Search

Objective: To analyze the RHD genotype of a blood donor with Del phenotype in Yunnan., Methods: Rh serological phenotype was identified. RHD gene was detected by PCR-SSP typing, and its 10 exons were sequenced. Exon 9 was amplified for sequencing and analysis. RHD zygosity was detected., Results: The Rh phenotype of this specimen was CcD el ee. Genomic DNA exhibited a 1 003 bp deletion spanning from intron 8, across exon 9 into intron 9. The deletion breakpoints occurred between two 7-bp short tandem repeat sequences. There was no variation in the sequences of the remaining exons. The Rh hybridization box test showed that there was one RHD negative allele., Conclusion: This specimen is Del type caused by deletion of RHD exon 9.

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid concentrated in the brain, is essential for normal brain functions, such as learning and memory and feeding behaviors. Sphingosine kinase 1 (SphK1), the primary kinase responsible for S1P production in the brain, is abundant within presynaptic terminals, indicating a potential role of the SphK1/S1P axis in presynaptic physiology. Altered S1P levels have been highlighted in many neurologic diseases with endocytic malfunctions. However, it remains unknown whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis in neurons. The present study evaluates potential functions of the SphK1/S1P axis in synaptic vesicle endocytosis by determining effects of a dominant negative catalytically inactive SphK1. Our data for the first time identify a critical role of the SphK1/S1P axis in endocytosis in both neuroendocrine chromaffin cells and neurons from mice of both sexes. Furthermore, our Ca 2+ imaging data indicate that the SphK1/S1P axis may be important for presynaptic Ca 2+ increases during prolonged stimulations by regulating the Ca 2+ permeable TRPC5 channels, which per se regulate synaptic vesicle endocytosis. Collectively, our data point out a critical role of the regulation of TRPC5 by the SphK1/S1P axis in synaptic vesicle endocytosis. SIGNIFICANCE STATEMENT Sphingosine kinase 1 (SphK1), the primary kinase responsible for brain sphingosine-1-phosphate (S1P) production, is abundant within presynaptic terminals. Altered SphK1/S1P metabolisms has been highlighted in many neurologic disorders with defective synaptic vesicle endocytosis. However, whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis is unknown. Here, we identify that the SphK1/S1P axis regulates the kinetics of synaptic vesicle endocytosis in neurons, in addition to controlling fission-pore duration during single vesicle endocytosis in neuroendocrine chromaffin cells. The regulation of the SphK1/S1P axis in synaptic vesicle endocytosis is specific since it has a distinguished signaling pathway, which involves regulation of Ca 2+ influx via TRPC5 channels. This discovery may provide novel mechanistic implications for the SphK1/S1P axis in brain functions under physiological and pathologic conditions., (Copyright © 2023 the authors.)

Objective: This study aimed to evaluate the results and complications related to revision total hip arthroplasty within a short-to-medium follow up period. Methods: From January 2016 to January 2020, we reviewed 31 prosthetic hip arthroplasty stem revisions using a fluted, tapered modular stem with distal fixation. The median age of the patients was 74.55-79 years. The survival rate was 100%, and there were no re-revisions. The Harris hip score improved from an average of 36.5 ± 7.8 before surgery to 81.8 ± 6.2 at the final follow-up. Results: The average final follow-up was 36 (24-60) months. During this time, there was no periprosthetic infection, no prosthesis loosening or breakage, and no sciatic nerve injury. Complications included four (12.9%) intraoperative fractures and eight (25.8%) dislocations that had no stem fractures. The postoperative limb was lengthened by 17.8 ± 9.8 mm. In most cases, bone regeneration was an early and important finding. Three cases underwent extended trochanteric osteotomy, and bone healing was achieved by the final follow-up. Conclusion: The modular tapered stem reviewed in this study was very versatile, could be used in most femoral revision cases, and allowed for rapid bone reconstruction. However, a long-term follow-up study is needed to confirm these results., 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 Xing, Huang, Li, Li and Ban.)

Context: Some studies have reported the early miscarriage rate is higher in polycystic ovary syndrome (PCOS) women. However, there is a lack of evidence as to whether the risk of embryo abnormalities increases in PCOS women., Objective: This work aimed to evaluate the association between PCOS and embryo ploidy., Methods: A secondary analysis of a multicenter, randomized controlled trial was conducted from July 2017 to June 2018. The original intent was to identify whether preimplantation genetic test for aneuploidy (PGT-A) improves the live birth rate as compared with in vitro fertilization (IVF). From 14 reproductive centers, 190 patients diagnosed with PCOS and 1:1 age-matched non-PCOS patients were chosen from a PGT-A group. A total of 380 patients with 1118 embryos were included in our study. Intervention included women diagnosed with PCOS, and the main outcome measures were embryonic aneuploidy and embryonic mosaic., Results: After adjusting for potential confounders, the rate of embryonic aneuploidy and embryonic mosaic in the PCOS group were comparable with the control group (embryonic aneuploid rate PCOS group: 14.0% vs control group: 18.3%, adjusted OR [95% CI]: 0.78 [0.54, 1.12]; P = .19; embryonic mosaic rate 10.9% vs 10.1%, adjusted OR [95% CI]: 0.91 [0.59, 1.40]; P = .66). We further stratified PCOS women into 4 groups according to phenotype. The rate of aneuploid and mosaic embryos was comparable between each PCOS phenotype and control group. There was still no significant difference of embryonic aneuploid and embryo mosaic rates among the 4 phenotypes., Conclusion: The risk of aneuploid and mosaic embryos did not increase in PCOS women. Thus, we suggest that the miscarriage rate arising from abnormal embryonic chromosomes could be similar between PCOS and non-PCOS women., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Meiotic recombinases RAD51 and DMC1 mediate strand exchange in the repair of DNA double-strand breaks (DSBs) by homologous recombination. This is a landmark event of meiosis that ensures genetic diversity in sexually reproducing organisms. However, the regulatory mechanism of DMC1/RAD51-ssDNA nucleoprotein filaments during homologous recombination in mammals has remained largely elusive. Here, we show that SPIDR (scaffold protein involved in DNA repair) regulates the assembly or stability of RAD51/DMC1 on ssDNA. Knockout of Spidr in male mice causes complete meiotic arrest, accompanied by defects in synapsis and crossover formation, which leads to male infertility. In females, loss of Spidr leads to subfertility; some Spidr-/- oocytes are able to complete meiosis. Notably, fertility is rescued partially by ablation of the DNA damage checkpoint kinase CHK2 in Spidr-/- females but not in males. Thus, our study identifies SPIDR as an essential meiotic recombination factor in homologous recombination in mammals., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: To develop and validate a predictive nomogram for tumor residue 3-6 months after treatment based on postradiotherapy plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA), clinical stage, and radiotherapy (RT) dose in patients with stage II-IVA nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT)., Methods: In this retrospective study, 1050 eligible patients with stage II-IVA NPC, who completed curative IMRT and underwent pretreatment and postradiotherapy (-7 to +28 days after IMRT) EBV DNA testing, were enrolled from 2012 to 2017. The prognostic value of the residue was explored using Cox regression analysis in patients (n=1050). A nomogram for predicting tumor residues after 3-6 months was developed using logistic regression analyses in the development cohort (n=736) and validated in an internal cohort (n=314)., Results: Tumor residue was an independent inferior prognostic factor for 5-year overall survival, progression-free survival, locoregional recurrence-free survival and distant metastasis-free survival (all P<0.001). A prediction nomogram based on postradiotherapy plasma EBV DNA level (0 vs. 1-499 vs. ≥500 copies/ml), clinical stage (II vs. III vs. IVA), and RT dose (68.00-69.96 vs. 70.00-74.00 Gy) estimated the probability of residue development. The nomogram showed better discrimination (area under the curve (AUC): 0.752) than either the clinical stage (0.659) or postradiotherapy EBV DNA level (0.627) alone in the development and validation cohorts (AUC: 0.728)., Conclusions: We developed and validated a nomogram model integrating clinical characteristics at the end of IMRT for predicting whether tumor will residue or not after 3-6 months. Thus, high-risk NPC patients who might benefit from immediate additional intervention could be identified by the model, and the probability of residue can be reduced in the future., (© 2023. The Author(s).)

HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Study Question: Can whole exome sequencing (WES) followed by trio bioinformatics analysis identify novel pathogenic genetic causes of first trimester euploid miscarriage?, Summary Answer: We identified genetic variants in six candidate genes that indicated plausible underlying causes of first-trimester euploid miscarriage., What Is Known Already: Previous studies have identified several monogenic causes of Mendelian inheritance in euploid miscarriages. However, most of these studies are without trio analyses and lack cellular and animal models to validate the functional effect of putative pathogenic variants., Study Design, Size, Duration: Eight unexplained recurrent miscarriage (URM) couples and corresponding euploid miscarriages were included in our study for whole genome sequencing (WGS) and WES followed by trio bioinformatics analysis. Knock-in mice with Rry2 and Plxnb2 variants and immortalized human trophoblasts were utilized for functional study. Additional 113 unexplained miscarriages were included to identify the mutation prevalence of specific genes by multiplex PCR., Participants/materials, Setting, Methods: Whole blood from URM couples and their <13 weeks gestation miscarriage products were both collected for WES, and all variants in selected genes were verified by Sanger sequencing. Different stage C57BL/6J wild-type mouse embryos were collected for immunofluorescence. Ryr2N1552S/+, Ryr2R137W/+, Plxnb2D1577E/+, and Plxnb2R465Q/+ point mutation mice were generated and backcrossed. Matrigel-coated transwell invasion assays and wound-healing assays were performed using HTR-8/SVneo cells transfected with PLXNB2 small-interfering RNA and negative control. Multiplex PCR was performed focusing on RYR2 and PLXNB2., Main Results and the Role of Chance: Six novel candidate genes, including ATP2A2, NAP1L1, RYR2, NRK, PLXNB2, and SSPO, were identified. Immunofluorescence staining showed that ATP2A2, NAP1L1, RyR2, and PLXNB2 were widely expressed from the zygote to the blastocyst stage in mouse embryos. Although compound heterozygous mice with Rry2 and Plxnb2 variants did not show embryonic lethality, the number of pups per litter was significantly reduced when backcrossing Ryr2N1552S/+ ♂ with Ryr2R137W/+ ♀ or Plxnb2D1577E/+ ♂ with Plxnb2R465Q/+ ♀ (P < 0.05), which were in accordance with the sequencing results of Family 2 and Family 3, and the proportion of Ryr2N1552S/+ offspring was significantly lower when Ryr2N1552S/+ female mice were backcrossed with Ryr2R137W/+ male mice (P < 0.05). Moreover, siRNA-mediated PLXNB2 knockdown inhibited the migratory and invasive abilities of immortalized human trophoblasts. Besides, additional 10 variants of RYR2 and PLXNB2 were detected in 113 unexplained euploid miscarriages by multiplex PCR., Limitations, Reasons for Caution: The relatively small number of samples is a limitation of our study which may result in the identification of variants in unique candidate genes with no definitive although plausible causal effect. Larger cohorts are needed to replicate these findings and additional functional research is needed to confirm the pathogenic effects of these variants. Moreover, the sequencing coverage restricted the detection of low-level parental mosaic variants., Wider Implications of the Findings: For first-trimester euploid miscarriage, variants in unique genes may be underlying genetic etiologies and WES on trio could be an ideal model to identify potential genetic causes, which could facilitate individualized precise diagnostic and therapeutic regimens in the future., Study Funding/competing Interests: This study was supported by grants from the National Key Research and Development Program of China (2021YFC2700604), National Natural Science Foundation of China (31900492, 82101784, 82171648), Basic Science Center Program of the National Natural Science Foundation of China (31988101), Key Research and Development Program of Shandong Province (2021LCZX02), Natural Science Foundation of Shandong Province (ZR2020QH051), Natural Science Foundation of Jiangsu Province (BK20200223), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201812154) and Young Scholars Program of Shandong University. The authors declare no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Importance: Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of implantation and pregnancy, although the evidence for efficacy is inadequate., Objective: To determine the efficacy of 10 mg of prednisone compared with placebo on live birth among women with recurrent implantation failure., Design, Setting, and Participants: A double-blind, placebo-controlled, randomized clinical trial conducted at 8 fertility centers in China. Eligible women who had a history of 2 or more unsuccessful embryo transfer cycles, were younger than 38 years when oocytes were retrieved, and were planning to undergo frozen-thawed embryo transfer with the availability of good-quality embryos were enrolled from November 2018 to August 2020 (final follow-up August 2021)., Interventions: Participants were randomized (1:1) to receive oral pills containing either 10 mg of prednisone (n = 357) or matching placebo (n = 358) once daily, from the day at which they started endometrial preparation for frozen-thawed embryo transfer through early pregnancy., Main Outcomes and Measures: The primary outcome was live birth, defined as the delivery of any number of neonates born at 28 or more weeks' gestation with signs of life., Results: Among 715 women randomized (mean age, 32 years), 714 (99.9%) had data available on live birth outcomes and were included in the primary analysis. Live birth occurred among 37.8% of women (135 of 357) in the prednisone group vs 38.8% of women (139 of 358) in the placebo group (absolute difference, -1.0% [95% CI, -8.1% to 6.1%]; relative ratio [RR], 0.97 [95% CI, 0.81 to 1.17]; P = .78). The rates of biochemical pregnancy loss were 17.3% in the prednisone group and 9.9% in the placebo group (absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04). Of those in the prednisone group, preterm delivery occurred among 11.8% and of those in the placebo group, 5.5% of pregnancies (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). There were no statistically significant between-group differences in the rates of biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, other adverse events, or mean birthweights., Conclusions and Relevance: Among patients with recurrent implantation failure, treatment with prednisone did not improve live birth rate compared with placebo. Data suggested that the use of prednisone may increase the risk of preterm delivery and biochemical pregnancy loss. Our results challenge the value of prednisone use in clinical practice for the treatment of recurrent implantation failure., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800018783.

