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Zi-Qing Mao,1 Hong-Xi Wu,1 Hui-Min Fan,1 Gen Li,2 Zhi-Peng You,1 Yun-Yu Tan1 1Department of Ophthalmology, Affiliated Eye Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Ophthalmology, Zhangshu People’s Hospital, Zhangshu, 331299, People’s Republic of ChinaCorrespondence: Zhi-Peng You, Department of Ophthalmology, Affiliated Eye Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China, Email 1289560272@qq.comObjective: To evaluate the feasibility and practicability of intraoperative optical coherence tomography (IOCT) in the surgery of idiopathic macular epiretinal membrane (IMM) without internal limiting membrane staining in all patients.Methods: Patients were selected from July 2018 to June 2020, and 32 patients (32 eyes) with IMM were operated with the use of IOCT. All patients underwent standard 23g vitrectomy. The internal limiting membrane was peeled off if there were obvious retinal folds. Intraoperative and postoperative complications, macular microstructural changes, and integrity of the detached membranes were recorded. The preoperative and postoperative best corrected visual acuity were compared.Results: The macular epiretinal membrane was completely removed in 75% (24 eyes) patients without internal limiting membrane staining, and in 15.6% (5 eyes) patients with combined internal limiting membrane stripping. The “starting point” of macular epiretinal membrane stripping was found in 75% (24 eyes), and the time required to find the best starting point ranged from 28s to 140s (mean 66 ± 15s). At 3 months after operation, 96.8% of the patients had stable or improved BCVA (p < 0.05). The central macular thickness of the affected eyes decreased significantly at 1 and 3 months after operation (p < 0.05).Conclusion: IOCT can significantly reduce the use of internal limiting membrane staining in idiopathic macular epiretinal membrane surgery, and it is safe, feasible and practical in idiopathic macular epiretinal membrane surgery without internal limiting membrane staining in all patients.Keywords: intraoperative optical coherence tomography, epiretinal membrane, inner limiting membrane

Objectives: In this study, artificial intelligence (AI) techniques were used to achieve automated diagnosis and classification of temporomandibular joint (TMJ) degenerative joint disease (DJD) on cone beam computed tomography (CBCT) images., Methods: An AI model utilizing the YOLOv10 algorithm was trained, validated and tested on 7357 annotated and corrected oblique sagittal TMJ images (3010 images of normal condyles and 4347 images of condyles with DJD) from 1018 patients who visited Peking University School and Hospital of Stomatology for temporomandibular disorders and underwent TMJ CBCT examinations. This model could identify DJD as well as the radiographic signs of DJD, namely, erosion, osteophytes, sclerosis and subchondral cysts. The diagnosis and classification performances of the model were evaluated on the test set. The accuracy of the model for evaluating images with one to four DJD signs was also evaluated., Results: The accuracy, precision, sensitivity, specificity, F1 score and mean average precision (mAP) at an intersection over union (IoU) threshold of 0.5 of the model for DJD detection all exceeded 0.95. The accuracies for identifying erosion, osteophytes, sclerosis and subchondral cysts were 0.91, 0.96, 0.91 and 0.96, respectively. The precisions, specificities and F1 scores for the DJD signs were all >0.90. The sensitivity ranged from 0.88 to 0.95, and the mAP (IoU=0.5) ranged from 0.87 to 0.97. The accuracies of the model for detecting one to four DJD signs in one image were 94 %, 84 %, 66 % and 63 %, respectively., Conclusions: A deep learning model based on the YOLOv10 algorithm can not only detect the presence of TMJ DJD on CBCT images but also differentiate the typical radiographic signs of DJD, including erosion, osteophytes, sclerosis and subchondral cysts, with acceptable accuracy., Clinical Significance: TMJ DJD is a very common disease that causes joint pain and mandibular dysfunction and affects patients' quality of life; therefore, early diagnosis and intervention are particularly important. However, identifying radiographic signs of early-stage TMJ DJD is difficult. AI can quickly review CBCT images and assist in the accurate and rapid diagnosis and classification of TMJ DJD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ZW, YS and HW are associated with LargeV, a corporation committed the development and industrialization of high-end medical devices. This study and its findings were unrelated to their affiliation. The authors take full responsibility for the content of this manuscript., (Copyright © 2025. Published by Elsevier Ltd.)

DX1002 is an oral vascular-disrupting agent and exhibits promising results in preclinical studies, leading to tumor vasculature destruction and xenografted tumor necrosis in various animal models. In the phase 1 trial, 17 patients with solid tumors receive DX1002 ranging from 50 to 1,100 mg. The maximum tolerated dose and recommended phase 2 dose of DX1002 are determined as 600 mg once daily. The most common treatment-related adverse events are nausea (23.5%), vomiting (17.6%), and fatigue (11.8%). All patients are evaluable for anti-tumor response, 12 of which achieve stable disease as best response. One patient with non-small cell lung cancer achieves a stable disease duration of 6.5 months. The median time to progression (TTP) is 2.70 months (95% confidence interval [CI], 0.90-4.60). Interestingly, reduced blood perfusion is observed by contrast-enhanced ultrasound in a patient with colon cancer. In conclusion, DX1002 is well tolerated and exhibits preliminary anti-tumor efficacy in patients with solid tumors. This study was registered at chictr.org.cn (ChiCTR2400080298)., Competing Interests: Declaration of interests L.-W.T., B.-L.C., and Z.-Q.Y. are employees of the Guangzhou Anhao Pharmaceuticals Co., Ltd., (Copyright © 2025. Published by Elsevier Inc.)

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are important polyunsaturated fatty acids (PUFAs) used as nutritional supplements. The natural EPA content in Schizochytrium sp. is low, and traditional strategies to increase EPA levels often compromise DHA content or lipid accumulation, hindering industrial coproduction. This study aims to modify the PUFA synthase pathway in Schizochytrium sp. to enable high levels of EPA accumulation while maintaining high levels of DHA production. The native acyltransferase (AT) domain in the PKS B subunit was replaced with an EPA-specific AT, increasing the EPA content nearly five-fold (3.94%). Additionally, adding food-grade phenolic compounds to boost EPA accumulation and overexpressing C16 elongase to alleviate lipid synthesis inhibition increased the EPA content from 0.80 to 7.86% in a 5L bioreactor. Ultimately, EPA and DHA titers reached 3.79 and 22.06 g/L, respectively. These findings highlight the potential of Schizochytrium sp. as an efficient cell factory for sustainable EPA and DHA coproduction on an industrial scale.

Introduction: Immune inflammatory response plays an important role in chronic obstructive pulmonary disease (COPD). However, the cellular immune status of patients with COPD at different phases is unclear. Herein, we aim to investigate the distribution and functional status of T cell subsets in different phases of COPD (acute exacerbation of COPD [AECOPD] and stable COPD [SCOPD])., Methods: This is an observational case-control study undertaken in West China Hospital. The distribution of T cell subsets in peripheral blood of AECOPD, SCOPD, and healthy controls (HCs) was measured using multi-color flow cytometry, and the functional status was analyzed by additional staining of activation markers., Results: A total of 43 HCs, 43 SCOPD patients, and 64 AECOPD patients were evaluated. The total number and percentage of lymphocytes and the CD4+/CD8+ T cells ratio were significantly lower in AECOPD patients when compared to HCs. HLA-DR expression in CD3+, CD4+, CD8+, CD8+ TCR aβ, and CD4+ TCR aβ T cells was upregulated in the AECOPD group. Similarly, the expressions of HLA-DR, CD57, and PD-1 were higher in T cell subsets in the AECOPD group. Compared with the SCOPD and HC groups, the AECOPD had a significantly lower proportion of CD4+CD27+CD28+ T cells, but opposite results were found for CD4+CD27-CD28- T cells. In addition, the proportion of CD4+CD39+ T cells and CD4+CD25+FoxP3+ T cells was significantly higher in the AECOPD and SCOPD groups when compared to the HC group ( P < 0.05)., Discussion: The distribution of nearly half the T cell subsets in AECOPD patients was significantly different from that in SCOPD patients and HCs. AECOPD patients may have cellular immune suppression, immune dysfunction, abnormal activation, and higher senescence depletion of T cells., Competing Interests: 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 © 2025 Xiong, Zhu, Wu, Wu, Fan and Cheng.)

