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Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Glioma is recognized as the most infiltrative and lethal form of central nervous system tumors and is known for its limited response to standard therapeutic interventions, high recurrence rate, and unfavorable prognosis. Recent progress in gene and immunotherapy presents a renewed sense of optimism in the treatment of glioblastoma. However, the barriers to overcome include the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB), as well as the suppressive immune microenvironment. Overcoming these barriers remains a significant challenge. Here, we developed a lipid nanoparticle platform incorporating a dual-functional peptide (cholesterol-DP7-ACP-T7-modified DOTAP or DAT-LNP) capable of targeting glioma across the BBB and BBTB for brain tumor immunotherapy. This system was designed to achieve two key functions. First, the system could effectively penetrate the BBB during accumulation within brain tissue following intravenous administration. Second, this system enhances the maturation of dendritic cells, the polarization of M1 macrophages, and the activation of cytotoxic CD8 + T cells. This multifaceted approach effectively mitigates the immunosuppressive tumor microenvironment of glioma and promotes robust antitumor immune responses. Overall, the intravenous administration of the delivery system designed in this study demonstrates significant therapeutic potential for glioma and holds promising applications in the field of cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no competition of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Primary stage IV breast cancer is associated with a poor prognosis. At present, the value of local surgical treatment for patients with stage IV breast cancer remains uncertain; therefore, treatment principles remain controversial. Because of the high heterogeneity of these patients, it is often difficult to evaluate their prognoses. As a result, this study aimed to establish a prognostic nomogram to evaluate the prognosis of patients with breast cancer experiencing primary bone metastasis., Methods: The clinical characteristics and follow-up data of patients with primary breast cancer and bone metastasis from 2010 to 2018 were collected from the Surveillance, Epidemiology, and End Results database and from 2013 to 2021 at the Peking Union Medical College Hospital. Patients were divided into training and validation groups. Multivariate Cox regression analysis was used to identify the independent prognostic variables for predicting cancer-specific survival (CSS). On the basis of these independent risk factors, a nomogram was developed and used calibration curves to evaluate its accuracy. Patients were divided into three risk groups according to their scores and surgery-related survival curves plotted using the log-rank test., Results: Overall, 6372 patients were included, with 6319 from the Surveillance, Epidemiology, and End Results database and 53 from the Peking Union Medical College Hospital Breast Surgery Department. Multivariate analysis showed that age, race, marital status, grade, tumor stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and burden of other metastatic lesions were all associated with CSS. Based on these results, a nomogram that predicted the 1-, 3-, and 5-year CSS rates in patients with primary breast cancer and bone metastasis (concordance index > 0.69) was developed. After dividing patients into low-risk, high-risk, or super-high-risk groups based on nomogram scoring criteria, survival analysis revealed that patients in the low- and high-risk groups had significant survival benefits from primary focal surgery., Conclusion: Independent risk factors for primary breast cancer in patients with bone metastasis were analyzed and a nomogram established to predict CSS. The prognostic tool derived in this study can assist clinicians in predicting the survival and surgical benefits of these patients through scoring, thereby providing further guidance for treatment strategies., (© 2024 American Cancer Society.)

Peptides with suitable aggregation behavior and electrical properties are potential siRNA delivery vectors. However, identifying suitable peptides with ideal delivery and safety features is difficult owing to the variations in amino acid sequences. Here, a holistic program based on computer modeling and single-cell RNA sequencing (scRNA-seq) is used to identify ideal siRNA delivery peptides. Stage one of this program consists of a sequential screening process for candidates with ideal assembly and delivery ability; stage two is a cell subtype-level analysis program that screens for high in vivo tissue safety. The leading candidate peptide selected from a library containing 12 amino acids showed strong lung-targeted siRNA delivery capacity after hydrophobic modification. Systemic administration of these compounds caused the least damage to liver and lung tissues and has little impact on macrophage and neutrophil numbers. By loading STAT3 siRNA, strong anticancer effects are achieved in multiple models, including patient-derived xenografts (PDX). This screening procedure may facilitate the development of peptide-based RNA interference (RNAi) therapeutics., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.

