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The annual number of human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) is increasing steadily. Comparative studies about haplo-HCT versus HCT with HLA-matched sibling donors (MSD-HCT) have been tried in acute myeloid leukemia and B-cell acute lymphoblastic leukemia/lymphoma (ALL). Few studies were reported in adult T-cell ALL (T-ALL). In this retrospective study, a total of 88 consecutive patients with T-ALL were enrolled who underwent MSD-HCT (n = 24) and haplo-HCT (n = 64) with antithymocyte globulin (ATG)-based graft versus host disease (GVHD) prophylaxis between 2010 and 2022. Median follow-up for survivors was similar (43.5 [range: 7-88] months for MSD-HCT versus 43.5 (range: 6-144) months in the Haplo-HCT group). The 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD) was similar, 33% (95% confidence interval [CI], 16%-52%) after MSD-HCT versus 44% (95% CI, 31%-55%) after haplo-HCT, P = 0.52. The cumulative incidences of grade III-IV aGVHD were 8% (95% CI, 1%-23%) in the MSD-HCT group and 5% (95% CI, 1%-12%) in the haplo-HCT group (P = 0.50). The 2-year cumulative incidence of chronic GVHD (limited and extensive) in the haplo-HCT, 11% (95% CI, 5%-20%) was significantly lower than that in the MSD-HCT group (42% [95% CI, 21%-62%], P = 0.002). The cumulative incidence of 4-year relapse rates (44% versus 37%, P = 0.56) and non-relapse mortality (7% versus 21%, P = 0.08) did not differ between these two groups. There were also no differences in 4-year overall survival (46% versus 47%, P = 0.44) and progression-free survival (49% versus 42%, P = 0.45) between these two groups. On multivariate analysis, using busulfan/fludarabine (BU/Flu) conditioning regimen was found to be associated with worse clinical outcome. Our results suggested that ATG-based haplo-HCT platform could work as an alternative to MSD-HCT for adult patients with T-ALL. Compared with MSD-HCT, haplo-HCT might carry a low risk for cGVHD.

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Background: Aging is the primary risk factor for the onset of Alzheimer's disease (AD). Inflamma-aging is a major feature in the process of aging, and the chronic neuroinflammation caused by inflamma-aging is closely related to AD. As the main participant of neuroinflammation, the polarization of microglia (MG) could influence the development of neuroinflammation. Objective: This study aims to observe the impact of YHD on microglia (MG) polarization and neuroinflammation to delay the onset and progression of AD. Methods: In vivo experiment, four-month senescence accelerated mouse prone 8 (SAMP8) were used as the model group, the SAMR1 mice of the same age were used as the control group. In YHD group, 6.24 g/kg YHD was intragastrically administrated continuously for 12 weeks, and Ibuprofen 0.026 g/kg in positive control group. Morris Water Maze test was used to evaluate the learning and memory ability, Nissl's staining and immunofluorescence double staining for neuron damage and MG M1/M2 polarization, Enzyme-Linked Immunosorbent Assay (ELISA) for neuroinflammation biomarkers in hippocampus, Western blot for key protein expression of TREM2/NF-κB signaling pathway. In vitro experiments, 10 µM/l Aß1-42 induced BV-2 cell model was used to re-verify the effect of YHD regulating MG polarization to reduce neuroinflammation. Also, TREM2 small interfering RNA (siRNA) was used to clarify the key target of YHD. Results: YHD could improve the learning and memory ability of SAMP8 mice evaluated by the Morris Water Maze test. Like Ibuprofen, YHD could regulate the M1/M2 polarization of MG and the levels of neuroinflammatory markers TNF-α and IL-10 in hippocampus, and relieve neuroinflammation and neuron loss. In addition, YHD could also regulate the expression of PU.1, TREM2, p-NF-κB P65 in the TREM2/NF-κB signaling pathway. Further in vitro experiments, we found that YHD had a significant regulatory effect on Aß1-42-induced BV-2 cell polarization, and it could significantly increase PU.1, TREM2, decrease p-NF-κB P65, p-IKKß, TNF-α, IL-6, IL-1ß. At the same time, using siRNA to inhibit TREM2, it proved that TREM2 was a key target for YHD to promote Aß1-42-induced BV-2 cell M2 polarization to reduce neuroinflammation. Conclusions: YHD could regulate the TREM2/NF-κB signaling pathway through TREM2, thereby to adjust MG polarization and reduce AD-related neuroinflammation.