Chaohu Lake is the fifth largest freshwater lake in China that meets the needs of surrounding industries for water, tourism, and flood storage, making it important for the socio-economic development and modernization of Anhui Province. As an important ecological wetland in the lower reaches of the Yangtze River, many rare bird habitats are present along the coast of Chaohu Lake. Therefore, it is eco-economically important to study antibiotic pollution in Chaohu Lake. To unveil antibiotic contamination in Chaohu Lake, surface water and sediment samples were collected from the main basin of Chaohu Lake by steamship in June 2022. Solid phase extraction and ultra-performance liquid chromatography-mass spectrometry （SPE-UPLC-MS） was used to determine the occurrence of 31 target antibiotics, including tetracyclines, sulfonamides, macrolides, and quinolones. The study focused on the spatial distribution, source analysis, and risk assessment of various antibiotics in the surface water and sediments of the main basin of Chaohu Lake. The occurrences of 20 different antibiotics were successively identified in the surface water and sediments of Chaohu Lake. These antibiotics included sulfonamides, quinolones, macrolides, tetracyclines, and others. Significant spatial differences in antibiotics were found between surface water and sediments. The horizontal spatial distribution results indicated differences in species and concentration of antibiotics in surface water and sediments. The vertical spatial distribution results showed that many types of antibiotics had consistent vertical distribution characteristics in surface water and sediments at the same point. The principal component analysis results indicated that the source of antibiotics in surface water was similar to that in sediment and considered with the actual distribution of existing industries around Chaohu Lake； the main sources were livestock and poultry breeding sewage, aquaculture sewage, and household sewage. The ecological risk quotient （RQ） results indicated that norfloxacin in the surface water of Chaohu Lake posed a high risk to algae （RQ &gt; 1）, while sulfamethoxazole and doxycycline posed a medium risk to algae （0.1 ≤ RQ &lt; 1）. The health risk quotient （HRQ） showed that the risk of exposure to antibiotics through drinking water was very low （HRQ &lt; 0.01）. Our findings provide scientific support for decision makers to control antibiotic pollution and reduce the management costs of antibiotic watershed pollution.

Sjogren's syndrome (SS) is a chronic, progressive autoimmune disorder characterized by gland fibrosis. We previously found a close correlation between gland fibrosis and the expression of G protein-coupled receptor kinase 2 (GRK2). In this study we explored the pathological and therapeutic significance of GRK2 in SS. Submandibular gland (SMG) antigen-induced SS mouse model was established in WT and GRK2 +/- mice. We showed that the expression levels of GRK2 were significantly up-regulated in glandular tissue and positively correlated with fibrotic morphology in SS patients and mice. Hemizygous knockout of GRK2 significantly inhibited the gland fibrosis. In mouse salivary gland epithelial cells (SGECs), we demonstrated that GRK2 interacted with Smad2/3 to positively regulate the activation of TGF-β-Smad signaling with a TGF-β-GRK2 positive feedback loop contributing to gland fibrosis. Hemizygous knockout of GRK2 attenuated TGF-β-induced collagen I production in SGECs in vitro and hindered gland fibrosis in murine SS though preventing Smad2/3 nuclear translocation. Around 28 days post immunization with SMG antigen, WT SS mice were treated with a specific GRK2 inhibitor paroxetine (Par, 5 mg·kg -1 ·d -1 , i.g. for 19 days). We found that Par administration significantly attenuated gland fibrosis and alleviated the progression of SS in mice. We conclude that genetic knockdown or pharmacological inhibition of GRK2 significantly attenuates gland fibrosis and alleviates the progression of SS. GRK2 binds to Smad2/3 and positively regulates the activation of TGF-β-Smad signaling. A TGF-β-GRK2 positive feedback loop contributes to gland fibrosis. Our research points out that GRK2 could be a promising therapeutic target for treating SS., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

In recent years, statistics and machine learning methods have been widely used to analyze the relationship between human gut microbial metagenome and metabolic diseases, which is of great significance for the functional annotation and development of microbial communities. In this study, we proposed a new and scalable framework for image enhancement and deep learning of gut metagenome, which could be used in the classification of human metabolic diseases. Each data sample in three representative human gut metagenome datasets was transformed into image and enhanced, and put into the machine learning models of logistic regression (LR), support vector machine (SVM), Bayesian network (BN) and random forest (RF), and the deep learning models of multilayer perceptron (MLP) and convolutional neural network (CNN). The accuracy performance of the overall evaluation model for disease prediction was verified by accuracy (A), accuracy (P), recall (R), F1 score (F1), area under ROC curve (AUC) and 10 fold cross-validation. The results showed that the overall performance of MLP model was better than that of CNN, LR, SVM, BN, RF and PopPhy-CNN, and the performance of MLP and CNN models was further improved after data enhancement (random rotation and adding salt-and-pepper noise). The accuracy of MLP model in disease prediction was further improved by 4%-11%, F1 by 1%-6% and AUC by 5%-10%. The above results showed that human gut metagenome image enhancement and deep learning could accurately extract microbial characteristics and effectively predict the host disease phenotype. The source code and datasets used in this study can be publicly accessed in https://github.com/HuaXWu/GM&#95;ML&#95;Classification.git.

Adipose tissue is composed of adipocytes, stromal vascular fraction, nerves, surrounding immune cells, and the extracellular matrix. Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called "adipose tissue plasticity". Adipose tissue plasticity includes changes in the size, species, number, lipid storage capacity, and differentiation function of adipocytes, as well as alterations in the distribution and cellular composition of adipose tissue. This plasticity has a major role in growth, obesity, organismal protection, and internal environmental homeostasis. Moreover, certain thresholds exist for this plasticity with significant individualized differences. Here, we comprehensively elaborate on the specific connotation of adipose tissue plasticity and the relationship between this plasticity and the development of many diseases. Meanwhile, we summarize possible strategies for treating obesity in response to adipose tissue plasticity, intending to provide new insights into the dynamic changes in adipose tissue and contribute new ideas to relevant clinical problems.

