating a diverse array of biomacromolecules for maintaining biological activities. Transporting artificial polymerizations from lab settings into biological contexts has expanded opportunities for understanding and managing biological events, creating novel cellular compartments, and introducing new functionalities. This review summarizes the recent advancements in artificial polymerizations, including those responding to external stimuli, internal environmental factors, and those that polymerize spontaneously. More importantly, the cutting-edge biomedical application scenarios of artificial polymerization, notably in safeguarding cells, modulating biological events, improving diagnostic performance, and facilitating therapeutic efficacy are highlighted. Finally, this review outlines the key challenges and technological obstacles that remain for polymerizations in biological organisms, as well as offers insights into potential directions for advancing their practical applications and clinical trials.

A generalized outcome-adaptive sequential multiple assignment randomized trial design.

A dynamic treatment regime (DTR) is a mathematical representation of a multistage decision process. When applied to sequential treatment selection in medical settings, DTRs are useful for identifying optimal therapies for chronic diseases such as AIDs, mental illnesses, substance abuse, and many cancers. Sequential multiple assignment randomized trials (SMARTs) provide a useful framework for constructing DTRs and providing unbiased between-DTR comparisons. A limitation of SMARTs is that they ignore data from past patients that may be useful for reducing the probability of exposing new patients to inferior treatments. In practice, this may result in decreased treatment adherence or dropouts. To address this problem, we propose a generalized outcome-adaptive (GO) SMART design that adaptively unbalances stage-specific randomization probabilities in favor of treatments observed to be more effective in previous patients. To correct for bias induced by outcome adaptive randomization, we propose G-estimators and inverse-probability-weighted estimators of DTR effects embedded in a GO-SMART and show analytically that they are consistent. We report simulation results showing that, compared to a SMART, Response-Adaptive SMART and SMART with adaptive randomization, a GO-SMART design treats significantly more patients with the optimal DTR and achieves a larger number of total responses while maintaining similar or better statistical power.

N6-methyladenosine RNA modification regulates photoperiod sensitivity in cotton.

The methylation of N6-methyladenosine (m6A) involves writers, erasers, and readers, acting synergistically in posttranscriptional regulation. These processes influence various biological processes, including plant floral transition. However, the specific role of m6A modifications in photoperiod sensitivity in cotton (Gossypium hirsutum) remains obscure. To elucidate this, in this study, we conducted transcriptome-wide m6A sequencing during critical flowering transition stages in the photoperiod-sensitive wild G. hirsutum var. yucatanense (yucatanense) and the photoperiod-insensitive cultivated cotton G. hirsutum acc. TM-1 (TM-1). Our results revealed significant variations in m6A methylation of 2 cotton varieties, with yucatanense exhibiting elevated m6A modification levels compared with TM-1 under long-day conditions. Notably, distinct m6A peaks between TM-1 and yucatanense correlated significantly with photoperiod sensitivity. Moreover, our study highlighted the role of the demethylase G. hirsutum ALKB homolog 5 (GhALKBH5) in modulating m6A modification levels. Silencing GhALKBH5 led to a decreased mRNA level of key photoperiodic flowering genes (GhADO3, GhAGL24, and GhFT1), resulting in delayed bud emergence and flowering. Reverse transcription quantitative PCR analyses confirmed that silencing GhADO3 and GhAGL24 significantly downregulated the expression of the floral integrator GhFT1. Collectively, our findings unveiled a transcriptional regulatory mechanism in which GhALKBH5-mediated m6A demethylation of crucial photoperiodic flowering transcripts modulated photoperiod sensitivity in cotton.

CircCDR1as orchestrates the advancement of asthma triggered by PM2.5 through the modulation of ferroptosis.