Cancer metastasis is a complex process influenced by various factors, including epithelial-mesenchymal transition (EMT), tumor cell proliferation, tumor microenvironment, and cellular metabolic status, which remains a significant challenge in clinical oncology, accounting for a majority of cancer-related deaths. TEAD4, a key mediator of the Hippo signaling pathway, has been implicated in regulating these factors that are all critical in the metastatic cascade. TEAD4 drives tumor metastasis and chemoresistance, and its upregulation is associated with poor prognosis in many types of cancers, making it an attractive target for therapeutic intervention. TEAD4 promotes EMT by interacting with coactivators and activating the transcription of genes involved in mesenchymal cell characteristics and extracellular matrix remodeling. Additionally, TEAD4 enhances the stemness of cancer stem cells (CSCs) by regulating the expression of genes associated with CSC maintenance. TEAD4 contributes to metastasis by modulating the secretion of paracrine factors and promoting heterotypic cellular communication. In this paper, we highlight the central role of TEAD4 in cancer metastasis and chemoresistance and its impact on various aspects of tumor biology. Understanding the mechanistic basis of TEAD4-mediated processes can facilitate the development of targeted therapies and combination approaches to combat cancer metastasis and improve treatment outcomes., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: To investigate the application effect of periareolar incision breast-conserving surgery in patients with early breast cancer., Methods: From January 2017 to November 2021, a clinician in our research center performed a total of 533 breast-conserving surgery. After screening, we collected the information of 209 patients through telephone, online questionnaires, and outpatient follow-up. One hundred seventeen patients with early breast cancer underwent breast-conserving surgery under the periareolar incision, while 92 patients underwent surgery through the tumor surface incision. We compared the differences between the 2 groups in the length of stay, postoperative complications, adjuvant therapy, and other clinical indicators, as well as the subjective and objective evaluation of the long-term postoperative breast aesthetic outcome, local recurrence, distant metastasis, and survival., Results: With a mean follow-up of 3.9 years, patients in the periareolar incision group (PAIG) and tumor surface incision group (TSIG) had no significant differences in clinical indicators, local recurrence, distant metastasis, and survival. However, PAIG patients had better subjective satisfaction with postoperative breast appearance. In the evaluation of objective aesthetic outcomes, PAIG was significantly better than TSIG in texture and elasticity, symmetry, sunken degree of the operative side, skin color, surgical scar, and breast compliance difference., Conclusion: By observing and comparing the clinical indicators, postoperative recurrence, and metastasis of the enrolled patients, this study found that periareolar incision surgery could achieve radical therapeutic effects similar to those achieved through tumor surface incision, and had advantages in improving postoperative aesthetic outcomes, which could provide certain references for clinical practice., Competing Interests: Disclosure The authors declare that they have no competing interests. We confirm that this work is original and has not been presented or published elsewhere, nor is it currently under consideration for publication elsewhere., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Oocyte maturation arrest, fertilization failure, and early embryonic arrest are important causes of female infertility, whereas the genetic events that contribute to these processes are largely unknown. Loss-of-function of PABPC1L in mice has been suggested to cause female infertility involved in the absence of mature oocytes or embryos in vivo or in vitro. However, the role of PABPC1L in human female reproduction remains largely elusive. In this study, we identified a homozygous missense mutation (c.536G>A, p.R179Q) and a compound heterozygous mutation (c.793C>T, p.R265W; c.1201C>T, p.Q401*) in PABPC1L in two unrelated infertile females characterized by recurrent oocyte maturation abnormalities and early embryonic arrest. These variants resulted in nonfunctional PABPC1L protein and were associated with impaired chromatin configuration and transcriptional silencing in GV oocytes. Moreover, the binding capacity of mutant PABPC1L to mRNAs related to oocyte maturation and early embryonic development was decreased significantly. Our findings revealed novel PABPC1L mutations causing oocyte maturation abnormalities and early embryonic arrest, confirming the essential role of PABPC1L in human female fertility., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite the remarkable success of immune checkpoint inhibitors (ICIs), primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment (TME). Oncolytic viruses (OVs) can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts. Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy. According to the diverse immune cell landscapes among different types of tumors, we rationally and precisely generated three recombinant oncolytic adenoviruses (OAds): OAd-SIRPα-Fc, OAd-Siglec10-Fc and OAd-TIGIT-Fc. These viruses were designed to locally deliver SIRPα-Fc, Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47, CD24 or CD155, respectively, in the TME to achieve enhanced antitumor effects. Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors, while OAd-TIGIT-Fc showed the best antitumor immunity in CD8 + T-cell-dominated tumors. Importantly, the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory. In addition, the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME. In summary, rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer., (© 2023. The Author(s).)