Background and Objectives: Smoothened (SMO), a key component of the hedgehog signaling pathway, represents a therapeutic target for triple negative breast cancer (TNBC), yet the chemotherapy response rate in TNBC patients is only 40-50%, underscoring the urgent need for the development of novel drugs to effectively treat this condition. The novel compound TPB15, an SMO inhibitor derived from [1,2,4] triazolo [4,3-α] pyridines, demonstrated superior anti-TNBC activity and lower toxicity compared to the first SMO inhibitor vismodegib in both in vitro and in vivo. However, the compound's pharmacokinetic properties remain unclear. The present work aims to develop a simple HPLC-MS/MS method to profile the pharmacokinetics and bioavailability of TPB15 in rats as a ground work for further clinical research., Methods: Separation was performed on an Agilent ZORBAX StableBond C18 column by gradient elution using acetonitrile and 0.1% formic acid as mobile phase at a flow rate of 0.3 mL/min. Multiple reaction monitoring(MRM) in positive mode with the transitions of m/z 454.2 → 100.0, 248.1 → 121.1 was employed to determine TPB15 and internal standard tinidazole, respectively. The specificity, intra- and inter- day precision and accuracy, extraction recovery, stability, matrix effect, dilution integrity and carryover of the method was validated. The pharmacokinetics and bioavailability  study of TPB15 were carried out on rats through intravenous injection at the dose of 5 mg/kg and oral gavage at the dose of 25 mg/kg, and the pharmacokinetics parameters were calculated by the non-compartment analysis using the pharmacokinetics software DAS 2.1.1., Results: The values of specificity, intra- and inter- day precision and accuracy, extraction recovery, stability, matrix effect, dilution integrity and carryover satisfied the acceptable limits. The lower limit of quantification of this method was 10 ng/mL with a linear range of 10-2000 ng/mL. The validated method was then applied to pharmacokinetics and bioavailability studies in rat by dosing with gavage (25 mg/kg) and intravenous injection(5 mg/kg), and the oral bioavailability of TBP15 in rat was calculated as 16.4 ± 3.5%. The pharmacokinetic parameters were calculated as following: maximum of plasma concentration (C max ) (PO: 2787.17 ± 279.45 µg/L), Time to maximum plasma concentration (T max ) (PO: 4.20 ± 0.90 h), the area under the concentration-time curve 0 to time (AUC 0-t ) (PO: 17,373.03 ± 2585.18 ng/mL·h, IV: 21,129.79 ± 3360.84 ng/mL·h), the area under the concentration-time curve 0 to infinity (AUC 0-∞ ) (PO: 17,443.85 ± 2597.63 ng/mL·h, IV: 17,443.85 ± 2597.63 ng/mL·h), terminal elimination half-life (t 1/2 ) (PO: 7.26 ± 2.16 h, IV: 4.78 ± 1.09 h)., Conclusions: TPB15, a promising candidate for treating TNBC, has demonstrated outstanding efficacy and safety in vitro and in vivo. This study established a simple, sensitive, and rapid HPLC-MS/MS bioanalytical method, developed and validated in accordance with FDA and EMA guidelines, for conducting pharmacokinetic and bioavailability studies of TPB15. The results revealed a favorable pharmacokinetic profile owing to its long t 1/2 . Nevertheless, the next phase of research should include formulation screening to enhance bioavailability, as well as clinical trials, metabolism pathway analysis, and assessment of potential drug-drug interactions., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

To develop a simple scoring system based on baseline inflammatory and nutritional markers to predict the long-term prognosis of patients with nasopharyngeal carcinoma (NPC). Conducted a retrospective analysis of clinical data from 1024 newly diagnosed non-metastatic NPC patients. A total of 15 pre-treatment inflammatory and nutritional markers were collected as candidate variables. Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff points for each parameter. Survival analysis was performed using Kaplan-Meier method and Cox regression analysis. Besides, the Inflammation Nutrition Risk Score (INRS) was calculated for each patient by assigning each independent prognostic factor a score of 1. Multivariate Cox regression analysis showed that serum albumin (ALB), systemic immune-inflammation index, and monocyte count (M) were independent prognostic factors for OS (P < 0.05). Survival analysis showed that higher INRS was associated with a worsened prognosis. Patients in the high-risk group had shorter OS than in the low-risk group. In the training group, the 3-, 5-, and 8-years OS rates for the low-risk group versus high-risk group were 92.5% versus 87.8%, 87.4% versus 75.1%, and 84.6% versus 62.2%, respectively (P < 0.05). In the validation group, the 3-, 5-, and 8-years OS rates for the low-risk group vs. high-risk group were 95.0% versus 86.4%, 92.1% versus 82.2%, and 89.5% versus 74.3%, respectively (P < 0.05). Further subgroup analysis showed a significant difference in the OS between the high-risk group and low-risk group in patients with locally advanced disease (P < 0.05). The ROC curve demonstrated that INRS had a similar predictive value for long-term survival in NPC patients compared to TNM staging and serum EBV-DNA levels. Pretreatment ALB, M, and SIRI are independent prognostic factors for long-term survival in patients with NPC. INRS constructed based on these three factors can serve as a long-term prognostic indicator for NPC., (© 2024. The Author(s).)

Background: Droplet digital PCR (ddPCR) is increasingly used in diagnosing clinical pathogens, but its effectiveness in cirrhosis patients with suspected ascites infection remains uncertain., Methods: The diagnostic performance of ddPCR was assessed in 305 ascites samples, utilizing culture and clinical composite standards. The quantitative value and potential clinical impact of ddPCR were further analyzed in patients with spontaneous bacterial peritonitis., Results: With culture standards, ddPCR demonstrated a sensitivity of 86.5% and specificity of 83.2% for bacterial or fungal detection. After adjustment of clinical composite criteria, specificity increased to 96.4%. Better diagnostic performance for all types of targeted pathogens, particularly fungi, was observed with ddPCR compared to culture, and more polymicrobial infections were detected (30.4% versus 5.7%, p < 0.001). Pathogen loads detected by ddPCR correlated with white blood cell count in ascites and blood, as well as polymorphonuclear cell (PMN) count in ascites, reflecting infection status rapidly. A positive clinical impact of 55.8% (43/77) was observed for ddPCR, which was more significant among patients with PMN count ≤ 250/mm 3 in terms of medication adjustment and new diagnosis. ddPCR results for fungal detection were confirmed by clinical symptoms and other microbiological tests, which could guide antifungal therapy and reduce the risk of short-term mortality., Conclusions: ddPCR, with appropriate panel design, has advantages in pathogen detection and clinical management of ascites infection, especially for patients with fungal and polymicrobial infections. Patients with atypical spontaneous bacterial peritonitis benefited more from ddPCR., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs)., Aim: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort., Methods: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed., Results: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods., Conclusion: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage., 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.)

Background: The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response., Methods: The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus., Results: Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine's rapid antidepressant response., Conclusions: Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling., (© 2024. The Author(s).)

A novel process using N -benzylhydroxylamine hydrochloride as a "C1N1 synthon" in [2+2+1] cyclization for the construction of 1,2,5-trisubstituted imidazoles has been described for the first time. The key to realizing this process lies in capturing arylamines by in situ generated novel acyl ketonitrone intermediates. Subsequent tautomerization activates the α-C(sp 3 )-H of N -benzylhydroxylamines, and thus breaks through its inherent reaction mode and achieves N , α-C site-selective cyclization. Furthermore, this method enables scale-up synthesis and late-stage modification of complex molecules.

Background: Forest geneticists typically use provenances to account for population differences in their improvement schemes; however, the historical records of the imported materials might not be very precise or well-aligned with the genetic clusters derived from advanced molecular techniques. The main objective of this study was to assess the impact of marker-based population structure on genetic parameter estimates related to growth and wood properties and their trade-offs in Norway spruce, by either incorporating it as a fixed effect (model-A) or excluding it entirely from the analysis (model-B)., Results: Our results indicate that models incorporating population structure significantly reduce estimates of additive genetic variance, resulting in substantial reduction of narrow-sense heritability. However, these models considerably improve prediction accuracies. This was particularly significant for growth and solid-wood properties, which showed to have the highest population genetic differentiation (Q ST ) among the studied traits. Additionally, although the pattern of correlations remained similar across the models, their magnitude was slightly lower for models that included population structure as a fixed effect. This suggests that selection, consistently performed within populations, might be less affected by unfavourable genetic correlations compared to mass selection conducted without pedigree restrictions., Conclusion: We conclude that the results of models properly accounting for population structure are more accurate and less biased compared to those neglecting this effect. This might have practical implications for breeders and forest managers where, decisions based on imprecise selections can pose a high risk to economic efficiency., (© 2024. The Author(s).)