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Skin pigmentation typically arises from the excessive secretion and accumulation of melanin, resulting in a darker complexion compared to normal skin. Currently, the local application of chemical drugs is a first-line strategy for pigmentation disorders, but the safety and efficacy of drugs still cannot meet clinical treatment needs. For long-term and safe medication, researchers have paid attention to natural products with higher biocompatibility. This article begins by examining the pathogenesis and treatment approaches of skin pigmentation diseases and summarizes the research progress and mechanism of natural products with lightening or whitening effects that are clinically common or experimentally proven. Moreover, we outline the novel formulations of natural products in treating pigmentation disorders, including liposomes, nanoparticles, microemulsions, microneedles, and tocosomes. Finally, the pharmacodynamic evaluation methods in the study of pigmentation disorder were first systematically analyzed. In brief, this review aims to collect natural products for skin pigmentation treatment and investigate their formulation design and efficacy evaluation to provide insights for the development of new products for this complex skin disease.

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Objective: This study aims to investigate the plantar biomechanics of healthy young males as they descend a single transition step from varying heights. Methods: Thirty healthy young males participated the experiment using the F-scan insole plantar pressure system in which participants made single transition steps descent from four step heights (5, 15, 25, and 35 cm), leading with their dominant or non-dominant foot. Plantar pressure data were collected for 5 s during the period between landing touchdown and standing on the ground. Landing at each step height was repeated three times, with a five-minute rest between different height trials. Results: At 5 cm and 15 cm steps, participants demonstrated a rearfoot landing strategy on both sides. However, forefoot contact was observed at heights of 25 cm and 35 cm. Parameters related to center of plantar pressure (COP) of the leading foot were significantly larger compared to the trailing foot (P < 0.001), increased with higher step heights. Vertical ground reaction forces for the biped, leading and trailing feet decreased with increasing step height (all P < 0.05). The leading foot had a higher proportion of overall and forefoot loads, and a lower proportion of rearfoot load compared to the trailing foot (P < 0.001). The overall load on the dominant side was lower than that on the non-dominant side for both the leading and trailing feet (P < 0.001). For the trailing foot, forefoot load on the dominant side was lower than that on the non-dominant side, however, the opposite result appeared in rearfoot load (P < 0.001). Upon the leading foot landing, forefoot load exceeded the rearfoot load for the dominant (P < 0.001) and non-dominant sides (P < 0.001). Upon the trailing foot landing, forefoot load was lower than the rearfoot load for the dominant (P < 0.001) and non-dominant sides (P = 0.019). Conclusion: When the characteristics of biomechanical stability are compromised by step height, landing foot, and footedness factors - due to altered foot landing strategies, changing COP, or uneven force distribution - ability to control motion efficiently and respond adaptively to the forces experienced during movement is challenged, increasing the likelihood of loss of dynamic balance, with a consequent increased risk of ankle sprains and falls.

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BACKGROUND: To systematically collect, evaluate, and synthesize evidence from randomized controlled trials (RCTs) supporting the use of electroacupuncture (EA) as an additional treatment option for Vascular mild cognitive impairment (VaMCI), a meta-analysis was carried out. METHODS: Electronic searches of eight databases were used to locate RCTs that evaluated EA as a VaMCI adjuvant therapy. The Cochrane Risk of bias was used to assess the included trials' methodological quality. Review Manager 5.4 was used to analyze the data. Trial sequential analysis (TSA) was conducted with the trial sequential analysis program. RESULTS: There were 15 RCTs with 1033 subjects in them. Compared to conventional therapy (CT) alone, the Montreal Cognitive Assessment (SMD 0.72, 95 percent CI [0.55, 0.88]), Mini-mental State Examination (SMD 0.73, 95 percent CI [0.60, 0.87]), and activities of daily living (SMD 0.83, 95 percent CI [0.54, 1.12]) were significantly improved while EA was used in conjunction with CT. The current studies exceeded the required information size, according to trial sequential analysis (TSA), demonstrating the reliability of EA adjuvant therapy VaMCI. CONCLUSIONS: According to the pooled data, EA as an adjunct therapy for the treatment of VaMCI increases clinical efficacy. Although the TSA confirms a stable conclusion, it is encouraged to conduct studies of the highest quality standards.

