Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

Epidermal ET-1 signal induces activation of resting hair follicles by upregulating the PI3K/AKT pathway in the dermis.

The prevalence of alopecia has increased recently. Hair loss is often accompanied by the resting phase of hair follicles (HFs). Dermal papilla (DP) plays a crucial role in HF development, growth, and regeneration. Activating DP can revive resting HFs. Augmenting WNT/ß-catenin signaling stimulates HF growth. However, the factors responsible for activating resting HFs effectively are unclear. In this study, we investigated epidermal cytokines that can activate resting HFs effectively. We overexpressed ß-catenin in both in vivo and in vitro models to observe its effects on resting HFs. Then, we screened potential epidermal cytokines from GEO DATASETs and assessed their functions using mice models and skin-derived precursors (SKPs). Finally, we explored the molecular mechanism underlying the action of the identified cytokine. The results showed that activation of WNT/ß-catenin in the epidermis prompted telogen-anagen transition. Keratinocytes infected with Ctnnb1-overexpressing lentivirus enhanced SKP expansion. Subsequently, we identified endothelin 1 (ET-1) expressed higher in hair-growing epidermis and induced the proliferation of DP cells and activates telogen-phase HFs in vivo. Moreover, ET-1 promotes the proliferation and stemness of SKPs. Western blot analysis and in vivo experiments revealed that ET-1 induces the transition from telogen-to-anagen phase by upregulating the PI3K/AKT pathway. These findings highlight the potential of ET-1 as a promising cytokine for HF activation and the treatment of hair loss.

FTO-mediated m6A modification of serum amyloid A2 mRNA promotes podocyte injury and inflammation by activating the NF-κB signaling pathway.

Diabetic kidney disease (DKD) is one of the severe complications of diabetes mellitus, yet there is no effective treatment. Exploring the development of DKD is essential to treatment. Podocyte injury and inflammation are closely related to the development of DKD. However, the mechanism of podocyte injury and progression in DKD remains largely unclear. Here, we observed that FTO expression was significantly upregulated in high glucose-induced podocytes and that overexpression of FTO promoted podocyte injury and inflammation. By performing RNA-seq and MeRIP-seq with control podocytes and high glucose-induced podocytes with or without FTO knockdown, we revealed that serum amyloid A2 (SAA2) is a target of FTO-mediated m6A modification. Knockdown of FTO markedly increased SAA2 mRNA m6A modification and decreased SAA2 mRNA expression. Mechanistically, we demonstrated that SAA2 might participate in podocyte injury and inflammation through activation of the NF-κB signaling pathway. Furthermore, by generating podocyte-specific adeno-associated virus 9 (AAV9) to knockdown SAA2 in mice, we discovered that the depletion of SAA2 significantly restored podocyte injury and inflammation. Together, our results suggested that upregulation of SAA2 promoted podocyte injury through m6A-dependent regulation, thus suggesting that SAA2 may be a therapeutic target for diabetic kidney disease.

Phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein PINLYP regulates type I interferon innate immunity.

Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaired the activation of IRF3 and production of IFN-ß induced by DNA virus, RNA virus, and various Toll-like receptor ligands in multiple cell types. Because PINLYP deficiency in mice engendered an early embryonic lethality in mice, we generated a conditional mouse in which PINLYP was depleted in dendritic cells. Mice lacking PINLYP in dendritic cells were defective in type I IFN induction and more susceptible to lethal virus infection. Thus, PINLYP is a positive regulator of type I IFN innate immunity and important for effective host defense against viral infection.

M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1ß.