Signaling by the transforming growth factor (TGF)-β superfamily is necessary for proper neural development and is involved in pain processing under both physiological and pathological conditions. Sensory neurons that reside in the dorsal root ganglia (DRGs) initially begin to perceive noxious signaling from their innervating peripheral target tissues and further convey pain signaling to the central nervous system. However, the transcriptional profile of the TGF-β superfamily members in DRGs during chronic inflammatory pain remains elusive. We developed a custom microarray to screen for transcriptional changes in members of the TGF-β superfamily in lumbar DRGs of rats with chronic inflammatory pain and found that the transcription of the TGF-β superfamily members tends to be downregulated. Among them, signaling of the activin/inhibin and bone morphogenetic protein/growth and differentiation factor (BMP/GDF) families dramatically decreased. In addition, peripherally pre-local administration of activins A and C worsened formalin-induced acute inflammatory pain, whereas activin C, but not activin A, improved formalin-induced persistent inflammatory pain by inhibiting the activation of astrocytes. This is the first report of the TGF-β superfamily transcriptional profiles in lumbar DRGs under chronic inflammatory pain conditions, in which transcriptional changes in cytokines or pathway components were found to contribute to, or be involved in, inflammatory pain processing. Our data will provide more targets for pain research., (© 2023. The Author(s) under exclusive licence to University of Navarra.)

A new spirostane, namely neohelicomyine B (1), together with six known steroids (2-7) were isolated from the fermentation of fungus Neohelicomyces hyalosporus. The structures of these compounds were elucidated by extensive analyses of spectroscopic methods including 1D and 2D NMR and HR-ESI-MS. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction. The bioactivities of compounds 1-7 were evaluated using cellular assays. Compound 1 displayed moderate cytotoxicity against HepG2 cells (hepatoma cells) with IC 50 value of 8.4±2.1 μM. Compound 7 also exhibited cytotoxic activity against HepG2 cells with the IC 50 value of 3.0±0.2 μM., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Funiu Mountains are located in a transition region between warm temperate zone and northern subtropical region, where a variety of plant species are distributed with sensitive response to climate change. Their response characteristics to climate change are still unclear. We developed the basal area increment (BAI) index chronologies of Pinus tabuliformis , P. armandii , and P. massoniana in the Funiu Mountains to examine their growth trend and their sensitivity to climatic change. The results showed that the BAI chronologies gave a clue that the three conife-rous species had similar radial growth rate. The large Gleichlufigkeit (GLK) indices among the three BAI chronologies also indicated that the three species had a similar growth trend. Results of correlation analysis showed that the three species also had similar response to climatic change to a certain extent. Radial growth of all the three species was significantly positively correlated with the total monthly precipitation in December of previous year and June of the current year, but negatively correlated with the precipitation in September and the mean monthly temperature in June of the current year. There were some differences in the responses of the three coniferous to climate change. P. massoniana had a significant negative correlation with the mean temperature in March, and a significant positive correlation with the precipitation in March, while P. armandii and P. massoniana were affected negatively by the maximum temperature in August. Results of the moving correlation analysis showed that the three coniferous species had some similar sensitivity to climate change. Their positive responses to precipitation in previous December consistently increased, as well as the negative correlation with precipitation in current September. As to P. masso-niana , they had a relatively stronger climatic sensitivity and higher stability than the other two species. It would be more suitable for P. massoniana trees on the southern slope of the Funiu Mountains under global warming.

Objective: The aim of this study was to clarify the relationships among large for gestational age (LGA) and cardiometabolic risk factors., Methods: PubMed, Web of Science, and the Cochrane Library databases were searched to identify studies on LGA and outcomes of interest, including BMI, blood pressure, glucose metabolism, and lipid profiles. Data were independently extracted by two reviewers. A meta-analysis was performed using a random-effects model. The Newcastle-Ottawa Scale and funnel graph were used to assess the quality and publication bias, respectively., Results: Overall, 42 studies involving 841,325 individuals were included. Compared with individuals born appropriate for gestational age, individuals born LGA had higher odds of overweight and obesity (odds ratios [OR] = 1.44, 95% CI: 1.31-1.59), type 1 diabetes (OR = 1.28, 95% CI: 1.15-1.43), hypertension (OR = 1.23, 95% CI: 1.01-1.51), and metabolic syndrome (OR = 1.43, 95%; CI: 1.05-1.96). No significant difference was found in hypertriglyceridemia and hypercholesterolemia. Stratified analyses showed that, compared with individuals born appropriate for gestational age, individuals born LGA had higher odds for overweight and obesity from toddler age to puberty age (toddler age: OR = 2.12, 95% CI: 1.22-3.70; preschool: OR = 1.81, 95% CI: 1.55-2.12; school age: OR = 1.53, 95% CI: 1.09-2.14; puberty: OR = 1.40, 95% CI: 1.11-1.77)., Conclusions: LGA is associated with increased odds of obesity and metabolic syndrome later in life. Future studies should focus on elucidating the potential mechanisms and identifying risk factors., (© 2023 The Obesity Society.)

Objectives: Both cachexia and sarcopenia have been considered adverse predictors for prognosis in patients with pancreatic cancer; although sarcopenia and cachexia share some similarities, they are still defined as distinct nutritional conditions. We aimed to explore the differential impacts of sarcopenia and cachexia on prognosis for pancreatic ductal adenocarcinoma (PDAC) patients following radical excision., Methods: From January 2015 to May 2022, 614 patients undergoing surgery for PDAC were retrospectively included. Sarcopenia was defined as the L3 total skeletal muscle index below 52.4 cm 2 /m 2 (men) and 38.5 cm 2 /m 2 (women). Cachexia was classified according to the following criteria: involuntary weight loss >5% over the past 6 months, or weight loss >2% and BMI <20 kg/m 2 , or weight loss >2% and sarcopenia., Results: Of the 614 patients included in the analysis, 62% and 48% were diagnosed with sarcopenia and cachexia, respectively. Kaplan-Meier analysis showed that sarcopenia and/or cachexia were significantly associated with worse overall survival (OS) rather than worse recurrence-free survival (RFS). Moreover, Cox regression analysis revealed that cachexia rather than sarcopenia was an adverse factor for OS in all PDAC patients. For poorly differentiated PDAC, both cachexia and sarcopenia were significantly associated with shorter OS. However, for moderately/well-differentiated PADC, cachexia was an independent factor for adverse OS, but not sarcopenia., Conclusions: Sarcopenia and cachexia have different effects on OS for PDAC patients undergoing radical excision. This difference may provide some important information for preoperative management., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To explore whether the risks of early- or late-onset preeclampsia vary among frozen embryo transfer (FET) with different regimens for endometrial preparation and fresh embryo transfer (FreET)., Methods: We retrospectively included a total of 24129 women who achieved singleton delivery during their first cycles of in vitro fertilization (IVF) between January 2012 and March 2020. The risks of early- and late-onset preeclampsia after FET with endometrial preparation by natural ovulation cycles (FET-NC) or by artificial cycles (FET-AC) were compared to that after FreET., Results: After adjustment via multivariable logistic regression, the total risk of preeclampsia was higher in the FET-AC group compared to the FreET group [2.2% vs. 0.9%; adjusted odds ratio (aOR): 2.00; 95% confidence interval (CI): 1.45-2.76] and FET-NC group (2.2% vs. 0.9%; aOR: 2.17; 95% CI: 1.59-2.96).When stratified by the gestational age at delivery based on < 34 weeks or ≥ 34 weeks, the risk of late-onset preeclampsia remained higher in the FET-AC group than that in the and FreET group (1.8% vs. 0.6%; aOR: 2.56; 95% CI: 1.83-3.58) and the FET-NC group (1.8% vs. 0.6%; aOR: 2.63; 95% CI: 1.86-3.73). We did not find a statistically significant difference in the risk of early-onset preeclampsia among the three groups., Conclusions: An artificial regimen for endometrial preparation was more associated with an increased risk of late-onset preeclampsia after FET. Given that FET-AC is widely used in clinical practice, the potential maternal risk factors for late-onset preeclampsia when using the FET-AC regimen should be further explored, considering the maternal origin of late-onset preeclampsia., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A two-dimensional phononic crystal sensor model with high-quality factor and excellent sensitivity for sensing acetone solutions and operating at 25-45 kHz is proposed. The model for filling solution cavities is based on reference designs of quasi-crystal and gradient cavity structures. The transmission spectrum of sensor is simulated by the finite element method. High-quality factor of 45,793.06 and sensitivity of 80,166.67 Hz are obtained for the acetone concentration with 1-9.1%, and quality factor of 61,438.09 and sensitivity of 24,400.00 Hz are obtained for the acetone concentration range of 10-100%, which indicated the sensor could still achieve high sensitivity and quality factor at operating frequencies from 25 to 45 kHz. To verify the application of the sensor to sensing other solutions, the sensitivity for sound velocity and density is calculated as 24.61 m -1 and 0.7764 m 3 /(kg × s), respectively. It indicates the sensor is sensitive to acoustic impedance changes of the solution and equally suitable for sensing other solutions. The simulation results reveal the phononic crystal sensor possessed high-performance in composition capture in pharmaceutical production and petrochemical industry, which can provide theoretical reference for the design of new biochemical sensors for reliable detection of solution concentration., (© 2023. The Author(s).)

Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics provides comprehensive and quantitative profiling of metabolites in clinical investigations. The use of whole metabolome profiles is a promising strategy for disease diagnosis but technically challenging. Here, we developed an approach, namely MetImage, to encode LC-MS-based untargeted metabolomics data into multi-channel digital images. Then, the images that represent the comprehensive metabolome profiles can be employed for developing deep learning-based AI models toward clinical diagnosis. In this work, we demonstrated the application of MetImage for clinical screening of esophageal squamous cell carcinoma (ESCC) in a clinical cohort with 1104 participants. A convolutional neuronal network-based AI model was trained to distinguish ESCC screening positive and negative subjects using their serum metabolomics data. Superior performances such as sensitivity (85%), specificity (92%), and area under curve (0.95) were validated in an independent testing cohort ( N = 442). Importantly, we demonstrated that our AI-based ESCC screening model is not a "black box". The encoded images reserved the characteristics of mass spectra from the raw LC-MS data; therefore, metabolite identifications in key image features were readily achieved. Altogether, MetImage is a unique approach that encodes raw LC-MS-based untargeted metabolomics data into images and facilitates the utilization of whole metabolome profiles for AI-based clinical applications with improved interpretability.

Background: Skin regeneration is a challenging issue worldwide. Increasing research has highlighted the role of immune cells in healing and the underlying regulatory mechanism. The purpose of this study was to identify the hotspots and trends in skin regeneration and inflammation research through bibliometrics and to provide insights into the future development of fundamental research and disease treatment., Methods: Publications were collected from the Web of Science Core Collection on March 1, 2022. Articles and reviews published in English from January 1, 1999, to December 31, 2022, were selected, and statistical analyses of countries, institutions, authors, references, and keywords were performed using VOSviewer 1.6.18 and CiteSpace 5.8., Results: A total of 3,894 articles and reviews were selected. The number of publications on skin inflammation and regeneration showed an increasing trend over time. Additionally, authors and institutions in the United States, United Kingdom, Canada, and China appeared to be at the forefront of research in the field of skin inflammation and regeneration. Werner Sabine published some of the most cited papers. Wound Repair and Regeneration was the most productive journal, while Journal of Investigative Dermatology was the most cited journal. Angiogenesis, diamonds, collagen, cytokine, and keratinocytes were the five most commonly used keywords., Conclusion: The number of publications on skin inflammation and regeneration show an increasing trend. Moreover, a series of advanced technologies and treatments for skin regeneration, such as exosomes, hydrogels, and wound dressings, are emerging, which will provide precise information for the treatment of skin wounds. This study can enhance our understanding of current hotspots and future trends in skin inflammation and regeneration research, as well as provide guidelines for fundamental research and clinical treatment., 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., (© 2023 Liu, Wang, Luo, Tan, Hou and Wang.)

The role of the epigenome in phenotypic plasticity is unclear presently. Here we used a multiomics approach to explore the nature of the epigenome in developing honey bee (Apis mellifera) workers and queens. Our data clearly showed distinct queen and worker epigenomic landscapes during the developmental process. Differences in gene expression between workers and queens become more extensive and more layered during the process of development. Genes known to be important for caste differentiation were more likely to be regulated by multiple epigenomic systems than other differentially expressed genes. We confirmed the importance of two candidate genes for caste differentiation by using RNAi to manipulate the expression of two genes that differed in expression between workers and queens were regulated by multiple epigenomic systems. For both genes the RNAi manipulation resulted in a decrease in weight and fewer ovarioles of newly emerged queens compared to controls. Our data show that the distinct epigenomic landscapes of worker and queen bees differentiate during the course of larval development., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC 50  = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 μM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC 50  = 253 nM) and MV4-11 (IC 50  = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML., (© 2023 Wiley Periodicals LLC.)

Immune dysregulation has long been proposed to be associated with adenomyosis, but the underlying mediators and mechanisms remain largely unexplored. Here, we used flow cytometry to investigate the alterations in immune cell subsets in adenomyotic uteri and analyze the phenotype and function of abnormal immune cells. We found that an increase in cluster of differentiation (CD)8 + T-cell number was the predominant alteration in ectopic lesions in patients with adenomyosis and was significantly associated with the severity of adenomyosis. Importantly, we identified an exhausted natural killer group protein 2A (NKG2A) + CD8 + T-cell subset that was associated with the severity of adenomyosis and found that the number of these cells was significantly increased in the eutopic endometrium and ectopic lesions. In addition, the increases in the expression of NKG2A ligand histocompatibility leucocyte antigen E and interleukin-15 in glandular epithelial cells in the adenomyotic microenvironment might contribute to CD8 + T-cell exhaustion by promoting NKG2A expression on CD8 + T cells or inhibiting the effector function of these cells. In conclusion, our data revealed a previously unrecognized role for NKG2A + CD8 + T-cell exhaustion in the pathogenesis of adenomyosis, indicating that therapeutic interventions designed to target and reinvigorate exhausted CD8 + T cells may be beneficial for patients with adenomyosis., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ion mobility (IM) adds a new dimension to liquid chromatography-mass spectrometry-based untargeted metabolomics which significantly enhances coverage, sensitivity, and resolving power for analyzing the metabolome, particularly metabolite isomers. However, the high dimensionality of IM-resolved metabolomics data presents a great challenge to data processing, restricting its widespread applications. Here, we develop a mass spectrum-oriented bottom-up assembly algorithm for IM-resolved metabolomics that utilizes mass spectra to assemble four-dimensional peaks in a reverse order of multidimensional separation. We further develop the end-to-end computational framework Met4DX for peak detection, quantification and identification of metabolites in IM-resolved metabolomics. Benchmarking and validation of Met4DX demonstrates superior performance compared to existing tools with regard to coverage, sensitivity, peak fidelity and quantification precision. Importantly, Met4DX successfully detects and differentiates co-eluted metabolite isomers with small differences in the chromatographic and IM dimensions. Together, Met4DX advances metabolite discovery in biological organisms by deciphering the complex 4D metabolomics data., (© 2023. The Author(s).)