Recent research on the water content of large igneous provinces (LIPs) has revealed that water has a significant impact on the formation of LIPs. However, most studies focus on the water content of mafic-ultramafic rocks, while relatively little attention has been paid to the water content of continental flood basalts (CFB), which form the major part of LIPs and are characterized by huge volumes (> 1 × 10 5 km 3 ) and short eruption times. Here, we determined water contents of clinopyroxene crystals from the Akesu diabase, which is co-genetic with flood basalts of the Tarim LIP in China. Based on these measurements, we obtained a water content of higher than 1.23 ± 0.49 wt.% for the parental magma to the Tarim CFB and a minimum water content of 1230 ± 490 ppm for the mantle source, thus indicating the presence of a hydrous mantle plume. Combined with previous studies, our results suggest that water plays a key role in the formation of the Tarim LIP. Additionally, the whole-rock compositions of the Akesu diabase indicate a contribution of pyroxenite in the mantle source. This is consistent with a model, in which water was brought into the Tarim mantle plume by a subducted oceanic plate that entered the deep mantle., (© 2024. The Author(s).)

Yang-deficiency constitution (YADC) is linked to a higher vulnerability to various diseases, such as cold coagulation and blood stasis (CCBS) syndrome and infertility. Endometrial hyperplastic processes (EHPs) are a leading cause of infertility in women and are characterized by CCBS. However, it remains unclear whether YADC is related to the development of EHPs., Methods: We recruited 202 EHPs patients including 147 with YADC (YEH group) and 55 with non-YADC (NYEH group). Fecal samples were collected from 8 YEH patients and 3 NYEH patients and analyzed using 16S rRNA V3-V4 sequencing for gut microbiota analysis. We obtained constitution survey data and a differential gut microbiota dataset from the literature for further analysis. Bioinformatics analysis was conducted using gut microbiota-related genes from public databases., Results: YADC was significantly more prevalent in EHPs than non-YADC (P < 0.001), suggesting it as a potential risk factor for EHPs occurrence (OR population survey = 13.471; OR healthy women = 5.173). The YEH group had higher levels of inflammation, estrogen, and tamoxifen-related flora compared to NYEH and healthy YADC groups. There was an interaction between inflammation, estrogen, differential flora, and EHPs-related genes, particularly the TNF gene (related to inflammation) and the EGFR gene (related to estrogen), which may play a crucial role in EHPs development., Conclusion: YEH individuals exhibit significant changes in their gut microbiota compared to NYEH and healthy YADC. The interaction between specific microbiota and host genes is believed to play a critical role in the progression of EHPs., Competing Interests: None., (IJCEP Copyright © 2024.)

Social devaluation of being overweight is common in daily life, but little is known about the weight stigma in romantic relationships. The present study investigated the roles of maladaptive and adaptive coping strategies in the relation between the experience of weight stigma in romantic relationships and depressive symptoms in men and women, respectively. Analyses of gender differences and structural equation modeling yielded several findings. First, while men and women experienced similar levels of weight stigma from their romantic partners, women were more likely to use exercise avoidance, disengagement coping, and reappraisal coping strategies, and to exhibit more depressive symptoms than men. Second, men who experienced weight stigma tended to cope with it through exercise avoidance and disengagement coping, which were related to greater depressive symptoms. Men also coped with weight stigma adaptively via reappraisal coping, which was additionally associated with more positive affect. Third, the relation between the experience of weight stigma and depressive symptoms in women was only explained by using disengagement coping. These findings extend the understanding of weight stigma to a specific context and provide some insight that future interventions to reduce the impacts of weight stigma should be tailored accordingly for men and women., (© 2023 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8 + T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8 + T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8 + T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8 + T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8 + T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8 + T cell infiltration and improve ICI efficacy., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

α-Linolenic acid (ALA) is an important nutrient component in rapeseed oil, and rapeseed breeders want to either restrain or enhance the function of fatty acid desaturases (FADs) in the ALA biosynthesis pathway. To determine the reason for the upregulation of rapeseed BnFAD genes in two high-ALA accessions, R8Q10 and YH25005, we compared their transcriptome profiles in the seed at 24 days after pollination (DAP) with those of two low-ALA lines, A28 and SW. The expression levels of twenty-eight important genes in the seed samples at 20, 27, and 34 DAP were also investigated using an RT-qPCR. The expression levels of genes involved in flavonoid and proanthocyanidin synthesis, including BnCHS , BnCHI , BnDFR , BnFLS1 , BnLDOX , BnBAN , BnTT10 , and BnTT12 and genes encoding the transcription factors BnTT1, BnTT2, BnTT8, and BnTT16 were lower in R8Q10 and YH25005 than in A28 and SW. The expression levels of genes encoding master transcription factors in embryo development, such as BnLEC1 , BnABI3 , BnFUS3 , BnL1L , BnAREB3 , and BnbZIP67 , were elevated significantly in the two high-ALA accessions. Combined with previous results in the Arabidopsis and rapeseed literature, we speculated that the yellow-seededness genes could elevate the activity of BnLEC1, BnABI3, BnFUS3, and BnbZIP67, etc., by reducing the expression levels of several transparent testa homologs, resulting in BnFAD3 and BnFAD7 upregulation and the acceleration of ALA synthesis. Yellow-seededness is a favorable factor to promote ALA synthesis in the two high-ALA accessions with the yellow-seeded trait. These findings provide initial insights into the transcriptomic differences between high-/low-ALA germplasms and a theoretic basis for seed quality breeding.