Stress-induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress-induced hair loss was related to an imbalanced immune microenvironment. Screening the skin-infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress-induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in-vivo and in-vitro studies confirm that NE can induce macrophage polarization toward M1 through the ß-adrenergic receptor, Adrb2. Transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase-1 inflammasome signaling and its downstream effector interleukin 18 (IL-18) and interleukin 1 beta (IL-1ß) were significantly upregulated in the NE-treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase-1, IL-18, and IL-1ß. Indeed, IL-18 and IL-1ß treatments lead to apoptosis of HFSCs. More importantly, blocking IL-18 and IL-1ß signals reversed HFSCs depletion in skin organoid models and attenuated stress-induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)-endocrine (NE)-immune (M1 macrophages) axis in stress-induced hair shedding and suggestes that IL-18 or IL-1ß may be promising therapeutic targets.

Changing Patterns of Stroke and Subtypes Attributable to High Systolic Blood Pressure in China From 1990 to 2019.

BACKGROUND: It is unknown whether high systolic blood pressure had a similar effect on the disease burden of stroke subtypes. The aim of our study is to compare the long-term trends of stroke subtypes and sex groups attributable to high systolic blood pressure in China from 1990 to 2019. METHODS: Data about the age-standardized mortality rate and the age-standardized disability-adjusted life-year rate of stroke subtypes attributable to high systolic blood pressure in China were extracted in GBD (Global Burden of Disease) 2019. The trends in the age-standardized mortality rate and the age-standardized disability-adjusted life-year rate were calculated using the liner regression and age-period-cohort method, adjusted for age, period, and cohort. RESULTS: The estimated annual percentage change for mortality of stroke attributable to high systolic blood pressure was different from subtypes, with an estimated annual percentage change and 95% CI of 0.56 (0.37-0.74) for ischemic stroke (IS), -1.52 (-1.97 to -1.07) for intracerebral hemorrhage, and -7.02 (-7.86 to -6.17) for subarachnoid hemorrhage (SAH). The curve of the net drifts showed a downward trend for intracerebral hemorrhage and SAH, but that showed a stable trend for IS. The curve of local drifts showed a slow upward trend with age for IS, a slow downward trend for intracerebral hemorrhage, and a sharp downward trend for SAH. The drift curves showed different trends for males and females. The proportion of stroke mortality in young males was gradually increasing. The cohort rate ratio varied by subtypes, with the greatest decline for SAH, a slight decrease for intracerebral hemorrhage, and a slight increase for IS. The period rate ratio had decreased over the past 3 decades, with the greatest decline for SAH and the weakest decrease for IS. Moreover, both the period and cohort rate ratios for IS mortality due to high systolic blood pressure in males have increased significantly over the past 3 decades. CONCLUSIONS: Our results provided strong evidence that the disease burden of stroke attributable to high systolic blood pressure varied by subtypes and sex in China from 1990 to 2019. The age-standardized mortality rate and the age-standardized disability-adjusted life-year rate decreased for hemorrhagic stroke but increased for IS. Males had a higher mortality and exposure risk but a slighter decreasing trend than females. Our study suggested that greater attention should be given to the prevention of the burden of IS attributable to systolic blood pressure in China, especially for males.

Membrane-Free Electrosynthesis of Epichlorohydrins Mediated by Bromine Radicals over Nanotips.

The industrial manufacture of epichlorohydrin (ECH) often suffers from excessive corrosive chlorine and multistep processes. Here, we report a one-pot membrane-free Br radical-mediated ECH electrosynthesis. Bromine radicals electro-oxidized from Br- ions initiate the reaction and then eliminate HBr from bromohydrin to give ECH and release Br- ions for reuse. A high energy barrier for *OH oxidation and isolated Br adsorption sites enables NiCo2O4 to suppress the competitive oxygen and bromine evolution reactions. The high-curvature nanotips with an increased electric field concentrate Br- and OH- ions to accelerate ECH electrosynthesis. This strategy delivers ECH with a Faradaic efficiency of 47% and a reaction rate of 1.4 mol h-1 gcat-1 at a high current density of 100 mA cm-2, exceeding the profitable target from the techno-economic analysis. Economically profitable electrosynthesis, methodological universality, and the extended synthesis of epoxide-drug blocks highlight their promising potential.