Soil organic carbon (SOC) sequestration is a key grassland ecosystem function, and the magnitude of SOC reservoirs depends on microbial involvement, especially that of fungi. Mycelia developed by macrofungi potentially influence carbon (C) fixation and decomposition; however, the mechanisms underlying their effects on SOC storage in grassland ecosystems remain poorly understood. The fairy rings formed by macrofungi in grasslands are natural platform for exploring macrofungal effects on SOC. In this study, we collected topsoil (0-10 cm) from four different fairy ring zones in a temperate steppe to reveal the macrofungal effects on SOC fractions, including particulate organic carbon (POC) and mineral-associated organic carbon (MAOC), and the SOC storage microbial mechanism using metagenomic sequencing technology. Both POC and MAOC decreased after macrofungal passage, resulting in a 7.37 % reduction in SOC. Macrofungal presence reduced microbial biomass carbon (MBC), but significantly enhanced the β-1,4-glucosidase (BG) activity, which increased dissolved organic carbon (DOC). In addition, the abundance of copiotrophs (Proteobacteria and Bacteroidetes) with lower C metabolic rates increased, and that of oligotrophs (Actinobacteria, Acidobacteria, Chloroflexi, and Verrucomicrobia) with higher substrate utilization efficiency decreased in the presence of macrofungi. This may further promote SOC decomposition. Correspondingly, there was a lower abundance of C-fixation genes but more C-degradation genes (especially hemicellulosic degradation genes) during macrofungal passage. Our results indicate that the presence of macrofungi can modulate the soil microbial community and functional genes to reduce SOC storage by inhibiting microbial C sequestration while promoting C decomposition in grassland ecosystems. These findings refine our mechanistic understanding of SOC persistence through the interactions between macrofungi and other microbes., 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 © 2023 Elsevier B.V. All rights reserved.)

In situ vaccination is a desirable strategy for cancer immunotherapy due to its convenience and capacity to target tumor antigens. Here, an in situ nanovaccine based on a cationic peptide with cholesterol-modified, DP7-C, for cancer immunotherapy is rationally designed, and developed a cancer nanovaccine that is easy to preparate. The nanovaccine includes cocktail small interfering RNAs (siRNAs) and immunologic adjuvant CpG ODNs, has synergistic effect in the cancer treatment. This nanovaccine can induce tumor cell death, promote antigen presentation and relieve immune suppression in the tumor microenvironment (TME). Moreover, this nanovaccine is administered to CT26 (hot) and B16F10 (cold) tumor model mice, in which it targeted the primary tumors and induced systemic antitumor immunity to inhibit metastasis. It is validated that the nanovaccine can convert cold tumors into hot tumors. Furthermore, the nanovaccine increased the immune response to anti-PD-1 therapy by modulating the TME in both CT26- and B16F10-tumor-bearing mice. The siRNA cocktail/CpG ODN/self-assembling peptide nanovaccine is a simple and universal tool that can effectively generate specific tumor cell antigens and can be combined with immuno-oncology agents to enhance antitumor immune activity. The versatile methodology provides an alternative approach for developing cancer nanovaccines., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Livestock grazing has a significant impact on the biodiversity of nature grassland ecosystems, which is mainly regulated by climate factors. Soil microbes are essential components of biogeochemical cycles. However, the coupling effects of grazing with MAT (mean annual temperature) and MAP (mean annual precipitation) on soil microbial communities remain inconsistent. Our study considered the various climates in four grasslands as natural temperature and precipitation gradients combined with grazing intensity (GI). We collected and analyzed vegetation and soil physiochemical properties from four grasslands. Our results showed that climate factors (CF) changed β diversity of soil bacteria and fungi while grazing intensity and their interaction merely affected fungi β diversity. Furthermore, climate factors and grazing intensity impacted changes in vegetation and soil physiochemical properties, with their interaction leading to changes in EC and MBC. Our analysis revealed that climate factors contributed 13.1% to bacteria community variation while grazing intensity contributed 3.01% to fungi community variation. Piecewise SEM analysis demonstrated that MAT and MAP were essential predictors of bacteria β diversity, which was significantly affected by vegetation and soil carbon and nitrogen. At the same time, MAP was an essential factor of fungi β diversity and was mainly affected by soil nitrogen. Our study indicated that bacteria and fungi β diversity was affected by different environmental processes and can adapt to specific grazing intensities over time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 Qiqige, Wei, Wei, Liu, Bi, Xu, Liu, Yang and Zhang.)