Phospholipase C zeta (PLCζ) is a key sperm-borne oocyte-activating factor that triggers Ca 2+ oscillations and the subsequent block to polyspermy following gamete fusion. Mutations in PLCZ1 , the gene encoding PLCζ, cause male infertility and intracytoplasmic sperm injection (ICSI) fertilization failure; and PLCζ expression and localization patterns are significantly correlated with ICSI fertilization rate (FR). However, in conventional in vitro fertilization (cIVF), whether and how sperm PLCζ affects fertilization remain unclear. Herein, we identified one previously reported and two novel PLCZ1 mutations associated with polyspermy in vitro that are characterized by excessive sperm-zona binding and a delay in pronuclei (PN) formation. Immunofluorescence staining and oocyte activation testing revealed that virtually all spermatozoa from patients lacked functional PLCζ and were thus unable to evoke Ca 2+ oscillations. ICSI with an artificial oocyte activation treatment successfully rescued the polyspermic phenotype and resulted in a live birth. Furthermore, we analyzed PLCζ in an additional 58 males after cIVF treatment in the Reproductive and Genetic Hospital of CITIC-Xiangya (Changsha, China) between February 2019 and January 2022. We found that the proportion of spermatozoa that expressed PLCζ was positively correlated with both 2PN rate and total FR. The optimal cutoff value below which males were likely to experience low FR (total FR ≤30%) after cIVF was 56.7% for the proportion of spermatozoa expressing PLCζ. Our study expands the mutation and the phenotypic spectrum of PLCZ1 and further suggests that PLCζ constitutes a promising biomarker for identifying low FRs cases in cIVF due to sperm-related oocyte activation deficiency and that sperm PLCζ analysis may benefit the wider male population and not only men with ICSI failure., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Background: Hepatocellular carcinoma (HCC) patients complicated with portal vein tumor thrombus (PVTT) exhibit poor prognoses and treatment responses., Aim: To investigate efficacies and safety of the combination of PD-1 inhibitor, transcatheter arterial chemoembolization (TACE) and Lenvatinib in HCC subjects comorbid with PVTT., Methods: From January 2019 to December 2020, HCC patients with PVTT types I-IV were retrospectively enrolled at Beijing Ditan Hospital. They were distributed to either the PTL or TACE/Lenvatinib (TL) group. The median progression-free survival (mPFS) was set as the primary endpoint, while parameters like median overall survival, objective response rate, disease control rate (DCR), and toxicity level served as secondary endpoints., Results: Forty-one eligible patients were finally recruited for this study and divided into the PTL ( n = 18) and TL ( n = 23) groups. For a median follow-up of 21.8 months, the DCRs were 88.9% and 60.9% in the PTL and TL groups ( P = 0.046), res-pectively. Moreover, mPFS indicated significant improvement (HR = 0.25; P < 0.001) in PTL-treated patients (5.4 months) compared to TL-treated (2.7 months) patients. There were no treatment-related deaths or differences in adverse events in either group., Conclusion: A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types I-IV., Competing Interests: Conflict-of-interest statement: All authors certify that there is no conflict of interest related to the manuscript., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Scots pine (Pinus sylvestris L.) is one of the most widespread and economically important conifer species in the world. Applications like genomic selection and association studies, which could help accelerate breeding cycles, are challenging in Scots pine because of its large and repetitive genome. For this reason, genotyping tools for conifer species, and in particular for Scots pine, are commonly based on transcribed regions of the genome. In this article, we present the Axiom Psyl50K array, the first single nucleotide polymorphism (SNP) genotyping array for Scots pine based on whole-genome resequencing, that represents both genic and intergenic regions. This array was designed following a two-step procedure: first, 192 trees were sequenced, and a 430K SNP screening array was constructed. Then, 480 samples, including haploid megagametophytes, full-sib family trios, breeding population, and range-wide individuals from across Eurasia were genotyped with the screening array. The best 50K SNPs were selected based on quality, replicability, distribution across the draft genome assembly, balance between genic and intergenic regions, and genotype-environment and genotype-phenotype associations. Of the final 49 877 probes tiled in the array, 20 372 (40.84%) occur inside gene models, while the rest lie in intergenic regions. We also show that the Psyl50K array can yield enough high-confidence SNPs for genetic studies in pine species from North America and Eurasia. This new genotyping tool will be a valuable resource for high-throughput fundamental and applied research of Scots pine and other pine species., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Studies have reported inconsistent results about the risk of incident chronic kidney disease (CKD) in people with metabolically healthy obesity (MHO). We designed this systematic review and meta-analysis to evaluate the risk of developing CKD in people with MHO and metabolically unhealthy normal weight (MUNW). We used a predefined search strategy to retrieve eligible studies from multiple databases up to June 20, 2022. Random-effects model meta-analyses were implied to estimate the overall hazard ratio (HR) of incident CKD in obesity phenotypes. Eight prospective cohort studies, including approximately 5 million participants with a median follow-up ranging between 3 and 14 years, were included in this meta-analysis. Compared to the metabolically healthy normal weight (MHNW), the mean differences in cardiometabolic and renal risk factors in MHO, MUNW, and metabolically unhealthy obesity (MUO) were evaluated with overall HR of 1.42, 1.49, and 1.84, respectively. Compared to MHNW, the mean estimated glomerular filtration rate (eGFR) and high-density lipoprotein (HDL) were significantly lower, and low-density lipoprotein (LDL), blood pressure, blood glucose, and triglycerides were higher in MHO and MUNW. In conclusion, MHO and MUNW are not benign conditions and pose a higher risk for incident CKD. Obesity, whether in the presence or absence of metabolic health, is a risk factor for CKD., (© 2023 World Obesity Federation.)

Background: The sequential anti-osteoporotic treatment for women with postmenopausal osteoporosis (PMO) is important, but the order in which different types of drugs are used is confusing and controversial. Therefore, we performed a network meta-analysis to compare the efficacy and safety of available sequential treatments to explore the most efficacious strategy for long-term management of osteoporosis., Methods: In this network meta-analysis, we searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to September 19, 2023 to identify randomised controlled trials comparing sequential treatments for women with PMO. The identified trials were screened by reading the title and abstract, and only randomised clinical trials involving sequential anti-osteoporotic treatments and reported relevant outcomes for PMO were included. The main outcomes included vertebral fracture risk, the percentage change in bone mineral density (BMD) in different body parts, and all safety indicators in the stage after switching treatment. A frequentist network meta-analysis was performed using the multivariate random effects method and evaluated using the surface under the cumulative ranking curve (SUCRA). Certainty of evidence was assessed using the Confidence in the Network Meta-Analysis (CINeMA) framework. This study is registered with PROSPERO: CRD42022360236., Findings: A total of 19 trials comprising 18,416 participants were included in the study. Five different sequential treatments were investigated as the main interventions and compared to the corresponding control groups. The intervention groups in this study comprised the following treatment switch protocols: switching from an anabolic agent (AB) to an anti-resorptive agent (AR) (ABtAR), transitioning from one AR to another AR (ARtAAR), shifting from an AR to an AB (ARtAB), switching from an AB to a combined treatment of AB and AR (ABtC), and transitioning from an AR to a combined treatment (ARtC). A significant reduction in the incidence of vertebral fractures was observed in ARtC, ABtAR and ARtAB in the second stage, and ARtC had the lowest incidence with 81.5% SUCRA. ARtAAR and ABtAR were two effective strategies for preventing fractures and improving BMD in other body parts. Especially, ARtAAR could improve total hip BMD with the highest 96.1% SUCRA, and ABtAR could decrease the risk of total fractures with the highest 94.3% SUCRA. Almost no difference was observed in safety outcomes in other comparisons., Interpretation: Our findings suggested that the ARtAAR and ABtAR strategy are the effective and safe sequential treatment for preventing fracture and improving BMD for PMO. ARtC is more effective in preventing vertebral fractures., Funding: The National Natural Science Foundation of China (82170900, 81970762), the Hunan Administration of Traditional Chinese Medicine, and the Hunan Province High-level Health Talents "225" Project., Competing Interests: None., (© 2024 The Author(s).)

Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo , but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To establish an evaluation model for occupational hazard prevention and control levels in coal mines, to explore the combination of Analytic Hierarchy Process (AHP) and fuzzy comprehensive evaluation, to evaluate the overall situation of occupational hazard prevention and control in coal mines. Methods: In November 2021, Collect information of occupational hazards and their prevention and control status in 30 coal mines. AHP model was first constructed for the elements of occupational hazard prevention and control in coal mines. Then, the AHP and fuzzy comprehensive evaluation method was applied to comprehensively evaluate and grade the occupational hazard prevention and control in coal mines, using the principles of maximum membership and weighted average. Results: The hierarchical fuzzy comprehensive evaluation results for typical coal mine were basically consistent with its occupational hazard prevention and control situation. The dust prevention and control situation was good, the noise prevention and control situation is average, the occupational health monitoring situation was good, the occupational health management situation was average, and the overall level of occupational hazard prevention and control was good. Conclusion: The hierarchical fuzzy comprehensive evaluation model for occupational hazard prevention and control levels, combined with the principles of maximum membership and weighted average, can objectively evaluate and reflect the overall situation of occupational hazard prevention and control in coal mines.

Background: Macular retinoschisis in patients with high myopia is one of the main reasons for a decline in visual function and the perceived deformation of visual objects., Objective: This study aimed to investigate the therapeutic effect of cataract phacoemulsification and foldable intraocular lens implantation (FILI) combined with internal limiting membrane stripping (ILMS) in the treatment of macular retinoschisis in patients with high myopia., Methods: A total of 52 patients (55 eyes) who had been diagnosed with macular retinoschisis with high myopia between June 2019 and June 2020 were enrolled in the present study. Patients in the control group (25 eyes) received 23G vitreous surgery and macular ILMS and long-term inert gas (C3F8) filling of the vitreous cavity; patients in the research group (30 eyes) were additionally treated with cataract phacoemulsification and soft intraocular lens on the same treatment basis as the control group., Results: The difference in average BCVA between the control and the research groups was not statistically significant before the surgery (P> 0.05) but was statistically significant 12 months after the procedure (P< 0.05). The minimum foveal thickness was significantly decreased in the two groups after the surgery compared with before the procedure (P< 0.05)., Conclusion: Cataract phacoemulsification and FILI further improved the therapeutic effect of ILMS in the treatment of macular retinoschisis in patients with high myopia.

