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Shu-Hui Lv,1– 3,* Wang-Zhong Li,1,2,* Hu Liang,1,2 Guo-Ying Liu,1,2 Wei-Xiong Xia,1,2 Yan-Qun Xiang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China; 3Medical Affairs Office, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Qun Xiang; Wei-Xiong XiaDepartment of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, ChinaTel\Fax +86-1866-6096-623 Email xiangyq@sysucc.org.cn; xiawx@sysucc.org.cnPurpose: We sought to assess the prognostic and predictive value of a circulating inflammation signature (CISIG) and develop CISIG-based tools for predicting prognosis and guiding individualized induction chemotherapy (ICT) in non-metastatic nasopharyngeal carcinoma (NPC).Patients and Methods: We retrospectively collected a candidate inflammatory biomarker panel from patients with NPC treated with definitive radiotherapy between 2012 and 2017. We developed the CISIG using candidate biomarkers identified by a least absolute shrinkage and selection operator (LASSO) Cox regression model. The Cox regression analyses were used to evaluate the CISIG prognostic value. A CISIG-based prediction model was constructed, validated, and assessed. Potential stratified ICT treatment effects were examined.Results: A total of 1149 patients were analyzed. Nine biomarkers selected by LASSO regression in the training cohort were used to construct the CISIG, including hyaluronidase, laminin, procollagen III, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, high-density lipoprotein, lactate dehydrogenase, and C-reactive protein-to-albumin ratio. CISIG was an independent prognostic factor for disease-free survival (DFS; hazard ratio: 2.65, 95% confidence interval: 1.93– 3.64; P < 0.001). High CISIG group (>− 0.2) was associated with worse 3-year DFS than low CISIG group in both the training (67.5% vs 88.3%, P < 0.001) and validation cohorts (72.3% vs 85.1%, P < 0.001). We constructed and validated a CISIG-based nomogram, which showed better performance than the clinical stage and Epstein–Barr virus DNA classification methods. A significant interaction between CISIG and the ICT treatment effect was observed (P for interaction = 0.036). Patients with high CISIG values did not benefit from ICT, whereas patients with low CISIG values significantly benefited from ICT.Conclusion: The developed CISIG, based on a circulating inflammatory biomarker panel, adds prognostic information for patients with NPC. The proposed CISIG-based tools offer individualized risk estimation to facilitate suitable ICT candidate identification.Keywords: nasopharyngeal carcinoma, inflammatory biomarkers, circulating inflammation signature, prognostic value, predictive value, induction chemotherapy

Wang-Zhong Li,1,2,* Xin Hua,3,* Shu-Hui Lv,1,2,* Hu Liang,1,2 Guo-Ying Liu,1,2 Nian Lu,1,2 Wei-Xin Bei,1,2 Wei-Xiong Xia,1,2 Yan-Qun Xiang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Qun Xiang; Wei-Xiong XiaDepartment of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of ChinaTel +86-1866-6096-623Email xiangyq@sysucc.org.cn; xiawx@sysucc.org.cnPurpose: We aimed to develop a simple scoring system based on baseline inflammatory and nutritional parameters to predict the efficacy of first-line chemotherapy and survival outcomes for de novo metastatic nasopharyngeal carcinoma (mNPC).Patients and Methods: We retrospectively collected ten candidate inflammatory and nutritional parameters from de novo mNPC patients who received platinum-based first-line chemotherapy treatment. We examined the effects of these ten candidate variables on progression-free survival (PFS) using the Cox regression model. We built a risk-scoring system based on the regression coefficients associated with the identified independent prognostic factors. The predictive accuracy of the scoring system was evaluated and independently validated.Results: A total of 460 patients were analyzed. Four independent prognostic factors were identified in a training cohort and were used to construct the scoring system, including nutritional risk index, C-reactive protein level, alkaline phosphatase level, and lactate dehydrogenase level. Based on the score obtained from the scoring system, we stratified patients into three prognostic subgroups (low: 0– 1 point, intermediate: 2– 3 points, and high: 4 points) associated with significantly different disease control rates (94.7% vs. 92.5% vs. 66.0%, respectively) and survival outcomes (3-year PFS: 55.8% vs. 29.1% vs. 11.9%, respectively). The scoring system had a good performance for the prediction of short-term disease control (area under the receiver operating characteristic curve [AUC]: 0.701) and long-term survival outcomes (time-dependent AUC for 5-year PFS: 0.713). The results were internally validated using an independent cohort (AUC for predicting disease control: 0.697; time-dependent AUC for 5-year PFS: 0.713).Conclusion: We developed and validated a clinically useful risk-scoring system that could predict the efficacy of first-line chemotherapy and survival outcomes in de novo mNPC patients. This system may help clinicians to design personalized treatment strategies.Keywords: metastatic nasopharyngeal carcinoma, nutritional status, cancer-related inflammation, chemotherapy efficacy, survival outcomes

Wei-Xiong Xia,1,2,* Hu Liang,1,2,* Xing Lv,1,2 Lin Wang,1,2 Yan-Fang Ye,3 Liang-Ru Ke,1,2 Lin-Hao Xu,4 Xiang Guo,1,2 Yan-Qun Xiang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4IBM Research China, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiang Guo; Yan-Qun XiangDepartment of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of ChinaTel +86 208 734 3392; +86 208 734 3379Email guoxiang@sysucc.org.cn; xiangyq@sysucc.org.cnPurpose: This large population-based analysis aims to investigate whether the additional induction chemotherapy to concurrent chemoradiotherapy improved overall survival (OS) and disease-free survival (DFS) for locoregionally advanced nasopharyngeal carcinoma (LRANPC).Patients and Methods: The study group comprised 3,980 patients who were treated either with IC+CCRT (1,888 patients) or CCRT alone (2,092 patients) between January 1998 and June 2013. Survival outcomes were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods. Primary outcome variables included OS and DFS.Results: Kaplan–Meier analysis showed that CCRT and IC+CCRT were of similar benefit to OS (P=0.099), whereas there was a marginal benefit of CCRT to DFS (P=0.063) in the overall cohort, which showed no differences between the two treatment regimens using multivariate Cox analysis and propensity score. Interestingly, for patients with 2D radiationtherapy (2DRT), CCRT had OS and DFS benefits for stage III, with 5-year and 10-year OS for CCRT vs IC+CCRT being 88% and 75% vs 81% and 67%, respectively (P=0.002); 5-year and 10-year DFS for CCRT vs IC+CCRT being 84% and 74% vs 76% and 66%, respectively (P=0.002). In contrast, IC + CCRT had OS and DFS benefits for stage IVa-b, with 5-year and 10-year OS for CCRT vs IC+CCRT being 71% and 55% vs 76% and 60%, respectively (P=0.037, HR=0.786); 5-year and 10-year DFS for CCRT vs IC+CCRT were 64% and 50% vs 69% and 58%, respectively (P=0.038, HR=0.801). No difference was found in intensity-modulated radiotherapy (IMRT) subgroup.Conclusion: Our study indicates that CCRT and IC+CCRT may have similar OS and DFS benefits for overall LRANPC. Stage-specific chemoradiotherapy may be administered based on the greatest benefit of IC+CCRT for stage IVa-b patients and CCRT alone for stage III patients received 2DRT. The optimal chemotherapy pattern in combination with IMRT needs further investigation.Trial registration: ClinicalTrials.gov ID: NCT02604472Keywords: nasopharyngeal carcinoma, concurrent chemotherapy, radiation therapy, induction chemotherapy, prognosis, stage specific

A series of monofunctionalized pillar[ n ]arenes skeleton macrocycles pillar[ m ]arene[1]phthalimide and pillar[ m ]arene[1]naphthalimide ( m = 4-6) were synthesized successfully through fragment coupling cyclization in a one-pot reaction. The introduction of pyromellitic diimide and naphthalene diimide units into the pillar[ n ]arenes skeleton not only disturbs the symmetry of the pillar[ n ]arenes but also changes their self-assembly behavior in the solid state. This functionalization approach greatly expands the structural diversity of the pillar[ n ]arenes.

