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An abstract of the conference paper "Crystal Structure Analysis of Anti-V2 mAb 2158 Suggests a Conformational Epitope Involving an N-Linked Glycan," by B. Spurrier and colleagues is presented.

An abstract of the conference paper "Structural Analyses of Antigen Binding Similarities and Differences Between Rabbit and Human Anti-gp120 V3 mAbs," by R. Pan and colleagues is presented.

An abstract of the research paper "Sequential exposure to specific antibody escape mutations may program neutralization breadth during subtype A HIV-1 infection," by M.K. Murphy and colleagues is presented.

At present, the characteristics of double-hit multiple myeloma (DHMM) are unknown. We retrospectively analyzed the clinical data from 433 new diagnosed MM patients and found that DHMM have a higher β2-MG level and percentage of bone marrow plasma cell. Cox regression analysis showed that the prognosis of DHMM was not limited by clinical indicators. The abnormal proliferation of bone marrow in DHMM is obvious, and the proportion of poorly differentiated plasma cell is high. By collecting specimens from our center and performing flow cytometry to analyze the immunophenotypic and functional characteristics of lymphocyte subpopulations, we found that DHMM had a higher ratio of Tregs cells, and the proportion of iTregs cells was also significantly higher than non-DHMM (P < 0.05). Moreover, DHMM had higher levels of TGF-β1 and IL-10, and TGF-β1 and IL-10 were positively correlated with iTregs (P < 0.05). In addition, DHMM was highly expressed PD-1 on CD8 + T cells and had a higher proportion of CD38 high Tregs cells. In vitro we have shown that the addition of TGF-β1 antibody or CD38 antibody can effectively inhibit the proportion of CD38 high Tregs. This study describes the characteristics of DHMM based on bicentric data, which is helpful to better provide theoretical support for the treatment of DHMM., Competing Interests: Declarations Ethics approval and consent to participate The studies involving human subjects were reviewed and approved by the Ethics Committee at Zhongnan Hospital of Wuhan University. The patients provided their written informed consent to participate in this study. All methods were carried out in accordance with declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Influenza remains a global public health concern. Understanding the vaccination-induced response in an aging population, which is susceptible and at high risk, is essential for disease prevention and control. Here, we report findings on the safety and immunogenicity of a quadrivalent influenza split-virion vaccine (15 µg/subtype/0.5 ml/dose) (hereinafter referred to as the "quadrivalent influenza vaccine") in a population aged ≥ 60 years., Methods: This open-label, pragmatic post-marketing trial enrolled 1399 older adults to receive one dose of an approved commercially available quadrivalent influenza vaccine manufactured by Hualan Biological Bacterin Inc. (hereinafter referred to as "Hualan Bio"). Participants with contraindications for the vaccine were excluded, while poor health condition was acceptable. All vaccinated subjects experienced adverse events collection within 30 days and serious adverse events within 180 days post-vaccination. 25% subjects, selected randomly, underwent venous blood sampling pre-vaccination and 30 days after post-vaccination, for detecting antibody titers against each subtype of influenza virus by hemagglutination inhibition assay. The incidences of adverse events and antibody titers against each subtype of influenza virus were statistically analyzed using SAS 9.4., Results: No grade 3 adverse reactions occurred within 30 days post-vaccination. The incidences of overall adverse reactions, local adverse reactions and systemic adverse reactions were 3.79%, 2.86% and 1.00%, respectively. No serious adverse reactions occurred within 180 days post-vaccination. There were 350 subjects who completed venous blood sampling pre-vaccination, among whom 348 subjects completed venous blood sampling at 30 days post-vaccination for immunogenicity assessment. With respect to hemagglutination inhibition antibodies against influenza viruses H1N1, H3N2, BV and BY subtypes, at 30 days post-vaccination, the seroconversion rates were 87.64%, 75.57%, 73.28% and 78.74%, respectively; the seropositive rates were 93.97%, 98.56%, 79.31% and 95.40%, respectively; and the geometric mean increase (GMI) in post-immunization/pre-immunization antibodies was 24.80, 7.26, 10.39 and 7.39, respectively., Conclusion: One 15 µg/subtype dose of the vaccine had a good safety profile and elicited favorable immunogenicity among subjects aged ≥ 60 years. The results of this study indicate that Hualan Bio quadrivalent influenza vaccine strike balance between safety and immunogenicity, supporting unnecessity to increase dosage or inoculation frequency for further enhancing immunogenicity., Trial Registration: Registered on ClinicalTrials.gov., Registration Number: NCT06334510. Registered on 28/03/2024 (retrospectively registered)., (© 2024. The Author(s).)

Background: The relationship between obesity and type 2 diabetes with bone health has always been a topic of debate. The weight-adjusted waist index has become a commonly used indicator for assessing central obesity, fat, and muscle mass. However, currently there is no research reporting the association between weight-adjusted waist index and risk of osteoporosis in populations of type 2 diabetes. Therefore, this study aims to provide new information on the association between weight-adjusted waist index and risk of osteoporosis in type 2 diabetes., Methods: This cross-sectional study involved 963 patients with type 2 diabetes who were admitted to the Department of Endocrinology of Cangzhou Central Hospital. Multivariate logistic regression models were used to assess the association between weight-adjusted waist index and osteoporosis. The potential nonlinear association was evaluated. The effects of interaction between subgroups were assessed using the likelihood ratio test., Results: Weight-adjusted waist index was positively associated with the risk of osteoporosis, regardless of traditional confounding factors. For each 1 unit increased in weight-adjusted waist index, the risk of osteoporosis increased by 67%. Furthermore, there was a nonlinear relationship between weight-adjusted waist index and osteoporosis. The subgroup analysis did not reveal any significant interactions., Conclusions: Our study indicated a positive association between weight-adjusted waist index and the risk of osteoporosis in adult Chinese type 2 diabetes patients, and this relationship was nonlinear., (© 2024. The Author(s).)

Alpha-fetoprotein (AFP) elevation is a well-known biomarker in various diseases, particularly in the diagnosis of hepatocellular carcinoma (HCC). Intracellular AFP has been previously implicated in promoting tumorigenesis. In this study, we discovered that AFP enhances the stability of oncoproteins c-MYC and c-MET, thereby facilitating the progression of liver and gastric tumors. Our findings suggest that AFP acts by stabilizing these oncoproteins, which are clients of heat shock protein 90 (HSP90), and prevents their degradation through ubiquitination. Intriguingly, we identified AFP as a novel co-chaperone of HSP90, demonstrating its ability to regulate the stabilization of HSP90 client proteins. Furthermore, our results indicate that inhibiting AFP or HSP90 enhances the cytotoxicity of chemotherapeutic agents in AFP-producing HCC and gastric cancer cells. These findings have significant implications for the development of therapeutic strategies targeting AFP-producing tumors, as the AFP-HSP90-mediated activation of c-MYC and c-MET provides new insights into potential treatment approaches. In summary, this study sheds light on the role of AFP in promoting tumor progression by stabilizing oncoproteins through its interaction with HSP90. The identification of this mechanism opens up new avenues for therapeutic interventions in AFP-producing tumors., (© 2024. The Author(s).)