Diabetic kidney disease (DKD) is a prominent etiological factor underlying the onset of end-stage kidney disease, which is characterized by the presence of microalbuminuria. Recent studies have found that high glucose can induce mitochondrial dysfunction and ferroptosis in podocytes, leading to renal impairment and proteinuria. Triptolide was extracted from traditional Chinese medicine Tripterygium wilfordii Hook F., which has anti-inflammatory, anti-oxidant, and podocyte protective activities. Multiple studies have shown that triptolide can ameliorate proteinuria in DKD. However, the specific mechanisms remain unclear. This study investigates whether triptolide can reverse proteinuria in DKD by inhibiting ferroptosis in db/db mice and its specific protective mechanisms. The results demonstrate that triptolide could preserve podocytes and reduce proteinuria in db/db mice via inhibiting ferroptosis. In vivo and in vitro , the expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH-1), and the cystine/glutamate reverse antiporter solute carrier family 7 member 11 (SLC7A11) were increased, and the production of transferrin receptor 1 (TFR-1) was decreased by triptolide. Moreover, triptolide suppressed oxidative stress and mitochondria dysfunction. Additionally, triptolide up-regulated the expression of NFE2-related factor 2 (Nrf2) and change the expression of its downstream targets related to ferroptosis. Furthermore, the podocyte actin cytoskeleton was stabilized by triptolide, and the transition from slit diaphragm (SD) to tight junction (TJ), which is a pivotal character of filtration barrier damage, was attenuated by triptolide. In conclusion, our results suggest that triptolide could stabilize the glomerular podocyte cytoskeleton and attenuate renal SD-TJ transition in DKD by upregulating Nrf2 and thereby inhibiting ferroptosis.

In recent years, remarkable breakthroughs have been reported on antibody-drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next-generation ADCs and the directions of clinical research., (© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Purpose: The aim of this study was to investigate the efficacy and safety of early cumulus cell removal (ECCR) during human in vitro fertilization (IVF)., Methods: A retrospective analysis was performed between January 2011 and December 2019. The study enrolled 1131 couples who underwent IVF treatment with ECCR. After propensity score matching at a 1:1 ratio, 1131 couples who underwent overnight coincubation of gametes were selected. The main outcome measure was the cumulative live birth rate. Secondary outcome measures included the cumulative pregnancy rate, polyspermy rate, available embryo rate, miscarriage rate, malformation rate, time to live birth, and oocyte-to-baby rate., Results: There were no significant differences found between the two groups in the polyspermy rate, available embryo rate, miscarriage rate, time to live birth, oocyte-to-baby rate, and neonatal congenital anomalies rate. The results of the study showed that ECCR was associated with a significantly higher cumulative live birth rate and cumulative pregnancy rate, along with a significantly lower fertilization rate., Conclusions: ECCR tended to confer increased cumulative live birth rate and had no negative effect on the neonatal malformation rate., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The genus Ciliochorella is a group of pestalotioid fungi, which typically occurs in subtropical and tropical areas. Species from the Ciliochorella genus play important roles in the decomposition of litter. In this study, we introduce two new species ( Ciliochorellachinensis sp. nov. and C.savannica sp. nov. ) that were found on leaf litter collected from savanna-like vegetation in hot dry valleys of southwestern China. Phylogenetic analyses of combined LSU, ITS and tub2 sequence datasets indicated that C.chinensis and C.savannica respectively form a distinct clade within the Ciliochorella genus. The comparison of the morphological characteristics indicated that the two new species are well differentiated within this genus species. Analysis of the evolutionary history suggests that Ciliochorella originated from the Eurasian continent during the Paleogene (38 Mya). Further, we find that both new species can produce cellulase and laccase, playing a decomposer role., Competing Interests: The authors have declared that no competing interests exist., (Jia-Yu Song, Hai-Xia Wu, Jin-Chen Li, Wei-Feng Ding, Cui-Ling Gong, Xiang-Yu Zeng, Nalin N. Wijayawardene, Da-Xin Yang.)

Perennial trees must maintain stem growth throughout their entire lifespan to progressively increase in size as they age. The overarching question of the molecular mechanisms that govern stem perennial growth in trees remains largely unanswered. Here we deciphered the genetic architecture that underlies perennial growth trajectories using genome-wide association studies (GWAS) for measures of growth traits across years in a natural population of Populus tomentosa. By analyzing the stem growth trajectory, we identified PtoP4H9, encoding prolyl 4-hydroxylase 9, which is responsible for the natural variation in the growth rate of diameter at breast height (DBH) across years. Quantifying the dynamic genetic contribution of PtoP4H9 loci to stem growth showed that PtoP4H9 played a pivotal role in stem growth regulation. Spatiotemporal expression analysis showed that PtoP4H9 was highly expressed in cambium tissues of poplars of various ages. Overexpression and knockdown of PtoP4H9 revealed that it altered cell expansion to regulate cell wall modification and mechanical characteristics, thereby promoting stem growth in Populus. We showed that natural variation in PtoP4H9 occurred in a BASIC PENTACYSTEINE transcription factor PtoBPC1-binding promoter element controlling PtoP4H9 expression. The geographic distribution of PtoP4H9 allelic variation was consistent with the modes of selection among populations. Altogether, our study provides important genetic insights into dynamic stem growth in Populus, and we confirmed PtoP4H9 as a potential useful marker for breeding or genetic engineering of poplars., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Context: Cardio-cerebrovascular events are severe complications of diabetes., Objective: We aim to compare the incident risk of cardio-cerebrovascular events in maturity onset diabetes of the young (MODY), type 1 diabetes, and type 2 diabetes., Methods: Type 1 diabetes, type 2 diabetes, and MODY were diagnosed by whole exome sequencing. The primary endpoint was the occurrence of the first major adverse cardiovascular event (MACE), including acute myocardial infarction, heart failure, stroke, unstable angina pectoris, and cardio-cerebrovascular-related mortality. Cox proportional hazards models were applied and adjusted to calculate hazard ratios (HRs) and 95% CIs for the incident risk of MACE in type 1 diabetes, type 2 diabetes, MODY, and MODY subgroups compared with people without diabetes (control group)., Results: Type 1 diabetes, type 2 diabetes, and MODY accounted for 2.7%, 68.1%, and 11.4% of 26 198 participants with diabetes from UK Biobank. During a median follow-up of 13 years, 1028 MACEs occurred in the control group, contrasting with 70 events in patients with type 1 diabetes (HR 2.15, 95% CI 1.69-2.74, P < .05), 5020 events in patients with type 2 diabetes (HR 7.02, 95% CI 6.56-7.51, P < .05), and 717 events in MODY (HR 5.79, 95% CI 5.26-6.37, P < .05). The hazard of MACE in HNF1B-MODY was highest among MODY subgroups (HR 11.00, 95% CI 5.47-22.00, P = 1.5 × 10-11)., Conclusion: MODY diagnosed by genetic analysis represents higher prevalence than the clinical diagnosis in UK Biobank. The risk of incident cardio-cerebrovascular events in MODY ranks between type 1 diabetes and type 2 diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

