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Xue-Hong Feng,1 Yang Wang,1 Lian-Yu Wang,1 Jun-Fei Shen,1 Chun-Yuan You,1 Qiu-Ting Feng2 1Department of Echocardiography, The Second Hospital of Wuxi Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214002, People’s Republic of China; 2Department of Cardiology, The Second Hospital of Wuxi Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214002, People’s Republic of ChinaCorrespondence: Qiu-Ting FengDepartment of Cardiology, The Second Hospital of Wuxi Affiliated to Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214002, Jiangsu Province, People’s Republic of ChinaTel +86-15961823329Email fengbiqu22538573@163.comObjective: To investigate the predictive value of PTEN and echocardiography in the treatment of heart failure with trimetazidine combined with metoprolol.Methods: A total of 100 patients with coronary heart disease and HF who admitted to our hospital from August 2018 to August 2020 were enrolled into research. All patients received routine treatment according to the guidelines and were treated with trimetazidine and metoprolol for a total course of 6 months. Echocardiographic parameters and PTEN levels were measured at baseline and after treatment. The patients were divided into groups according to the quartile of basic PTEN level, and the total effective rates were compared. The echocardiographic parameters of patients with different prognosis were analyzed. Bivariate correlation analysis was used to evaluate the correlation between PTEN, echocardiography and treatment effect.Results: Compared with that before treatment, the level of PTEN increased significantly after treatment (P < 0.01). According to the quartile of basic PTEN level, the total effective rate of patients with different levels of basic PTEN was was statistically different (P < 0.01). There was a linear correlation between the level of basic PTEN and the treatment effect, and the total effective rate of patients with high level of basic PTEN was higher than that of patients with low level of PTEN. Compared with before treatment, LVEF, SV, E/A and lvfs increased significantly after treatment (P < 0.01). There was a correlation between the basic echocardiographic parameters and the treatment effect of patients. The basic echocardiographic parameters of patients with poor prognosis were worse than those with good prognosis. PTEN expression in patients’ serum was only positively correlated with E/A, but not with LVFE, SV and LVFS (P < 0.01).Conclusion: PTEN and echocardiographic parameters serve as a good method to evaluate the short-term therapeutic effect of trimetazidine combined with metoprolol in patients with heart failure.Keywords: PTEN, echocardiographic parameter, heart failure, trimetazidine, metoprolol, efficacy prediction

Jing Xiao, Weijun Chen, Xinhui Feng, Wenyi Liu, Zhenxing Zhang, Li He, Zhibin Ye Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China Objectives: We aimed to investigate the association of serum uric acid (UA) levels with bone mineral density (BMD) at all skeletal sites in healthy Chinese males >50 years of age. Methods: A cross-sectional study of 385 Chinese males >50 years of age who underwent health checkup in Huadong Hospital Affiliated to Fudan University in Shanghai, China, was conducted. Clinical and bone characteristics were compared in different UA tertiles (UA1: UA 50 years that serum UA levels are positively correlated with lumbar spine BMD and T-values, suggesting that UA may exert protective effect on bone density at the lumbar spine in Chinese males >50 years of age. Keywords: T-value, Z-value, parathyroid hormone, bone turnover marker

This study aimed to assess the correlation between estimated pulse wave velocity (ePWV) and mortality rates related to all-cause and cardiovascular disease (CVD) among individuals diagnosed with chronic kidney disease (CKD) in the United States. A total of 4669 participants with CKD were identified from the National Health and Nutrition Examination Survey conducted between 1999 and 2018. We calculated the incidence of CKD using an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m 2 . Our study examined the association between ePWV and mortality risk based on weighted Kaplan-Meier plots and multivariate Cox regression. Linear testing between ePWV and mortality from all causes and CVD was performed using restricted cubic splines and Cox regression. This study included 4669 patients with CKD from the NHANES, representing 37 million Americans with CKD. There was a mean age of 71.9 years, and 48.1% of participants were male. With every increase of 1 m/s in ePWV measurement, there is a corresponding 31% (hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.28-1.34) increase in the rate of mortality from all causes and a 32% (HR: 1.32, 95% CI: 1.27-1.37) increase in the rate of mortality from CVD. A significantly higher rate of cardiovascular and all-cause mortality was observed in patients with CKD with elevated ePWV than in those with lower ePWV, as shown in the weighted Kaplan-Meier plots. Patients with CKD have a significant relationship between ePWV and all-cause and cardiovascular mortality., (© 2025 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo , whereas knockout of ZNRF3 / RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data highlight ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptors, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer., Competing Interests: Competing interests Authors declare that they have no competing interests.