Respiratory failure, intracranial hemorrhage and infection were more common in hyperleukocytic acute myeloid leukemia patients than in non-hyperleukocytic leukemia patients. Compared with non-apheresis treatment, the white blood cells decreased significantly and the infection rate decreased after apheresis treatment. However, the treatment time of leukapheresis in patients with hyperleukocytic leukemia is very long, while it is more damaging to cells. In this study, which conducted a retrospective analysis on patients with hyperleukocytic acute myeloid leukemia, the process of centrifugation of normal cells and patients' cells by apheresis machine was simulated in vitro. Through selecting 5 healthy persons and 11 patients with hyperleukocytic acute myeloid leukemia, extracting their blood samples and performing in vitro centrifugation at different speeds or duration, we observed the changes of the numbers and morphology of peripheral blood cells in healthy people and patients, so as to explore the optimal centrifugation parameters during leukapheresis. The cells obtained by the optimal centrifugation parameters were cryopreserved and two groups of mice (10 mice in each group) were used to establish leukemia animal models. Through the research, it is found that when the centrifugal speed is below 6000 rpm, the damage to blood cells in healthy people and in patients with hyperleukocytic leukemia is not obvious. When the centrifugal speed is above 6000 rpm, the platelets will be damaged significantly. The cells obtained under the optimal centrifugation parameters can be successfully cryopreserved and used to establish leukemia animal models. This study is of great significance for improving the efficiency and reducing the side effects of leukapheresis, and is helpful to improve the treatment of white blood cells reduction., (© 2024. The Author(s).)

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4 CRBN , and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies., (© 2024. The Author(s).)

Background: Premature ovarian failure (POF) caused by cisplatin is a severe and intractable sequela for young women with cancer who received chemotherapy. Cisplatin causes the dysfunction of granulosa cells and mainly leads to but is not limited to its apoptosis and autophagy. Ferroptosis has been also reported to participate, while little is known about it. Our previous experiment has demonstrated that endometrial stem cells (EnSCs) can repair cisplatin-injured granulosa cells. However, it is still unclear whether EnSCs can play a repair role by acting on ferroptosis., Methods: Western blotting and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were applied to detect the expression levels of ferroptosis-related genes. CCK-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to evaluate cell viability. Transmission electron microscopy (TEM) was performed to detect ferroptosis in morphology. And the extent of ferroptosis was assessed by ROS, GPx, GSSG and MDA indicators. In vivo, ovarian morphology was presented by HE staining and the protein expression in ovarian tissue was detected by immunohistochemistry., Results: Our results showed that ferroptosis could occur in cisplatin-injured granulosa cells. Ferroptosis inhibitor ferrostatin-1 (Fer-1) and EnSCs partly restored cell viability and mitigated the damage of cisplatin to granulosa cells by inhibiting ferroptosis. Moreover, the repair potential of EnSCs can be markedly blocked by ML385., Conclusion: Our study demonstrated that cisplatin could induce ferroptosis in granulosa cells, while EnSCs could inhibit ferroptosis and thus exert repair effects on the cisplatin-induced injury model both in vivo and in vitro. Meanwhile, Nrf2 was validated to participate in this regulatory process and played an essential role., (© 2024. The Author(s).)

Background: Supracrestal gingival tissue dimensions (SGTDs) has been considered to be an essential element of periodontal phenotype (PP) components. This study aimed to explore the relationship between SGTDs and other PP components by digital superposition method that integrated cone beam computed tomography (CBCT) with intraoral scanning., Methods: This cross-sectional study was conducted at the Stomatology Hospital of Fujian Medical University. Participants were recruited based on the inclusion and exclusion criteria. The data obtained from the digital scanner (TRIOS 3, 3Shape, Denmark) and CBCT images were imported into the TRIOS software (Implant Studio, 3Shape, Denmark) for computing relevant parameters. The significant level was set at 0.05., Results: A total of 83 participants with 498 maxillary anterior teeth were finally included. The mean values of supracrestal gingival height (SGH) and the distance from the cementoenamel junction (CEJ) to the crest of the alveolar ridge (CEJ-ABC) on the buccal site were significantly higher than palatal SGH (SGH-p) and palatal CEJ-ABC (CEJ-ABC-p). Men exhibited taller CEJ-ABC and SGH-p than women. Additionally, tooth type was significantly associated with the SGH, SGH-p and CEJ-ABC-p. Taller SGH was associated with wider crown, smaller papilla height (PH), flatter gingival margin, thicker bone thickness (BT) and gingival thickness (GT) at CEJ, the alveolar bone crest (ABC), and 2 mm apical to the ABC. Smaller SGH-p displayed thicker BT and GT at CEJ, the ABC, and 2 and 4 mm apical to the ABC. Higher CEJ-ABC showed lower interproximal bone height, smaller PH, flatter gingival margin, thinner GT and BT at CEJ, and 2 mm apical to the ABC. Smaller CEJ-ABC-p displayed thicker BT at CEJ and 2 and 4 mm apical to the ABC. On the buccal, thicker GT was correlated with thicker BT at 2 and 4 mm below the ABC., Conclusion: SGTDs exhibited a correlation with other PP components, especially crown shape, gingival margin and interdental PH. The relationship between SGTDs and gingival and bone phenotypes depended on the apico-coronal level evaluated., Trial Registration: This study was approved by the Biomedical Research Ethics Committee of Stomatology Hospital of Fujian Medical University (approval no. 2023-24)., (© 2024. The Author(s).)

Objective: Postoperative fasting following thoracoscopic surgery can cause intense thirst and oral discomfort. However, there is currently no research on ultraearly oral hydration (UEOH) in middle-aged or elderly patients after thoracoscopic surgery. The aim of this study was to investigate the effectiveness and safety of UEOH for improving oral discomfort after thoracoscopic surgery., Methods: This single-center prospective double-blind randomized controlled trial was conducted from April 2022 to November 2023. A total of 64 middle-aged and elderly patients who underwent the first thoracoscopic surgery on the day were enrolled at our institution. Postoperatively, in the Postanesthesia Care Unit (PACU), patients were randomly assigned at a 1:1 ratio to either the UEOH group or the standard care (SC) group. The primary outcome was the patient's thirst score at 6 h after surgery. Secondary outcomes included the incidence of postoperative oral discomfort; pain scores; the occurrence of adverse reactions such as nausea, vomiting, regurgitation and aspiration; anxiety scores on the first postoperative day; the time to first flatus; and recovery satisfaction scores., Results: The demographic and surgical characteristics were similar between the two groups. Patients in the UEOH group had lower thirst scores 6 h after surgery than did those in the SC group(16.1 ± 6.70 vs. 78.4 ± 8.42, P < 0.01). The incidence of postoperative oral discomfort (P < 0.01), anxiety scores on the first postoperative day (P<0.05), and time to first flatus (P<0.05) were better in the UEOH group. Additionally, the incidences of adverse reactions, such as postoperative nausea, vomiting, regurgitation and aspiration, were similar between the two groups (P>0.05)., Conclusion: For middle-aged and elderly patients undergoing thoracoscopic surgery, the use of a modified UEOH protocol postoperatively can improve thirst and promote gastrointestinal recovery without increasing complications., Trial Registration: This single-center, prospective, RCT has completed the registration of the Chinese Clinical Trial Center at 07/12/2023 with the registration number ChiCTR2300078425., (© 2024. The Author(s).)

Background: MULTIPLEX is a single-scan three-dimensional multi-parametric MRI technique that provides 1 mm isotropic T1-, T2*-, proton density- and susceptibility-weighted images and the corresponding quantitative maps. This study aimed to investigate its feasibility of clinical application in Parkinson's disease (PD)., Methods: 27 PD patients and 23 healthy control (HC) were recruited and underwent a MULTIPLEX scanning. All image reconstruction and processing were automatically performed with in-house C + + programs on the Automatic Differentiation using Expression Template platform. According to the HybraPD atlas consisting of 12 human brain subcortical nuclei, the region-of-interest (ROI) based analysis was conducted to extract quantitative parameters, then identify PD-related abnormalities from the T1, T2* and proton density maps and quantitative susceptibility mapping (QSM), by comparing patients and HCs., Results: The ROI-based analysis revealed significantly decreased mean T1 values in substantia nigra pars compacta and habenular nuclei, mean T2* value in subthalamic nucleus and increased mean QSM value in subthalamic nucleus in PD patients, compared to HCs (all p values < 0.05 after FDR correction). The receiver operating characteristic analysis showed all these four quantitative parameters significantly contributed to PD diagnosis (all p values < 0.01 after FDR correction). Furthermore, the two quantitative parameters in subthalamic nucleus showed hemicerebral differences in regard to the clinically dominant side among PD patients., Conclusions: MULTIPLEX might be feasible for clinical application to assist in PD diagnosis and provide possible pathological information of PD patients' subcortical nucleus and dopaminergic midbrain regions., (© 2024. The Author(s).)