Seven undescribed guaiane-type sesquiterpenoids named biscogniauxiaols A-G ( 1 - 7 ) were isolated from the endophytic fungus Biscogniauxia petrensis on Dendrobium orchids. Their structures were determined by extensive spectroscopic analyses, electronic circular dichroism (EC) and specific rotation (SR) calculations. Compound 1 represented a new family of guaiane-type sesquiterpenoids featuring an unprecedented [5/6/6/7] tetracyclic system. A plausible biosynthetic pathway for compounds 1 - 7 was proposed. The anti-fungal, anti-inflammatory and multidrug resistance reversal activities of the isolates were evaluated. Compounds 1 , 2 and 7 exhibited potent inhibitory activities against Candida albicans with MIC values ranging from 1.60 to 6.30 μM, and suppressed nitric oxide (NO) production with IC 50 ranging from 4.60 to 20.00 μM. Additionally, all compounds (100 μg/mL) enhanced the cytotoxicity of cisplatin in cisplatin-resistant non-small cell lung cancer cells (A549/DDP). This study opened up a new source for obtaining bioactive guaiane-type sesquiterpenoids and compounds 1 , 2 , and 7 were promising for further optimization as multifunctional inhibitors for anti-fungal ( C . albicans ) and anti-inflammatory purposes.

Increasing evidence has manifested that circular RNAs (circRNAs) exhibited critical function in regulating various signaling pathways related to hepatocellular carcinoma (HCC) recurrence. However, the role and mechanism of the circRNAs in the HCC early recurrence remain elusive. In this study, high-throughput RNA-sequencing (RNA-seq) analysis was conducted to identify the expression profile of circRNAs in HCC tissues and circ&#95;0005218 was identified as one circRNA that significantly up-regulated in early recurrent HCC tissues. And patients with high expression of circ&#95;0005218 showed worsen overall survival (OS) and disease-free survival (DFS). Moreover, the promotion effects of circ&#95;0005218 on HCC cells in term of proliferation, invasion and metastasis were confirmed both in vitro and vivo by gain- and loss-of function assays. In addition, dual-luciferase reporter assays showed that circ&#95;0005218 could competitively bind to micro-RNA (miR)-31-5p. Furthermore, we showed that suppression of CDK1 by miR-31-5p could be partially rescued by up-regulating circ&#95;0005218. Taken together, the present study indicates that circ&#95;0005218 absorbed miR-31-5p as a sponge to weaken its suppression on CDK1 expression, and thus boost HCC cell invasion and migration, which would act as a potential biomarker to predict the HCC early recurrence and as a new therapeutic target for treatment of HCC., (© 2023 The Authors.)

Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging bunyavirus, causes severe fever with thrombocytopenia syndrome (SFTS), with a high fatality rate of 20%-30%. At present, however, the pathogenesis of SFTSV remains largely unclear and no specific therapeutics or vaccines against its infection are currently available. Therefore, animal models that can faithfully recapitulate human disease are important to help understand and treat SFTSV infection. Here, we infected seven Chinese rhesus macaques ( Macaca mulatta ) with SFTSV. Virological and immunological changes were monitored over 28 days post-infection. Results showed that mild symptoms appeared in the macaques, including slight fever, thrombocytopenia, leukocytopenia, increased aspartate aminotransferase (AST) and creatine kinase (CK) in the blood. Viral replication was persistently detectable in lymphoid tissues and bone marrow even after viremia disappeared. Immunocyte detection showed that the number of T cells (mainly CD8 + T cells), B cells, natural killer (NK) cells, and monocytes decreased during infection. In detail, effector memory CD8 + T cells declined but showed increased activation, while both the number and activation of effector memory CD4 + T cells increased significantly. Furthermore, activated memory B cells decreased, while CD80 + /CD86 + B cells and resting memory B cells (CD27 + CD21 + ) increased significantly. Intermediate monocytes (CD14 + CD16 + ) increased, while myeloid dendritic cells (mDCs) rather than plasmacytoid dendritic cells (pDCs) markedly declined during early infection. Cytokines, including interleukin-6 (IL-6), interferon-inducible protein-10 (IP-10), and macrophage inflammatory protein 1 (MCP-1), were substantially elevated in blood and were correlated with activated CD4 + T cells, B cells, CD16 + CD56 + NK cells, CD14 + CD16 + monocytes during infection. Thus, this study demonstrates that Chinese rhesus macaques infected with SFTSV resemble mild clinical symptoms of human SFTS and provides detailed virological and immunological parameters in macaques for understanding the pathogenesis of SFTSV infection., 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 Li, Huang, He, He, Wang, Lin, Zhao, Zheng and Pang.)

The acrosome is a membranous organelle positioned in the anterior portion of the sperm head and is essential for male fertility. Acrosome biogenesis requires the dynamic cytoskeletal shuttling of vesicles toward nascent acrosome which is regulated by a series of accessory proteins. However, much remains unknown about the molecular basis underlying this process. Here, we generated Ssh2 knockout (KO) mice and HA-tagged Ssh2 knock-in (KI) mice to define the functions of Slingshot phosphatase 2 (SSH2) in spermatogenesis and demonstrated that as a regulator of actin remodeling, SSH2 is essential for acrosome biogenesis and male fertility. In Ssh2 KO males, spermatogenesis was arrested at the early spermatid stage with increased apoptotic index and the impaired acrosome biogenesis was characterized by defective transport/fusion of proacrosomal vesicles. Moreover, disorganized F-actin structures accompanied by excessive phosphorylation of COFILIN were observed in the testes of Ssh2 KO mice. Collectively, our data reveal a modulatory role for SSH2 in acrosome biogenesis through COFILIN-mediated actin remodeling and the indispensability of this phosphatase in male fertility in mice., Competing Interests: KX, XS, KF, YL, TH, ML, ZW, YY, TM, SL, XC, JJ, JL, WC, JM, GL, ZC, HL No competing interests declared, (© 2023, Xu, Su, Fang et al.)

The proper development of primordial germ cells (PGCs) is an essential prerequisite for gametogenesis and mammalian fertility. The Fanconi anemia (FA) pathway functions in maintaining the development of PGCs. FANCT/UBE2T serves as an E2 ubiquitin-conjugating enzyme that ubiquitylates the FANCD2-FANCI complex to activate the FA pathway, but its role in the development of PGCs is not clear. In this study, we found that Ube2t knockout mice showed defects in PGC proliferation, leading to severe loss of germ cells after birth. Deletion of UBE2T exacerbated DNA damage and triggered the activation of the p53 pathway. We further demonstrated that UBE2T counteracted transcription-replication conflicts by resolving R-loops and stabilizing replication forks, and also protected common fragile sites by resolving R-loops in large genes and promoting mitotic DNA synthesis to maintain the genome stability of PGCs. Overall, these results provide new insights into the function and regulatory mechanisms of the FA pathway ensuring normal development of PGCs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

It remains poorly understood about the regulation of gene and transposon transcription during human early embryogenesis. Here, we report that broad H3K27ac domains are genome-widely distributed in human 2-cell and 4-cell embryos and transit into typical peaks in the 8-cell embryos. The broad H3K27ac domains in early embryos before zygotic genome activation (ZGA) are also observed in mouse. It suggests that broad H3K27ac domains play conserved functions before ZGA in mammals. Intriguingly, a large portion of broad H3K27ac domains overlap with broad H3K4me3 domains. Further investigation reveals that histone deacetylases are required for the removal or transition of broad H3K27ac domains and ZGA. After ZGA, the number of typical H3K27ac peaks is dynamic, which is associated with the stage-specific gene expression. Furthermore, P300 is important for the establishment of H3K27ac peaks and the expression of associated genes in early embryos after ZGA. Our data also indicate that H3K27ac marks active transposons in early embryos. Interestingly, H3K27ac and H3K18ac signals rather than H3K9ac signals are enriched at ERVK elements in mouse embryos after ZGA. It suggests that different types of histone acetylations exert distinct roles in the activation of transposons. In summary, H3K27ac modification undergoes extensive reprogramming during early embryo development in mammals, which is associated with the expression of genes and transposons., (© 2023. The Author(s).)