Chimeric antigen receptor (CAR)-T cell therapy is a promising form of immunotherapy that has seen significant advancements in the past few decades. It involves genetically modifying T cells to target cancer cells expressing specific antigens, providing a novel approach to treating various types of cancer. However, the initial success of first-generation CAR-T cells was limited due to inadequate proliferation and undesirable outcomes. Nonetheless, significant progress has been made in CAR-T cell engineering, leading to the development of the latest fifth-generation CAR-T cells that can target multiple antigens and overcome individual limitations. Despite these advancements, some shortcomings prevent the widespread use of CAR-T therapy, including life-threatening toxicities, T-cell exhaustion, and inadequate infiltration for solid tumors. Researchers have made considerable efforts to address these issues by developing new strategies for improving CAR-T cell function and reducing toxicities. This review provides an overview of the path of CAR-T cell development and highlights some of the prominent advances in its structure and manufacturing process, which include the strategies to improve antigen recognition, enhance T-cell activation and persistence, and overcome immune escape. Finally, the review briefly covers other immune cells for cancer therapy and ends with the discussion on the broad prospects of CAR-T in the treatment of various diseases, not just hematological tumors, and the challenges that need to be addressed for the widespread clinical application of CAR-T cell therapies., Competing Interests: The authors declare no competing financial interest.

Introduction: A previous study suggested that loss of CFAP47 function is involved in multiple morphological abnormalities of the sperm flagella (MMAF) in humans and mice. However, the comprehensive role of CFAP47 in spermatogenesis is largely unknown., Methods: Whole-exome sequencing (WES) was conducted to identify pathogenic variant in two patients with MMAF. The functional effect of the identified mutations was investigated by immunofluorescence staining and western blotting. Intracytoplasmic sperm injection (ICSI) was used to assist fertilization for the patient with MMAF., Results: In this study, we identified a novel missense mutation (c.1414G>A; p.V472M) in CFAP4 7 in two unrelated patients with oligoasthenoteratozoospermia. Intriguingly, in addition to the MMAF phenotype very analogous to the previous report, the two patients notably presented abnormal morphology of sperm heads, the sperm mitochondrial sheath was obviously disorganized, and the sperm annulus were almost defective. Further functional experiments confirmed that the expression of CFAP47 was markedly reduced in the spermatozoa of the patients. Mechanism analysis suggested that CFAP47 might regulate the expression of CFAP65, CFAP69 and SEPTIN4 through their physical interactions and thus modulating sperm morphogenesis., Conclusion: we revealed a novel mutation in CFAP47 and further expanded the phenotype and mutation spectrum of CFAP47 , as well as the potential mechanism of CFAP47 manipulating spermatogenesis, finally providing important guidance for genetic counseling and targeted treatment for CFAP47 mutation-related male infertility., 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 Liu, Dai, Zhang, Yang, Shen, Liu, Yang, Jiang and Tian.)

Purpose: Immuno-combination therapy is emerging as an effective treatment for advanced non-small cell lung carcinoma (NSCLC). However, compared to monotherapy, such as monoclonal antibodies or kinase inhibitors, whether combination therapy can enhance antitumor efficacy or alleviate side effects remains unclear., Methods: A systematic literature search was undertaken using the PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases to identify eligible studies concentrating on treatment with erlotinib or erlotinib plus monoclonal antibodies in NSCLC patients published between January 2017 and June 2022. The primary outcomes included progression-free survival (PFS), overall survival (OS), response rate (RR) and treatment-related adverse events (AEs)., Results: Seven independent randomized, controlled clinical trials including 1513 patients were obtained for the final analysis. Erlotinib plus monoclonal antibodies was significantly associated with the improvement of PFS (hazards ratio [HR], 0.60; 95% CI 0.53-0.69; z = 7.59, P < 0.01) and with moderate performance regarding OS (HR, 0.81; 95% CI 0.58-1.13; z = 1.23, P = 0.22) and RR (odds ratio [OR], 1.25; 95% CI 0.98-1.59; z = 1.80, P = 0.07), irrespective of EGFR mutation status. In the safety evaluation, erlotinib plus monoclonal antibodies had a markedly higher occurrence of adverse events (AEs) of Clavien grade 3 or higher (OR, 3.32; 95% CI 2.66-4.15; z = 10.64, P < 0.01)., Conclusion: Compared with erlotinib alone, combination therapy (erlotinib plus monoclonal antibodies) was associated with significantly improved PFS in NSCLC therapy, accompanied by increased treatment-related AEs., Registration: Our systematic review protocol was registered in the PROSPERO international register of systematic reviews (CRD42022347667)., 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 © 2023 Elsevier B.V. All rights reserved.)