Background: Broncho-esophageal fistula (BEF) secondary to esophageal diverticulum is a rare clinical condition, which is often misdiagnosed for a long time. The aim of our study is to summarize and clarify the advantages of MSCT in diagnosing BEF secondary to esophageal diverticulum., Methods: We retrospectively analyzed patients clinically diagnosed with BEF from January 2005 to January 2022 at Jilin University First Hospital. Only those patients with BEF secondary to esophageal diverticulum and complete clinical data met our enrolled standard. All patients' clinicopathologic characteristics and MSCT features were systemically evaluated., Results: 17 patients were eligible for our cohort study, including male 10 and female 7. The patient's mean age was 42.3 ± 12.5. The chronic cough occurred in all seventeen patients and bucking following oral fluid intake was documented in nine patients. MSCT distinctly suggested the fistulous tract between the bronchi and the esophagus in all patients. The mean diameter of the orifices in the wall of the esophagus was 4.40 ± 1.81 mm. The orifice in the midthoracic esophagus side was 15 cases and 2 cases at the lower thoracic esophagus. The involved bronchus included 13 cases at the right lower lobe bronchus, 1 at the right middle lobe bronchus and 3 at the left lower lobe bronchus. The contrast agent was observed in the pulmonary parenchyma in 10 of 13 patients who underwent esophagogram. No definite fistula was observed in 3 of 11 who underwent gastroscopy, while the intra-operative findings supported the existence of fistula., Conclusions: BEF secondary to esophageal diverticulum tends to occur between the midthoracic esophagus and the right lower lobe bronchus. Compared with esophagography and gastroscopy, MSCT shows more comprehensive information about the fistulous shape, size, course and lung involvement, which are helpful for establishing diagnosis and guiding subsequent treatment., (© 2024. The Author(s).)

Background: Resistance can develop during treatment of advanced endometrial cancer (EC), leading to unsatisfactory results. Fanconi anemia complementation group D2 (Fancd2) has been shown to be closely related to drug resistance in cancer cells. Therefore, this study was designed to explore the correlation of Fancd2 with EC resistance and the mechanism of Fancd2., Methods: Real-time quantitative PCR (RT-qPCR) was used to detect the expression of Fancd2 in EC tissues and cells. EC cells (Ishikawa) and paclitaxel-resistant EC cells (Ishikawa/TAX) were transfected to knock down Fancd2. In addition, the ferroptosis inhibitor Ferrostatin-1 was adopted to treat Ishikawa/TAX cells. The sensitivity of cancer cells to chemotherapeutic agents was observed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and inhibitory concentration (IC)50 was calculated. Reactive oxygen species (ROS) levels were measured by flow cytometry, the activity of malondialdehyde (MDA) and the levels of glutathione (GSH) and Fe 2+ in cells were detected by corresponding kits, and protein expression of solute farrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was obtained through western blot., Results: Compared with the normal tissues and endometrial epithelial cells, Fancd2 expression was significantly increased in EC tissues and Ishikawa cells, respectively. After knock-down of Fancd2, Ishikawa cells showed significantly increased sensitivity to chemotherapeutic agents. Besides, compared with Ishikawa cells, the levels of ROS, the activity of MDA, and the levels of GSH and Fe 2+ were significantly decreased in Ishikawa/TAX cells, while the expression levels of SLC7A11 and GPX4 were significantly increased. Knock-down of Fancd2 significantly increased the ferroptosis levels in Ishikawa/TAX cells, but this effect could be reversed by Ferrostatin-1., Conclusion: Fancd2 increases drug resistance in EC cells by inhibiting the cellular ferroptosis pathway., (© 2024. The Author(s).)

Background: Bone fragility is a recognized complication of type 1 diabetes (T1D). Thus, lower trabecular bone score (TBS) measurements in T1D patients can be predicted. However, the results of current studies on TBS in patients with T1D are inconsistent. In this context, the present study aimed to test the hypothesis that T1D is associated with lower TBS through a meta-analysis., Methods: An electronic search of the literature was conducted using PubMed, Embase and Web of science databases to identify studies related to TBS and T1D, supplemented by an additional manual check of the reference list of relevant original and review articles. All data was analyzed using a random effects model. Results were compared using standardized mean differences (SMD) and 95% confidence intervals (CI). P ≤ 0.05 was considered statistically significant. Review Manager 5.4 software and Stata 17.0 software were used for statistical analysis., Results: Seven cross-sectional studies involving 848 participants were included. TBS was lower in T1D patients than in healthy controls on random effects analysis, with no heterogeneity (SMD =  - 0.39, 95% CI [- 0.53, - 0.24], P < 0.001; I 2  = 0%). In addition, by subgroup analysis, T1D patients were strongly associated with reduced TBS in different regions and age groups, and the results were independent of covariate adjustment., Conclusion: This study showed that TBS was lower in patients with T1D than in healthy individuals with normal blood glucose levels, suggesting that TBS may be a useful measure to assess fracture risk in T1D., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Although WD repeat and high-mobility group box DNA binding protein 1 (WDHD1) played an essential role in DNA replication, chromosome stability, and DNA damage repair, the panoramic picture of WDHD1 in human tumors remains unclear. Hence, this study aims to comprehensively characterize WDHD1 across 33 human cancers., Methods: Based on publicly available databases such as TCGA, GTEx, and HPA, we used a bioinformatics approach to systematically explore the genomic features and biological functions of WDHD1 in pan-cancer., Results: WDHD1 mRNA levels were significantly increased in more than 20 types of tumor tissues. Elevated WDHD1 expression was associated with significantly shorter overall survival (OS) in 10 tumors. Furthermore, in uterine corpus endometrial carcinoma (UCEC) and liver hepatocellular carcinoma (LIHC), WDHD1 expression was significantly associated with higher histological grades and pathological stages. In addition, WDHD1 had a high diagnostic value among 16 tumors (area under the ROC curve [AUC] > 0.9). Functional enrichment analyses suggested that WDHD1 probably participated in many oncogenic pathways such as E2F and MYC targets (false discovery rate [FDR] < 0.05), and it was involved in the processes of DNA replication and DNA damage repair (p.adjust < 0.05). WDHD1 expression also correlated with the half-maximal inhibitory concentrations (IC50) of rapamycin (4 out of 10 cancers) and paclitaxel (10 out of 10 cancers). Overall, WDHD1 was negatively associated with immune cell infiltration and might promote tumor immune escape. Our analysis of genomic alterations suggested that WDHD1 was altered in 1.5% of pan-cancer cohorts and the "mutation" was the predominant type of alteration. Finally, through correlation analysis, we found that WDHD1 might be closely associated with tumor heterogeneity, tumor stemness, mismatch repair (MMR), and RNA methylation modification, which were all processes associated with the tumor progression., Conclusions: Our pan-cancer analysis of WDHD1 provides valuable insights into the genomic characterization and biological functions of WDHD1 in human cancers and offers some theoretical support for the future use of WDHD1-targeted therapies, immunotherapies, and chemotherapeutic combinations for the management of tumors., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Early metastasis is a hallmark of osteosarcoma (OS), a highly common type of malignant tumor. Members of the potassium inwardly rectifying channel family exert oncogenic effects in various cancers. However, the role of the potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) in OS is unclear., Methods: The expression of KCNJ2 in OS tissues and cell lines was measured using bioinformatic analysis, immunohistochemistry, and western blotting. Wound-healing assays, Transwell assays, and lung metastasis models were used to analyze the effects of KCNJ2 on mobility of OS cells. The molecular mechanisms linking KCNJ2 and HIF1α in OS were explored by mass spectrometry analysis, immunoprecipitation, ubiquitination detection, and chromatin-immunoprecipitation quantitative real-time polymerase chain reaction., Results: KCNJ2 was found to be overexpressed in advanced-stage OS tissues, as well as in cells with high metastatic potential. High expression of KCNJ2 was associated with a shorter survival rate of OS patients. KCNJ2-inhibition repressed the metastasis of OS cells, whereas KCNJ2-elevation induced the opposite effects. Mechanistically, KCNJ2 binds to HIF1α and inhibits its ubiquitination, thus increasing the expression of HIF1α. Interestingly, HIF1α binds directly to the KCNJ2 promoter and increases its transcription under hypoxic conditions., Conclusion: Taken together, our results indicated that a KCNJ2/HIF1α positive feedback loop exists in OS tissues, which significantly promotes OS cell metastasis. This evidence may contribute to the diagnosis and treatment of OS. Video Abstract., (© 2023. The Author(s).)