µ-Conotoxin GIIIB (µ-CTX GIIIB) is a polypeptide containing three disulfide bridges, produced by the sea snail Conus geographus. This study was aimed to explored the cytotoxic effects of µ-CTX GIIIB on mouse skeletal musculoblast (Sol8). Sol8 cells were exposed to ouabain and veratridine to establish the cell injury model, and then treated with µ-CTX GIIIB. CCK-8 was adopted to evaluate the cytotoxicity of µ-CTX GIIIB. Then, proteomics and transcriptome were conducted, and the explore the differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) affected by µ-CTX GIIIB were found. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to investigate the affected signaling pathways. µ-CTX GIIIB increased the cell survival rate of injured Sol8 cells. We found and identified 1,663 DEGs and 444 DEPs influenced by µ-CTX GIIIB. 106 pairs of correlated DEGs and DEPs were selected by combining transcriptome and proteome data. The results of KEGG and GO analysis showed that µ-CTX GIIB affected the cell cycle, apoptosis, DNA damage and repair, lipid metabolism and other biological processes of Sol8 cells. µ-CTX GIIIB could affected cell cycle regulation, DNA damage repair, and activation of tumor factors, with potential carcinogenic effects. Our results provide an important basis for the study of in vitro toxicity, the mechanism of toxicity and injury prevention by µ-CTX GIIIB., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Depressive disorder is manifested as emotional and physical abnormality. Theoretically, the governor vessel is distributed along the spine, related to the brain and communicated with five zang and six fu organs. It is the key meridian for understanding the various symptoms of depressive disorder. Depressive disorder is caused by dysfunction, stagnation or emptiness of the governor vessel, resulting in malnutrition of the brain. In clinical diagnosis and treatment, based on the theory of the governor vessel, the etiology and pathogenesis are analyzed in the patients with depressive disorder. In order to achieve harmonizing mutually the mental and physical conditions, acupuncture is delivered to adjust the spirit and physical state, moving cupping is to regulate the governor vessel, tuina manipulation is to promote meridians and collaterals and physical exercise is to coordinate the body and the spirit.

Metabolically healthy or unhealthy obesity is closely related to metabolic syndrome (MetS). To validate a more accurate diagnostic method for obesity that reflects the risk of metabolic disorders in a pre-clinical mouse model, C57BL/6J mice were fed high-sucrose-high-fat and chow diets for 12 weeks to induce obesity. MRI was performed and analysed by chemical shift-encoded fat-water separation based on the transition region extraction method. Abdominal fat was divided into upper and lower abdominal regions at the horizontal lower border of the liver. Blood samples were collected, and the glucose level, lipid profile, liver function, HbA1c and insulin were tested. k-means clustering and stepwise logistic regression were applied to validate the diagnosis of hyperglycaemia, dyslipidaemia and MetS, and to ascertain the predictive effect of MRI-derived parameters to the metabolic disorders. Pearson or Spearman correlation was used to assess the relationship between MRI-derived parameters and metabolic traits. The receiver-operating characteristic curve was used to evaluate the diagnostic effect of each logistic regression model. A two-sided p value less than 0.05 was considered to indicate statistical significance for all tests. We made the precise diagnosis of obesity, dyslipidaemia, hyperglycaemia and MetS in mice. In all, 14 mice could be diagnosed as having MetS, and the levels of body weight, HbA1c, triglyceride, total cholesterol and low-density lipoprotein cholesterol were significantly higher than in the normal group. Upper abdominal fat better predicted dyslipidaemia (odds ratio, OR = 2.673; area under the receiver-operating characteristic curve, AUC ROC  = 0.9153) and hyperglycaemia (OR = 2.456; AUC ROC  = 0.9454), and the abdominal visceral adipose tissue (VAT) was better for predicting MetS risk (OR = 1.187; AUC ROC  = 0.9619). We identified the predictive effect of fat volume and distribution in dyslipidaemia, hyperglycaemia and MetS. The upper abdominal fat played a better predictive role for the risk of dyslipidaemia and hyperglycaemia, and the abdominal VAT played a better predictive role for the risk of MetS., (© 2023 John Wiley & Sons Ltd.)

Background: The efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC (AGC)., Methods: The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice. Cytometry by Time-of-Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics., Results: Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8 + T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor β1 (TGFβ1) release from GC cells by suppressing cyclooxygenase 2 (COX2)-prostaglandin synthesis, which consequently reprogrammed TME to promote anti-tumor T cell activation., Conclusions: MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation., (© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Objective: To investigate the effects of mild moxibustion at 45°C on the chronic inflammatory response of the abdominal aorta in rats with hyperlipidemia and the effects of different moxibustion durations., Methods: Thirty-six SD rats were randomly divided into the following groups： blank control group (2 weeks), model group (2 weeks), moxibustion group (2 weeks), blank group (4 weeks), model group (4 weeks), and moxibustion group (4 weeks). A model of hyperlipidemia with chronic inflammation was established through high-fat diet feeding for 8 weeks. Rats in the moxibustion groups received mild moxibustion treatment at bilateral "Zusanli"(ST36) at 45 °C, 10 min every time, once a day, for consecutive 2 or 4 weeks. The morphology of the abdominal aorta in each group was observed by using HE staining. Contents of serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), oxidized low-density lipoprotein (ox-LDL), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), endothelin-1 (ET-1) and the contents of nitric oxide (NO), ox-LDL, and ET-1 in the abdominal aorta were measured by using ELISA. Protein and mRNA expressions of IL-6 and TNF-α in the abdominal aorta of rats in each group were detected by using Western blot and real-time fluorescence quantitative PCR respectively. The positive expression of IL-6 in the abdominal aorta of rats was detected by Immunofluorescence., Results: Compared to the blank control group, rats in the model group had increased contents of LDL, TC, TG, ox-LDL, VCAM-1, ICAM-1, IL-6, TNF-α, and ET-1 in the serum, increased contents of ox-LDL and ET-1 in the abdominal aorta, increased protein and mRNA expressions of IL-6 and TNF-α in the abdominal aorta( P <0.01, P <0.05, P <0.001), with decreased HDL content in the serum, decreased NO content in the abdominal aorta ( P <0.01, P <0.05), as well as dark pink abdominal aorta, rough textures in the adventitia, media, and intima, and rough endothelial layer. Compared to the model group(2 weeks), LDL, ICAM-1, ET-1 contents in the serum, ox-LDL content in the abdominal aorta were decreased( P <0.05), while serum IL-6 and TNF-α contents, and NO content in the abdominal aorta were significantly increased( P <0.01, P <0.05), with smoother vascular walls, and relatively clear nucleus and surrounding tissue structures of abdominal aorta in the moxibustion group(2 weeks). Compared to the model group(4 weeks), contents of LDL, TC, TG, VCAM-1, ICAM-1, IL-6, TNF-α, ox-LDL, and ET-1 in the serum, ox-LDL and ET-1 contents in abdominal aorta, protein and mRNA expressions of IL-6 and TNF-α in the abdominal aorta were significantly decreased( P <0.05, P <0.01), while HDL content in the serum and NO content in the abdominal aorta were significantly increased( P <0.05, P <0.01), with smoother vascular walls, and relatively clear nucleus and surrounding tissue structures of abdominal aorta in the moxibustion group(4 weeks). In addition, content of HDL in the serum were significantly increased( P <0.05), while TNF-α content in the serum, protein expression of IL-6 in the abdominal aorta were significantly decreased ( P <0.001, P <0.05), with smoother vascular walls, and clearer nucleus and surrounding tissue structures of abdominal aorta in the moxibustion group(4 weeks), in comparison with the moxibustion group(2 weeks)., Conclusion: Mild moxibustion of 45 °C at ST36 can improve vascular endothelial damage and inflammatory response induced by high-fat diet by regulating serum lipids, vascular tone, adhesion molecules, and inflammatory factors, of which the effect of moxibustion intervention for 4 weeks is more significant.