Exposure to fine particulate matter (PM2.5) in the ambient environment augments susceptibility to respiratory ailments. Circular RNAs, a distinctive subclass of endogenous non-coding RNAs, have been acknowledged as pivotal regulators of pathological conditions. Ferroptosis, an innovative iron-dependent form of cellular demise, has emerged as a consequential participant in numerous maladies. Despite the established association between PM2.5 exposure and the exacerbation of asthma, scant investigations have probed into the implication of circRNAs and ferroptosis in PM2.5-induced asthma. Consequently, this inquiry sought to scrutinize the potential involvement of circCDR1as and ferroptosis in PM2.5-induced asthma. Through the formulation of a PM2.5 exposure model in asthmatic mice and an in vitro cellular model, it was discerned that PM2.5 induced ferroptosis, thereby intensifying asthma progression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed an upregulation of circCDR1as in the PM2.5-stimulated asthma cell model. Molecular biology assays demonstrated that diminished circCDR1as expression hindered the onset of ferroptosis in response to PM2.5 exposure. Notably, Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, manifested the ability to impede the advancement of asthma. Mechanistically, RNA pull-down and molecular biology experiments substantiated that circCDR1as selectively bound to insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), thereby modulating the occurrence of ferroptosis. CircCDR1as emerged as a potential orchestrator of asthma progression by regulating ferroptosis under PM2.5 exposure. Additionally, PM2.5 exposure elicited activation of the Wnt/ß-catenin signaling pathway, subsequently influencing the expression of C-myc and Cyclin D1, ultimately exacerbating asthma development. In summation, the interaction between circCDR1as and IGF2BP2 in regulating ferroptosis was identified as a critical facet in the progression of asthma under PM2.5 exposure. This investigation underscores the pivotal roles of circCDR1as and ferroptosis in PM2.5-induced asthma, offering a novel theoretical foundation for the therapeutic and preventive approaches to asthma.

Biosensor-based active ingredient recognition system for screening potential small molecular Severe acute respiratory syndrome coronavirus 2 entry blockers targeting the spike protein from Rugosa rose.

The traditional formulation Hanchuan zupa granules (HCZPs) have been widely used for controlling coronavirus disease 2019 (COVID-19). However, its active components remain unknown. Here, HCZP components targeting the spike receptor-binding domain (S-RBD) of SARS-CoV-2 were investigated using a surface plasmon resonance (SPR) biosensor-based active ingredient recognition system (SPR-AIRS). Recombinant S-RBD proteins were immobilized on the SPR chip by amine coupling for the prescreening of nine HCZP medicinal herbs. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) identified gallic acid (GA) and methyl gallate (MG) from Rosa rugosa as S-RBD ligands, with KD values of 2.69 and 0.95 µM, respectively, as shown by SPR. Molecular dynamics indicated that GA formed hydrogen bonds with G496, N501, and Y505 of S-RBD, and MG with G496 and Y505, inhibiting S-RBD binding to angiotensin-converting enzyme 2 (ACE2). SPR-based competition analysis verified that both compounds blocked S-RBD and ACE2 binding, and SPR demonstrated that GA and MG bound to ACE2 (KD = 5.10 and 4.05 µM, respectively), suggesting that they blocked the receptor and neutralized SARS-CoV-2. Infection with SARS-CoV-2 pseudovirus showed that GA and MG suppressed viral entry into 293T-ACE2 cells. These S-RBD inhibitors have potential for drug design, while the findings provide a reference on HCZP composition and its use for treating COVID-19.

DDX19A promotes gastric cancer cell proliferation and migration by activating the PI3K/AKT pathway.

BACKGROUND: DEAD-box RNA helicase 19 A (DDX19A) is overexpressed in cervical squamous cell carcinoma. However, its role in gastric cancer remains unclear. The present study aimed to explore the role and underlying mechanism of DDX19A in the development of gastric cancer. METHODS: The expression of DDX19A in gastric cancer and paracancerous tissues was evaluated through quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The biological functions of DDX19A in gastric cancer were determined using CCK8, plate colony-forming, and Transwell migration assays. The specific mechanism of DDX19A in gastric cancer cells was studied using western blotting, RNA-binding protein immunoprecipitation, mRNA half-life detection, and nuclear and cytoplasmic RNA isolation. RESULTS: DDX19A was highly expressed in gastric cancer and positively associated with malignant clinicopathological features and poor prognosis. Additionally, DDX19A promoted gastric cancer cell proliferation, migration, and epithelial-mesenchymal transition phenotypes. Mechanistically, DDX19A activated the PI3K/AKT pathway by upregulating phosphatidylinositol-3-kinase (PIK3CA) expression. Furthermore, DDX19A interacted with PIK3CA mRNA, stabilized it, and facilitated its export from the nucleus. CONCLUSIONS: Our study reveals a novel mechanism whereby DDX19A promotes the proliferation and migration of gastric cancer cells by enhancing the stability and nuclear export of PIK3CA mRNA, thereby activating the PI3K/AKT pathway.