Range of DNA repair in response to double-strand breaks induced in human preimplantation embryos remains uncertain due to the complexity of analyzing single- or few-cell samples. Sequencing of such minute DNA input requires a whole genome amplification that can introduce artifacts, including coverage nonuniformity, amplification biases, and allelic dropouts at the target site. We show here that, on average, 26.6% of preexisting heterozygous loci in control single blastomere samples appear as homozygous after whole genome amplification indicative of allelic dropouts. To overcome these limitations, we validate on-target modifications seen in gene edited human embryos in embryonic stem cells. We show that, in addition to frequent indel mutations, biallelic double-strand breaks can also produce large deletions at the target site. Moreover, some embryonic stem cells show copy-neutral loss of heterozygosity at the cleavage site which is likely caused by interallelic gene conversion. However, the frequency of loss of heterozygosity in embryonic stem cells is lower than in blastomeres, suggesting that allelic dropouts is a common whole genome amplification outcome limiting genotyping accuracy in human preimplantation embryos., (© 2023. The Author(s).)

Background: Growth hormone (GH) supplementation has been shown to improve oocyte quality and live birth, but few studies have examined whether GH can reduce embryonic aneuploidy. Chromosomal abnormalities in preimplantation embryos have been regarded as the principal cause of implantation failure and miscarriage, and an increased percentage of aneuploid embryos has been observed in patient cohorts with unexplained recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and advanced maternal age., Methods: This prospective cohort study was conducted on women whose previous PGT-A cycle ended up with no transferrable blastocysts, or the aneuploidy rate was above 50% and no live birth was acquired. The participants were divided into GH co-treatment and comparison groups according to whether GH was administered in the subsequent PGT-A cycle. In addition, within the GH co-treatment group, the previous failed cycle constituted the self-control group., Results: 208 women were recruited in the study (GH co-treatment group: 96 women, comparison group: 112 women). Compared to the self-control and comparison groups, the rate of euploid blastocysts was significantly higher in the GH co-treatment group (GH vs self-control: 32.00% vs 9.14%, odds ratio [OR]: 4.765, 95% confidence interval [CI]: 2.420-9.385, P < 0.01; GH vs comparison: 32.00% vs. 21.05%, OR: 1.930, 95% CI: 1.106-3.366, P = 0.021), and their frozen embryo transfers resulted in more pregnancies and live births. In the subgroup analysis, for the <35 and 35-40 years groups, the euploidy rate in the GH co-treatment group was significantly higher than those in the self-control and comparison groups, but in the >40 years group, there was no difference in euploidy rate., Conclusion: Our study presents preliminary evidence that GH supplementation may ameliorate blastocyst aneuploidy and improve pregnancy outcomes in women who have previously experienced pregnancy failures along with high aneuploidy rates, particularly in those younger than 40 years. Therefore, the use of GH in such women should be considered. However, considering the limited sample size and mixed indications for PGT-A, further scientific research on the underlying mechanism as well as clinical trials with larger sample sizes are needed to confirm the effects and optimal protocols., 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 Guo, Liu, Zhou, Xia, Li, Lu, Ma, Chen and Yan.)

Objective: To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions., Materials and Methods: A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUC 0-t and AUC 0-∞ ) and the maximal plasma concentration (C max ). Safety was assessed mainly from the occurrence of adverse events (AEs)., Results: A single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUC 0-t were 95.4 - 100.9% and 97.8 - 103.8%, and for AUC 0-∞ were 95.3 - 100.6% and 98.3 - 104.3% under fasting (36 subjects) and fed (27 subjects) conditions, respectively. Similarly, the 90% CIs for C max were 94.6 - 103.1% and 88.8 - 102.0% under fasting (36 subjects) and the fed (27 subjects) conditions, respectively. Therefore, the 90% CIs for the T/R AUC and C max ratios were within the standard range for bioequivalence (80.0 - 125.0%). There were no serious adverse events (SAEs)., Conclusion: The test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.

The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63+/ΔTID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63+/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63+/ΔTID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

When DNA interstrand crosslink lesions occur, a core complex of Fanconi anemia proteins promotes the ubiquitination of FANCD2 and FANCI, which recruit downstream factors to repair the lesion. However, FANCD2 maintains genome stability not only through its ubiquitination-dependent but also its ubiquitination-independent functions in various DNA damage response pathways. Increasing evidence suggests that FANCD2 is essential for fertility, but its ubiquitination-dependent and ubiquitination-independent roles during germ cell development are not well characterized. In this study, we analyzed germ cell development in Fancd2 KO and ubiquitination-deficient mutant (Fancd2 K559R/K559R ) mice. We showed that in the embryonic stage, both the ubiquitination-dependent and ubiquitination-independent functions of FANCD2 were required for the expansion of primordial germ cells and establishment of the reproductive reserve by reducing transcription-replication conflicts and thus maintaining genome stability in primordial germ cells. Furthermore, we found that during meiosis in spermatogenesis, FANCD2 promoted chromosome synapsis and regulated crossover formation independently of its ubiquitination, but that both ubiquitinated and nonubiquitinated FANCD2 functioned in programmed double strand break repair. Finally, we revealed that on meiotic XY chromosomes, H3K4me2 accumulation required ubiquitination-independent functionality of FANCD2, while the regulation of H3K9me2 and H3K9me3 depended on FANCD2 ubiquitination. Taken together, our findings suggest that FANCD2 has distinct functions that are both dependent on and independent of its ubiquitination during germ cell development., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Phenotypic dimorphism between queens and workers is an important biological characteristic of honeybees that has been the subject of intensive research. The enormous differences in morphology, lifespan, physiology, and behavior between queens and workers are caused by a complicated set of factors. Epigenetic modifications are considered to play an important role in this process. In this study, we analyzed the differences in chromosome interactions and H3K27ac and H3K4me1 modifications between the queens and workers using high-throughput chromosome conformation capture (Hi-C) and Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) technologies. We found that the queens contain more chromosome interactions and more unique H3K27ac modifications than workers; in contrast, workers have more H3K4me1 modifications than queens. Moreover, we identified Map3k15 as a potential caste gene in queen-worker differentiation. Our results suggest that chromosomal conformation and H3K27ac and H3K4me1 modifications are involved in regulating queen-worker differentiation, which reveals that the queen-worker phenotypic dimorphism is regulated by multiple epigenetic modifications., Competing Interests: The authors declare no competing interest. All authors were involved in the preparation of the final manuscript., (© 2023 The Author(s).)

Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and β-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced β-cell function and decreased β-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca 2+ stores in β-cells by inhibiting Ca 2+ re-uptake via SERCA2 and inducing Ca 2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving β-cell mass. Moreover, treatment with alnustone inhibits THADA's function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies., (© 2023. The Author(s).)

Objective: This study aimed to identify neuroimaging predictors to predict the response of cognitive behavioral therapy (CBT) in patients with obsessive-compulsive disorder (OCD) based on indices of resting-state functional magnetic resonance imaging (rs-fMRI)., Methods: Fifty patients with OCD were enrolled and allocated to either high or low responder groups after CBT using a 50 % response rate as the delineator. The pre-treatment amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC) in each cerebrum region, defined by automated anatomical labeling atlas, were extracted. Least absolute shrinkage and selection operator and logistic regression were used to select features and establish models., Results: The combination of multilevel rs-fMRI indices achieved the best performance, with a cross-validation area under the receiver operating characteristic curve (AUC) of 0.900. In this combined model, an increase of interquartile range (IQR) in fALFF of right inferior orbital frontal gyrus (IOFG), and ReHo of left hippocampus and superior occipital gyrus (SOG) corresponded to a 26.52 %, 38.67 % and 24.38 % increase in the possibility to be high responders of CBT, respectively. ALFF of left thalamus and ReHo of left putamen were negatively associated with the response to CBT, with a 14.30 % and 19.91 % decrease per IQR increase of the index value., Conclusion: The combination of ALFF, fALFF and ReHo achieved a better predictive performance than separate index. Pre-treatment ALFF of the left thalamus, fALFF of the right IOFG, ReHo of the left hippocampus, SOG and putamen can be used as predictors of CBT response., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Silver-catalyzed deuteration of nitroaromatics has been achieved using D 2 O as the deuterium source. Distinct from the well-established directing group-guided hydrogen-isotope exchange, this protocol showed an interesting deuteration pattern, where considerable deuterium accumulation was observed around the aromatic rings. Controlling experiments suggested that the deuteration was initiated by a silver-promoted C-H activation. Therefore, a tentative two-stage deuteration mechanism involving aryl-silver species was proposed to explain the deuteration on meta - and para -positions.

Polycystic ovary syndrome (PCOS) is one of the most common, heterogenous endocrine disorders and is the leading cause of ovulatory obstacle associated with abnormal folliculogenesis. Dysfunction of ovarian granulosa cells (GCs) is recognized as a major factor that underlies abnormal follicle maturation. Angiopoietin-like 4 (ANGPTL4) expression in GCs differs between patients with and without PCOS. However, the role and mechanism of ANGPTL4 in impaired follicular development are still poorly understood. Here, the case-control study was designed to investigate the predictive value of ANGPTL4 in PCOS while cell experiments in vitro were set for mechanism research. Results found that ANGPTL4 levels in serum and in follicular fluid, and its expression in GCs, were upregulated in patients with PCOS. In KGN and SVOG cells, upregulation of ANGPTL4 inhibited the proliferation of GCs by blocking G1/S cell cycle progression, as well as the molecular activation of the EGFR/JAK1/STAT3 cascade. Moreover, the STAT3-dependent CDKN1A(p21) promoter increased CDKN1A transcription, resulting in remarkable suppression effect on GCs. Together, our results demonstrated that overexpression of ANGPTL4 inhibited the proliferation of GCs through EGFR/JAK1/STAT3-mediated induction of p21, thus providing a novel epigenetic mechanism for the pathogenesis of PCOS., (© 2023 Federation of American Societies for Experimental Biology.)

Isolated congenital alar rim defects are extremely rare, and there has been no standard technique for the reconstruction of remarkable aesthetic deformity. Herein, we introduce a trifoliate flap for the correction of isolated congenital alar rim defects in pediatric patients. Fifteen cases undergoing nasal alar sulcus rotation flap surgery were analyzed retrospectively. This rotation flap including 3 triangles was a modified flap based on prior studies. Clinical medical notes and photographs were reviewed. Patients' (or their parents) reported satisfactions with aesthetic outcome were also evaluated during the post-operative follow-up period. In all patients, the isolated congenital alar rim defects were successfully reconstructed. The rotation flap survived and the wound healed primarily. The follow-up period ranged from 6 to 22 months (average 11 months). There were no incidents of flap loss, step-off deformities, nasal obstruction, or alar retraction. At follow-up of post-operative 3 months, pale red scars were observed in the operative area in few patients (2/15). However, these scars gradually became invisible at post-operative 6 months. All patients (or their parents) were satisfied with the aesthetic outcome of this operation. This newly designed trifoliate flap can be an alternative method for the reconstruction of isolated congenital alar rim defects in pediatric patients. The scars of this procedure can be unobvious with fine surgical suture., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

Poly(A)-tail-mediated post-transcriptional regulation of maternal mRNAs is vital in the oocyte-to-embryo transition (OET). Nothing is known about poly(A) tail dynamics during the human OET. Here, we show that poly(A) tail length and internal non-A residues are highly dynamic during the human OET, using poly(A)-inclusive RNA isoform sequencing (PAIso-seq). Unexpectedly, maternal mRNAs undergo global remodeling: after deadenylation or partial degradation into 3'-UTRs, they are re-polyadenylated to produce polyadenylated degradation intermediates, coinciding with massive incorporation of non-A residues, particularly internal long consecutive U residues, into the newly synthesized poly(A) tails. Moreover, TUT4 and TUT7 contribute to the incorporation of these U residues, BTG4-mediated deadenylation produces substrates for maternal mRNA re-polyadenylation, and TENT4A and TENT4B incorporate internal G residues. The maternal mRNA remodeling is further confirmed using PAIso-seq2. Importantly, maternal mRNA remodeling is essential for the first cleavage of human embryos. Together, these findings broaden our understanding of the post-transcriptional regulation of maternal mRNAs during the human OET., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A robust output feedback nonlinear control method is proposed for output tracking of an uncertain three-tank system by using only the level sensor of the target tank. By using a coordinate transformation, we first transform the system model into a canonical form with uncertainties. The canonical system's state variables are estimated by a higher-order sliding mode differentiator based on the measurement of the target tank's liquid level. Then based on the estimated state variables, a continuous full-order sliding mode controller is constructed which can eliminate the effects of both the additive and multiplicative uncertainties. Rigorous analysis is carried out to clarify the control performance. And the effectiveness of the proposed method is verified by experimental studies on the Inteco Multi-tank system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 ISA. Published by Elsevier Ltd. All rights reserved.)