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Myocardial infarction (MI) leads to substantial cellular necrosis as a consequence of reduced blood flow and oxygen deprivation. Stimulating cardiomyocyte proliferation and angiogenesis can promote functional recovery after cardiac events. In this study, we explored a novel therapeutic strategy for MI by synthesizing a biomimetic nanovesicle (NV). This biomimetic NVs are composed of exosomes sourced from umbilical cord mesenchymal stem cells, which have been loaded with placental growth factors (PLGF) and surface-engineered with a cardiac-targeting peptide (CHP) through covalent bonding, termed Exo-P-C NVs. With the help of the myocardial targeting effect of homing peptides, NVs can be enriched in the MI site, thus improve cardiac regeneration, reduce fibrosis, stimulate cardiomyocyte proliferation, and promote angiogenesis, ultimately resulted in improved cardiac functional recovery. It was demonstrated that Exo-P-C NVs have the potential to offer novel therapeutic strategies for the improvement of cardiac function and management of myocardial infarction.

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Extensive research has shown that PR domain 16 (PRDM16) plays a critical role in adipose tissue metabolism, including processes such as browning and thermogenesis of adipocytes, beigeing of adipocytes, and adipogenic differentiation of myoblasts. These functions have been associated with diseases such as obesity and diabetes. Additionally, PRDM16 has been correlated with various other conditions, including migraines, heterochromatin abnormalities, metabolic syndrome, cardiomyopathy, sarcopenia, nonsyndromic cleft lip, and essential hypertension, among others. However, there is currently no systematic or comprehensive conclusion regarding the mechanism of PRDM16 in human tumours, including haematologic and solid tumours. The aim of this review is to provide an overview of the research progress on PRDM16 in haematologic and solid tumours by incorporating recent literature findings. Furthermore, we explore the prospects of PRDM16 in the precise diagnosis and treatment of human haematologic and solid tumours.

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Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.

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Background: Anlotinib and apatinib, both vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), are clinically established in the treatment of advanced non-small cell lung cancer (NSCLC) in China, with anlotinib emerging as a standard treatment strategy. This study was conducted to evaluate the efficacy and safety of apatinib and anlotinib, and to compare their differences in treating patients with advanced NSCLC. Patients and Methods: We retrospectively analyzed the data of patients with advanced NSCLC treated with apatinib or anlotinib at a hospital in Eastern China from January 2017 to December 2021. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profile. Results: A total of 145 patients were included in this study. Median PFS (mPFS) was 3.53 months for the apatinib group and 5.3 months for the anlotinib group (HR = 0.59, 95% CI: 0.41-0.84; P = 0.004), and median OS (mOS) was 7.6 months versus 15.6 months (HR = 0.68, 95% CI: 0.46-1.00; P = 0.048), which all showed significant differences after adjusting for confounders (P < 0.05). Subgroup analysis revealed that the presence or absence of bone metastases significantly influenced PFS in both treatment groups. The ORR was 3.03% in the anlotinib group versus 10.13% in the apatinib group (P = 0.12), the DCR was 72.73% versus 51.90% (P = 0.21). No unanticipated adverse events (AEs) were observed. The incidence of grade 3-4 AEs was significantly higher in the apatinib group (31.65% vs 13.64%, P < 0.05). Conclusion: Anlotinib demonstrated greater efficacy and safety compared to apatinib in the treatment of advanced NSCLC, particularly in patients with bone metastases and EGFR(-).

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BACKGROUND: Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis. OBJECTIVES: This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM. METHODS: A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites. RESULTS: MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM. CONCLUSION: This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM.

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Non-healing diabetic wounds and ulcer complications, with persistent cell dysfunction and obstructed cellular processes, are leading causes of disability and death in patients with diabetes. Currently, there is a lack of guideline-recommended hypoglycemic drugs in clinical practice, likely due to limited research and unclear mechanisms. In this study, it is demonstrated that liraglutide significantly accelerates wound closure in diabetic mouse models (db/db mice and streptozotocin-induced mice) by improving re-epithelialization, collagen deposition, and extracellular matrix remodeling, and enhancing the proliferation, migration, and adhesion functions of keratinocytes. However, these effects of improved healing by liraglutide are abrogated in dedicator of cytokinesis 5 (Dock5) keratinocyte-specific knockout mice. Mechanistically, liraglutide induces cellular function through stabilization of unconventional myosin 1c (Myo1c). Liraglutide directly binds to Myo1c at arginine 93, enhancing the Myo1c/Dock5 interaction by targeting Dock5 promoter and thus promoting the proliferation, migration, and adhesion of keratinocytes. Therefore, this study provides insights into liraglutide biology and suggests it may be an effective treatment for diabetic patients with wound-healing pathologies.