Background: There is lack of the clinical evidence of optimized perioperative analgesic protocol for uniportal video-assisted thoracoscopic surgery (uVATS)., Methods: We performed a RCT enrolling participants scheduled for uVATS (Trial registration: NCT06016777; registration date: Aug 28, 2023). Participants were randomized for thoracic paravertebral block combined with patient-controlled intravenous analgesia (PVB + PCIA), erector spinae block combined with PCIA (ESPB + PCIA), or PCIA group. Participants were followed-up till 6 months. Primary outcome was total opioid consumption. Secondary outcomes included postoperative rest and cough pain scores, ambulation time, chest tube duration, length of stay, anaesthesia expense and adverse events., Results: We enrolled 108 participants between October 16th, 2023 to April 14th, 2024. Neural block did not reduce opioid consumption. Postoperative rest and cough pain scores did not differ among the groups at all the follow-up time points. None of the participants experienced chronic pain. The ambulation time, duration of chest tube maintenance and length of stay did not differ among groups. Duration of anaesthesia procedure was significantly prolonged in both neural blockade groups compared to PCIA group (p = 0.033). Anaesthesia expenses were significantly higher in both nerve block groups than in the PCIA group (p < 0.001). Adverse events related to neural blockade occurred in 17.9% in PVB + PCIA group and 2.9% in ESPB + PCIA group (p = 0.010), including local haemorrhage and block failure. Adverse events related to opioid use did not differ among groups., Conclusions: Both PVB and ESPB did not exhibit analgesic advantage for uVATS. Neural block may carry the risk of haemorrhage and block failure, prolonged the anaesthesia procedure and increased the anaesthesia expenses., Trial Registration: Clinical Trial Number was NCT06016777, trial registration date was Aug 28th, 2023., Competing Interests: Declarations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Hylurgus ligniperda (Fabricius) is an important pest that attacks Pinus species in China. It impacts the vitality of local pine vegetation, reduces the ability to prevent windbreak and sand fixation, and causes ecological loss. MaxEnt and ArcGIS are used to predict and analyze the changes in suitable distribution areas of H. ligniperda under current and future climate scenarios, based on 12 climate factor datasets and 1,001 field distribution data points for this pest. The environmental variables used significantly influence the potential distribution of H. ligniperda. Highly suitable areas of this beetle are located in western Europe, central Asia, and the southeastern regions of Oceania, with sporadic occurrences across North America, South America, and Africa. Highly suitable areas in China occur across the east, central south, and southwest regions. There is a significant increase in the high and medium suitability areas, while the area of low suitability decreases under the 4 future climate scenarios (SSP126, SSP245, SSP370, and SSP585). The suitable distribution area for H. ligniperda shows an overall trend of moving northwestward. The purpose of this current study is to provide important theoretical support for the prevention and management of this pest by predicting and analyzing suitable distribution areas under current and future climate scenarios., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Nilaparvata lugens, the brown planthopper (BPH), is a notorious pest threatening rice production across Asia. The heavy reliance on synthetic insecticides for control has led to resistance and raised ecological concerns. Substrate-borne vibrational communication, integral to species-specific mate recognition systems in insects, presents a potential avenue for pest management through mating disruption. However, the molecular mechanisms regulating vibrational signals in BPH remain poorly understood. In this study, we cloned and analyzed the clock gene period from BPH. The open reading frame of Nlper is 3708 bp, encoding a 1235-amino acid protein with two conserved domains: the Per-ARNT-Sim domain and the Period protein 2/3C-terminal region. It shares a closer evolutionary relationship with Laodelphax striatellus and Frankliniella occidentalis. Spatiotemporal expression analysis showed that Nlper was consistently expressed across all life stages and adult tissues, with the highest levels in macropterous males and male head, respectively. Rhythmic expression exhibited significant circadian oscillations under both light-dark and constant darkness conditions, peaking at 00:00 and reaching a trough at 12:00, with fold changes ranging from 2.47 to 3.39. Moreover, after dsRNA injection, Nlper expression decreased by 77.21%-84.26% from day 2 to day 5, disrupting the circadian oscillation of female vibrational signals (FVS) and causing a significant peak shift, along with a 30.56% reduction in FVS frequency on day 5. These findings underscore the essential role of Nlper in regulating the circadian rhythm of courtship vibrational signals, deepening our understanding of the genetic basis of insect communication and opening new possibilities for innovative pest management approaches., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background : Sjögren's syndrome (SS), an autoimmune disease, was characterized by sicca syndrome and systemic manifestations, presenting significant treatment challenges. Exosomes, naturally derived nanoparticles containing bioactive molecules, have garnered interest in regenerative medicine. The present study aimed to elucidate the immunoregulatory properties and mechanism of exosomes obtained from the stem cells derived from human exfoliated deciduous teeth (SHED-exos) in SS-induced sialadenitis. Methods : SHED-exo nanoparticles were injected into submandibular glands (SMGs) of 14-week-old nonobese diabetic (NOD) mice, a classic animal model of SS. At 21 weeks, the saliva flow rate (SFR) was measured. Lymphocyte proportions were examined via flow cytometry. Inflammatory cytokine levels were examined by the Quantibody mouse Th1/Th2/Th17 array and ELISA. miR-29a-3p expression and its regulatory effect on T-bet was detected using FISH and luciferase reporter gene assay, respectively. Results : SHED-exos injected into SMGs increased SFR, reduced lymphocytic infiltration, and decreased inflammatory cytokine levels in serum, SMG tissues, and saliva. Mechanistically, SHED-exos suppressed the Th1 proportion in spleen lymphocytes in NOD mice. Exosomal miR-29a-3p targeted and suppressed T-bet expression, which is a Th1-specific transcription factor. In vitro, SHED-exos (but not miR-29a-3p-inhibited exosomes) decreased the level of Th1 differentiation and IFN-γ and TNF-α production. Furthermore, SHED-exos (but not miR-29a-3p-inhibited exosomes) blocked the increase in IFN-γ and TNF-α production induced by T-bet overexpression. In vivo, miR-29a-3p-inhibited exosomes neither increase saliva secretion in NOD mice nor decrease lymphocytic infiltration, T-bet expression, and IFN-γ and TNF-α levels in SMGs. Conclusion : SHED-exos suppress Th1 cell differentiation and response through the miR-29a-3p/T-bet axis, contributing to amelioration of SS-induced hyposalivation.