The testis-specific adenosine deaminase domain-containing (ADAD) protein family, including ADAD1 and ADAD2, has been confirmed to be essential in mouse male fertility. However, the roles of ADAD1 and ADAD2 in human reproductive biology are unclear. Herein, whole-exome sequencing was conducted for 337 infertile patients to detect pathogenic variants in ADAD1 and ADAD2. Importantly, a novel deleterious biallelic variant of NM&#95;001159285.2:c.1408G > T (p.V470F) and NM&#95;001159285.2:c.1418A > G (p.E473G) in ADAD1 and a pathogenic homozygous missense variant of NM&#95;001145400.2:c.1381C > T (p.R461W) in ADAD2 were identified in this infertile cohort with frequencies of 0.29 (1/337) and 0.59% (2/337), respectively. Electron microscopy revealed an abnormal morphology and severely disorganized ultrastructure of sperm from the patients. Immunofluorescence and western blotting showed a sharp decrease in ADAD1 and ADAD2 expression in sperm from the patients. Mechanistically, bioinformatics analysis suggested that ADAD2 interacts with DNAH17. Furthermore, we demonstrated that the expression of DNAH17 was markedly downregulated in the sperm of patients harboring ADAD2 variants. In addition, the expression of several autophagy regulators was significantly disrupted in the sperm of patients harboring ADAD2 variants. In conclusion, we identified novel ADAD1 and ADAD2 variants in three infertile patients from a large infertile cohort, first providing evidence that ADAD1 and ADAD2 variants might be a candidate genetic cause of human male infertility. Moreover, an important new dimension to our understanding of the genotype-phenotype correlations between the ADAD gene family and male infertility in humans has been uncovered, providing valuable information for the genetic diagnosis of male infertility., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Breast cancer is the most prevalent malignancy in patients with coronavirus disease 2019 (COVID-19). However, vaccination data of this population are limited., Methods: A cross-sectional study of COVID-19 vaccination was conducted in China. Multivariate logistic regression models were used to assess factors associated with COVID-19 vaccination status., Results: Of 2,904 participants, 50.2% were vaccinated with acceptable side effects. Most of the participants received inactivated virus vaccines. The most common reason for vaccination was "fear of infection" (56.2%) and "workplace/government requirement" (33.1%). While the most common reason for nonvaccination was "worry that vaccines cause breast cancer progression or interfere with treatment" (72.9%) and "have concerns about side effects or safety" (39.6%). Patients who were employed (odds ratio, OR = 1.783, p  = 0.015), had stage I disease at diagnosis (OR = 2.008, p  = 0.019), thought vaccines could provide protection (OR = 1.774, p  = 0.007), thought COVID-19 vaccines were safe, very safe, not safe, and very unsafe (OR = 2.074, p  < 0.001; OR = 4.251, p  < 0.001; OR = 2.075, p  = 0.011; OR = 5.609, p  = 0.003, respectively) were more likely to receive vaccination. Patients who were 1-3 years, 3-5 years, and more than 5 years after surgery (OR = 0.277, p  < 0.001; OR = 0.277, p  < 0.001, OR = 0.282, p  < 0.001, respectively), had a history of food or drug allergies (OR = 0.579, p  = 0.001), had recently undergone endocrine therapy (OR = 0.531, p  < 0.001) were less likely to receive vaccination., Conclusion: COVID-19 vaccination gap exists in breast cancer survivors, which could be filled by raising awareness and increasing confidence in vaccine safety during cancer treatment, particularly for the unemployed individuals., 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 Xu, Li, Li, Li, Song, Liu, Chen, Zhan, Wang, Feng, Liu, Wang, Liu, Qu, Li, Li and Sun.)