Sensitive Determination of Arsenic by Photochemical Vapor Generation with Inductively Coupled Plasma Mass Spectrometry: Synergistic Effect from Antimony and Cadmium.

A novel method for the determination of trace arsenic (As) by photochemical vapor generation (PVG) with inductively coupled plasma mass spectrometry measurement was developed in this study. The synergistic effect from antimony (Sb) and cadmium (Cd) was found for the photochemical reduction of As for the first time. Effective photochemical reduction of As was obtained in the system containing 10% (v/v) acetic acid, 5.0 mg L-1 Sb(III), and 20.0 mg L-1 Cd(II) with 100 s UV irradiation. Analytical sensitivity of As(III) was comparable with that of As(V) under the tested conditions, making direct determination of total As feasible. Compared to the pneumatic nebulization method, analytical sensitivity of the developed method was enhanced about 50 folds. The PVG efficiency was estimated up to be 99 ± 3%. The limit of detection (LOD) (3σ) was found to be 2.1 ng L-1 for As, which was improved about 30-fold compared to that using direct sample introduction solution nebulization. Considering the sample dilution prior to analysis (usually one-fold), the LOD was actually enhanced about 15 folds. The relative standard deviations of seven replicate measurements of 1.0 µg L-1 As(III) and As (V) standard solutions were 2.3 and 2.9% for As(III) and As(V), respectively. The proposed method was successfully applied for the detection of As in certified reference materials of sediments (GBW07303a and GBW07305a), as well as three water samples. The mechanism of the PVG system was investigated by using gas chromatography mass spectrometry, electron paramagnetic resonance, and X-ray photoelectron spectroscopy. (CH3)3As along with (CH3)3Sb were synthesized under UV irradiation. Besides, volatile species of Cd were also found. The result obtained in this study is useful for developing efficient "sensitizers" in PVG and understanding the transformation of As in the presence of hydride/cold vapor forming elements in the photochemical process.

Integrating network pharmacology and experimental validation reveals therapeutic effects of D-mannose on NAFLD through mTOR suppression.

Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition and metabolic disorder, has emerged as a significant health issue worldwide. D-mannose, a natural monosaccharide widely existing in plants and animals, has demonstrated metabolic regulatory properties. However, the effect and mechanism by which D-mannose may counteract NAFLD have not been studied. In this study, network pharmacology followed by molecular docking analysis was utilized to identify potential targets of mannose against NAFLD, and the leptin receptor-deficient, genetically obese db/db mice was employed as an animal model of NAFLD to validate the regulation of D-mannose on core targets. As a result, 67 targets of mannose are predicted associated with NAFLD, which are surprisingly centered on the mechanistic target of rapamycin (mTOR). Further analyses suggest that mTOR signaling is functionally enriched in potential targets of mannose treating NAFLD, and that mannose putatively binds to mTOR as a core mechanism. Expectedly, repeated oral gavage of supraphysiological D-mannose ameliorates liver steatosis of db/db mice, which is based on suppression of hepatic mTOR signaling. Moreover, daily D-mannose administration reduced hepatic expression of lipogenic regulatory genes in counteracting NAFLD. Together, these findings reveal D-mannose as an effective and potential NAFLD therapeutic through mTOR suppression, which holds translational promise.

Gestational diabetes mellitus is associated with greater incidence of dementia during long-term post-partum follow-up.