Background: Frailty has been considered to be associated with major mortality and increased length of stay after cardiac surgery. This study aimed to explore the predictive potential of frailty assessment in the prognosis of elderly patients undergoing bypass surgery., Methods: This study assessed the preoperative frailty according to the Fried's frailty phenotype, and included 150 frail and 150 non-frail elderly patients (≥ 65 y) who underwent bypass surgery. The present study evaluated the prognosis of elderly patients based on sequential organ failure assessment (SOFA) score, and collected clinical indicators to construct logistic regression models with the prognosis as the dependent variable, to explore the potential predictive ability of preoperative frailty. Moreover, this study focused on the complications and analyzed the relationship between preoperative frailty and postoperative complications., Results: In the present study, 244 patients were divided into the favorable prognosis group and 56 patients were divided into the unfavorable prognosis group. Logistic regression analysis showed that increased myoglobin and high cardiac function classification were independent risk factors for unfavorable prognosis in elderly patients undergoing bypass surgery. The discrimination of the clinical prediction model was determined by the receiver operating characteristic (ROC) curve, and the area under curve (AUC) was 0.928. After adding preoperative frailty assessment, the AUC was improved to 0.939. This study found a significant correlation between preoperative frailty and postoperative complications, mainly in the circulatory system., Conclusion: Preoperative frailty assessment could be a predictive factor for the prognosis of elderly patients undergoing coronary artery bypass grafting. According to our study, frailty assessment and appropriate intervention before bypass surgery may be beneficial to the enhanced recovery after cardiac surgery., Trial Registration: The clinical study was approved by the Medical Ethics Committee of The First Affiliated Hospital of Nanjing Medical University (2021-SR-393). All patients signed an informed consent form., (© 2023. The Author(s).)

Background: Behcet's disease is a form of systematic vasculitis that affects vessels of various sizes anywhere in the body. Aortic pseudoaneurysm is the most hazardous lesion in Behcet's disease and is associated with high mortality rate once rupture., Case Presentation: In this report, we presented a patient with a known history of Behcet's disease, whose recurrent aortic-arch pseudoaneurysm eroding into the left main bronchus was identified after a 4-year duration of thoracic endovascular aortic repair for thoracic descending aortic pseudoaneurysm ruptured into the left lung. Repeated thoracic endovascular aortic repair combined with the chimney stent effectively controlled massive hemoptysis under the life-threatening circumstance, and the patient was in good condition at the 7-year follow-up., Conclusions: Thoracic endovascular aortic repair can be used as an effective and problem-solving treatment approach for thoracic aortic aneurysms eroded into the lung, even recurrent pseudoaneurysm after thoracic endovascular aortic repair in BD patients. Among the imaging methods assessing the technical success, outcome and complications, computed tomography angiography offers a fast, accessible and sensitive imaging modality., (© 2023. The Author(s).)

Background: Coronavirus disease 2019 (COVID-19) has become a pandemic infectious disease and become a serious public health crisis. As the COVID-19 pandemic continues to spread, it is of vital importance to detect COVID-19 clusters to better distribute resources and optimizing measures. This study helps the surveillance of the COVID-19 pandemic and discovers major space-time clusters of reported cases in European countries. Prospective space-time scan statistics are particularly valuable because it has detected active and emerging COVID-19 clusters. It can prompt public health decision makers when and where to improve targeted interventions, testing locations, and necessary isolation measures, and the allocation of medical resources to reduce further spread., Methods: Using the daily case data of various countries provided by the European Centers for Disease Control and Prevention, we used SaTScan™ 9.6 to conduct a prospective space-time scan statistics analysis. We detected statistically significant space-time clusters of COVID-19 at the European country level between March 1st to October 2nd, 2020 and March 1st to October 2nd, 2021. Using ArcGIS to draw the spatial distribution map of COVID-19 in Europe, showing the emerging clusters that appeared at the end of our study period detected by Poisson prospective space-time scan statistics., Results: The results show that among the 49 countries studied, the regions with the largest number of reported cases of COVID-19 are Western Europe, Central Europe, and Eastern Europe. Among the 49 countries studied, the country with the largest cumulative number of reported cases is the United Kingdom, followed by Russia, Turkey, France, and Spain. The country (or region) with the lowest cumulative number of reported cases is the Faroe Islands. We discovered 9 emerging clusters, including 21 risky countries., Conclusion: This result can provide timely information to national public health decision makers. For example, a country needs to improve the allocation of medical resources and epidemic detection points, or a country needs to strengthen entry and exit testing, or a country needs to strengthen the implementation of protective isolation measures. As the data is updated daily, new data can be re-analyzed to achieve real-time monitoring of COVID-19 in Europe. This study uses Poisson prospective space-time scan statistics to monitor COVID-19 in Europe., (© 2022. The Author(s).)

Background: Osteochondromas, also known as exostoses, are the most common benign tumors of bone and can be classified into isolated and multiple osteochondromas. A great majority of osteochondromas is asymptomatic, painless, slow-growing mass, and incidentally found. However, osteochondromas occurring in adolescence or in adult patients can grow in size and become symptomatic as a result of mechanical irritation of the surrounding soft tissues or peripheral nerves, spinal cord compression, or vascular injury., Case Presentation: We present a case of a 13-year-old girl with spontaneous hemothorax, the cause of which was identified by limited thoracotomy with the aid of video-assisted thoracic surgery to be bleeding from a diaphragmatic laceration incurred by a costal exostosis on the left sixth rib. Preoperative chest computed tomography (CT) depicted a bony projection arising from the rib and bloody effusion in the intrathoracic cavity, but was unable to discern the bleeding cause from the lung or the diaphragm. This case will highlight our awareness that costal exostosis possibly results in bloody pleural effusion. Meanwhile, English literatures about solitary costal exostosis associated with hemothorax were searched in PubMed and nineteen case reports were obtained. Combined our present case with available literature, a comprehensive understanding of this rare disease entity will further be strengthened., Conclusions: Injury to the diaphragm is the primary cause of hemothorax caused by costal osteochondroma, including the present case. Thoracic CT scan can help establish a diagnosis of preoperative diagnosis of costal osteochondroma. Surgical intervention should be considered for those patients with symptomatic osteochondroma of the rib. Combined with our case and literature, prophylactic surgical removal of intrathoracic exostosis should be advocated even in asymptomatic patients with the presentation of an inward bony spiculation., (© 2022. The Author(s).)