Gastric cancer is a common malignant tumor with high incidence and mortality. The overexpression of Human epidermal growth factor receptor 2 (HER2) is associated with increased metastatic potential and poor clinical outcome in gastric cancer. Despite the proven clinical response rates of approved HER2-targeted therapies, including Trastuzumab combined with chemotherapy, their limited long-term clinical benefits and inevitable disease progression still pose significant challenges to the clinical treatment of gastric cancer. Hence, exploring novel strategies to enhance therapeutic outcomes for HER2-positive patients is extremely crucial and urgent. Here, we reported that DX126-262, a novel HER2-targeted antibody-drug conjugate, generated by conjugating a potent Tubulysin B analogue (Tub-114) to humanized anti-HER2 monoclonal antibody, exhibited a significant synergistic inhibitory effect with both Cisplatin and 5-FU in HER2-positive gastric cancer NCI-N87 cells. Moreover, the triple-drug combination strategy of DX126-262 combined with Cisplatin and 5-FU showed much better in vitro and in vivo therapeutic efficacy than monotherapy or double-drug combination (Cisplatin plus 5-FU) or first-line standard-of-care (SOC, Herceptin plus Cisplatin and 5-FU), and comparable or even superior in vivo efficacy than third-line SOC (DS-8201a) in NCI-N87 cells and xenograft models. Meanwhile, the triple-drug combination therapy did not exhibit superimposed toxicity. Taken together, our findings provide compelling evidence that DX126-262 in combination with Cisplatin and 5-FU exerts synergistic antitumor activity and is a promising strategy to improve the clinical efficacy of HER2-positive advanced or metastatic gastric cancer., Competing Interests: R.Y.Z. is the President of Hangzhou DAC Biotechnology Co., Ltd., which holds the intellectual property right of the product DX126-262. X.C., M.C., and Q.Y. are employees of Hangzhou DAC Biotechnology Co., Ltd., (AJCR Copyright © 2024.)

Maxillary sinus is located in the maxilla bone with the largest volume in all sinuses and is closest to the roots of maxillary posterior teeth, especially the mesiobuccal root of the maxillary second molar. The thickness of the normal maxillary sinus mucosa is about 1 mm. When stimulated or infected, it shows thickening of the mucosa. Periodontitis is one of the most common oral diseases in human beings, and the complex root anatomy of the maxillary molars aggravates the difficulty of inflammation control. Severe periodontitis of maxillary molars without effective treatment can affect the maxillary sinus, increasing the possibility of the mucosa thickening, and is also one of the reasons for the occurrence of odontogenic maxillary sinusitis (OMS). There are many different schemes for the treatment of OMS caused by severe periodontitis of maxillary molars. Extraction of teeth with severe periodontal disease without retention value or successful periodontal treatment can significantly reduce the thickness of maxillary sinus mucosa. For the patients with uncontrollable sinusitis by using drug treatment and eliminating odontogenic causes, or ones with severe symptoms, periodontal treatment and endoscopic sinus surgery can be combined to effectively control the periodontitis related maxillary sinusitis.

Introduction: Periodontitis is a chronic multifactorial inflammatory disease which eventually lead to tooth loss (TL). Therefore, a retrospective study was conducted to evaluate the status of tooth survival within 11 years after non-surgical periodontal treatment (NSPT) and to analyze the risk factors especially crown-root ratio (CRR) that affected TL in Chinese with advanced periodontitis., Methods: 3481 teeth of 131 subjects who underwent NSPT were examined retrospectively within a mean follow-up period of 11.6 years. The association of risk factors including clinical and radiographic parameters with TL was assessed using univariate and multivariate Cox regression analyses. Smooth curve fitting and segmented regression model were conducted to show the nonlinear relationship and the threshold effect between CRR and the risk of TL., Results: 347 teeth were lost in 97 patients in this study. Male, diabetes mellitus, heavy-smoker, molar, probing depth (PD), attachment loss (AL), bleeding on probing (BOP), tooth mobility, and radiographic bone loss were significantly associated with tooth loss (P < 0.05). A nonlinear relationship between CRR and the risk of TL was found, with different turning point values between molars and non-molars (1.9 vs. 2.76)., Conclusions: The findings based on practice-based clinical and radiographic data do suggest a nonlinear relationship between CRR and the survival of teeth, and provide evidence to help clinicians to determine the prognosis of teeth for patients with advanced periodontitis., Clinical Significance: Based on clinical and radiographic data, this study provides an individualized basis for clinicians to judge the dental prognosis of patients with advanced periodontitis according to the different tooth sites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b +  F4/80 + TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity., (© 2024. The Author(s).)

Background: Previous studies have suggested a potential link between the crown-to-root ratio (CRR) and root morphology in patients with mild chronic periodontitis, which may be associated with tooth mobility. However, these findings have not been thoroughly investigated. Our previous study found that 76% of patients with aggressive periodontitis, particularly those with premolar involvement, exhibited abnormal root morphology, severe alveolar bone loss, and increased tooth mobility, leading to poor clinical outcomes. This study aims to investigate the specific correlations among alveolar bone resorption, root morphology, CRR, and periodontal clinical indicators with premolar mobility in stage III/IV grade C periodontitis patients aged ≤ 35 years., Materials and Methods: A total of 1,064 premolars from 151 stage III/IV grade C periodontitis patients aged ≤ 35 years were included in the study. Clinical periodontal parameters and radiographic measurements were recorded. Logistic regression analysis was used to explore the relationships between these indicators and tooth mobility., Results: Significant variations in premolar root lengths were observed, ranging from 6.80 mm to 20.96 mm. Teeth with shorter roots (mean length: 10.22 mm) exhibited grade I mobility with only 28% alveolar bone resorption, whereas those with medium-length (mean length: 12.67 mm) and longer roots (mean length: 14.91 mm) exhibited mobility at 34% and 37% bone resorption, respectively. Regression models incorporating the bone-level CRR, average probing depth, and root length demonstrated strong predictive accuracy for tooth mobility (P < 0.001, AIC = 1700.574)., Conclusion: Premolar mobility is influenced by variations in root length, alveolar bone resorption, and probing depth. The bone-level CRR is an effective predictor for assessing tooth mobility, especially when there are differences in root length and alveolar bone resorption., (© 2024. The Author(s).)