Comparative Analysis of Ketorolac and Parecoxib for Postoperative Pain Management in Uvulopalatopharyngoplasty.

Background/Objectives: Uvulopalatopharyngoplasty (UPPP) is a prevalent surgical procedure for treating obstructive sleep apnea. Effective postoperative pain management is crucial for patient comfort and recovery. This study aimed to compare the analgesic efficacies of parecoxib and ketorolac in patients undergoing UPPP. Methods: A prospective, randomized, double-blind study was conducted on 83 patients who received either parecoxib (40 mg intravenously every 12 h) or ketorolac (30 mg intravenously every 8 h) for 2 days following UPPP. Postoperative pain and swallowing discomfort were assessed using visual analog scales (VASs) at 4, 24, 48, and 72 h. The time to resume eating and adverse reactions were also recorded. Results: At 24 and 48 h postoperatively, the mean VAS score was significantly higher in the ketorolac group compared to the parecoxib group (5.0 ± 2.3 vs. 3.6 ± 2.2, p = 0.005 and 3.9 ± 2.2 vs. 2.5 ± 1.7, p < 0.001, respectively). However, no significant difference in the mean VAS scores was observed between the two groups at 72 h postoperatively. With regards to postoperative swallowing pain, the ketorolac group exhibited significantly higher mean VAS scores than the parecoxib group at 4, 24, 48, and 72 h postoperatively. Conclusions: Intravenous parecoxib may offer superior analgesic benefits in the early postoperative period, particularly in alleviating swallowing pain, compared to ketorolac in UPPP procedures.

Exploring the Characteristics and Source-attributed Health Risks Associated with Polycyclic Aromatic Hydrocarbons and Metal Elements in Atmospheric PM2.5 during Warm and Cold Periods in the Northern Metropolitan Area of Taiwan.

Polycyclic aromatic hydrocarbons (PAHs) and metal elements are commonly considered hazardous air pollutants due to their toxic, mutagenic, and carcinogenic properties. However, few studies have simultaneously examined their potential sources and health effects. This study aimed to quantify the PAHs and metal elements in atmospheric PM2.5, investigating their characteristics and potential sources to assess associated health risks in the northern metropolitan area of Taiwan. The measurements indicated that the mean concentrations of total PAHs and metal elements in PM2.5 were 0.97±0.52 ng m-3 and 590±200 ng m-3, respectively. Utilizing the positive matrix factorization profiles, the PAH pollution was classified into two sources: industrial emissions, traffic emissions, and coal combustion (69%) were the predominant sources of PAHs, with petroleum volatilization and biomass burning (31%) making a lesser contribution. Similarly, we traced metal elements to three potential sources: natural sources (48%), a combined source of industrial emissions, coal combustion, and traffic exhaust (32%), and a blend of non-exhaust emissions from traffic and waste incineration sources (20%). Results from the potential source contribution function model suggested that the emissions of PAHs and metals could be influenced by the eastern regions of China, although local sources, including waste incinerators, traffic, shipping, and harbor activities, were identified as the primary contributors. Source-attributed excess cancer risk revealed that industry, traffic, and coal combustion had the highest cancer risk posed by PAHs in the cold period (1.0×10-5), while the greatest cancer risk among metal elements was linked to non-exhaust emissions from traffic and waste incineration emissions (2.0×10-5). This research underscores the importance of considering source contributions to health risk and emission reduction when addressing PM2.5 pollution. These findings have direct implications for policymakers, providing them with valuable insights to develop strategies that protect public health from the detrimental effects of PAH and metal element exposure.

High-yield extracellular vesicle production from HEK293T cells encapsulated in 3D auxetic scaffolds with cyclic mechanical stimulation for effective drug carrier systems.