Background: NLRP3 inflammasome-mediated neuroinflammation plays a critical role in the pathogenesis and development of Alzheimer's disease (AD). Microglial autophagic degradation not only decreases the deposits of extracellular Aβ fibrils but also inhibits the activation of NRLP3 inflammasome. Here, we aimed to identify the potent autophagy enhancers from Penthorum chinense Pursh (PCP) that alleviate the pathology of AD via inhibiting the NLRP3 inflammasome., Methods: At first, autophagic activity-guided isolation was performed to identify the autophagy enhancers in PCP. Secondly, the autophagy effect was monitored by detecting LC3 protein expression using Western blotting and the average number of GFP-LC3 puncta per microglial cell using confocal microscopy. Then, the activation of NLRP3 inflammasome was measured by detecting the protein expression and transfected fluorescence intensity of NLRP3, ASC, and caspase-1, as well as the secretion of proinflammatory cytokines. Finally, the behavioral performance was evaluated by measuring the paralysis in C. elegans, and the cognitive function was tested by Morris water maze (MWM) in APP/PS1 mice., Results: Four ellagitannin flavonoids, including pinocembrin-7-O-[4″,6″-hexahydroxydiphenoyl]-glucoside (PHG), pinocembrin-7-O-[3″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-glucoside (PGHG), thonningianin A (TA), and thonningianin B (TB), were identified to be autophagy enhancers in PCP. Among these, TA exhibited the strongest autophagy induction effect, and the mechanistic study demonstrated that TA activated autophagy via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways. In addition, TA effectively promoted the autophagic degradation of NLRP3 inflammasome in Aβ(1-42)-induced microglial cells and ameliorated neuronal damage via autophagy induction. In vivo, TA activated autophagy and improved behavioral symptoms in C. elegans. Furthermore, TA might penetrate the blood-brain barrier and could improve cognitive function and ameliorate the Aβ pathology and the NLRP3 inflammasome-mediated neuroinflammation via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways in APP/PS1 mice., Conclusion: We identified TA as a potent microglial autophagy enhancer in PCP that promotes the autophagic degradation of the NLRP3 inflammasome to alleviate the pathology of AD via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways, which provides novel insights for TA in the treatment of AD., (© 2022. The Author(s).)

Background: Antibiotic resistome has been found to strongly interact with the core microbiota in the human gut, yet little is known about how antibiotic resistance genes (ARGs) correlate with certain microbes in large rivers that are regarded as "terrestrial gut.", Results: By creating the integral pattern for ARGs and antibiotic-resistant microbes in water and sediment along a 4300-km continuum of the Yangtze River, we found that human pathogen bacteria (HPB) share 13.4% and 5.9% of the ARG hosts in water and sediment but contribute 64% and 46% to the total number of planktonic and sedimentary ARGs, respectively. Moreover, the planktonic HPB harbored 79 ARG combinations that are dominated by "natural" supercarriers (e.g., Rheinheimera texasensis and Noviherbaspirillum sp. Root189) in river basins., Conclusions: We confirmed that terrestrial HPB are the major ARG hosts in the river, rather than conventional supercarriers (e.g., Enterococcus spp. and other fecal indicator bacteria) that prevail in the human gut. The discovery of HPB as natural supercarriers in a world's large river not only interprets the inconsistency between the spatial dissimilarities in ARGs and their hosts, but also highlights the top priority of controlling terrestrial HPB in the future ARG-related risk management of riverine ecosystems globally. Video Abstract., (© 2022. The Author(s).)

Background: Respiratory involvement is common in immunoglobulin G4-related disease (IgG4-RD). However, severe asthma as the initial clinical manifestation of IgG4-RD is rare and might be neglected by respiratory clinicians. We aimed to explore the clinical characteristics and prognoses of patients with immunoglobulin G4-related disease (IgG4-RD) manifesting as severe asthma., Methods: A retrospective analysis of the clinical characteristics and prognoses of patients with severe asthma who were eventually diagnosed with IgG4-RD was performed in the Peking Union Medical College Hospital from 2013 to 2019., Results: Twelve patients (5males, 7 females) were included. The mean age at enrollment and age of asthma onset were 59.4 ± 10.1 and 53.8 ± 10.4 years, respectively. The mean duration of asthma symptoms was 5.7 ± 2.0 years. In all patients, the proportion (25.1 ± 10.3%) and count (2.0 ± 1.1) × 10 9 /L of eosinophils in peripheral blood increased. Additionally, all patients exhibited elevated total immunoglobulin E [IgE, (1279.3 ± 1257.9) KU/L] and IgG4 (9155.8 ± 9247.6) mg/dL. Bronchial wall thickening (n = 11) and mediastinal/hilar lymphadenopathy (n = 11) were major chest CT manifestations. All were pathologically diagnosed through surgical biopsy; submandibular gland (n = 8), supraclavicular lymph node (n = 2), stomach (n = 1), rashes (n = 1), lacrimal gland (n = 1) and thoracoscopic lung (n = 1) biopsies were performed. Asthma was well controlled by oral glucocorticoids (GCs), but some patients relapsed during tapering (n = 11). The refractory condition was controlled after increasing the dosage of GCs and add-on immunosuppressants., Conclusions: For patients with middle age-onset severe asthma with elevated eosinophils, total IgE and IgG4 levels and available salivary gland ultrasound imaging, ruling out IgG4-RD is recommended. GCs used in combination with immunosuppressants is recommended to prevent relapse., (© 2022. The Author(s).)

Background: The morning glories (Convolvulaceae) are distributed worldwide and produce economically important crops, medicinal herbs, and ornamentals. Members of this family are diverse in morphological characteristics and trophic modes, including the leafless parasitic Cuscuta (dodders). Organelle genomes were generally used for studying plant phylogeny and genomic variations. Notably, plastomes in parasitic plants always show non-canonical features, such as reduced size and accelerated rates. However, few organelle genomes of this group have been sequenced, hindering our understanding of their evolution, and dodder mitogenome in particular., Results: We assembled 22 new mitogenomes and 12 new plastomes in Convolvulaceae. Alongside previously known ones, we totally analyzed organelle genomes of 23 species in the family. Our sampling includes 16 leafy autotrophic species and 7 leafless parasitic dodders, covering 8 of the 12 tribes. Both the plastid and mitochondrial genomes of these plants have encountered variations that were rarely observed in other angiosperms. All of the plastomes possessed atypical IR boundaries. Besides the gene and IR losses in dodders, some leafy species also showed gene and intron losses, duplications, structural variations, and insertions of foreign DNAs. The phylogeny reconstructed by plastid protein coding sequences confirmed the previous relationship of the tribes. However, the monophyly of 'Merremieae' and the sister group of Cuscuta remained uncertain. The mitogenome was significantly inflated in Cuscuta japonica, which has exceeded over 800 kb and integrated massive DNAs from other species. In other dodders, mitogenomes were maintained in small size, revealing divergent evolutionary strategies. Mutations unique to plants were detected in the mitochondrial gene ccmFc, which has broken into three fragments through gene fission and splicing shift. The unusual changes likely initially happened to the common ancestor of the family and were caused by a foreign insertion from rosids followed by double-strand breaks and imprecise DNA repairs. The coding regions of ccmFc expanded at both sides after the fission, which may have altered the protein structure., Conclusions: Our family-scale analyses uncovered unusual scenarios for both organelle genomes in Convolvulaceae, especially in parasitic plants. The data provided valuable genetic resources for studying the evolution of Convolvulaceae and plant parasitism., (© 2022. The Author(s).)