Correlation between echocardiographic and pathoanatomic variables and their prognostic value in murine cardiomyopathy models remain unknown. Using echocardiography, morphometrics, and survival monitoring, we characterized transgenic (TG) mice with dilated cardiomyopathy due to cardiac overexpression of β 2 -adrenoceptors focusing on predicting heart failure (HF) risk and HF mortality. In 12-month-old non-TG and TG mice, echocardiography was performed to determine left ventricular (LV) dimensions (d), wall thickness (h), and fractional shortening (FS). Animals were monitored for 3 months for survival. Organ weights and pathological events indicating left HF were determined. TG mice (n = 76) had reduced FS and enlarged LV, and 79% died of HF or likely arrhythmias during the follow-up period while all non-TG mice (n = 26) survived. These mice with left HF also had pulmonary congestion and hypertrophy/dilatation of the right ventricle (RV). Weights of lungs, RV, and atria were intercorrelated (r = 0.79-0.83) and also negatively correlated with FS × (h/d) index (r = -0.502 to -0.609). By FS × (h/d) tertiles, TG mice of low tertiles were identified with the highest mortality (96%) largely due to HF (76%). In conclusion, in aged cardiomyopathy mice a good correlation existed between echocardiographic and pathoanatomic variables. Echocardiography-derived LV function and remodeling were useful in identifying a subgroup of TG mice with a high risk of HF and HF fatality., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B-E (GSDMB-GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical and radiologic characteristics of children with congenital pseudarthrosis of the tibia (CPT) in a single center. Methods: This is a retrospective case series study. According to inclusion and exclusion criteria, clinical data of 497 children(507 limbs) with CPT who were treated at Department of Orthopedics, the Children's Hospital Affiliated to Xiangya School of Medicine, Central South University from January 2011 to December 2020 were collected. Baseline data included gender, age at initial visit, age at onset of symptoms, accompanying symptoms, domicile, whether first treated at our hospital, and treatment-related information such as surgical or conservative treatment, surgical complications, etc., were extracted and analyzed using the health information system. Imaging data of the children, including Crawford classification, bilateral leg lengths, presence of fibular pseudarthrosis, and location of pseudarthrosis along the tibia segment, were analyzed using the Picture Archiving and Communication System. Data were compared using independent sample t test or χ 2 tests. Results: Among 497 children with CPT, there were 305 males (61.4%) and 192 females (38.6%). The age at initial visit was (3.6±3.2) years (range: 0.1 to 16.2 years). Neurofibromatosis type 1 (NF1) symptoms were positive in 340 children (68.4%), and negative in 157 children (31.6%). Among NF1-positive children, those with symptoms onset before 1 year of age were significantly more than NF1-negative children (74.1%(252/340) vs . 66.2%(104/157); χ 2 =9.24, P =0.001), and the proportion of fractures (92.9%,316/340) was significantly higher than that in the NF1-negative group (84.7%,133/157) ( χ 2 =8.33, P =0.004). According to imaging data, Crawford type Ⅳ was the most common type, with 321 limbs (63.3%), followed by type Ⅱ in 100 limbs (19.7%), type Ⅲ in 54 limbs (10.7%) and type Ⅰ in 32 limbs (6.3%). Pseudarthrosis occurred in the proximal third of the tibia in 14 limbs (2.8%), in the middle third in 185 limbs (36.5%), and in the distal third in 308 limbs (60.8%). Seventy-four children (14.9 %) had associated fibular pseudarthrosis. The lateral proximal tibial angle was 86.91°±5.21°(range: 72.17° to 102.08°), and the lateral distal tibial angle was 87.27°±10.73°(range: 51.07° to 128.17°). A total of 421 children (84.7%) underwent surgical treatment with (3.1±2.4) surgeries performed per child (range:0 to 12 surgeries); 76 children (15.3%) received conservative treatment. Postoperative complications mainly included ankle valgus (77 cases), leg length discrepancy (71 cases),refracture (48 cases), osteomyelitis (11 cases), and hardware failure (10 cases). NF1-positive children underwent more surgeries than NF1-negative children ((5.1±2.2)times vs .(2.1±1.8)times; t =14.93, P <0.01). Conclusions: Crawford type Ⅳ is the most common type of CPT in children in this study. CPT predominantly occurs in the middle or distal third of the tibia. The majority of children with CPT experienced symptoms and were seen at outpatient clinics before the age of 3 years. The main surgical complications currently associated with CPT treatment are ankle valgus and leg length discrepancy. Compared with CPT without NF1, children with NF1-positive CPT tend to have earlier symptom onset and may require more frequent treatments.