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Carbon dots (CDs), a type of nanoparticle with excellent optical properties, good biocompatibility, and small size, are finding increasing application across the fields of biology and biomedicine. In recent years, biomass-derived CDs with pharmacological activity (BP-CDs) derived from herbal medicines (HMs), HMs extracts and other natural products with demonstrated pharmaceutical activity have attracted particular attention. Herein, we review recent advances in the development of BP-CDs, covering the selection of biomass precursors, different methods used for the synthesis of BP-CDs from natural sources, and the purification of BP-CDs. Additionally, we summarize the many remarkable properties of BP-CDs including optical properties, biocompatibility and pharmaceutical efficacy. Moreover, the antibacterial, antiviral, anticancer, biosensing, bioimaging, and other applications of BP-CDs are reviewed. Thereafter, we discuss the advantages and disadvantages of BP-CDs and Western drug-derived CDs, highlighting the excellent performance of BP-CDs. Finally, based on the current state of research on BP-CDs, we suggest several aspects of BP-CDs that urgently need to be addressed and identify directions that should be pursued in the future. This comprehensive review on BP-CDs is expected to guide the precise design, preparation, and future development of BP-CDs, thereby advancing the application of BP-CDs in biomedicine.

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Background: Myocardial ischemia-reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia-reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. Methods: A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE's risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). Results: According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages-prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion-showed satisfactory results. Conclusions: Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies.

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Family environment, emotion regulation and biological sensitivity have been shown to be associated with adolescents' externalizing problem behaviours. However, findings regarding respiratory sinus arrhythmia (RSA) reactivity are mixed and sometimes contradictory. This study aims to clarify the roles of RSA reactivity and anger regulation in the relationship between negative family expressiveness (NFE) and adolescents' externalizing behaviour by measuring RSA reactivity during the Parent-Adolescent Interaction Task (PAIT), designed to simulate a naturalistic negative family environment. In this study, 125 Chinese adolescents (M = 13.95 years, SD = 0.95; 48% male) completed questionnaires assessing negative family expressiveness, anger regulation and externalizing problems. Additionally, we collected electrocardiogram and respiration data during both the resting period and a 10-min PAIT. Results showed that anger regulation mediated the relationship between NFE and externalizing problem behaviours. Moreover, adolescents' RSA reactivity moderated this mediation effect, even after controlling for baseline RSA. Greater RSA suppression potentially indicated greater susceptibility, with the relationship between NFE and anger regulation being more pronounced in adolescents with greater RSA suppression compared to those with lesser RSA suppression. These findings highlight the importance of considering physiological systems, especially within the context of adverse family environments, when studying the relationships with externalizing problems.

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PURPOSE: To investigate the effects of erbium laser pretreatment on the bond strength of dentin and enamel,as well as microleakage at the edge of tooth defects repaired with computer-aided design (CAD) and computer-assisted manufacturing (CAM) glass-ceramic restorations for repairing dental defects. METHODS: A total of 62 fresh, nondecayed, nondiscoloration and noncracked wisdom teeth were collected from the Oral Surgery Clinic between January 2020 and January 2023. According to different pretreatment methods, they were randomly divided into two groups, erbium laser group and phosphoric acid group, with 31 teeth in each group. Each group was further divided into two subsets for bond strength testing (16 teeth) and microleakage testing (15 teeth).The shear bond strength between enamel and dentin of both groups was compared, as well as the degree and distribution of microleakage.Statistical analysis was performed with SPSS 17.0 software package. RESULTS: The shear bond strength between enamel and dentin of the erbium laser group was significantly higher than that of the phosphoric acid group (P＜0.05); the degree and distribution of microleakage at the lateral walls and gumline of the erbium laser group were significantly lower than those of the phosphoric acid group (P＜0.05). The scores of microleakage at the lateral walls of the erbium laser group mainly concentrated in grade 1 and 2, whereas those of the phosphoric acid group mainly concentrated in grade 2. There was significant difference in the distribution of lateral wall microleakage scores between the two groups (P＜0.05). The scores of microleakage at the gumline of the erbium laser group mainly concentrated in grade 1 and 2, whereas those of the phosphoric acid group mainly concentrated in grade 2 and 3. There was significant difference in the distribution of gumline microleakage scores between the two groups (P＜0.05). CONCLUSIONS: Erbium laser pretreatment can improve bonding strength between glass ionomer cement and dentin and enamel, reduce microleakage at the edge of CAD/CAM glass ionomer cement restorations, and enhance marginal fit.