BACKGROUND: The impact of gestational diabetes mellitus (GDM) on incident dementia is unknown. Our aim was to evaluate the relationship between GDM and all-cause dementia and the mediating effects of chronic diseases on this relationship. METHODS: This prospective cohort study included women from the UK Biobank who were grouped based on GDM history. Multivariate Cox proportional hazard models were used to explore the associations between GDM and dementia. We further analysed the mediating effects of chronic diseases on this relationship and the interactions of covariates. RESULTS: A total of 1292 women with and 204,171 women without a history of GDM were included. During a median follow-up period of 45 years after first birth, 2921 women were diagnosed with dementia. Women with a GDM history had a 67% increased risk of incident dementia (hazard ratio 1.67, 95% confidence interval: 1.03-2.69) compared with those without a GDM history. According to mediation analyses, type 2 diabetes, coronary heart disease, chronic kidney disease and comorbidities (diagnosed with any two of the three diseases) explained 34.5%, 8.4%, 5.2% and 18.8% of the mediating effect on the relationship. Subgroup analyses revealed that physical activity modified the association between GDM history and dementia (p for interaction = 0.030). Among physically inactive women, GDM was significantly associated with incident dementia; however, this association was not observed among physically active women. CONCLUSIONS: A history of GDM was associated with a greater risk of incident dementia. Type 2 diabetes partially mediated this relationship. Strategies for dementia prevention might be considered for women with a history of GDM.

GOLPH3 promotes tumor malignancy via inhibition of ferroptosis by upregulating SLC7A11 in cholangiocarcinoma.

Golgi phosphoprotein 3 (GOLPH3) has been reported as an oncogene in various tumors; however, the role and function of GOLPH3 and its relevant molecular mechanism in cholangiocarcinoma (CCA) are unclear. Herein, GOLPH3 expression in CCA tissues was observed to be significantly higher than that in paired adjacent noncancerous tissues. Clinicopathological analysis showed that GOLPH3 expression correlated positively with the tumor-node-metastasis stage. In addition, GOLPH3 expression correlated inversely with the overall survival of patients with CCA. Multivariate analysis showed that GOLPH3 was an independent prognostic factor for patients with CCA. Transcriptome analysis (RNA sequencing) of GOLPH3 knockdown cells showed that the expression levels of nine ferroptosis-related genes were significantly changed, indicating the important biological function of GOLPH3 in ferroptosis in CCA cells. Furthermore, GOLPH3 knockdown could significantly promote Erastin-induced ferroptosis in vitro and suppress tumor growth in vivo. Overexpression of GOLPH3 had the opposite effect on this phenotype. Further studies revealed that GOLPH3 knockdown was significantly associated with a decrease in cysteine content, an accumulation of the lipid peroxidation product malondialdehyde, an increase in reactive oxygen species, and sensitized CCA cells to Erastin-induced ferroptosis. Moreover, changes in GOLPH3 expression were found to be consistent with the expression of light chain subunit solute carrier family 7 member 11 (SLC7A11). Thus, our study suggested that GOLPH3 functions as an oncoprotein in CCA and may suppress ferroptosis by facilitating SLC7A11 expression, suggesting that GOLPH3 could serve as a therapeutic target for CCA treatment.

A new framework for drug-disease association prediction combing light-gated message passing neural network and gated fusion mechanism.

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug-disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug-disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug-disease associations.

Membrane-bound CD95 ligand modulates CD19-mediated B cell receptor signaling and EBV activation.

Post-transplant lymphoproliferative disorders (PTLDs) are associated with Epstein-Barr virus (EBV) infection in transplant recipients. Most of lymphoblastoid cell lines (LCLs) derived from EBV-immortalized B cells or PTLDs are sensitive to CD95-mediated apoptosis and cytotoxic T cell (CTL) killing. CD95 ligand (CD95L) exists as a transmembrane ligand (mCD95L) or a soluble form (sCD95L). Using recombinant mCD95L and sCD95L, we observed that sCD95L does not affect LCLs. While high expression of mCD95L in CTLs promotes apoptosis of LCLs, low expression induces clathrin-dependent CD19 internalization, caspase-dependent CD19 cleavage, and proteasomal/lysosomal-dependent CD19 degradation. The CD95L/CD95-mediated CD19 degradation impairs B cell receptor (BCR) signaling and inhibits BCR-mediated EBV activation. Interestingly, although inhibition of the caspase activity restores CD19 expression and CD19-mediated BCR activation, it fails to rescue BCR-mediated EBV lytic gene expression. EBV-specific CTLs engineered to overexpress mCD95L exhibit a stronger killing activity against LCLs. This study highlights that engineering EBV-specific CTLs to express a higher level of mCD95L could represent an attractive therapeutic approach to improve T cell immunotherapy for PTLDs.