As climate change, such as global warming, has become a global environmental issue, clarifying the mechanism driving the carbon budget based on land use change has become an inevitable path to realize the "double carbon" goal. Based on the land use change characteristics in the Hangzhou Metropolitan Area from 1995 to 2020, this study employed the inventory accounting method, concentration index, and panel regression models to investigate the driving mechanisms of carbon budget dynamics influenced by land use changes. Moreover, the study utilized a "scenario-actor" policy analysis framework to propose low-carbon strategies through the integration of land use management within territorial spatial planning. The research findings were as follows： ① The carbon source capacity in the study area significantly surpassed its carbon sink capacity. The overall carbon budget concentration index had yet to exceed the 0.4 "alert threshold," with spatial concentration levels as follows： Hangzhou &gt; Huangshan &gt; Shaoxing &gt; Quzhou &gt; Jiaxing ≈ Huzhou. ② For croplands, larger areas and greater shape regularity contributed to a reduction in carbon budgets. Conversely, for constructed lands, expansive areas and increased fragmentation intensified the carbon budget levels, primarily driven by other urban land categories. ③ An increased proportion of croplands and higher land use heterogeneity promoted spatial equilibrium in carbon budgets, whereas the larger coverage and fragmentation of industrial and other urban lands led to an uneven spatial distribution of carbon budgets. ④ Low-carbon optimization of territorial space needs to adjust for the structure and form of carbon source functional land use as a key driver. At the policy implementation level, the central government and urban residents demonstrated strong support for low-carbon territorial control. However, cooperation from local governments, enterprises, and rural residents was suboptimal, necessitating complementary policies for effective guidance. This study holds practical significance for enhancing land use efficiency and promoting low-carbon urban development.

RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in the Hippo pathway are substrates of RNF214. RNF214 induces non-proteolytic ubiquitylation at a conserved lysine residue of TEADs, enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling. Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a signaling axis of RNF214-TEAD-YAP and suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy., (© 2024. The Author(s).)

Clarifying the mechanism of influence of urban form on carbon emissions is an important prerequisite for achieving urban carbon emission reduction. Taking the Yangtze River Economic Belt as an example, this study elaborated on the general mechanism of urban form on carbon emissions, used multi-source data to quantitatively evaluate the urban form, and explored the impacts of urban form indicators on carbon emissions from 2005 to 2020 at global and sub-regional scales with the help of spatial econometric models and geodetector, respectively. The results showed that:① The carbon emissions of the Yangtze River Economic Belt increased from 2 365.31 Mt to 4 230.67 Mt, but the growth rate gradually decreased. Its spatial distribution pattern was bipolar, with high-value areas mainly distributed in core cities such as Shanghai and Chongqing and low-value areas concentrated in the western regions of Sichuan and Yunnan. ② The area of construction land in the study area expanded over the past 15 years, but the population density of construction land had been decreasing. The degree of urban fragmentation was decreasing, and the difference between cities was also progressively narrowing. The average regularity of urban shape improved, and the compactness increased significantly. ③ All indicators of urban scale had significant positive effects on carbon emissions at the global scale, urban fragmentation had a significant negative effect in 2005, and the effective mesh size (MESH) indicator of urban compactness showed a significant negative correlation with carbon emissions in the study period. ④ Total class area, patch density, and effective mesh size had the most significant impacts on carbon emissions in upstream cities. Effective mesh size, mean perimeter-area ratio, and total class area had higher influences in midstream cities. Effective mesh size, percentage of like adjacencies, and largest patch index were the key factors to promote carbon reduction in downstream cities. Cities in different regions should comprehensively consider the impacts of various urban form indicators on carbon emissions and then optimize their urban form to promote sustainable development.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg -1 ·d -1 , i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 μM) significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The family of secreted dimeric proteins known as the Transforming Growth Factor-β (TGF-β) family plays a critical role in facilitating intercellular communication within multicellular animals. A recent symposium on TGF-β Biology - Signaling, Development, and Diseases, held on December 19-21, 2023, in Hangzhou, China, showcased some latest advances in our understanding TGF-β biology and also served as an important forum for scientific collaboration and exchange of ideas. More than twenty presentations and discussions at the symposium delved into the intricate mechanisms of TGF-β superfamily signaling pathways, their roles in normal development and immunity, and the pathological conditions associated with pathway dysregulation., (© 2024. The Author(s).)

The chromatin modifier GRAIN WEIGHT 6a (GW6a) enhances rice grain size and yield. However, little is known about its gene network determining grain size. Here, we report that MITOGEN-ACTIVED PROTEIN KINASE 6 (OsMAPK6) and E3 ligase CHANG LI GENG 1 (CLG1) interact with and target GW6a for phosphorylation and ubiquitylation, respectively. Unexpectedly, however, in vitro and in vivo assays reveal that both of the two post-translational modifications stabilize GW6a. Furthermore, we uncover two major GW6a phosphorylation sites (serine142 and threonine186) targeted by OsMAPK6 serving an important role in modulating grain size. In addition, our genetic and molecular results suggest that the OsMAPK6-GW6a and CLG1-GW6a axes are crucial and operate in a non-additive manner to control grain size. Overall, our findings identify a previously unknown mechanism by which phosphorylation and ubiquitylation non-additively stabilize GW6a to enhance grain size, and reveal correlations and interactions of these posttranslational modifications during rice grain development., (© 2024. The Author(s).)