Sestrin 2, a highly conserved stress-induced protein, participates in the pathological processes of metabolic and age-related diseases. This p53-inducible protein also regulates cell growth and metabolism, which is closely related to malignant tumorigenesis. Sestrin 2 was reported to regulate various cellular processes, such as tumor cell proliferation, invasion and metastasis, apoptosis, anoikis resistance, and drug resistance. Although sestrin 2 is associated with colorectal, lung, liver, and other cancers, sestrin 2 expression varies among different types of cancer, and the effects and mechanisms of action of this protein are also different. Sestrin 2 was considered a tumor suppressor gene in most studies, whereas conflicting reports considered sestrin 2 an oncogene. Thus, this review aims to examine the literature regarding sestrin 2 in various cancers, summarize its roles in suppression and tumorigenesis, discuss potential mechanisms in the regulation of cancer, and provide a basis for follow-up research and potential cancer treatment development., (© 2021. The Author(s).)

Background: Left-right (LR) asymmetry is an essential feature of bilateral animals. Studies in vertebrates show that LR asymmetry formation comprises three major steps: symmetry breaking, asymmetric gene expression, and LR morphogenesis. Although much progress has been made in the first two events, mechanisms underlying asymmetric morphogenesis remain largely unknown due to the complex developmental processes deployed by vertebrate organs., Results: We here addressed this question by studying Pitx gene function in the basal chordate amphioxus whose asymmetric organogenesis, unlike that in vertebrates, occurs essentially in situ and does not rely on cell migration. Pitx null mutation in amphioxus causes loss of all left-sided organs and incomplete ectopic formation of all right-sided organs on the left side, whereas Pitx partial loss-of-function leads to milder phenotypes with only some LR organs lost or ectopically formed. At the N1 to N3 stages, Pitx expression is gradually expanded from the dorsal anterior domain to surrounding regions. This leads to activation of genes like Lhx3 and/or Prop1 and Pit, which are essential for left-side organs, and downregulation of genes like Hex and/or Nkx2.1 and FoxE4, which are required for right-side organs to form ectopically on the left side. In Pitx mutants, the left-side expressed genes are not activated, while the right-side genes fail to decrease expression on the left side. In contrast, in embryos overexpressing Pitx genes, the left-side genes are induced ectopically on the right side, and the right-side genes are inhibited. Several Pitx binding sites are identified in the upstream sequences of the left-side and right-side genes which are essential for activation of the former and repression of the latter by Pitx., Conclusions: Our results demonstrate that (1) Pitx is a major (although not the only) determinant of asymmetric morphogenesis in amphioxus, (2) the development of different LR organs have distinct requirements for Pitx activity, and (3) Pitx controls amphioxus LR morphogenesis probably through inducing left-side organs and inhibiting right-side organs directly. These findings show much more dependence of LR organogenesis on Pitx in amphioxus than in vertebrates. They also provide insight into the molecular developmental mechanism of some vertebrate LR organs like the lungs and atria, since they show a right-isomerism phenotype in Pitx2 knockout mice like right-sided organs in Pitx mutant amphioxus. Our results also explain why some organs like the adenohypophysis are asymmetrically located in amphioxus but symmetrically positioned in vertebrates., (© 2021. The Author(s).)

Background: Peanut embryo development is a complex process involving a series of gene regulatory pathways and is easily affected by various elements in the soil. Calcium deficiency in the soil induces early embryo abortion in peanut, which provides an opportunity to determine the mechanism underlying this important event. MicroRNA (miRNA)-guided target gene regulation is vital to a wide variety of biological processes. However, whether miRNAs participate in peanut embryo abortion under calcium deficiency has yet to be explored., Results: In this study, with the assistance of a recently established platform for genome sequences of wild peanut species, we analyzed small RNAs (sRNAs) in early peanut embryos. A total of 29 known and 132 potential novel miRNAs were discovered in 12 peanut-specific miRNA families. Among the identified miRNAs, 87 were differentially expressed during early embryo development under calcium deficiency and sufficiency conditions, and 117 target genes of the differentially expressed miRNAs were identified. Integrated analysis of miRNAs and transcriptome expression revealed 52 differentially expressed target genes of 20 miRNAs. The expression profiles for some differentially expressed targets by gene chip analysis were consistent with the transcriptome sequencing results. Together, our results demonstrate that seed/embryo development-related genes such as TCP3, AP2, EMB2750, and GRFs; cell division and proliferation-related genes such as HsfB4 and DIVARICATA; plant hormone signaling pathway-related genes such as CYP707A1 and CYP707A3, with which abscisic acid (ABA) is involved; and BR1, with which brassinosteroids (BRs) are involved, were actively modulated by miRNAs during early embryo development., Conclusions: Both a number of miRNAs and corresponding target genes likely playing key roles in the regulation of peanut embryo abortion under calcium deficiency were identified. These findings provide for the first time new insights into miRNA-mediated regulatory pathways involved in peanut embryo abortion under calcium deficiency.

Background: Waterlogging is one of the main abiotic stresses that limit wheat production. Quantitative proteomics analysis has been applied in the study of crop abiotic stress as an effective way in recent years (e.g. salt stress, drought stress, heat stress and waterlogging stress). However, only a few proteins related to primary metabolism and signal transduction, such as UDP - glucose dehydrogenase, UGP, beta glucosidases, were reported to response to waterlogging stress in wheat. The differentially expressed proteins between genotypes of wheat in response to waterlogging are less-defined. In this study, two wheat genotypes, one is sensitive to waterlogging stress (Seri M82, named as S) and the other is tolerant to waterlogging (CIGM90.863, named as T), were compared in seedling roots under hypoxia conditions to evaluate the different responses at proteomic level., Results: A total of 4560 proteins were identified and the number of differentially expressed proteins (DEPs) were 361, 640, 788 in S and 33, 207, 279 in T in 1, 2, 3 days, respectively. These DEPs included 270 common proteins, 681 S-specific and 50 T-specific proteins, most of which were misc., protein processing, DNA and RNA processing, amino acid metabolism and stress related proteins induced by hypoxia. Some specific proteins related to waterlogging stress, including acid phosphatase, oxidant protective enzyme, S-adenosylmethionine synthetase 1, were significantly different between S and T. A total of 20 representative genes encoding DEPs, including 7 shared DEPs and 13 cultivar-specific DEPs, were selected for further RT-qPCR analysis. Fourteen genes showed consistent dynamic expression patterns at mRNA and protein levels., Conclusions: Proteins involved in primary metabolisms and protein processing were inclined to be affected under hypoxia stress. The negative effects were more severe in the sensitive genotype. The expression patterns of some specific proteins, such as alcohol dehydrogenases and S-adenosylmethionine synthetase 1, could be applied as indexes for improving the waterlogging tolerance in wheat. Some specific proteins identified in this study will facilitate the subsequent protein function validation and biomarker development.