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INTRODUCTION: Although pressure support ventilation is one of the most commonly used assisted ventilation modes in intensive care units, there is still a lack of precise strategies for setting pressure support. By performing an end-inspiratory airway occlusion, the difference between the peak and plateau airway pressure, which is defined as pressure muscle index (PMI), can be easily measured on the ventilator screen. Previous studies have shown that PMI is accurate in detecting high and low inspiratory effort. No study has been conducted to investigate the use of PMI as an indicator for setting inspiratory pressure support. METHOD AND ANALYSIS: This is a study protocol for a prospective, single-centre, randomised controlled, pilot trial. Sixty participants undergoing pressure support ventilation will be randomly assigned in a 1:1 ratio to the control group or intervention group, with pressure support adjusted according to standard care or guided by the PMI strategy for 48 hours, respectively. The feasibility of the PMI-guided strategy will be evaluated. The primary endpoint is the proportion of inspiratory effort measurements within a well-accepted 'normal' range, which is predefined as oesophageal pressure-time product per minute between 50 and 200 cmH2O⋅s/min, for each patient during 48 hours of pressure support adjustment. ETHICS AND DISSEMINATION: The study protocol has been approved by Beijing Tiantan Hospital (KY2023-005-02). The data generated in the present study will be available from the corresponding author on reasonable request. The results of the trial will be submitted to international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05963737; ClinicalTrials.org.

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The objective of this study was to investigate the potential targets and mechanisms of UA in the treatment of PD. The efficacy of UA in PD was assessed through network pharmacology, molecular docking, and experimental methods. Common target protein-protein interaction (PPI) networks were constructed and visualized using Cytoscape. As a result, 9 key genes, namely CASP3, IL6, IL1B, PTGS2, CREB1, TNF, MAPK3, JUN, and CASP8, were selected. Molecular docking simulations were performed using Discovery Studio 2019 to validate the correlation between UA and the core targets. The results demonstrated a favorable binding affinity between UA and CASP8, IL1B, CASP3, TNF, MAPK3 and IL6. In vivo studies showed UA ameliorated motor dysfunction, and UA can significantly increase the protein expression of tyrosine hydroxylase (TH) in PD mice model. In addition, in vitro experiments confirmed that UA effectively reduced the protein expression of CASP8, CASP3 and MAPK3 in PD cell models and suppressed the gene expression of TNF-α, IL-6, and IL-1ß. These findings indicate that the therapeutic effects of UA on PD could be due to its influence on various targets within both the apoptosis and neuroinflammatory signaling pathways. Consequently, this study provides a methodological and theoretical foundation for further elucidating the pharmacological mechanism of UA.

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Background: ET, one of the most prevalent neurological disorders, presents a significant challenge in terms of disability. Despite the growing focus on ET in recent years, comprehensive bibliometric analysis has been lacking. Methods: This study delves into essential tremor research covering the period from 2013 to 2023, utilizing the Web of Science (WOS) database. Employing CiteSpace for quantitative analysis, it examines an array of metrics including annual publication trends, contributions from countries and institutions, authorship patterns, key terminologies, and patterns of reference co-citation. The primary objective is to use CiteSpace for a detailed visual exploration of the literature over the last decade, pinpointing the evolving landscape and key areas of focus in essential tremor research, and thus providing a foundation for future investigative endeavors. Results: There were 2,224 literary works included in all. The amount of published works has been steadily rising in recent years. Of them, the majority originate from the United States, Louis, Elan D. is the publisher of the most publications (161 articles), and Movement Disorders is the journal that receives the most citations. The key words contribution and co-cited literatures suggest that the main research hotspots in recent years are the physiological and pathological mechanism of essential tremor, the determination of optimal targets for deep brain stimulation (DBS) and surgery transcranial magnetic resonance-guided focused ultrasound (MRgFUS) in the surgical management of essential tremor and the innovative research of botulinum toxin administration method.

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Serine protease 50 (PRSS50/TSP50) is highly expressed in spermatocytes. Our study investigated its role in testicular development and spermatogenesis. Initially, PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes. To further explore this, we generated PRSS50 knockout ( Prss50 -/- ) mice ( Mus musculus), which exhibited abnormal spermatid nuclear compression and reduced male fertility. Furthermore, dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50 -/- mice, accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells. Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and elevated levels of MAP kinase phosphatase 3 (MKP3), a specific ERK antagonist, potentially accounting for testicular dysplasia in adolescent Prss50 -/- mice. Taken together, these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis, with the MKP3/ERK signaling pathway playing a significant role in this process.

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PURPOSE: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance. METHODS: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis. RESULTS: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers. CONCLUSION: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.