Objective: The leptin receptor, encoded by the LEPR gene, is involved in tumorigenesis. A potential functional variant of LEPR , rs1137101 (Gln223Arg), has been extensively investigated for its contribution to the risk of digestive system (DS) cancers, but results remain conflicting rather than conclusive. Here, we performed a case-control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk., Methods: A total of 1,727 patients with cancer (gastric/liver/colorectal: 460/480/787) and 800 healthy controls were recruited. Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and confirmed using Sanger sequencing. Twenty-four eligible studies were included in the meta-analysis., Results: After Bonferroni correction, the case-control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population. The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS, gastric, and liver cancer in the Chinese population., Conclusion: The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers (especially liver and gastric cancer) in the Chinese population., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Objective: To evaluate the correlation between peri-implant probing depth (PPD) and radiographic bone level (rBL) in implants with peri-implantitis. Methods: From January 2019 to December 2022, 24 patients with 30 implants who suffered from peri-implantitis at the Department of Periodontology, Peking University School and Hospital of Stomatology were included in the present research. SPSS 26.0 software was used to simple random sampling select 30 healthy implants from which with electronic examination records in Department of Periodontology, Peking University School and Hospital of Stomatology from January 2007 to June 2023 as the control group. On the premise of retaining the implant prosthesis, PPD (distance between pocket bottom and peri-implant soft tissue margin) was examined using a Williams periodontal probe with a light force (about 0.2 N), and a total of 4 sites were recorded for each implant. Periapical radiography and cone beam CT were applied to measure the rBL (distance between the reference point at the neck of the implant and the apical point of the bone defect) and the width of the bone defect (DW), and the type of the bone defect was recorded. The correlation and consistency between the diagnosis of PPD and rBL were analyzed. Results: PPD was significantly correlated with rBL in a total of 60 implants in 180 sites ( r =0.64, P <0.001). The chi-square test showed an 8.15-fold increase in the detection rate of PD≥6 mm at sites with rBL≥1 mm ( P <0.001). Multivariate logistic regression analysis showed that rBL was still statistically associated with PPD after adjustment for jaw position and examination position of implants. Take rBL <1 mm as reference, the odds ratios ( OR ) of 1 mm≤rBL<2 mm, 2 mm≤rBL<3 mm and rBL≥3 mm group with PPD were 6.23 ( P =0.014), 2.77 ( P =0.183) and 10.87 ( P =0.001), respectively. Conclusions: There is a positive correlation between PPD and rBL in implants with peri-implantitis. PPD can be used as a clinical examination index to assist in estimating the level of peri-implant bone under the premise of retaining the prosthesis.

Lysosomal Storage Disorders (LSDs), which share common phenotypes, including enlarged lysosomes and defective lysosomal storage, are caused by mutations in lysosome-related genes. Although gene therapies and enzyme replacement therapies have been explored, there are currently no effective routine therapies against LSDs. During lysosome reformation, which occurs when the functional lysosome pool is reduced, lysosomal lipids and proteins are recycled to restore lysosome functions. Here we report that the sorting nexin protein SNX8 promotes lysosome tubulation, a process that is required for lysosome reformation, and that loss of SNX8 leads to phenotypes characteristic of LSDs in human cells. SNX8 overexpression rescued features of LSDs in cells, and AAV-based delivery of SNX8 to the brain rescued LSD phenotypes in mice. Importantly, by screening a natural compound library, we identified three small molecules that enhanced SNX8-lysosome binding and reversed LSD phenotypes in human cells and in mice. Altogether, our results provide a potential solution for the treatment of LSDs., (© 2024. The Author(s).)

Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.

Background: This study aimed to investigate the association between estimated pulse wave velocity (ePWV) and mortality outcomes among individuals with hypertension., Methods and results: Based on the National Health and Nutrition Examination Survey (NHANES) 1999-2018, a total of 14,396 eligible participants with hypertension were enrolled. The ePWV was calculated using the equation based on blood pressure and age. The mortality outcomes of included participants were directly acquired from the National Death Index database. The multivariable Cox regression analysis was used to examine the relationship between ePWV and mortality outcomes. Moreover, the restricted cubic spline (RCS) was also used to explore this relationship. Receiver operating characteristics curves (ROC) were adopted to evaluate the prognostic ability of ePWV for predicting mortality outcomes of patients with hypertension. The median follow-up duration was 10.8 years; individuals with higher an ePWV had higher risks of mortality from both all causes (HR: 2.79, 95% CI: 2.43-3.20) and cardiovascular diseases (HR: 3.41, 95% CI: 2.50-4.64). After adjusting for confounding factors, each 1 m/s increase in ePWV was associated with a 43% increase in all-cause mortality risk (HR: 1.43, 95% CI: 1.37-1.48) and a 54% increase in cardiovascular mortality risk (HR: 1.54, 95% CI: 1.43-1.66)., Conclusions: This study indicates that ePWV is a novel prognostic indicator for predicting the risks of mortality among patients with hypertension.

Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-β tumor-suppressive activity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Protein lipidation, which regulates numerous biological pathways and plays crucial roles in the pharmaceutical industry, is not encoded by the genetic code but synthesized post-translationally. In the present study, we report a computational approach for designing lipidation mimics that fully recapitulate the biochemical properties of natural lipidation in membrane association and albumin binding. Furthermore, we establish an engineered system for co-translational incorporation of these lipidation mimics into virtually any desired position of proteins in Escherichia coli and mammalian cells. We demonstrate the utility of these length-tunable lipidation mimics in diverse applications, including improving the half-life and activity of therapeutic proteins in living mice, anchoring functional proteins to membrane by substituting natural lipidation, functionally characterizing proteins carrying different lengths of lipidation and determining the plasma membrane-binding capacity of a given compound. Our strategy enables gain-of-function studies of lipidation in hundreds of proteins and facilitates the creation of superior therapeutic candidates., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The Hippo pathway has important roles in organ development, tissue homeostasis and tumour growth. Its downstream effector TAZ is a transcriptional coactivator that promotes target gene expression through the formation of biomolecular condensates. However, the mechanisms that regulate the biophysical properties of TAZ condensates to enable Hippo signalling are not well understood. Here using chemical crosslinking combined with an unbiased proteomics approach, we show that FUS associates with TAZ condensates and exerts a chaperone-like effect to maintain their proper liquidity and robust transcriptional activity. Mechanistically, the low complexity sequence domain of FUS targets the coiled-coil domain of TAZ in a phosphorylation-regulated manner, which ensures the liquidity and dynamicity of TAZ condensates. In cells lacking FUS, TAZ condensates transition into gel-like or solid-like assembles with immobilized TAZ, which leads to reduced expression of target genes and inhibition of pro-tumorigenic activity. Thus, our findings identify a chaperone-like function of FUS in Hippo regulation and demonstrate that appropriate biophysical properties of transcriptional condensates are essential for gene activation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The S3 level clinical practice guideline for the prevention and treatment of peri-implant diseases, developed by the European Federation of Periodontology, was published in June, 2023 (DOI: 10.1111/jcpe.13823), which culminated in the recommendations for implementation of various different interventions before, during and after implant placement/loading. Aim of the present article is to summarize and interpret the key points of this guideline and help clinicians understand this guideline better, in order to standardize the prevention and treatment of peri-implant diseases.

Objective: To investigate the effects of the B7-H4 gene rs10754339 and miR-125a gene rs12976445 on cancer susceptibility through a case-control study and meta-analysis., Methods: A total of 1,490 cancer patients (lung/gastric/liver/: 550/460/480) and 800 controls were recruited in this case-control study. The meta-analysis was performed by pooling the data from previous related studies and the present study., Results: The results of this study showed that in the Hubei Han Chinese population, the rs10754339 gene was significantly associated with the risk of lung and gastric cancer but not liver cancer, and the rs12976445 gene was significantly associated with the risk of lung cancer but not liver or gastric cancer. The meta-analysis results indicated that rs10754339 and rs12976445 contributed to cancer susceptibility in the Chinese population and also revealed a significant association between rs10754339 and breast cancer risk, as well as between rs12976445 and lung cancer risk., Conclusion: The B7-H4 gene rs10754339 and miR-125a gene rs12976445 may be the potential genetic markers for cancer susceptibility in the Chinese population, which should be validated in future studies with larger sample sizes in other ethnic populations., (Copyright © 2023 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

A deep understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions is crucial to developing effective therapeutics and addressing the threat of emerging coronaviruses. The role of noncoding regions of viral RNA (ncrRNAs) has yet to be systematically scrutinized. We developed a method using MS2 affinity purification coupled with liquid chromatography-mass spectrometry and designed a diverse set of bait ncrRNAs to systematically map the interactome of SARS-CoV-2 ncrRNA in Calu-3, Huh7, and HEK293T cells. Integration of the results defined the core ncrRNA-host protein interactomes among cell lines. The 5' UTR interactome is enriched with proteins in the small nuclear ribonucleoproteins family and is a target for the regulation of viral replication and transcription. The 3' UTR interactome is enriched with proteins involved in the stress granules and heterogeneous nuclear ribonucleoproteins family. Intriguingly, compared with the positive-sense ncrRNAs, the negative-sense ncrRNAs, especially the negative-sense of 3' UTR, interacted with a large array of host proteins across all cell lines. These proteins are involved in the regulation of the viral production process, host cell apoptosis, and immune response. Taken together, our study depicts the comprehensive landscape of the SARS-CoV-2 ncrRNA-host protein interactome and unveils the potential regulatory role of the negative-sense ncrRNAs, providing a new perspective on virus-host interactions and the design of future therapeutics. Given the highly conserved nature of UTRs in positive-strand viruses, the regulatory role of negative-sense ncrRNAs should not be exclusive to SARS-CoV-2. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic affecting millions of lives. During replication and transcription, noncoding regions of the viral RNA (ncrRNAs) may play an important role in the virus-host interactions. Understanding which and how these ncrRNAs interact with host proteins is crucial for understanding the mechanism of SARS-CoV-2 pathogenesis. We developed the MS2 affinity purification coupled with liquid chromatography-mass spectrometry method and designed a diverse set of ncrRNAs to identify the SARS-CoV-2 ncrRNA interactome comprehensively in different cell lines and found that the 5' UTR binds to proteins involved in U1 small nuclear ribonucleoprotein, while the 3' UTR interacts with proteins involved in stress granules and the heterogeneous nuclear ribonucleoprotein family. Interestingly, negative-sense ncrRNAs showed interactions with a large number of diverse host proteins, indicating a crucial role in infection. The results demonstrate that ncrRNAs could serve diverse regulatory functions., Competing Interests: The authors declare no conflict of interest.