Purpose: Osteocytes in vivo exhibit different functional states, but no specific marker to distinguish these is currently available., Materials and Methods: To simulate the differentiation process of pre-osteoblasts to osteocytes in vitro , MC3T3-E1 cells were cultured on type I collagen gel and a three-dimensional (3D) culture system was established. The Notch expression of osteocyte-like cells in 3D culture system was compared with that of in situ osteocytes in bone tissues., Results: Immunohistochemistry demonstrated that Notch1 was not detected in "resting" in situ osteocytes, but was detected in normal cultured osteocyte-like cell line MLO-Y4. Osteocytes obtained from conventional osteogenic-induced osteoblasts and long-term cultured MLO-Y4 cells could not replicate the Notch1 expression pattern from in situ osteocytes. From day 14-35 of osteogenic induction, osteoblasts in 3D culture system gradually migrated into the gel to form canaliculus-like structures similar to bone canaliculus. On day 35, stellate-shaped osteocyte-like cells were observed, and expression of DMP1 and SOST, but not Runx2, was detected. Notch1 was not detected by immunohistochemistry, and Notch1 mRNA level was not significantly different from that of in situ osteocytes. In MC3T3-E1 cells, down-regulation of Notch2 increased Notch1 , Notch downstream genes ( β-catenin and Nfatc1 ), and Dmp1 . In MLO-Y4 cells, Notch2 decreased after Notch1 siRNA transfection. Downregulation of Notch1 or Notch2 decreased Nfatc1 , β-catenin , and Dmp1 , and increased Sost ., Conclusions: We established "resting state" osteocytes using an in vitro 3D model. Notch1 can be a useful marker to help differentiate the functional states of osteocytes (activated vs. resting state).

Objective: To observe the effect of Dong 's extraordinary point needling technique on postoperative complications of anal fistula., Methods: A total of 241 patients undergoing anal fistula surgery were randomly divided into an observation group (121 cases, 3 cases dropped off) and a control group (120 cases, 2 cases dropped off). The patients in the control group were treated with intramuscular injection of compound diclofenac sodium injection and oral administration of tamsulosin hydrochloride sustained release capsules. In addition to the treatment in the control group, the patients in the observation group were treated with Daoma needling technique at the " Sanqi points" ( Qimen point, Qijiao point, and Qizheng point) combined with Dongqi needling technique at " Sanhuang points" (sub- Tianhuang point, Dihuang point, Renhuang point), with each session lasting 30 min. The treatment in the two groups both started on the first day after surgery, and was given once daily for 14 consecutive days. Visual analog scale (VAS) score was compared between the two groups on postoperative day 1, 7, and 14; bladder residual urine volume, spontaneous voiding volume, and urinary catheterization frequency were assessed after treatment on postoperative day 1; and anorectal dynamic indexes (anal canal resting pressure, rectal resting pressure, maximum squeeze pressure of the anal canal, and minimum rectal sensory threshold) were evaluated before surgery and on postoperative day 4. Clinical efficacy was assessed in both groups one month after surgery., Results: On postoperative day 7 and 14, the VAS scores of both groups were lower than those on postoperative day 1 ( P <0.05), and the VAS scores in the observation group were lower than those in the control group ( P <0.05). The bladder residual urine volume and urinary catheterization frequency in the observation group were lower than those in the control group ( P <0.05), while the spontaneous voiding volume was higher than that in the control group ( P <0.05). On postoperative day 4, the anal canal resting pressure, maximum squeeze pressure of the anal canal, and the minimum rectal sensory threshold were lower than preoperative values ( P <0.05), while the rectal resting pressure was higher than preoperative value ( P <0.05) in both groups. The anal canal resting pressure, maximum squeeze pressure of the anal canal, and minimum rectal sensory threshold were lower than those in the control group, and the rectal resting pressure was higher than that in the control group ( P <0.05). The effective rate was 93.2% (110/118) in the observation group, which was higher than 84.7% (100/118) in the control group ( P <0.05)., Conclusion: Dong 's extraordinary point needling technique could reduce postoperative pain, alleviate urinary retention, and improve defecation in patients undergoing anal fistula surgery.

Background: Inflammation has been recognized to be a factor that substantially influences tumorigenesis and tumor prognosis. Hence, this study was aimed to investigate an inflammatory marker with the most potent prognostic ability and to evaluate the survival estimation capability of dynamic change in this marker for patients suffered from oral squamous cell carcinoma (OSCC)., Methods: 469 patients' inflammatory indicators including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory response index (SIRI), were calculated. Their predictive abilities for overall survival (OS) were evaluated by Kaplan-Meier curves to screen for the one with the most potent prognostic value. The predictive ability of dynamic changes in this marker was verified and a predictive nomogram incorporating inflammatory indicators was developed., Results: A high LMR was identified to be an indicator of a satisfactory survival rate. Compared with that of other inflammatory markers, area under the receiver operating characteristics (ROC) curve (AUC) of LMR for 1-year and 3-year OS was significantly larger (P<0.001). Dynamic LMR change remained an significant parameter for predicting OS (OR: 2.492, 95% CI: 1.246-4.981, p = 0.010). The nomogram incorporating LMR exhibited a superior prognostic significance than the TNM system, as suggested by the C-index (0.776 vs 0.651 in primary cohort; 0.800 vs 0.707 in validation cohort, P<0.001) and AUC., Conclusions: LMR was demonstrated to possess a more potent survival estimation capability than the other three inflammatory parameters. Dynamic changes in LMR serves as a significant parameter for overall survival estimation of primary OSCC patients. The established nomogram incorporating inflammatory markers showed more accuracy and sensitivity for survival estimation of primary OSCC patients., Competing Interests: 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 © 2023 Wu, Cheng, Liu, Lin, Huang, Wang, Zhou, Liu and Cao.)

Objective: To underscore the paramount significance of incorporating comprehensive rehabilitation therapy as a crucial aspect of managing lymphedema caused by breast cancer surgery, and to illuminate our first-hand experience and insights gained in utilizing this approach., Methods: We present a case report of a breast cancer survivor who had been suffering from persistent left upper-limb edema for over 15 years, who was effectively treated with a combination of conventional rehabilitation (seven-step decongestion therapy) and a comprehensive rehabilitation program (seven-step decongestion therapy, along with core and respiratory function training, as well as functional brace wearing). The efficacy of the rehabilitation therapy was evaluated through a comprehensive assessment., Results: Although the patient underwent the conventional rehabilitation program for one month, only limited improvement was observed. However, after an additional month of comprehensive rehabilitation treatment, the patient exhibited significant improvement in both lymphedema and the overall function of the left upper limb. The patient's progress was quantified by measuring the reduction in arm circumference, which demonstrated a notable decrease. Furthermore, improvements in joint range of motion were observed, with forward flexion of the shoulder enhancing by 10°, forward flexion improving by 15°, and elbow flexion increasing by 10°. In addition, manual muscular strength tests revealed an increase in strength from Grade 4 to Grade 5. The patient's quality of life was also significantly improved, as evidenced by the increase in the Activities of Daily Living score from 95 to 100 points, the increase in the the Functional Assessment of Cancer Therapy: Breast score from 53 to 79 points, and the decrease in the Kessler Psychological Distress Scale score from 24 to 17 points., Conclusion: While seven-step decongestion therapy has been shown to be effective in reducing upper-limb lymphedema caused by breast cancer surgery, it has limitations in treating more chronic cases of the condition. However, when combined with core and respiratory function training and functional brace wearing, seven-step decongestion therapy has been shown to be even more effective in reducing lymphedema and improving limb function, ultimately leading to significant improvements in quality of life., Competing Interests: 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 © 2023 Sui, Tong, Lin, Wu, Shi, Wang, Tang and Song.)