Extracellular vesicles (EVs) show promise in drug loading and delivery for medical applications. However, the lack of scalable manufacturing processes hinders the generation of clinically suitable quantities, thereby impeding the translation of EV-based therapies. Current EV production relies heavily on non-physiological 2D cell culture or bioreactors, requiring significant resources. Additionally, EV-derived ribonucleic acid cargo in 3D and 2D culture environments remains largely unknown. In this study, we optimized the biofabrication of 3D auxetic scaffolds encapsulated with human embryonic kidney 293T (HEK293T) cells, focusing on enhancing the mechanical properties of the scaffolds to significantly boost EV production through tensile stimulation in bioreactors. The proposed platform increased EV yields approximately 115-fold compared to conventional 2D culture, possessing properties that inhibit tumor progression. Further mechanistic examinations revealed that this effect was mediated by the mechanosensitivity of YAP/TAZ. EVs derived from tensile-stimulated HEK293T cells on 3D auxetic scaffolds demonstrated superior capability for loading doxorubicin compared to their 2D counterparts for cancer therapy. Our results underscore the potential of this strategy for scaling up EV production and optimizing functional performance for clinical translation.

M2 macrophage infusion ameliorates diabetic glomerulopathy via the JAK2/STAT3 pathway in db/db mice.

Objectives: To explore the therapeutic effects of M2 macrophages in diabetic nephropathy (DN) and their mechanism.Methods: We infused M2 macrophages stimulated with IL-4 into 10-week-old db/db mice once a week for 4 weeks through the tail vein as M2 group. Then we investigated the role of M2 macrophages in alleviating the infammation of DN and explored the mechanism.Results: M2 macrophages hindered the progression of DN, reduced the levels of IL-1ß (DN group was 34%, M2 group was 13%, p < 0.01) and MCP-1 (DN group was 49%, M2 group was 16%, p < 0.01) in the glomeruli. It was also proven that M2 macrophages alleviate mesangial cell injury caused by a high glucose environment. M2 macrophage tracking showed that the infused M2 macrophages migrated to the kidney, and the number of M2 macrophages in the kidney reached a maximum on day 3. Moreover, the ratio of M2 to M1 macrophages was 2.3 in the M2 infusion group, while 0.4 in the DN group (p < 0.01). Mechanistically, M2 macrophages downregulated Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 in mesangial cells.Conclusions: Multiple infusions of M2 macrophages significantly alleviated inflammation in the kidney and hindered the progression of DN at least partially by abrogating the M1/M2 homeostasis disturbances and suppressing the JAK2/STAT3 pathway in glomerular mesangial cells. M2 macrophage infusion may be a new therapeutic strategy for DN treatment.

The clinical effect of Dienogest on urinary and sexual symptoms in endometriosis patients.

BACKGROUND: To evaluate the effect on urinary symptoms and sexual functioning of Dienogest within a 6-month period of follow-up. METHODS: A total of 22 women who were diagnosed as having endometriosis with pelvic pain and irritative urinary symptoms were recruited in this study. The participating patients took a daily dose of 2 mg DNG and underwent outpatient visits at the beginning, 1, 2, 3 and 6 months following treatment. RESULTS: Our data showed a significant improvement of the VAS score since the 1st month till the 6th month after treatment of DNG. OABSS, UDI-6 and IIQ-7 were significantly improved after the treatment of DNG. Besides, serum estradiol was also decreased. Our data also showed that DNG treatment for 6 months did not affect FSFI score. Some patients with heavy menstruation were also improved; however, some patients with regular periods missed or dropped a period after DNG treatment, while other adverse effects were also shown. CONCLUSION: Our study demonstrated that DNG could not only alleviate endometriosis pelvic pain but reduce urinary symptoms within the 6-month follow-up as well. DNG did not affect sexual function in FSFI score, although some adverse effects were recorded.

Effects of Bifidobacterium bifidum tetragonum tablets and Jin Gui Ren Qi Pill on intestinal flora and metabolism in patients with diabetic kidney disease.