Genotype-phenotype correlation in Prader-Willi syndrome: A large-sample analysis in China.

The genotype-phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes of PWS in children. We aimed to explore the influence of specific gene changes on the clinical symptoms of PWS and the value of early screening and early intervention of the condition. All data in this study were extracted from the database of the XiaoPang Weili Rare Disease Care Center. The collected information included basic demographics, maternal pregnancy information, endocrine abnormalities, growth and development abnormalities, and other clinical phenotypes. The relationships between genotypes and phenotypes in the major categories of PWS were analyzed. A total of 586 PWS cases with confirmed molecular diagnosis and genotyping were included in this study. Among them, 83.8% belonged to the deletion type, 10.9% the uniparental disomy (UPD) type, and 5.3% the imprinting defect (ID) type. Age-wide comparison among the three groups: The rate of hypopigmentation in the deletion group was higher than that in the UPD group (88.8% vs. 60.9%; p < 0.05); A total of 62 patients (14.2%) had epilepsy; and no statistical significance was found among the three groups (p = 0.110). Age-wide comparison between the deletion and non-deletion types: the rate of skin hypopigmentation and epilepsy in the deletion group was significantly higher than that in the non-deletion group (88.8% vs. 68.4%, p < 0.001; 15.9% vs. 7.6%, p = 0.040). The intergroup comparison for the >2-year age group: there were significant intergroup differences in the language development delay among the three groups (p < 0.001). The incidence of delayed language development was the highest in the deletion group, followed by the UPD group, and the lowest in the ID group. The rates of obesity and hyperphagia in the deletion group were also higher than those in the non-deletion group (71.1% vs. 58.9%, p = 0.041; 75.7% vs. 62.0%, p = 0.016). There are significant differences in the rates of skin hypopigmentation and language developmental delay among the deletion, UPD, and ID genotypes. The patients with deletion type had significantly higher rates of lighter skin color, obesity, hyperphagia, language developmental delay, and epilepsy. The results of this study will help clinicians better understand the impact of different PWS molecular etiologies on specific phenotypes.

NAC transcription factor SlNOR-like1 plays a dual regulatory role in tomato fruit cuticle formation.

The plant cuticle is an important protective barrier on the plant surface, constructed mainly by polymerized cutin matrix and a complex wax mixture. Although the pathway of plant cuticle biosynthesis has been clarified, knowledge of the transcriptional regulation network underlying fruit cuticle formation remains limited. In the present work, we discovered that tomato fruits of the NAC transcription factor SlNOR-like1 knockout mutants (nor-like1) produced by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9] displayed reduced cutin deposition and cuticle thickness, with a microcracking phenotype, while wax accumulation was promoted. Further research revealed that SlNOR-like1 promotes cutin deposition by binding to the promoters of glycerol-3-phosphate acyltransferase6 (SlGPAT6; a key gene for cutin monomer formation) and CUTIN DEFICIENT2 (SlCD2; a positive regulator of cutin production) to activate their expression. Meanwhile, SlNOR-like1 inhibits wax accumulation, acting as a transcriptional repressor by targeting wax biosynthesis, and transport-related genes 3-ketoacyl-CoA synthase1 (SlKCS1), ECERIFERUM 1-2 (SlCER1-2), SlWAX2, and glycosylphosphatidylinositol-anchored lipid transfer protein 1-like (SlLTPG1-like). In conclusion, SlNOR-like1 executes a dual regulatory effect on tomato fruit cuticle development. Our results provide a new model for the transcriptional regulation of fruit cuticle formation.