The number of patients with periodontal disease in China is large, and the ratio of doctors to patients is seriously imbalanced, especially in the insufficient number of periodontal specialists and periodontal teachers. Strengthening the cultivation of professional postgraduates in periodontology can effectively solve this problem. This paper summarizes the experiences of Peking University School and Hospital of Stomatology in the teaching of periodontal postgraduate students for more than 30 years, in cluding teaching objectives formulation, teaching resources allocation and enhancement of the quality control system of clinical teaching, for ensuring that the periodontal professional postgraduates could reach the expected level after training. This formed the current "Peking University Model". There are both opportunities and challenges in clinical teaching of periodontal postgraduates in domestic stomatology community. The authors hope that the continuous exploration and improvement of this teaching system will promote the vigorous development of clinical teaching for the postgraduates majoring in periodontology in China.

Aims: To understand the status quo of self-directed learning ability, self-efficacy and academic burnout of junior nursing college students, since the closed management mode was implemented during COVID-19 pandemic disease., Design: Cross-sectional study., Methods: Participants came from 3,051 junior nursing college students of a college in Zhengzhou City, Henan Province, China. Data were collected by online questionnaire and analysed by SPSS25.0 (a statistical package for social science) and AMOS24.0 software., Results: High self-directed learning ability and self-efficacy were related to low levels of academic burnout (p < .01). In addition, the analysis of mediation effect indicated that the influence of self-directed learning ability on academic burnout was not mediated by self-efficacy., (© 2022 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Background & Aims: Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action., Methods: Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase., Results: We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage., Conclusions: In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals., Impact and Implications: Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Grain size is a key component of grain yield and quality in crops. Several core players of auxin signaling have been revealed to modulate grain size; however, to date, few genetically defined pathways have been reported, and whether phosphorylation could boost degradation of Aux/IAA proteins is uncertain. Here, we show that TGW3 (also called OsGSK5) interacts with and phosphorylates OsIAA10. Phosphorylation of OsIAA10 facilitates its interaction with OsTIR1 and subsequent destabilization, but this modification hinders its interaction with OsARF4. Our genetic and molecular evidence identifies an OsTIR1-OsIAA10-OsARF4 axis as key for grain size control. In addition, physiological and molecular studies suggest that TGW3 mediates the brassinosteroid response, the effect of which can be relayed through the regulatory axis. Collectively, these findings define a auxin signaling pathway to regulate grain size, in which phosphorylation of OsIAA10 enhances its proteolysis and potentiates OsIAA10-OsARF4-mediated auxin signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers, best exemplified by loss-of-function mutations in genes encoding components of the TGF-β signaling pathway in colorectal and pancreatic cancers. Alternatively, gain-of-function oncogene mutations can also disrupt antiproliferative TGF-β signaling. However, the molecular mechanisms underlying oncogene-induced modulation of TGF-β signaling have not been extensively investigated. Here, we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia (CML) and the cellular ABL1 tyrosine kinases phosphorylate and inactivate Smad4 to block antiproliferative TGF-β signaling. Mechanistically, phosphorylation of Smad4 at Tyr195, Tyr301, and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP, thereby blocking the ability of Smad4 to activate the expression of cyclin-dependent kinase (CDK) inhibitors and induce cell cycle arrest. In contrast, the inhibition of BCR-ABL1 kinase with Imatinib prevented Smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic responses. Furthermore, expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of Smad4 in Smad4-null CML cells enhanced antiproliferative responses to TGF-β, whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-β signaling and enhanced the in vivo growth of CML cells. These findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-β signaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-β anti-growth responses., (© 2023. The Author(s).)

Peri-implantitis (PI) has been defined as an inflammatory lesion of the mucosa surrounding an endosseous implant and with progressive loss of supporting peri-implant bones. In recent years, histopathological differences between PI and periodontitis of natural teeth had been described in animal experiments and a certain number of human experiments. In this paper, we review the histopathological differences between PI and periodontitis reported in the existing literature and try to find the differences in the occurrence and progression of these two diseases. Overall, inflammatory cell infiltrate (ICT) is more extensive in PI than in periodontitis, extending to the alveolar ridge, with dense infiltration of plasma cells, lymphocytes, macrophages, polymorphonuclear leukocytes and a greater number of osteoclasts in the connective tissue, but with less vascular density within ICT than in periodontitis. In addition, foreign bodies are found in PI lesions. The histopathological differences between the two diseases in terms of inflammatory infiltration, vascularity, bone loss, and foreign bodies could partially explain the more rapid progression of PI than periodontitis, suggesting that PI should be taken seriously by physicians. Early diagnosis and treatment are essential to control the progression of PI. In addition, targeted therapy against specific inflammatory cells may become a new direction for PI treatment; reducing titanium particles released into peri-implant tissue by friction or electrochemical corrosion may help to prevent PI.