Background: Oral general course (OGC) is a basic subject of medical education. The implementation of multidisciplinary team (MDT) meets the individual needs of patients. Based on the concept of MDT, this study combined the theory and practice of flipped classroom teaching method to evaluate the teaching effect, so as to provide a basis and reference for the thinking transformation of medical students to clinicians., Methods: The participants of the study were 760 clinical undergraduates in OGC training in Hainan Medical University from 2021 to 2023. A total of 760 students were divided into a control group and an observation group of 380 cases, each using the random number table method. The control group used traditional teaching methods, the observation group adopted the MDT combined with flipped classroom teaching model and organized dental postgraduates team to participate in the teaching task. A unified assessment of the teaching outcomes was conducted after 1 semester study duration., Results: The basic theory, independent learning ability and case analysis scores of the observation group were higher than those in the control group, and the differences were statistically significant (P < 0.05). Except there was no statistically significant difference in literature searching ability between the two groups (P > 0.05), the other indicators of teaching satisfaction in the observation group were higher than those in the control group, and the difference was statistically significant (P < 0.05). The postgraduates team gave relatively good feedback to the MDT combined flipped classroom teaching model., Conclusion: MDT combined flipped classroom teaching model had outstanding effect in OGC, this student-centered teaching method was a beneficial supplement to their clinical thinking and practical ability, and worth further promotion., Trial Registration: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval for this study was obtained from the Ethics Committee of School Stomatology of Hainan Medical University. All methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all subjects involved in this study. This study adhered to the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Most previous studies have focused on the clinical efficacy after intervention of ESDM, particularly in core symptoms. However, only a few have paid attention to the effectiveness of ESDM on emotional dysregulation and behavior problems in children with ASD. This study aimed to explore the effect of the ESDM on addressing emotional dysregulation and behavior problems in children with ASD in China, as well as its correlation with core symptoms of ASD., Methods: A total of 319 children aged 1.5 to 5 years were included in this study and received treatment based on the ESDM intervention program Baseline assessment (T0) was conducted before intervention, including Children Behavior Checklist (CBCL), Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS). All children with ASD were examined in the assessment (T1) after 12 weeks of treatment. Emotional dysregulation and behavior problems in children with ASD were measured using CBCL, while ABC and CARS were used to evaluate the core symptoms., Results: In the T1 assessment, the core symptoms of children with ASD in ABC and CARS showed significant differences. Subscale scores of ABC and the severity of CARS, including senses, relationships, stereotypes objects to use, self-help and social also exhibited significant differences. The children showed significant differences in both total score and subscale scores of CBCL(P < 0.05), which included emotionally/reactive, anxious/depressed, somatic complaints, withdrawal, sleep problems, attention problems, aggressive behavior, internalization and externalization. The children demonstrated significant differences in scores of CBCL-AAA (P < 0.05), taking into account the combined total of attention, aggression and anxious/depressed CBCL T scores. In addition, a consistent positive correlation was observed between the overall scores of CBCL and the core symptoms of children with ASD as indicated by ABC and CARS in both T0 and T1(P < 0.01). In T0, the CBCL-AAA scores were positively associated with the core symptoms of children with ASD as reflected by CARS(P < 0.01), as well as senses of ABC( P < 0.05). During T1, a noteworthy significant positive correlation was observed between the CBCL-AAA scores and the core symptoms of children with ASD as indicated by both ABC and CARS assessment (P < 0.05)., Conclusions: Children with ASD benefit from ESDM, not only in terms of improving their core symptoms, but also in terms of improving their emotional dysregulation and behavior problems, and ESDM could be considered as one of the early treatment options for overall psychological promotion. The core symptoms of children with ASD are significantly associated with emotional dysregulation and behavior problems in young children, both cross-sectionally and prospectively for the short term over time. Emotional dysregulation and behavior problems represent an important comorbidity, and could be considered as potential treatment targets for treatment for improving emotional stability in ASD., Competing Interests: Declarations. Ethical approval: This study was approved by the Department of Developmental and Behavioral Pediatrics of the First Hospital of Jilin University in Changchun (approval no: 20170107). Consent for publication: All caregivers of toddlers with ASD were informed of the associated benefits and risks, and then voluntarily signed informed consent before intervention. Competing interests: The authors declare no competing interests. ASELCC: Autism specific early learning and care center; MSEL: Mullen scales of early learning; SCQ: Social communication questionnaire; VABS-II: Vineland adaptive behavior scales second edition; DQ: Developmental quotient.. Authors information: WXL, YML and YLOY and postgraduate students in the medical technology direction of the School of Nursing, Jilin University, studying and researching the diagnosis and treatment of pediatric common diseases and frequent-onset diseases. Especially the diagnosis and treatment of neurological diseases in children, such as autism, mental retardation, learning problems, children’s attention deficit hyperactivity disorder, tic disorder, and other diseases. LS and YX are pediatricians who specialize in the diagnosis and treatment of pediatric neurological diseases, such as cerebral palsy, autism, mental retardation, learning problems, attention deficit hyperactivity disorder, tic disorder and other diseases in children. CLL is a child rehabilitation therapist, specializing in the rehabilitation of children with neurodevelopmental disorders, especially good at ESDM. FYJ is the director of developmental behavioral Pediatrics, chief physician, professor, doctoral supervisor of the First Hospital of Jilin University, deputy leader of Developmental Behavioral Group of Pediatrics Branch of the Chinese Medical Association, member of the Children’s Rehabilitation Professional Committee of the Chinese Rehabilitation Medical Association, editorial board member of the international Journal of Pediatrics, skilled in the diagnosis and treatment of common pediatric diseases and frequent diseases. Especially good at the diagnosis and treatment of neurological diseases in children, cerebral palsy, autism, mental retardation, epilepsy, children’s psychology, learning problems, children’s attention deficit hyperactivity disorder, tic disorder, migraine, demyelination and other diseases have profound attests., (© 2024. The Author(s).)

Porcine deltacoronavirus (PDCoV) and transmissible gastroenteritis coronavirus (TGEV), the two causative agents of porcine diarrhea, have been reported to be at risk of cross-species transmission, including to humans. However, the potential host range in which these two CoVs interact remains unclear. We screened 16 animal counterparts for porcine aminopeptidase N (APN), the receptor of PDCoV and TGEV, and found that APNs from eight of 17 animals could bind to the receptor-binding domains (RBDs) of PDCoV and TGEV. Furthermore, the animal APNs that could bind to the RBDs could mediate cellular infection by both viruses. Dog APN (dAPN) has been identified as the animal receptor with the highest capability to mediate the virus infection. We further resolved the complex structures of dAPN bound to the PDCoV RBD/TGEV RBD, respectively, establishing its divergent receptor-binding modes. We identified R325 of dAPN as an important residue in the PDCoV RBD-dAPN interaction, and found the central role of Q746 and T749 in dAPN in the interaction with the TGEV RBD. These findings provide the molecular basis of the potential cross-species transmission of these two porcine CoVs and shed light on future surveillance of these CoVs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The role of the intrarenal renin-angiotensin system (iRAS) in diabetic kidney disease (DKD) progression remains unclear. In this study, we generated mice with renal tubule-specific deletion of angiotensinogen (Agt; RT-Agt-/-) in both Akita and streptozotocin (STZ)-induced mouse model of diabetes. Both Akita RT-Agt-/- and STZ-RT-Agt-/- mice exhibited significant attenuation of glomerular hyperfiltration, urinary albumin/creatinine ratio, glomerulomegaly and tubular injury. Urinary Agt, Angiotensin II (Ang II) and oxidative stress were decreased in Akita RT-Agt-/- mice cf. Akita mice. Moreover, thickened glomerular basement membranes, podocyte foot process effacement and podocyte loss were ameliorated in Akita RT-Agt-/- mice cf. Akita mice. Mechanistically, intra-vital microscopy revealed that attenuation of glomerular hyperfiltration in Akita RT-Agt-/- mice was mediated via efferent arteriole (EA) vasodilation and afferent arteriole (AA) vasoconstriction. The AA vasoconstriction was regulated, at least partially, through tubulo-glomerular feedback by down-regulation of sodium-glucose co-transporter 2 (SGLT2) expression in renal proximal tubules. The renal protective effect of iRAS inactivation in Akita RT-Agt-/- mice was more evident than in Akita mice treated with RAS blockers. In vitro, Ang II stimulated, losartan and apocynin inhibited SGLT2 expression in immortalized human renal proximal tubular cells. These findings suggest targeting the iRAS may constitute effective treatment for DKD., (© 2025 by the American Diabetes Association.)