Background: Trastuzumab has been prevailingly accepted as a beneficial treatment for gastric cancer (GC) by targeting human epidermal growth factor receptor 2 (HER2)-positive. However, the therapeutic resistance of trastuzumab remains a major obstacle, restricting the therapeutic efficacy. Therefore, identifying potential key genes and pathways is crucial to maximize the overall clinical benefits., Methods: The gene expression profile GSE77346 was retrieved to identify the differentially expressed genes (DEGs) associated with the trastuzumab resistance in GC. Next, the DEGs were annotated by the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The DEGs-coded protein-protein interaction (PPI) networks and the prognostic values of the 20 hub genes were determined. Correlation of the hub genes were analyzed in The Cancer Genome Atlas. The prognostic values of hub genes were further validated by Kaplan-Meier (KM) plotter., Results: A total of 849 DEGs were identified, with 374 in upregulation and 475 in downregulation. Epithelium development was the most significantly enriched term in biological processes while membrane-bounded vesicle was in cellular compartments and cell adhesion molecular binding was in molecular functions. Pathways in cancer and ECM-receptor interaction were the most significantly enriched for all DEGs. Among the PPI networks, 20 hub genes were defined, including CD44 molecule (CD44), HER-2, and cadherin 1 (CDH1). Six hub genes were associated with favorable OS while eight were associated with poor OS. Mechanistically, 2'-5'-oligoadenylate synthetase 1, 3 (OAS1, OAS3) and CDH1 featured high degrees and strong correlations with other hub genes., Conclusions: This bioinformatics analysis identified key genes and pathways for potential targets and survival predictors for trastuzumab treatment in GC.

Background: Bupleurum yinchowense Shan et Y. Li is widely used to treat depressive and anxiety disorders for hundreds of years in China. Total saikosaponins (TSS) is the major ingredient of Bupleurum yinchowense. A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and subsequent mammalian target of rapamycin (mTOR) signaling is responsible for synaptic maturation and may contribution to the synaptic alteration underlying depression. The aim of the study was to investigate the antidepressant-like and anxiolytic effect of TSS in chronic corticosterone-treated mice. The effect of TSS on synaptic proteins expression and AMPA receptor-mTOR signaling pathway alteration was also evaluated., Methods: Dose-response effect of TSS (12.5, 25, 50 mg/kg) was investigated in forced swim test (FST) in ICR male mice. In the chronic corticosterine-treated model, TSS was given intragastrically once a day for 2 weeks and continued through the behavior testing period. Behavior tests and AMPA receptor related signaling pathway were investigated., Results: TSS (25 and 50 mg/kg) decreased the immobility time in the FST when compared with the control group. TSS (25 mg/kg) showed antidepressant-like and anxiolytic effects in the chronic corticosterone treatment model in mice. TSS increased hippocampal synaptic proteins (synapsin-1 and postsynaptic density protein 95) expression. Immunohistochemistry analysis showed that TSS significantly increased the synapsin-1 expression in CA3 of hippocampus. TSS also increased hippocampal phosphorylation expression of GluR1 Ser 845 (AMPA receptor subunit) and its downstream regulators extracellular signaling-regulated kinase (ERK), protein kinase B (Akt) and mTOR., Conclusion: TSS produces antidepressant-like and anxiolytic effects and increases synaptic proteins expression which may be mediated by induction of AMPA receptor and subsequent mTOR signaling pathway.

Background: Staphylococcus aureus is an important pathogen that causes various infections in medical facilities. However, resistance to multiple drugs has made this infection difficult to manage. Thus, new therapeutic strategies are urgently needed to solve this worldwide public health problem. The Streptococcus lactis L16 strain was isolated from the fermented hot chili sauce. To explore whether it can be used as a protective agent against S. aureus infection, we designed a mouse model of S. aureus infection to evaluate the therapeutic potency of S. lactis. Mice were grouped into pre-(P) and post-(T) S. aureus infection groups following oral administration of S. lactis L16. The protection and treatment effects were assessed by examining body weight, internal organ weight, serum cytokines and intestinal secretory IgA alternations., Result: Oral administration of the S. lactis L16 strain reduced the loss of body weight in mice post-infection and alleviated infection-induced hepatomegaly. In particular, the PL16 group (protection with L16) showed more effective resistance to S. aureus than the TL16 group (treatment with L16). The level of serum cytokine interferon gamma following oral administration of the L16 strain was remarkably increased during infection, as were interleukin-4 levels during convalescence. The probiotic L16 strain induced more sIgA production than S. aureus., Conclusion: Our data suggest that S. lactis L16 is an effective strain with anti-Staphylococcus activity. By regulating the Th1/Th2 response, S. lactis can effectively reduce lesions from infection, indicating its therapeutic potential in overcoming antibiotic resistance in this mouse infection model that mimics infections observed in humans.

Background: Loss of neural function is a critical but unsolved issue after cerebral ischemia insult. Neuronal plasticity and remodeling are crucial for recovery of neural functions after brain injury. Buyang Huanwu decoction, which is a classic formula in traditional Chinese medicine, can positively alter synaptic plasticity. This study assessed the effects of Buyang Huanwu decoction in combination with physical exercise on neuronal plasticity in cerebral ischemic rats., Methods: Cerebral ischemic rats were administered Buyang Huanwu decoction and participated in physical exercise after the induction of a permanent middle cerebral artery occlusion. The neurobehavioral functions and infarct volumes were evaluated. The presynaptic (SYN), postsynaptic (GAP-43) and cytoskeletal (MAP-2) proteins in the coronal brain samples were evaluated by immunohistochemistry and western blot analyses. The ultrastructure of the neuronal synaptic junctions in the same region were analyzed using transmission electron microscopy., Results: Combination treatment of Buyang Huanwu decoction and physical exercise ameliorated the neurobehavioral deficits (p < 0.05), significantly enhanced the expression levels of SYN, GAP-43 and MAP-2 (p < 0.05), and maintained the synaptic ultrastructure., Conclusions: Buyang Huanwu decoction facilitated neurorehabilitation following a cerebral ischemia insult through an improvement in synaptic plasticity. Graphical abstract The Buyang Huanwu decoction (BYHWD) combined with physical exercise (PE) attenuates synaptic disruption and promotes synaptic plasticity following cerebral ischemia (stroke).

Background: Our previous study demonstrated that a store-operated calcium channel (SOCC) inhibitor (YM-58483) has central analgesic effects. However, the cellular and molecular mechanisms of such effects remain to be determined. It is well-known that glial cells play important roles in central sensitization. SOC entry (SOCE) has been implicated in many cell types including cortical astrocytes. However, the role of the SOCC family in the function of astrocytes has not been determined. Here, we thoroughly investigated the expression and the functional significance of SOCCs in spinal astrocytes., Methods: Primary cultured astrocytes were prepared from neonatal (P2-P3) CD1 mice. Expressions of mRNAs and proteins were respectively assessed by real-time PCR and Western blot analysis. SOCE was measured using a calcium imaging system. Live-cell STIM1 translocation was detected using a confocal microscope. Cytokine levels were measured by the enzyme-linked immunosorbent assay., Results: We found that the SOCC family is expressed in spinal astrocytes and that depletion of calcium stores from the endoplasmic reticulum by cyclopiazonic acid (CPA) resulted in a large sustained calcium entry, which was blocked by SOCC inhibitors. Using the siRNA knockdown approach, we identified STIM1 and Orai1 as primary components of SOCCs in spinal astrocytes. We also observed thapsigargin (TG)- or CPA-induced puncta formation of STIM1 and Orai1. In addition, activation of SOCCs remarkably promoted TNF-α and IL-6 production in spinal astrocytes, which were greatly attenuated by knockdown of STIM1 or Orai1. Importantly, knockdown of STIM2 and Orai1 dramatically decreased lipopolysaccharide-induced TNF-α and IL-6 production without changing cell viability., Conclusions: This study presents the first evidence that STIM1, STIM2, and Orai1 mediate SOCE and are involved in cytokine production in spinal astrocytes. Our findings provide the basis for future assessment of SOCCs in pain and other central nervous system disorders associated with abnormal astrocyte activities.