The unscientific application of synthetic pesticides has brought various negative effects on the environment, hindering the sustainable development of agriculture. Nanoparticles can be applied as carriers to improve pesticide delivery, showing great potential in the development of pesticide formulation in recent years. Herein, a star polymer (SPc) was constructed as an efficient pesticide nanocarrier/adjuvant that could spontaneously assemble with thiocyclam or monosultap into a complex, through hydrophobic association and hydrogen bonding, respectively, with the pesticide-loading contents of 42.54% and 19.3%. This complexation reduced the particle sizes of thiocyclam from 543.54 to 52.74 nm for pure thiocyclam, and 3 814.16 to 1 185.89 nm for commercial preparation (cp) of thiocyclam. Interestingly, the introduction of SPc decreased the contact angles of both pure and cp thiocyclam on plant leaves, and increased the plant uptake of cp thiocyclam to 2.4-1.9 times of that without SPc. Meanwhile, the SPc could promote the bioactivity of pure/cp thiocyclam against green peach aphids through leaf dipping method and root application. For leaf dipping method, the 50% lethal concentration decreased from 0.532 to 0.221 g/L after the complexation of pure thiocyclam with SPc, and that decreased from 0.390 to 0.251 g/L for cp thiocyclam. SPc seems a promising adjuvant for nanometerization of both pure and cp insecticides, which is beneficial for improving the delivery efficiency and utilization rate of pesticides., (© 2022 Institute of Zoology, Chinese Academy of Sciences.)

Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Due to the high prevalence of hepatitis B virus (HBV) infection in China, the incidence of HCC in China is high, and liver cirrhosis caused by chronic hepatitis also brings great challenges to treatment. This paper reviewed the latest research progress on minimally invasive treatments for HCC, including percutaneous thermal ablation and new nonthermal ablation techniques, and introduced the principles, advantages, and clinical applications of various therapeutic methods in detail., Data Sources: The data of treatments for HCC were systematically collected from the PubMed, ScienceDirect, American Chemical Society and Web of Science databases published in English, using "minimally invasive" and "hepatocellular carcinoma" or "liver cancer" as the keywords., Results: Percutaneous thermal ablation is still a first-line strategy for the minimally invasive treatment of HCC. The effect of microwave ablation (MWA) on downgrading treatment before liver transplantation is better than that of radiofrequency ablation (RFA), while RFA is more widely used in the clinical practice. High-intensity focused ultrasound (HIFU) is mainly used for the palliative treatment of advanced liver cancer. Electrochemotherapy (ECT) delivers chemotherapeutic drugs to the target cells while reducing the blood supply around HCC. Irreversible electroporation (IRE) uses a microsecond-pulsed electric field that induces apoptosis and necrosis and triggers a systemic immune response. The nanosecond pulsed electric field (nsPEF) has achieved a good response in the ablation of mice with HCC, but it has not been reported in China for the treatment of human HCC., Conclusions: A variety of minimally invasive treatments provide a sufficient survival advantage for HCC patients. Nonthermal ablation will lead to a new wave with its unique advantage of antitumor recurrence and metastasis., (Copyright © 2022 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Lack of evidence exists on whether air pollution exposure may affect ovarian reserve, especially for Chinese women., Objectives: To explore the association between exposure to various air pollutants and anti-Müllerian hormone (AMH), a predictor of ovarian reserve, over different exposure windows in Shandong Province, China., Methods: We enrolled 18,878 women who had AMH measurements in the Center for Reproductive Medicine, Shandong University during 2010-2019. Daily average concentrations of ambient particulate matter with diameters ≤1 μm/2.5 μm/10 μm (PM 1 , PM 2.5 , and PM 10 ), nitrogen dioxide (NO 2 ) and ozone (O 3 ) were developed at a spatial resolution of 0.01° × 0.01°, and assigned to the residential addresses. Three exposure windows were considered, i.e., the process from primary to small antral follicle stage (W1), from primary to secondary follicle stage (W2), and from secondary to small antral follicle stage (W3). The air pollution-AMH association was fitted using the multivariable linear mixed effect model with adjustment for potential confounders. Stratified analyses were performed by age group, overweight status, residential region, and educational level., Results: The level of AMH changed by -8.8% (95% confidence interval (CI): -12.1%, -5.3%), -2.1% (95% CI: -3.5%, -0.6%), -1.9% (95% CI: -3.3%, -0.5%), and -4.5% (95% CI: -7.1%, -1.9%) per 10 μg/m 3 increase in PM 1 , PM 2.5 , PM 10 , and NO 2 , respectively, during W1. The effect estimates were significant during W2 for PM 1 , PM 2.5 and NO 2 while minimal association was observed in W3. Greater vulnerability for certain air pollutants were observed for women who lived in inland areas and were less educated., Conclusions: We found that ovarian reserve was negatively associated with air pollution exposure for women, particularly from the primary to secondary follicle stage. The effect estimate increased by the reduction in the diameter of PMs, which also varied across population sub-groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Premature ovarian insufficiency (POI) is a major cause of female infertility due to early loss of ovarian function. POI is a heterogeneous condition, and its molecular etiology is unclear. To identify genetic variants associated with POI, here we performed whole-exome sequencing in a cohort of 1,030 patients with POI. We detected 195 pathogenic/likely pathogenic variants in 59 known POI-causative genes, accounting for 193 (18.7%) cases. Association analyses comparing the POI cohort with a control cohort of 5,000 individuals without POI identified 20 further POI-associated genes with a significantly higher burden of loss-of-function variants. Functional annotations of these novel 20 genes indicated their involvement in ovarian development and function, including gonadogenesis (LGR4 and PRDM1), meiosis (CPEB1, KASH5, MCMDC2, MEIOSIN, NUP43, RFWD3, SHOC1, SLX4 and STRA8) and folliculogenesis and ovulation (ALOX12, BMP6, H1-8, HMMR, HSD17B1, MST1R, PPM1B, ZAR1 and ZP3). Cumulatively, pathogenic and likely pathogenic variants in known POI-causative and novel POI-associated genes contributed to 242 (23.5%) cases. Further genotype-phenotype correlation analyses indicated that genetic contribution was higher in cases with primary amenorrhea compared to that in cases with secondary amenorrhea. This study expands understanding of the genetic landscape underlying POI and presents insights that have the potential to improve the utility of diagnostic genetic screenings., (© 2023. The Author(s).)

Objective: To discover the relationship between matrix remodeling associated 7 ( MXRA7 ) and acute B lymphoblastic leukemia (B-ALL), and explore the effect of MXRA7 on the biological functions of B-ALL cell line REH., Methods: The expression of MXRA7 in blood diseases was searched and analyzed through BloodSpot database. Real-time qPCR was used to detect the expression level of MXRA7 in B-ALL cell line 697 and REH cells. Lentivirus-mediated shRNA interference technology was utilized to knock down the expression of MXRA7 in REH cells. The effects of MXRA7 on the biological functions of REH cells were studied by in vitro experiments. Cell proliferation was detected by CCK-8 assay, cell cycle was detected by PI staining, cell apoptosis was detected by Annexin V and 7-AAD staining, and the expression of apoptosis pathway related proteins was detected by Western blot., Results: Database analysis showed that MXRA7 was highly expressed in B-ALL patients, and real-time qPCR results showed that MXRA7 was also highly expressed in cell lines 697 and REH cells. Knockdown of MXRA7 in REH cells inhibited the cell proliferation and increased the percentage of G 0 /G 1 phase cells. After treatment with cytarabine, the apoptotic ratio was increased in MXRA7 -impaired REH cells, and the activation of caspase-3 and caspase-9 were also increased., Conclusion: Knockdown of MXRA7 can reduce the malignancy of REH cells by inhibiting the cell proliferation and increasing the sensitivity of REH cells to cytarabine. These results indicate MXRA7 may be as a novel target for the treatment of B-ALL, and the potential usefulness of MXRA7 in B-ALL deserves further investigation.

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)