Effects of toothpaste containing inactivated Lacticaseibacillus paracasei Probio-01 on plaque-induced gingivitis and dental plaque microbiota.

Plaque-induced gingivitis is an inflammatory response in gingival tissues resulting from bacterial plaque accumulation at the gingival margin. Postbiotics can promote the proliferation of beneficial bacteria and optimise the state of microbiota in the oral cavity. In this study, we investigated the effect of inactivated Lacticaseibacillus paracasei Probio-01 on plaque-induced gingivitis and the dental plaque microbiota. A total of 32 healthy gingival participants (Group N, using blank toothpaste for 3 months) and 60 patients with plaque-induced gingivitis (30 in Group F, using inactivated Probio-01 toothpaste for 3 months, and 30 in Group B, using blank toothpaste for 3 months, respectively) were recruited. Clinical indices, which included bleeding on probing (BOP), gingival index (GI), and plaque index (PI), were used to assess the severity of gingivitis. Furthermore, 16SrDNA amplicon sequencing was used to explore changes in the gingival state and dental plaque microbiota in patients with plaque-induced gingivitis. The results showed that inactivated Probio-01 significantly reduced clinical indices of gingivitis, including BOP, GI, and PI, in participants with plaque-induced gingivitis and effectively relieved gingival inflammation, compared with that observed in the control group (group B). Inactivated Probio-01 did not significantly influence the diversity of dental plaque microbiota, but increased the relative abundance of dental plaque core bacteria, such as Leptotrichia and Fusobacterium (P < 0.05). Strong correlations were observed between the indices and abundance of dental plaque microbiota. Overall, the inactivated Probio-01 significantly reduced the clinical indices of gingivitis and effectively improved gingival inflammation in patients with plaque-induced gingivitis. The activity of inactivated Probio-01 against plaque-induced gingivitis was possibly mediated by its ability to regulate the dental plaque microbiota, as indicated by the close correlation between the plaque microbiota and clinical indices of gingivitis.

Muscle-specific overexpression of Atg2 gene and endurance exercise delay age-related deteriorations of skeletal muscle and heart function via activating the AMPK/Sirt1/PGC-1α pathway in male Drosophila.

Atg2 is a key gene in autophagy formation and plays an important role in regulating aging progress. Exercise is an important tool to resist oxidative stress in cells and delay muscle aging. However, the relationship between exercise and the muscle Atg2 gene in regulating skeletal muscle aging remains unclear. Here, overexpression or knockdown of muscle Atg2 gene was achieved by constructing the AtgUAS/MhcGal4 system in Drosophila, and these flies were also subjected to an exercise intervention for 2 weeks. The results showed that both overexpression of Atg2 and exercise significantly increased the climbing speed, climbing endurance, cardiac function, and lifespan of aging flies. They also significantly up-regulated the expression of muscle Atg2, AMPK, Sirt1, and PGC-1α genes, and they significantly reduced muscle malondialdehyde and triglyceride. These positive benefits were even more pronounced when the two were combined. However, the effects of Atg2 knockdown on skeletal muscle, heart, and lifespan were reversed compared to its overexpression. Importantly, exercise ameliorated age-related changes induced by Atg2 knockdown. Therefore, current results confirmed that both overexpression of muscle Atg2 and exercise delayed age-related deteriorations of skeletal muscle, the heart function, and lifespan, and exercise could also reverse age-related changes induced by Atg2 knockdown. The molecular mechanism is related to the overexpression of the Atg2 gene and exercise, which increase the activity of the AMPK/Sirt1/PGC-1α pathway, oxidation and antioxidant balance, and lipid metabolism in aging muscle.

The influence of gender-specific factors influencing severe anxiety in psychotic major depression: role of thyroid hormones and depression severity.