The Cancer/Testis Antigen (CTA) genes comprise a group of genes whose expression under physiological conditions is restricted to the testis but is activated in many human cancers. Depending on the particular expression pattern, the CTA genes are speculated to play a role in spermatogenesis, but evidence is limited thus far. Here, we reported patients with a hemizygous nonsense mutation in cancer-testis antigen 55 (CT55) suffering from male infertility with extreme disruption in sperm production, morphology, and locomotion. Specifically, the insufficiency of sperm individualization, excessive residue of unnecessary cytoplasm, and defects in acrosome development were evident in the spermatozoa of the patients. Furthermore, mouse models with depletion of Ct55 showed accelerated infertility with age, mimicking the defects in sperm individualization, unnecessary cytoplasm removal, and meanwhile exhibiting the disrupted cumulus-oocyte complex penetration. Mechanistically, our functional experiments uncovered CT55 as a new autophagic manipulator to regulate spermatogenesis via selectively interacting with LAMP2 and GABARAP (which are key regulators in the autophagy process) and further fine-tuning their expression. Therefore, our findings revealed CT55 as a novel CTA gene involved in spermatogenesis due to its unprecedented autophagy activity., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

This study aimed to construct an immune-related prognostic model and a nomogram to predict the 1-, 3-, and 5-year overall survival (OS) of breast cancer patients. We applied single-sample gene set enrichment analysis to classify 1,053 breast cancer samples from The Cancer Genome Atlas (TCGA) database into high and low immune cell infiltration clusters. In cluster construction and validation, the R packages "GSVA," "hclust," "ESTIMATE," and "CIBERSORT" and GSEA software were utilized. ImmPort, univariate Cox regression analysis, and Venn analysis were then used to identify 42 prognostic immune-related genes. Eventually, the genes TAPBPL , RAC2 , IL27RA , ULBP2 , PSMB8 , SOCS3 , NFKBIE , IGLV6-57 , CXCL1 , IGHD , AIMP1 , and CXCL13 were chosen for model construction utilizing least absolute shrinkage and selection operator regression analysis. The Kaplan-Meier curves of both the training and validation sets indicated that the overall survival of patients in the low-risk group was superior to that of patients in the high-risk group ( p < .05). The areas under curves (AUCs) of the model at 1, 3, and 5 years were, respectively, .697, .710, and .675 for the training set and .930, .688, and .712 for the validation set. Regarding clinicopathologic characteristics, breast cancer-related genes, and tumor mutational burden, effective differentiation was achieved between high-risk and low-risk groups. A nomogram integrating the risk model and clinicopathologic factors was constructed using the "rms" R software package. The nomogram's 1-, 3-, and 5-year AUCs were .828, .783, and .751, respectively. Overall, our study developed an immune-related model and a nomogram that could reliably predict OS for breast cancer patients, and offered insights into tumor immune and pathological mechanisms., 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, Li, Liu, Li and Sun.)