Objective: Anti-angiogenic therapy and immune checkpoint blockade therapy are currently important treatments for non-small cell lung cancer. However, the combined use of the two therapies is controversial, and few studies have investigated the effects of different time sequences of the two therapies on treatment outcomes., Methods: The tumor-bearing mouse model was established and the mice were divided into four groups, including AA-ICB sequence group, ICB-AA sequence group, synchronization group and the control group. Immunohistochemistry was used to assess tumor microvessels and PD-L1 expression. Selected immune cell populations were evaluated using flow cytometry. Meta-analysis and clinical information were used to elucidate the clinical effects of administration sequence., Results: We found that anti-PD-L1 treatment followed by anti-VEGFR2 therapy exerts the best inhibitory effect on tumor growth. Different sequences of anti-angiogenic therapy and immune checkpoint blockade therapy resulted in different proportions of tumor microvessels and immune cell populations in the tumor microenvironment. We further revealed that the administration of anti-PD-L1 before anti-VEGFR brought more normalized tumor blood vessels and CD8 + T cell infiltration and reduced immunosuppressive cells in the tumor microenvironment. Subsequent re-transplantation experiments confirmed the long-term benefits of this treatment strategy. The meta-analysis reinforced that immunotherapy prior to anti-angiogenic therapy or combination therapy have better therapeutic effects in advanced non-small cell lung cancer., Conclusion: Our study demonstrated that the therapeutic effect of anti-angiogenic treatment after immune checkpoint therapy was superior to that of concurrent therapy, whereas anti-angiogenic therapy followed by immunotherapy did not bring more significant clinical benefits than independent monotherapy., 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. Published by Elsevier Inc.)

Large metacarpal and phalangeal bone defects are a hot topic for orthopedic surgeons due to its high clinical incidence, disability rate, and postsurgical amputation rate, along with its difficult treatment, long treatment course, high cost, and poor effect, all of which have a negative impact on the appearance and function of the patient's hands. There are currently a variety of treatment options for large metacarpal and phalangeal bone defects, each with its own benefits and drawbacks. However, there is no treatment method capable of perfectly resolving all the problems of patients with these defects. In this paper, the authors introduce several common plans for and progress of large metacarpal and phalangeal bone defect treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Long interspersed nuclear element‑1 (L1) is highly expressed in the early embryos of humans, rodents and fish. To investigate the molecular mechanisms underlying high expression of L1 during early embryonic development, a C1‑open reading frame (ORF)2 vector was constructed in which ORF2 of human L1 (L1‑ORF2) was inserted into a pEGFP‑C1 plasmid. C1‑ORF2 vector was injected into early zebrafish embryos (EZEs) to observe expression of EGFP reporter protein by fluorescence microscopy. RNA‑seq and RT‑qPCR were used to detect the effects of lipovitellin (LV)  on gene expression in EZEs. The binding ability of LV to L1‑ORF2 DNA was detected by electrophoretic mobility‑shift assay (EMSA). The chromatin recombinant DNase I digestion and ATAC‑seq assay were used to evaluate the accessibility of plasmid DNA. C1‑ORF2 vector induced high expression of enhanced green fluorescent protein (EGFP) reporter gene after it had been injected into 0 h post‑fertilization (hpf) zebrafish embryos, although histone octamer inhibited expression of EGFP in C1‑ORF2. SDS‑PAGE was used to show that LV was the predominant protein binding ORF2 DNA in 0 hpf zebrafish embryo lysate (ZEL). Both ZEL and purified LV from ZEL attenuated the inhibitory effects induced by histone. LV bound histone to interfere with the binding of histone to ORF2 DNA. Both in vitro chromatin reconstitution experiments and assay for transposase‑accessible chromatin with sequencing with HeLa cells were utilized to demonstrate that the interference induced by LV resulted in increased accessibility of C1‑ORF2. Transcription experiments in vitro verified that LV could enhance the mRNA levels of zebrafish early embryo expression genes grainyhead‑like transcription factor 3 (GRHL3), SRY‑box transcription factor 19a (SOX19A) and nanor (NNR) and also of the EGFP gene. LV was found to increase the expression levels of the zebrafish early embryo expression genes in liver tissue after LV had been injected into the abdominal cavity of adult male zebrafish. Taken together, the findings of the present study demonstrated that LV activates the expression of EGFP induced by ORF2 in EZEs by enhancing the accessibility of ORF2 DNA.

Raccoon dog was proposed as a potential host of SARS-CoV-2, but no evidence support such a notion. In our study, we investigated the binding affinities of raccoon dog ACE2 (rdACE2) to the spike (S) protein receptor binding domain (RBD) of SARS-CoV-2 prototype (PT) and its variants. It revealed that the binding affinities of RBD from SARS-CoV-2 variants were generally lower than that of the PT RBD. Through structural and functional analyses, we found amino acids H34 and M82 play pivotal roles in maintaining the binding affinity of ACE2 to different SARS-CoV-2 sub-variants. These results suggest that raccoon dogs exhibit lower susceptibility to SARS-CoV-2 compared to those animal species with a high prevalence of SARS-CoV-2 transmission., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Luo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Hyperuricemia has traditionally been associated with obesity and dyslipidemia. However, the relationship between waist circumference (WC) and hyperuricemia in normal-weight men is still unclear, particularly regarding the roles of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). The aim of this research was to explore the mediating roles of TG and HDL-C in the association between WC and hyperuricemia in normal-weight men., Methods: A retrospective observational study was conducted among normal-weight men (18.5 ≤ BMI < 24 kg/m 2 ) aged ≥ 18 years who underwent health checkups in Nanjing from 2021-2023. Relationships between WC, blood lipids, and hyperuricemia were investigated by multivariable regression models and mediation analysis., Results: We enrolled 35,984 participants, with an overall hyperuricemia prevalence of 24.2%. The research found a significant positive association between WC and hyperuricemia in normal-weight men ( P < 0.001). For hyperuricemia across rising WC quartiles, with WC divided as follows: Q1 (59 ≤ WC < 77 cm), Q2 (77 ≤ WC < 81 cm), Q3 (81 ≤ WC < 85 cm), and Q4 (85 ≤ WC ≤ 107 cm), the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.00 (reference), 1.09 (1.01, 1.18), 1.26 (1.15, 1.37), and 1.34 (1.22, 1.46), respectively (all P < 0.001). The mediation analysis indicated that WC had a significant total effect on hyperuricemia (Coefficient = 0.0046, 95% CI: 0.0028, 0.0070, P < 0.001), with significant indirect effects mediated through TG and HDL-C, contributing mediation proportions of 22.3% and 18.3%, respectively (both P < 0.05)., Conclusion: Elevated WC is associated with an increased likelihood of hyperuricemia in normal-weight men. TG and HDL-C play substantial mediating roles in this association. These findings suggest that monitoring WC and lipid profiles in normal-weight men could help identify those at higher risk of hyperuricemia, even in the absence of general obesity., Competing Interests: The authors report no potential conflicts of interest relevant to this article., (© 2024 Cui et al.)