BACKGROUND: Psychotic major depression (PMD) is characterized by major depressive disorder (MDD) accompanied by delusions or hallucinations. While the prevalence of PMD and its association with anxiety have been studied, gender-specific differences and the role of thyroid hormones in PMD-related anxiety remain less explored. METHODS: A total of 1718 first-episode and drug-naïve MDD patients was assessed for the presence of PMD and severe anxiety. Clinical assessments, including Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions-Severity (CGI-S) scale, were conducted to assess depression, anxiety, psychotic symptoms, and clinical severity, respectively. Blood samples were collected to measure thyroid function parameters. RESULTS: The prevalence of severe anxiety was higher in PMD patients compared to non-psychotic MDD patients (71.3% vs. 5.3%). No significant gender differences were observed in the prevalence of severe anxiety among PMD patients. However, elevated thyroid-stimulating hormone (TSH) levels and increased depression severity (HAMD scores) were identified as independent risk factors for severe anxiety in female PMD patients. In contrast, no significant risk factors were found in male PMD patients. The area under the receiver operating characteristic (AUCROC) analysis revealed that the HAMD score and TSH level showed acceptable discriminatory capacity for distinguishing between female PMD patients with and without severe anxiety. CONCLUSION: This study highlights the heightened prevalence of severe anxiety in PMD patients, with TSH levels and depression severity emerging as gender-specific risk factors for anxiety in females. These findings suggest the importance of thyroid hormone assessment and tailored interventions for managing anxiety in female PMD patients.

Theoretical Study and Design for Thermally Activated Delayed Fluorescence Emitters with Through-Space Charge Transfer from an Acridine Derivative Donor to an O-Bridged Triphenylboron Boroxy Acceptor.

The through-space charge transfer thermally activated delayed fluorescence (TSCT-TADF) properties of a series of molecules were characterized and tested theoretically by density functional theory and time-dependent density functional theory. By analyzing the weak interaction of the molecules at the ground state and calculating the transition contribution ratio of the donor, acceptor, and bridge in the excited state, we verified the through-space charge transfer characteristic of these molecules. We designed new molecules on the basis of the reported molecules (non-TADF molecule 1 and TADF molecule 2) to improve the performance. Smaller singlet-triplet energy gaps and larger spin-orbit coupling were obtained in the designed molecules, which is beneficial to obtain higher intersystem crossing and reverse intersystem crossing rates (kRISC). In addition, we calculated the radiation rate and the singlet-triplet reorganization energy, which is used to characterize the nonradiation rate. The comprehensive evaluation of both radiative and nonradiative processes shows that molecules 4 and 6 have the potential to be highly efficient TSCT-TADF materials.

Experiences of financial toxicity among caregivers of cancer patients: a meta-synthesis of qualitative studies.

OBJECTIVES: The purpose of this study was to explore the experience of financial toxicity among caregivers of cancer patients and to provide recommendations for subsequent intervention strategies. METHODS: Computer searches of PubMed, EmBase, The Cochrane Library, Web of Science, CINAHL (EBSCO), CNKI, Wanfang database, and SinoMed for qualitative studies experience of financial toxicity among caregivers cancer patients. The search time frame was from the establishment of the database to May 2023. The quality of included studies was assessed using the Qualitative Research Checklist from the Joanna Briggs Institute (JBI) Reviewer's Manual. The meta-synthesis was integrated following the meta-aggregation method proposed by the Joanna Briggs Institute (JBI) and reported following the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines. RESULTS: A total of nine studies were included, distilling 25 qualitative findings into nine new categories and synthesizing three synthesized findings: caregivers have strong negative experiences that affect their family relationships, daily work and life; caregivers use different strategies to cope with financial toxicity; needs and expectations of caregivers coping with financial toxicity. CONCLUSIONS: Financial toxicity among caregivers of cancer patients affects their daily lives. Receiving timely recognition of this financial burden and providing assistance to enhance their coping skills are crucial in mitigating its impact. Healthcare professionals should focus on the financial toxicity experienced by caregivers of people with cancer, address their supportive needs, and develop a comprehensive support system to improve caregivers' coping abilities and quality of life.