Background: Lung cancer is a malignant tumor with high morbidity and mortality among cancers. Surgery is currently one of the primary methods of treating lung cancer. Although it can slow down the progression of the disease by removing the lesion, this invasive surgery inevitably damages the integrity of the patient's chest. Moreover, the patient's pulmonary function may have a low compensatory capacity after surgery, causing various respiratory diseases such as atelectasis, respiratory function decline, and even serious cardiovascular disease. All of these have great negative impacts on the surgical effect and the prognosis of patients. With the continuous exploration and development of nursing, continuous nursing and respiratory exercise nursing have been gradually applied in the nursing of patients after lung cancer surgery, and have achieved good nursing results., Aim: To investigate the effect of continuous nursing combined with respiratory exercise nursing on the pulmonary function of postoperative patients with lung cancer., Methods: A total of 80 patients with lung cancer who underwent surgery in our hospital from January 2021 to December 2021 were selected as the study subjects. All subjects were randomly divided into the control group ( n = 40 cases) and the experimental group ( n = 40 cases). Patients with lung cancer in the control group were given conventional nursing after surgery, while the experimental group was given continuous nursing combined with respiratory exercise nursing based on conventional nursing. The recovery of pulmonary function and respiratory symptoms was observed before and after 3 mo of intervention in both groups. The pulmonary function parameters, blood gas analysis, MD Anderson Symptom Inventory-lung cancer module (MDASI-LC) scores, incidence of pulmonary complications, and Morisky compliance scores were compared between the two groups before and after 3 mo of intervention., Results: There was no significant difference in pulmonary function and blood gas analysis between the two groups before intervention ( P > 0.05). 3 mo after the intervention, the pulmonary function parameters in the experimental group (SpO 2 , VC, MVV, FEV1, FEV1% pred, and FEV1/FVC) were higher than those in the control group, and the differences were statistically significant ( P < 0.05). There was no significant difference in blood gas analysis between the two groups before intervention ( P > 0.05). PaO 2 in the experimental group was significantly higher than that in the control group, and PaCO 2 was significantly lower than that in the control group 3 mo after the intervention. The difference had statistical significance ( P < 0.05). 3 mo after the intervention, the MDASI score of respiratory symptoms in the experimental group was significantly lower than that in the control group ( P < 0.05), and the incidence of pulmonary complications was lower than that in the control group ( P < 0.05). In addition, the treatment compliance and nursing satisfaction of patients in the experimental group were higher than those in the control group, and the differences were statistically significant ( P < 0.05)., Conclusion: Continuous nursing combined with respiratory exercise nursing can significantly accelerate the recovery of respiratory function in postoperative lung cancer patients, reduce the incidence of postoperative complications of lung cancer as well as improve the treatment compliance of patients., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

YAP/TAZ transcriptional co-activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST-LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCF β-TrCP . When the MST-LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate TEAD-dependent gene transcription. Hippo signaling-independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to β-TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer., (© 2023 The Authors.)

TGF-β signaling is crucial for modulating osteoarthritis (OA), and protein phosphatase magnesium-dependent 1A (PPM1A) has been reported as a phosphatase of SMAD2 and regulates TGF-β signaling, while the role of PPM1A in cartilage homeostasis and OA development remains largely unexplored. In this study, we found increased PPM1A expression in OA chondrocytes and confirmed the interaction between PPM1A and phospho-SMAD2 (p-SMAD2). Importantly, our data show that PPM1A KO substantially protected mice treated with destabilization of medial meniscus (DMM) surgery against cartilage degeneration and subchondral sclerosis. Additionally, PPM1A ablation reduced the cartilage catabolism and cell apoptosis after the DMM operation. Moreover, p-SMAD2 expression in chondrocytes from KO mice was higher than that in WT controls with DMM induction. However, intraarticular injection with SD-208, repressing TGF-β/SMAD2 signaling, dramatically abolished protective phenotypes in PPM1A-KO mice. Finally, a specific pharmacologic PPM1A inhibitor, Sanguinarine chloride (SC) or BC-21, was able to ameliorate OA severity in C57BL/6J mice. In summary, our study identified PPM1A as a pivotal regulator of cartilage homeostasis and demonstrated that PPM1A inhibition attenuates OA progression via regulating TGF-β/SMAD2 signaling in chondrocytes and provided PPM1A as a potential target for OA treatment.

Hydrogen sulfide (H 2 S) and nitric oxide (NO) play a well-organized protective mechanism in coping with oxidative stress induced by toxic metals. However, the comparative effects of H 2 S and NO on enzymatic and non-enzymatic antioxidants in plants under Cr(III) stress have not been defined. In this study, we mathematically evaluate the importance of sodium hydrosulfide (NaHS) and sodium nitroprusside (SNP) on these two antioxidant systems in rice seedlings under Cr(III) stress. The results displayed that the optimal dose of NaHS and SNP was 100 μM and 75 μM, respectively, in rice tissues under Cr(III) stress, judging by the reactive oxygen species (ROS) levels in rice tissues. When rice seedlings were exposed to Cr(III) at concentrations of 3.57, 7.24, 26.52 mg Cr/l, Cr-induced ROS accumulation had a significant (p < 0.05) effect on the lipid peroxidation of cell membrane in rice tissues, and decreased the response of SOD, CAT, Pro, GSH, and AsA in rice tissues. Application of exogenous NaHS and SNP effectively (p < 0.05) alleviated the toxic effects of Cr(III) in rice seedlings by activating different antioxidants. A novel physiological response model suggested that the regulatory effect of NaHS and SNP on non-enzymatic antioxidants was stronger than that of enzymatic antioxidants. Moreover, NaHS-mediated response intensity of both enzymatic and non-enzymatic antioxidants was greater than that of SNP, suggesting the importance of utilizing NaHS over SNP as antioxidant regulators during detoxification of Cr(III) in rice seedlings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)