The mammalian target of rapamycin (mTOR) is a critical signaling hub for sustaining cancer survival. Targeting mTOR and inducing autophagic cell death downstream of it represent promising therapeutic strategies for cancer prevention. A US Food and Drug Administration-approved drug library containing 616 small molecules is used to screen anticancer drugs against colorectal cancer (CRC) cells that rely on mTOR. This led to the identification of an antipsychotic drug aripiprazole, which significantly induced mTOR inhibition and autophagic apoptosis in CRC, in vitro and in vivo. The use of drug affinity response target stability identified lysosome-associated membrane protein 2A (LAMP2a) as a direct target of aripiprazole. LAMP2a-deficient CRC cells are refractory to aripiprazole. High LAMP2a expression is associated with poor survival of patients with CRC and negatively correlated with expression of ribonuclease inhibitor 1 (RNH1), which is later confirmed as a novel substrate of LAMP2a. Mechanistically, aripiprazole bound to the Lys401-His404 of LAMP2a and repressed its activity, subsequently inactivating RNH1/miR-99a/mTOR signaling and inducing autophagy-mediated apoptosis, thereby suppressing tumorigenesis. Liposome-mediated delivery of aripiprazole in combination with fluorouracil elicited superior therapeutic benefits in CRC, as compared to single treatments, thereby highlighting that aripiprazole may be repurposed as a novel therapeutic agent for CRC treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Introduction: Drug discovery research targeting SARS-CoV-2 and other emerging pathogens remains critically important. Active compounds derived from plants frequently serve as lead compounds for further drug discovery; however, numerous unrelated chemical constituents in crude extracts may obscure the effective ingredients in LC-MS analysis., Objective: The aim of this study is to construct a biolayer interferometry (BLI)-based system for recognizing active ingredients that inhibit the main protease (Mpro) of SARS-CoV-2 and to identify the active chemical components binding to Mpro from herbal medicines., Methodology: We developed a novel FRET fluorogenic probe by linking the amino acid sequences of the fluorescent proteins Lssmorange and mKate2 (Ls-mK). The interaction between traditional Chinese medicine and Mpro was analyzed using BLI. Ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was employed to analyze the composition of herbal medicines., Results: Fluorescence detection and spectroscopy confirmed the successful construction of an Mpro inhibitor screening system. Lanqin Oral Liquid (LQL) and Gardeniae fructus exhibited strong inhibitory effects on Mpro. Ten compounds were identified from G. fructus extracts; among them, deacetyl asperulosidic acid methyl ester (DAAME) and Gardoside were found to strongly bind to Mpro, with dissociation constants (KD) of 3.41 μM and 801 nM, respectively. The half-maximal inhibitory concentrations (IC50) of DAAME and Gardoside for Mpro were 27.46 and 13.7 μM, respectively., Conclusion: This study established a functional Mpro inhibitor screening system. Among the 10 components identified from G. fructus that bind to Mpro, DAAME and Gardoside displayed strong binding and inhibitory activity, indicating their potential as lead compounds for inhibiting SARS-CoV-2 viral replication., (© 2024 John Wiley & Sons Ltd.)

The 1957 H2N2 influenza pandemic virus [A(H2N2)pdm1957] has disappeared from humans since 1968, while H2N2 avian influenza viruses (AIVs) are still circulating in birds. It is necessary to reveal the recurrence risk and potential cross-species infection of these AIVs from avian to mammals. We find that H2 AIVs circulating in domestic poultry in China have genetic and antigenic differences compared to the A(H2N2)pdm1957. One H2N2 AIV has a dual receptor-binding property similar to that of the A(H2N2)pdm1957. Molecular and structural studies reveal that the N144S, and N144E or R137M substitutions in hemagglutinin (HA) enable H2N2 avian or human viruses to bind or preferentially bind human-type receptor. The H2N2 AIV rapidly adapts to mice (female) and acquires mammalian-adapted mutations that facilitated transmission in guinea pigs and ferrets (female). These findings on the receptor-binding, infectivity, transmission, and mammalian-adaptation characteristics of H2N2 AIVs provide a reference for early-warning and prevention for this subtype., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Biological invasion is a major global problem, leading to the loss of biodiversity and species extinction, and causing huge economic losses to countries. Obolodiplosis robiniae is a major invasive forest pest that has caused economic losses in Asia and Europe. Here, the chromosome- level genome of O. robiniae was assembled using the PacBio platform and Hi-C technology. A contig-level genome with a length of 199.49 Mb and a contig N50 of 4.66 Mb was assembled. Approximately 98.05% of contigs were successfully anchored to four chromosomes using Hi-C assisted genome assembly. The genome integrity was assessed to be 90.3% based on BUSCOs analysis. The high-quality genome provides valuable data for the study of invasive species, and a foundation for the understanding the biology and ecology of O. robiniae., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Genome transcription and replication of influenza A virus (FluA), catalyzed by viral RNA polymerase (FluAPol), are delicately controlled across the virus life cycle. A switch from transcription to replication occurring at later stage of an infection is critical for progeny virion production and viral non-structural protein NS2 has been implicated in regulating the switch. However, the underlying regulatory mechanisms and the structure of NS2 remained elusive for years. Here, we determine the cryo-EM structure of the FluAPol-NS2 complex at ~3.0 Å resolution. Surprisingly, three domain-swapped NS2 dimers arrange three symmetrical FluPol dimers into a highly ordered barrel-like hexamer. Further structural and functional analyses demonstrate that NS2 binding not only hampers the interaction between FluAPol and the Pol II CTD because of steric conflicts, but also impairs FluAPol transcriptase activity by stalling it in the replicase conformation. Moreover, this is the first visualization of the full-length NS2 structure. Our findings uncover key molecular mechanisms of the FluA transcription-replication switch and have implications for the development of antivirals., (© 2024. The Author(s).)

During surveys conducted in 2020, severe symptoms associated with death and decline were observed on >30-year-old Metasequoia glyptostroboides (Chinese redwood) trees in the shelter-forests along Yangtze River in Jingzhou city, Hubei province, China. A previous study showed that Phytophthora acerina was one of the causal agents of the decline of the Chinese redwood. In this study, a total of 147 fungal isolates were obtained from the diseased roots and xylem of trunks of declining M. glyptostroboides trees. Through morphology and multi-locus phylogenetic analysis, these isolates were identified as eight species belonging to the genera Fusarium and Neocosmospora including F. fujikuroi , F. irregulare , F. odoratissimum , F. reticulatum ， N. falciformis , N. keratoplastica , N. solani , and N. tonkinensis . Single inoculation and co-inoculation with P. acerina assays of these Fusarium and Neocosmospora species were then performed to test pathogenicity on three-year-old seedlings of M. glyptostroboides . Lesions (i.e., on seedling stems) caused by species of the genera Neocosmopora and Fusarium were smaller than those caused by P. acerina . Co-inoculation of F. fujikuroi and P. acerina , as well as the co-inoculation of F. reticulatum and P. acerina caused larger lesions than inoculations with P. acerina alone. All these species of Fusarium and Neocosmospora were shown to have the potential to be pathogenic to M. glyptostroboides . This study provided evidence that the decline of M. glyptostroboides in Jingzhou is a disease complex.