Background: Multiple morphological abnormalities of the sperm flagella (MMAF), which is characterized as asthenoteratospermia involving absent, short, bent, coiled, and/or irregular-caliber flagella, is a rare recessive inherited disorder associated with male infertility. To date, genetic causes of MMAF cases are not fully explored., Methods: Whole-exome sequencing was conducted to identify pathogenic variants in a patient with MMAF. The functional effect of the identified mutations was investigated by immunofluorescence staining and western blotting. Intracytoplasmic sperm injection was used to assist fertilization for the patient with MMAF., Results: We identified novel biallelic mutations, a splicing variant NC&#95;000004.12:g.146937593C>T (c.254+1G>A), and a nonsense mutation NM&#95;001300761.4:c.1185C>G (NP&#95;001287690.1:p.Tyr395*), in TTC29 from an infertile patient. In addition to the typical MMAF phenotype, the patient also presented aberrant morphology of sperm heads. Further functional experiments confirmed the absence of TTC29 expression in the spermatozoa. We also explored the specific expression pattern of TTC29 in human and mouse spermatogenesis. The outcome of intracytoplasmic sperm injection in the patient was unsuccessful, while additional female risk factors should not be excluded., Conclusions: Our study revealed the novel biallelic mutations in TTC29 in a MMAF patient, which findings expand the mutational spectrum of TTC29 and further contribute to the diagnosis, genetic counseling, and prognosis of male infertility., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Ultrasound is more widely used than mammography for early diagnosis of breast cancer in China as most Chinese women have small and dense mammary glands. This study compared the diagnostic performance of ultrasound and mammography for breast cancer among Chinese women with suspected breast lesions., Methods: From November 2019 to November 2021, we compared the results of ultrasound and mammography for breast lesion diagnosis in 2737 consecutive participants with suspected breast lesions; all patients underwent biopsies. We measured the sensitivity, specificity, and diagnostic accuracy separately., Results: Among the 2737 participants, 2844 breast lesions were detected, including 1935 (68.0%) breast cancers and 909 (32.0%) benign lesions. Of the breast cancers, ultrasound detected 1851 (95.7%), whereas mammography detected 1527 (78.9%). The sensitivity of ultrasound for breast cancer diagnosis was significantly higher than that of mammography (95.7% vs. 78.9%, p < 0.001), whereas the specificity was significantly lower than that of mammography (42.9% vs. 62.3%, p < 0.001). The receiver operating characteristic curves revealed that ultrasound was more accurate in detecting breast cancer than mammography (76.8% vs. 71.3%, p < 0.001). Age, body mass index, and breast density did not influence ultrasound sensitivity and accuracy., Conclusions: Ultrasound is more sensitive and accurate than mammography and detects more breast cancers with a lower specificity., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Centrosomal protein dysfunction might cause ciliopathies. However, the role of centrosomal proteins in male infertility remains poorly defined. Here, we identified a pathogenic splicing mutation in CEP78 in male infertile patients with severely reduced sperm number and motility, and the typical multiple morphological abnormalities of the sperm flagella phenotype. We further created Cep78 knockout mice, which showed an extremely low sperm count, completely aberrant sperm morphology, and approximately null sperm motility. The infertility of the patients and knockout mice could not be rescued by an intracytoplasmic sperm injection treatment. Mechanistically, CEP78 might regulate USP16 expression, which further stabilizes Tektin levels via the ubiquitination pathway. Cep78 knockout mice also exhibited impairments in retina and outer hair cells of the cochlea. Collectively, our findings identified nonfunctional CEP78 as an indispensable factor contributing to male infertility and revealed a role for this gene in regulating retinal and outer hair cell function in mice.

Research Question: Testis-specific PRSS55 is a chymotrypsin-like serine protease that is highly conserved among mammalian species. The essential role of Prss55 in mouse male fertility has been established. What is the role of PRSS55 in human reproduction?, Design: Whole exome sequencing was used to identify the genetic cause in an infertile male with teratozoospermia. Papanicolaou staining, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to explore morphological defects in the patient's spermatozoa. Immunofluorescence staining and western blot analysis were conducted to assess the pathogenicity of the identified variant. Intracytoplasmic sperm injection (ICSI) was used to assist the patient with fertilization., Results: Sanger sequencing of the pedigree demonstrated that the infertile man carried a novel homozygous mutation in PRSS55 (c.575C>T [p.A192V]). Morphological defects in the sperm head, neck, midpiece and tail were demonstrated by Papanicolaou staining, SEM and TEM. Immunofluorescence staining and western blotting of the patient's spermatozoa showed that the point mutation changed the conformation of PRSS55 and caused a sharp decrease in the PRSS55 protein concentration. The expression and subcellular localization of PRSS55 in the testis and spermatozoa of mice and humans showed that PRSS55 was expressed in the head and flagella of spermatids and epididymal spermatozoa. Moreover, ICSI treatment for this kind of infertile patient was shown to be effective., Conclusions: These findings revealed a novel mutation in PRSS55 in an infertile patient, suggesting for the first time the crucial role of PRSS55 in human fertility. This study provides new insight into genetic counselling diagnoses and subsequent treatment for male infertility., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Carbon emissions from civil buildings refer to the carbon emissions generated during the operation of civil buildings. With the continuous development of the urban economy and the improvement of people's living standards, this part of carbon emission puts tremendous pressure on China to achieve the goal of carbon peaking and carbon neutral. In the context of rapid urbanization, studying the spatiotemporal characteristics and influencing factors of the carbon emissions from civil buildings have strong practical significance for China to achieve the "dual carbon" goal. Based on the emission data from 104 prefecture-level cities in China, we examine the spatiotemporal characteristics of the civil building carbon emissions from the perspectives of temporal evolution trend, spatial distribution and its dynamic evolution, spatial difference and its decomposition, and spatial autocorrelation characteristics. Finally, we reveal the influencing factors of the carbon emissions from civil buildings using static panel data models and spatial dynamic panel data models. The results of the study show that: (1) During the sample period, the carbon emissions from civil buildings have increased year by year. The civil building carbon emissions have become an important source of China's overall carbon emissions. Realizing energy saving and emission reduction in the operational stage of civil buildings is crucial to realizing China's "dual carbon" goal. (2) According to the estimated results, there is a significant inverted U-shaped non-linear relationship between urbanization and civil building carbon emissions. Most Chinese cities are located in the upward part of the inverted U-shaped curve at present. Thus, the traditional economic growth model characterized by high energy consumption and high emission during rapid urbanization should be abandoned to reduce the carbon emissions from civil buildings. (3) Technological progress and fixed asset investment can effectively reduce the carbon emissions from civil buildings. At the same time, the level of marketization and social consumption expenditure positively affect the carbon emissions from civil buildings. It is necessary to improve the relevant market mechanisms, policy subsidies, and other means to encourage the application of green energy-saving technologies in civil buildings. Also, it is needed to guide the urban residents' consumption structure and lifestyle in a low-carbon direction, to reduce the energy consumption and carbon emissions during the operation of civil buildings., Competing Interests: The authors have declared that no competing interests exist.