RNA interference holds tremendous potential as one of the most powerful therapeutic strategies. However, the properties of short interfering RNA (siRNA), such as hydrophilicity, negative charge, and instability in serum have limited its applications; therefore, significant efforts have been undertaken to improve its cellular uptake. Cell penetrating peptides have been utilized to deliver various biologically active molecules, such as proteins, liposomes, nanoparticles, peptide nucleic acids, and recently small interfering RNAs. Here, we introduce a new cell penetrating peptide GL1(Ac-GLWRAWLWKAFLASNWRRLLRLLR-NH2) to improve the intracellular uptake of siRNA. This peptide consists of four tryptophan residues that facilitated its binding with the cell membrane, five arginine residues and one lysine residue which are positively charged at physiological pH, which induced the formation of peptide-siRNA complexes and enhanced the affinity of the peptide and cell membrane. Moreover, GL1 adopted helical secondary structure due to the altered distribution of polar and nonpolar residues in the sequence. In this study, we investigated the effect of peptide/siRNA molar ratio on the particle size, surface charge, secondary structure, and uptake efficiency. The results showed that GL1 formed stable complexes with siRNA mainly through electrostatic interaction and hydrophobic interaction, and the complexes displayed a spherical shape with the size of ~100 nm and positive surface charge. Utilizing the techniques of fluorescence microscopy and flow cytometry, the intracellular localization of Cy3-labeled GAPDH siRNA was visualized and the cellular uptake was quantified. It is worth noting that in the serum free environment, compared to Lipofectamine 2000, GL1 achieved higher cellular uptake of siRNA (~95%); in the presence of serum, GL1 retained the same level of siRNA cellular uptake (~84%) as Lipofectamine 2000. In addition, the viability of cells treated by GL1 in all studied molar ratios was >85%, which was significantly higher than that treated by Lipofectamine 2000 (~70%). Taken together, the peptide GL1 demonstrated promise as a siRNA delivery system.

Background: Female commercial sex workers (FSWs) are at high risk of human immunodeficiency virus (HIV) transmission in China. This study was designed to examine the predictors of condom use with clients during vaginal intercourse among FSWs based on the Information-Motivation-Behavioral Skills (IMB) model and to describe the relationships between IMB model constructs., Methods: A cross-sectional study was conducted in Jinan of Shandong Province, from May to October, 2009. Participants (N = 432) were recruited using Respondent-Driven Sampling (RDS). A self-administered questionnaire was used to collect data. Structural equation modeling was used to assess the IMB model., Results: A total of 427 (98.8%) participants completed their questionnaires. Condom use was significantly predicted by social referents support, experiences with and attitudes toward condoms, self-efficacy, and health behaviors and condom use skills. Significant indirect predictors of condom use mediated through behavioral skills included HIV knowledge, social referents support, and substance use., Conclusions: These results suggest that the IMB model could be used to predict condom use among Chinese FSWs. Further research is warranted to develop preventive interventions on the basis of the IMB model to promote condom use among FSWs in China.

Background: The microtubule-associated protein tau is able to interact with actin and serves as a cross-linker between the microtubule and actin networks. The microtubule-binding domain of tau is known to be involved in its interaction with actin. Here, we address the question of whether the other domains of tau also interact with actin., Results: Several tau truncation and deletion mutants were constructed, namely N-terminal region (tauN), proline-rich domain (tauPRD), microtubule binding domain (tauMTBD) and C-terminal region (tauC) truncation mutants, and microtubule binding domain (tauDeltaMTBD) and proline-rich domain/microtubule binding domain (tauDeltaPRD&MTBD) deletion mutants. The proline-rich domain truncation mutant (tauPRD) and the microtubule binding domain deletion mutant (tauDeltaMTBD) promoted the formation of actin filaments. However, actin assembly was not observed in the presence of the N-terminal and C-terminal truncation mutants. These results indicate that the proline-rich domain is involved in the association of tau with G-actin. Furthermore, results from co-sedimentation, solid phase assays and electron microscopy showed that the proline-rich domain is also capable of binding to F-actin and inducing F-actin bundles. Using solid phase assays to analyze apparent dissociation constants for the binding of tau and its mutants to F-actin resulted in a sequence of affinity for F-actin: tau >> microtubule binding domain > proline-rich domain. Moreover, we observed that the proline-rich domain was able to associate with and bundle F-actin at physiological ionic strength., Conclusion: The proline-rich domain is a functional structure playing a role in the association of tau with actin. This suggests that the proline-rich domain and the microtubule-binding domain of tau are both involved in binding to and bundling F-actin.

Background: Virus-binding activity is one of the important functions of fibronectin (FN). It has been reported that a high concentration of FN in blood improves the transmission frequency of hepatitis viruses. Therefore, to investigate a protease that hydrolyzes FN rapidly is useful to decrease the FN concentration in blood and HBV infection. So far, however, no specific protease digesting FN in serum has been reported., Methods: We employed a purified earthworm protease to digest serum proteins. The rapidly cleaved protein (FN) was identified by MALDI-TOF MS and western blotting. The cleavage sites were determined by N-terminus amino acid residues sequencing. The protease was orally administrated to rats to investigate whether serum FN in vivo became decreased. The serum FN was determined by western blotting and ELISA. In cytological studies, the protease was added to the medium in the culture of HepG2.2.15 cells and then HBsAg and HBeAg were determined by ELISA., Results: The protease purified from earthworm Eisenia fetida was found to function as a fibronectinase (FNase). The cleavage sites on FN by the FNase were at R and K, exhibiting a trypsin alkaline serine-like function. The earthworm fibronectinase (EFNase) cleaved FN at four sites, R259, R1005, K1557 and R2039, among which the digested fragments at R259, K1557 and R2039 were related to the virus-binding activity as reported. The serum FN was significantly decreased when the earthworm fibronectinase was orally administrated to rats. The ELISA results showed that the secretion of HBeAg from HepG2.2.15 cells was significantly inhibited in the presence of the FNase., Conclusion: The earthworm fibronectinase (EFNase) cleaves FN much faster than the other proteins in serum, showing a potential to inhibit HBV infection through its suppressing the level of HBeAg. This suggests that EFNase is probably used as one of the candidates for the therapeutic agents to treat hepatitis virus infection.

Background: In terms of structure and function, the skull is one of the most complicated organs in the body. It is also one of the most important parts in terms of developmental and evolutionary origins. This complexity makes it difficult to obtain evolutionary assessments if, as is usually the case with fossils, only part of the skull is available. For this reason this study involves a set of comparisons whereby the smallest functional units are studied first, and these built up, through a triple-nested hierarchical design, into more complex anatomical regions and eventually into the skull-as-a-whole. This design has been applied to macaques (Macaca) in order to reveal patterns of variation at the different levels. The profiles of such variation have been obtained both within and between species. This has lead to a search for the skull parts that have undergone similar selection pressures during evolution and comparable development patterns in both ontogeny and phylogeny., Results: Morphometric analysis (Principal Components) was used to obtain these profiles of species and sex separations based on 77 cranial variables from 11 species of macaques. The results showed that 7 functional units could be aggregated into three functionally reasonable anatomical regions on the basis of similarities in profiles. These were: the masticatory apparatus containing mandible, lower teeth and upper teeth, the face as a whole combining maxilla (actually lower face) and upper face, and the cranium as a whole involving cranium and calvaria. Twenty-six variables were finally selected for analyzing the morphology of the whole skull. This last showed an overall profile similar to that revealed in the masticatory apparatus but also contained additional information pertaining to individual species and species-groups separations., Conclusions: The study provides a model for carrying out analysis of species separations and sex variation simultaneously. Through this design it seems possible to see cranio-dental elements that may result from similar developmental processes, have similar functional adaptations, and show an appropriately integrated structure morphologically. This study also implies that the biological information drawn from part of skull alone, e.g. as in studies of incomplete fossils may provide misleading information.