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). We studied a Grn knockout (Grn-KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9-encoded regulatory subunit of the "K + ATP" channel that is well-tolerated in humans. Aged (13 months) Grn-KO and wild-type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral performance, neuropathology, and gene expression. Mortality was significantly higher for aged Grn-KO mice (particularly females), but there was a conspicuous improvement in survival for both sexes treated with nicorandil. Grn-KO mice performed worse on some cognitive tests than WT mice, but Morris Water Maze performance was improved with nicorandil treatment. Neuropathologically, Grn-KO mice had significantly increased levels of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytosis but not ionized calcium binding adaptor molecule 1 (IBA-1)-immunoreactive microgliosis, indicating cell-specific inflammation in the brain. Expression of several astrocyte-enriched genes, including Gfap, were also elevated in the Grn-KO brain. Nicorandil treatment was associated with a subtle shift in a subset of detected brain transcript levels, mostly related to attenuated inflammatory markers. Nicorandil treatment improved survival outcomes, cognition, and inflammation in aged Grn-KO mice., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

A molecular editing reaction for converting pyrrole rings into benzene rings through a sequential pathway of Diels-Alder and cheletropic reactions was developed. The nitrogen atom in a N-bridged intermediate is eliminated in the form of N 2 O by a strain-releasing pathway, ultimately leading to the formation of substituted benzene and naphthalene derivatives., (© 2024 Wiley-VCH GmbH.)

Background: Internet addiction jeopardizes teenagers' physical and mental health, as well as their academic performance, and causes a variety of cognitive dysfunctions and psychological and mental health illnesses, among other things. It is a huge issue that families, schools, and society must address immediately., Objectives: This study used network meta-analysis to evaluate the impact of several interventions on college students' Internet addiction. The goal was to identify the most effective interventions and establish a reference for future interventions. We systematically searched relevant literature in domestic and international databases such as Web of Science, PubMed, EMBASE, Cochrane Library, Pro Quest, China Knowledge, Wan fang, Wipo, etc. We assessed the risk of bias according to the revised Cochrane Randomized Trials Risk of Bias Tool (RoB2) and used R Studio Software and Stata 14.0 for traditional meta-analysis and network meta-analysis. A network meta-analysis based on the IAT scale showed that comprehensive interventions had the highest probability of being the best intervention for IA (SUCRA = 90.6 % based on IAT); focused solution short-term therapy had the highest probability of being the best intervention for IA based on the CIAS-R (19 White Feather) scale (SUCRA = 100 %)., Conclusions: The majority of interventions have a significant influence on the treatment of IA, and improvements in Internet addiction symptoms are more noticeable when a combination of interventions is used rather than just one., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Porous organic cages (POCs) with permanent porosity and excellent host-guest property hold great potentials in regulating ion transport behavior, yet their feasibility as solid-state electrolytes has never been testified in a practical battery. Herein, we design and fabricate a quasi-solid-state electrolyte (QSSE) based on a POC to enable the stable operation of Li-metal batteries (LMBs). Benefiting from the ordered channels and cavity-induced anion-trapping effect of POC, the resulting POC-based QSSE exhibits a high Li + transference number of 0.67 and a high ionic conductivity of 1.25 × 10 -4 S cm -1 with a low activation energy of 0.17 eV. These allow for homogeneous Li deposition and highly reversible Li plating/stripping for over 2000 h. As a proof of concept, the LMB assembled with POC-based QSSE demonstrates extremely stable cycling performance with 85% capacity retention after 1000 cycles. Therefore, our work demonstrates the practical applicability of POC as SSEs for LMBs and could be extended to other energy-storage systems, such as Na and K batteries., (© 2024. The Author(s).)

Porcine epidemic diarrhea virus (PEDV) causes the third most important disease in the pig industry, after African swine fever and porcine reproductive and respiratory syndrome, and leads to illness or death of the entire litter, causing significant economic losses. In this study, three PEDV strains (HN-1, HN-2, and SC2023) were isolated from swine farms with suspected PEDV infections in Sichuan and Henan provinces. Phylogenetic analysis based on complete S gene sequences showed that all three strains belonged to the G2c subgroup. HN-1 adapted readily to cell culture, grew to a viral titer as high as 2 × 10 8 TCID 50 /mL in Vero cells, and caused the formation of large syncytia. We analyzed the amino acid sequence of the HN-1 isolate and found that its S1 subunit contained a three-amino-acid insertion ( 355 KRL 358 ). A seven-amino-acid-deletion ( 1377 FEKVHVQ 1383 ) in the S2 subunit resulted in the partial deletion of the endocytosis signal YxxΦ and the complete deletion of the endoplasmic reticulum retrieval signal (ERRS) KVHVQ in the cytoplasmic tail of the S protein. Consequently, HN-1 is predicted to be less pathogenic than its parent strain, an attribute that facilitates rapid cell-to-cell spread by enhancing syncytium formation. In addition, strain HN-1 was found to have the mutation 884-885 SG→RR, which may favor adaptation to cell culture by providing new trypsin cleavage sites. These results suggest that HN-1 is a G2c subtype variant that adapts well to cell culture and can be used to study the adaptive mechanisms of PEDV and develop attenuated vaccines., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Kidney-yang deficiency syndrome (KYDS) is characterized by a metabolic disorder stemming from neuroendocrine dysregulation, often associated with hepatic dysfunction. In traditional Chinese medicine, Psoralea corylifolia Linn. (BGZ) is commonly utilized for treating KYDS. However, the specific therapeutic effects of BGZ on liver function regulation remain unclear. To evaluate the protective effects of BGZ against KYDS in rats, organ index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and other biochemical indices were analyzed. Hematoxylin and eosin (HE) staining was utilized to assess liver histopathology. Additionally, transcriptomic and metabolomic analyses were conducted to identify potential biomarkers. BGZ treatment led to a significant reduction in ALT and AST levels, accompanied by improvements in liver histopathology in rats with KYDS. Moreover, BGZ induced significant alterations in 92 differentially expressed genes (DEGs) and 20 metabolites in the KYDS rat model. The comprehensive examination of metabolites and DEGs identified potential mechanisms underlying the therapeutic effects of BGZ, highlighting the neuroactive ligand-receptor interaction, cAMP signaling pathway, calcium signaling pathway, and cytokine-cytokine receptor interaction as key mechanisms. Validation of key targets within the cAMP pathway was substantiated through enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction. The cAMP pathway emerges as a plausible mechanism through which BGZ exerts protective effects against KYDS. The findings of this study contribute to an improved understanding of the therapeutic actions of BGZ and establish a groundwork for further research into the complex pathways involved, as well as the potential for drug-targeted therapies for KYDS., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jin-Fa Tang reports was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

The novel HLA-A*33:03:68 allele differs from HLA-A*33:03:01:01 by 1 variation in exon 3., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Liver cancer is one of the most prevalent malignant tumors worldwide, and its early detection and treatment are crucial for enhancing patient survival rates and quality of life. However, the early symptoms of liver cancer are often not obvious, resulting in a late-stage diagnosis in many patients, which significantly reduces the effectiveness of treatment. Developing a highly targeted, widely applicable, and practical risk prediction model for liver cancer is crucial for enhancing the early diagnosis and long-term survival rates among affected individuals., Aim: To develop a liver cancer risk prediction model by employing machine learning techniques, and subsequently assess its performance., Methods: In this study, a total of 550 patients were enrolled, with 190 hepatocellular carcinoma (HCC) and 195 cirrhosis patients serving as the training cohort, and 83 HCC and 82 cirrhosis patients forming the validation cohort. Logistic regression (LR), support vector machine (SVM), random forest (RF), and least absolute shrinkage and selection operator (LASSO) regression models were developed in the training cohort. Model performance was assessed in the validation cohort. Additionally, this study conducted a comparative evaluation of the diagnostic efficacy between the ASAP model and the model developed in this study using receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA) to determine the optimal predictive model for assessing liver cancer risk., Results: Six variables including age, white blood cell, red blood cell, platelet counts, alpha-fetoprotein and protein induced by vitamin K absence or antagonist II levels were used to develop LR, SVM, RF, and LASSO regression models. The RF model exhibited superior discrimination, and the area under curve of the training and validation sets was 0.969 and 0.858, respectively. These values significantly surpassed those of the LR (0.850 and 0.827), SVM (0.860 and 0.803), LASSO regression (0.845 and 0.831), and ASAP (0.866 and 0.813) models. Furthermore, calibration and DCA indicated that the RF model exhibited robust calibration and clinical validity., Conclusion: The RF model demonstrated excellent prediction capabilities for HCC and can facilitate early diagnosis of HCC in clinical practice., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The patient is a 12-year-old male who has experienced recurrent perianal abscesses for over 10 years, along with recurrent oral ulcers and deformities in the joints of hands and feet. Gastrointestinal endoscopy and capsule endoscopy revealed multiple ulcers in the digestive tract. Combined with his histopathological examinations, the patient was diagnosed with Crohn's disease. Whole exome sequencing and peripheral blood karyotype analysis indicated a karyotype of 47,XY,+8. The patient was treated with a "step-up" strategy. His clinical symptoms were under control, with significant improvement observed during endoscopic examination. This case suggests that early-onset inflammatory bowel disease may have genetic susceptibility, and when accompanied by other multi-system involvement, the possibility of chromosomal abnormalities, such as trisomy 8, should be considered and given due attention.