Objective: To investigate the effects of Bifidobacterium bifidum tetragonum tablets and Jin Gui Ren Qi Pill on intestinal flora and metabolism in patients with diabetic kidney disease. Methods: In the study conducted at Heping Hospital of Changzhi Medical College from March 2021 to December 2022, 30 cases of patients diagnosed with diabetic nephropathy were meticulously selected as study subjects. Employing a double-blind randomized table method, these patients were randomly allocated into three groups: the control group (n = 10), the Bifidobacterium bifidum tetragonum tablets group (n = 10), and the Jin Gui Ren Qi Pill group (n = 10). The control group received standard western medical treatments for diabetic nephropathy, including serum glucose, blood lipids, blood pressure management, and other conventional therapies. In addition to the standard treatments, the Bifidobacterium bifidum tetragonum tablets group received Bifidobacterium bifidum tetragonum tablets, while the Jin Gui Ren Qi Pill group received Jin Gui Ren Qi Pill. Before and after a 4-week treatment period, various baseline parameters were assessed, including fasting blood glucose, 2-h postprandial blood glucose, triglycerides, serum total cholesterol, serum low-density lipoprotein cholesterol, serum high-density lipoprotein cholesterol, random urine microalbumin/creatinine ratio (ACR), blood creatinine (SCr), and traditional Chinese medicine evidence scores. Stool specimens were collected from all three groups before and after treatment for 16S rDNA high-throughput sequencing, followed by comprehensive analyses including OUT clustering, Alpha diversity, Beta diversity, species composition analysis, LEfSe analysis, and KEGG function prediction. Spearman correlation analysis was employed to explore the relationship between intestinal flora and clinical indicators. Furthermore, fasting peripheral venous blood was collected from patients in the Bifidobacterium tetrapunctate tablets group and the control group before and after intervention to measure the optical density values of tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interleukin-6 (IL-6) using the Beijing Biolite ELISA kit. This study was conducted with the approval of the Ethics Committee of Changzhi Medical College. Results: 1. The 2hPBG, total cholesterol and LDL levels were observed among patients with diabetic kidney disease (DKD) across all groups: the Jin Gui Ren Qi Pill group, the Bifidobacterium bifidum tetragonum tablets group, and the control group (p < 0.05). 2. The Jin Gui Ren Qi Pill demonstrated superior efficacy in alleviating TCM symptoms and reducing the ACR compared to both the Bifidobacterium bifidum tetragonum tablets group and the control group. Conversely, Bifidobacterium bifidum tetragonum tablets exhibited a more pronounced reduction in TC levels compared to both the Jin Gui Ren Qi Pill and control groups. Notably, Bifidobacterium bifidum tetragonum tablets effectively decreased (IL-2) levels in patients with DKD. 3. Bifidobacterium bifidum tetragonum tablets also demonstrated efficacy in reducing IL-2 levels in DKD patients. 4. Analysis of intestinal microorganism abundance and diversity before and after the intervention, as well as among the three groups, revealed no significant alterations. Similarly, comparisons of ACE, Chao, Simpson, and Shannon indices showed no statistically significant differences (p > 0.05). 5. Qualitative analysis of intestinal microorganisms before and after intervention, as well as among the three groups, indicated no significant differences. Anosim test results also did not reveal qualitative distinctions (Anosim test R = 0.021, p = 0.215). 6. LEfSe analysis unveiled a noteworthy increase in Prevotella_7 abundance within the Jin Gui Ren Qi Pill group post-intervention (p < 0.05). 7. Furthermore, Chinese medicine evidence scores, body mass index, TC, and LDL levels correlated positively with the relative abundance of Tyzzerella_3 bacterial flora. Conversely, age, disease duration, and 2hPBG correlated positively with the relative abundance of Christensenellaceae_R_7 flora, while TC and LDL levels displayed a negative correlation with the relative abundance of Christensenellaceae_R_7 flora. Conclusion: The combination of Jin Gui Ren Qi Pill with western medical treatment exhibited superior efficacy in ameliorating clinical symptoms and reducing the ACR in patients with DKD compared to western medical treatment alone. Furthermore, this combination therapy led to an increase in the abundance of Prevotella_7 within the intestinal flora of patients, suggesting a potential enhancement in carbohydrate metabolism by the intestinal microbiota. On the other hand, Bifidobacterium bifidum tetragonum tablets bacterial tablets combined with western medical treatment demonstrated enhanced efficacy in reducing TC levels in DKD patients compared to western medical treatment alone. Additionally, this combination therapy effectively reduced the levels of IL-2 in DKD patients, thus mitigating inflammation in these individuals.