Background: Many late adolescents experience a state of psychological sub-health, requiring early recognition and intervention. This study aims to assess the psychological state of late Chinese adolescents and uncover developmental trend of mental health through network analysis., Method: We analyzed data from 9072 Chinese high school adolescents in Shandong Province surveyed in 2020-2021, and divided them into the normal, the suspected, and the abnormal groups based on Symptom Checklist 90 (SCL-90) scores. Network analysis was employed to identify the core symptoms and bridge symptoms across different states., Results: Anxiety and depression were the most central symptoms, without gender differences. Core symptoms, network structure, and network invulnerability varied across different psychological states. The abnormal group exhibited the highest value of natural connectivity, followed by the suspected and normal groups. This pattern extended to bridge networks. While not meeting diagnostic criteria, the suspected group demonstrated abnormalities in network edge invariance and global strength invariance., Limitations: The cross-sectional design cannot establish causality, and biases in self-report measurements cannot be ignored., Conclusion: Compared to traditional scale indicators, network structural characteristics may be a more sensitive assessment indicator., Competing Interests: Declaration of competing interest The authors have no conflicts of interest regarding this research study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To explore the risk factors of radiation-induced oral mucositis (RIOM) in patients with head and neck tumors undergoing radiotherapy., Methods: A retrospective collection was conducted on patients with head and neck tumors who underwent radiotherapy and chemotherapy in our hospital from April 1, 2015 to April 1, 2019. They were divided into an incidence group (n = 48) and a non-incidence group (n = 76) based on whether RIOM occurred, and relevant data was collected for comparison., Results: There were statistically significant differences between the two groups of patients in terms of tumor type, smoking percentage, education level percentage, tumor stage, oral mucosal inflammation stage, radiotherapy dose, mucosal protectants, and oral hygiene condition(P < 0.05); The regression analysis results showed that smoking (OR=1.274, 95 % CI: 1.095-2.007), high-dose radiotherapy (OR=1.223, 95 % CI: 1.098-2.077), and poor oral hygiene (OR=1.367, 95 % CI: 1.024-2.890) were risk factors for RIOM., Conclusion: Smoking, high-dose radiotherapy, and poor oral hygiene were risk factors for RIOM in head and neck patients after radiotherapy and chemotherapy., 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 Masson SAS. All rights reserved.)

Purpose: To complete a reanalysis study of two similarly designed prospective controlled studies exploring prognostic factors associated with the surgical outcomes of reconstructive treatment of peri-implantitis., Materials and Methods: Individual patient data of both studies were gathered. The initial study employed a submerged healing approach via primary wound closure with implant suprastructure removal and complete coverage of grafted sites. The second study employed a nonsubmerged healing protocol in which healing abutments were kept in place and the implants were not fully submerged. Both studies measured all prognostic factors at similar time points throughout 1 year and included clinical defect fill (DF) and radiographic defect fill (RDF), reduction of pocket depth (PDR), and bleeding on probing (BoP). Multilevel regression was used for statistical assessment of outcomes relative to the impact of site, local, surgical, and patient-related variables., Results: Overall, 59 implants (30 submerged and 29 nonsubmerged) were treated. Statistically significant higher DF (on average 0.9 mm higher), RDF (1.7 mm), and PDR (1.3 mm) were observed when a submerged reconstructive approach was performed, whereas BoP reduction was similar. After controlling for treatment (submerged/ nonsubmerged), there were no other significant associations with patient-related (age, sex, smoking, prior periodontitis etc), or implant-related (previous prosthesis type, arch, keratinized tissue width [KTW], etc) factors., Conclusions: Within the study's limitations, we conclude that a submerged reconstructive approach for surgical management of peri-implantitis leads to significantly enhanced clinical and radiographic outcomes when compared to a nonsubmerged approach.

The aim of this study was to evaluate the role of angiotensin-converting enzyme 1 (ACE1) in H2O2-induced trophoblast cell injury and the potential molecular mechanisms. Oxidative stress was modeled by exposing HTR-8/SVneo cells to 200 μM H2O2. Western blot and real-time quantitative PCR methods were used to detect protein and mRNA expression level of ACE1 in chorionic villus tissue and trophoblast HTR-8/SVneo cell. Inhibition of ACE1 expression was achieved by transfection with small interfering RNA. Then flow cytometry, Cell Counting Kit-8, and Transwell assay was used to assess apoptosis, viability, and migration ability of the cells. Reactive oxygen species (ROS) were detected by fluorescent probes, and malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) activities were determined by corresponding detection kits. Angiotensin-converting enzyme 1 expression was upregulated in chorionic villus tissue of patients with missed abortion (MA) compared with individuals with normal early pregnancy abortion. H2O2 induced elevated ACE1 expression in HTR-8/SVneo cells, promoted apoptosis, and inhibited cell viability and migration. Knockdown of ACE1 expression inhibited H2O2-induced effects to enhance cell viability and migration and suppress apoptosis. Additionally, H2O2 stimulation caused increased levels of ROS and MDA and decreased SOD and GSH activity in the cells, whereas knockdown of ACE1 expression led to opposite changes of these oxidative stress indicators. Moreover, knockdown of ACE1 attenuated the inhibitory effect of H2O2 on the Nrf2/HO-1 pathway. Angiotensin-converting enzyme 1 was associated with MA, and it promoted H2O2-induced injury of trophoblast cells through inhibiting the Nrf2 pathway. Therefore, ACE1 may serve as a potential therapeutic target for MA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Ticks, which are obligate blood-feeding parasites, transmit a wide range of pathogens during their hematophagic process. Certain enzymes and macromolecules play a crucial role in inhibition of several tick physiological processes, including digestion and reproduction. In the present study, genes encoding type 2 cystatin were cloned and characterized from Haemaphysalis doenitzi, and the potential role of cystatin in tick control was further assessed., Results: Two cystatin genes, HDcyst-1 and HDcyst-2, were successfully cloned from the tick H. doenitzi. Their open reading frames are 390 and 426 base pairs, and the number of coding amino acids are 129 and 141, respectively. In the midgut, salivary glands, Malpighian tubules and ovaries of ticks, the relative expression of HDcyst-1 was higher in the midgut and Malpighian tubules, and HDcyst-2 was higher in the salivary glands of H. doenitzi, respectively. Lipopolysaccharide (LPS) injection and low-temperature stress elevated cystatin expression in ticks. Enzyme-linked immunosorbent assay showed that both rHDcyst-1 and rHDcyst-2 protein vaccines increased antibody levels in immunized rabbits. A vaccination trial in rabbits infected with H. doenitzi showed that both recombinant cystatin proteins significantly reduced tick engorgement weights and egg mass weight, in particular, rHDcyst-1 significantly prolonged tick engorgement time by 1 day and reduced egg hatching rates by 16.9%. In total, rHDcyst-1 and rHDcyst-2 protein vaccinations provided 64.1% and 51.8% protection to adult female ticks, respectively., Conclusion: This is the first report on the immunological characterization of the cystatin protein and sequencing of the cystatin gene in H. doenitzi. Cystatin proteins are promising antigens that have the potential to be used as vaccines for infestation of H. doenitzi control. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

In the face of carbon, nitrogen, and phosphorus starvation, microorganisms have evolved adaptive mechanisms to maintain growth. In a previous study, we identified a protein predicted to contain acyl-CoA-binding domains in the plant pathogenic fungus Verticillium dahliae . The predicted protein, designated VdAcb1, possesses an atypical signal peptide. However, the functions of this acyl-CoA-binding protein in V. dahliae are not clear. In this research, in vivo or in vitro assays confirmed that VdAcb1 is secreted extracellularly from V. dahliae , although it does not have the typical signal peptide. Furthermore, the unconventional secretion of VdAcb1 was dependent on VdGRASP, a member of the compartment for unconventional protein secretion (CUPS). The deletion mutant strain of VdAcb1 (Δ VdAcb1) exhibited significant sensitivity to carbon starvation. RNA-seq revealed that the expression of genes related to filamentous growth (MSB2 pathway) and sugar transport were regulated by VdAcb1 under conditions of carbon starvation. Yeast one-hybrid experiments further showed that the expression of VdAcb1 was positively regulated by the transcription factor VdMsn4. The Δ VdAcb1 strain showed significantly reduced virulence on Gossypium hirsutum and Nicotiana benthamiana . We hypothesize that under conditions of carbon starvation, the expression of VdAcb1 is activated by VdMsn4 and VdAcb1 is secreted into the extracellular space. In turn, this activates the downstream MAPK pathway to enhance filamentous growth and virulence of V. dahliae ., Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00175-3., Competing Interests: Conflict of interestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All authors declare that they have no competing interests., (© The Author(s) 2024.)

Objectives: Confirm that stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-exos) can limit inflammation-triggered epithelial cell apoptosis and explore the molecular mechanism., Methods: SHED-exos were injected into the submandibular glands (SMGs) of non-obese diabetic (NOD) mice, an animal model of Sjögren's syndrome (SS). Cell death was evaluated by western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining., Results: SHED-exos treatment promoted the saliva flow rates of NOD mice, accompanied by decreased cleaved caspase-3 levels and apoptotic cell numbers in SMGs. SHED-exos inhibited autophagy, pyroptosis, NETosis, ferroptosis, necroptosis and oxeiptosis marker expression in SS-damaged glands. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis of exosomal miRNAs suggested that the rat sarcoma virus (RAS)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway might play an important role. In vivo, the expression of Kirsten RAS, Harvey RAS, MEK1/2 and p-ERK1/2 was upregulated in SMGs, and this change was blocked by SHED-exos treatment. In vitro, SHED-exos suppressed p-ERK1/2 activation and increased cleaved caspase-3 and apoptotic cell numbers, which were induced by IFN-γ., Conclusion: SHED-exos suppress epithelial cell death, which is responsible for promoting salivary secretion. SHED-exos inhibited inflammation-triggered epithelial cell apoptosis by suppressing p-ERK1/2 activation, which is involved in these effects., (© 2023 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

Background: Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery., Aims: We started this largest-to-date meta-analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery., Materials & Methods: Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups., Results: Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3-year and 5-year local recurrence, disease-free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches., Conclusion: Laparoscopy is non-inferior to open surgery for rectal cancer with respect to oncological outcomes and long-term survival. Moreover, laparoscopic surgery provides short-term advantages, including faster recovery and less complications., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Ethnopharmacological Relevance: As reported in the Ancient Chinese Medicinal Books, Ginkgo biloba L. fruit has been used as a traditional Chinese medicine for the treatment asthma and cough or as a disinfectant. Our previous study demonstrated that G. biloba exocarp extract (GBEE), an extract of a traditional Chinese herb, inhibits the formation of methicillin-resistant Staphylococcus aureus (MRSA) biofilms. However, GBEE is a crude extract that contains many components, and the underlying mechanisms of purified GBEE fractions extracted with solvents of different polarities are unknown., Aim of the Study: This study aimed to investigate the different components in GBEE fractions extracted with solvents of different polarities and their antibacterial effects and mechanisms against MRSA and Staphylococcus haemolyticus biofilms both in vitro and in vivo., Methods: The components in different fractions were detected by high-performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS). Microbroth dilution assays and time growth curves were used to determine the antibacterial effects of the fractions on 15 clinical bacterial isolates. Crystal violet staining, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to identify the fractions that affected bacterial biofilm formation. The potential MRSA targets of the GBEE fraction obtained with petroleum ether (PE), denoted GBEE-PE, were screened by transcriptome sequencing, and the gene expression profile was verified by quantitative polymerase chain reaction (qPCR)., Results: HPLC-HRMS analysis revealed that the four GBEE fractions (extracted with petroleum ether, ethyl acetate, n-butanol, and water) contained different ginkgo components, and the antibacterial effects decreased as the polarity of the extraction solvent increased. The antibacterial activity of GBEE-PE was greater than that of the GBEE fraction extracted with ethyl acetate (EA). GBEE-PE improved H. illucens survival and reduced MRSA colonization in model mouse organs. Crystal violet staining and SEM and TEM analyses revealed that GBEE-PE inhibited MRSA and S. haemolyticus biofilm formation. Transcriptional analysis revealed that GBEE-PE inhibits MRSA biofilms by altering ion transport, cell wall metabolism and virulence-related gene expression. In addition, the LO2 cell viability and H. illucens toxicity assay data showed that GBEE-PE at 20 mg/kg was nontoxic., Conclusion: The GBEE fractions contained different components, and their antibacterial effects decreased with increases in the polarity of the extraction solvent. GBEE-PE limited MRSA growth and biofilm formation by affecting ion transport, cell wall synthesis, and virulence-related pathways. This research provides a more detailed overview of the mechanism by which GBEE-PE inhibits MRSA both in vitro and in vivo and suggests that GBEE-PE is a new prospective antimicrobial with the potential to be used in MRSA therapeutics in the future., 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 B.V. All rights reserved.)

Objective: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma., Design: Phase 3, open label, multicentre, randomised trial., Setting: Four hospitals located in China between September 2019 and August 2022., Participants: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma., Interventions: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m 2 on day 1), cisplatin (60 mg/m 2 on day 1), and capecitabine (1000 mg/m 2 twice on days 1-14) or gemcitabine (1 g/m 2 on days 1 and 8) and cisplatin (80 mg/m 2 on day 1)., Main Outcome Measures: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population., Results: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up., Conclusion: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival., Trial Registration: Chinese Clinical Trial Registry ChiCTR1900027112., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Guangdong Basic and Applied Basic Research Foundation, National Natural Science Foundation of China, CPSF, and Postdoctoral Fellowship Program of CPSF for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)