Male infertility has become a serious health and social problem troubling approximately 15% of couples worldwide; however, the genetic and phenotypic heterogeneity of human infertility poses a substantial obstacle to effective diagnosis and therapy. A previous study reported that heterozygous mutations in solute carrier family 26 member 8 (SLC26A8, NG&#95;033897.1) were causatively linked to asthenozoospermia. Interestingly, in our research, three deleterious heterozygous mutations of SLC26A8 were separately detected in three unrelated patients who were suffered from teratozoospermia. These three heterozygous mutations resulted in the reduction of SLC26A8 expression in transfected cells, while no disrupted expression of SLC26A8 was observed in sperm from the affected individuals. Noticeably, two of the three SLC26A8 heterozygous mutations detected in the patients were inherited from their fertile fathers. Thus, we suggested that male infertility associated with SLC26A8 mutations should be involved in a recessive-inherited pattern, considering the infertile homozygous Slc26a8 KO male mice, the contribution of heterozygous mutations in SLC26A8 in male infertility needs further deep research., (© 2022 Wiley Periodicals LLC.)

Background and Objectives: Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids., Methods: Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach., Results: Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids., Conclusions: Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids., Clinical Trial Registration: ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend)., (© 2021. The Author(s).)

Murine infection models are needed to develop therapeutics and vaccines to combat the Plasmodium parasites causing malaria. Herein, we describe an easy to perform flow cytometry-based methodology for detecting green fluorescent protein-expressing Plasmodium berghei in the peripheral red blood cells (RBC) of mice. This methodology uses one-step staining and simplified gating strategies to streamline the process of Plasmodium quantification and can detect parasitemia at an earlier time point after infection compared to traditional light microscopy-based techniques., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Non-obstructive azoospermia (NOA) is an important cause of male infertility, and the genetic pathogenesis is still incompletely understood. The previous study reported that heterozygous mutation of c.346-1G > A in spermatogenesis and oogenesis specific basic helix-loop-helix 1 (SOHLH1) was identified in two NOA patients and suggested it is the pathogenic factor for NOA. However, in our research, this heterozygous mutation was confirmed in three Chinese infertile patients who suffered from teratozoospermia, but they had normal sperm number. Intriguingly, a homozygous mutation of c.346-1G > A in SOHLH1 was detected in a severe oligozoospermia (SOZ) patient, characterized with severely decreased sperm count. Notably, we unprecedently revealed that this homozygous mutation of c.346-1G > A in SOHLH1 leads to the sharp decrease in various germ cells and spermatogenesis dysfunction, which is similar to the phenotype of SOHLH1 knockout male mice. Moreover, western blotting confirmed that the homozygous mutation declined SOHLH1 protein expression. Additionally, we correlated the good prognosis of intracytoplasmic sperm injection (ICSI) in the patients carrying the mutation of c.346-1G > A in SOHLH1. Thus, we suggested that the heterozygous mutation of c.346-1G > A in SOHLH1 is responsible for teratozoospermia, and this homozygous mutation in SOHLH1 impairs spermatogenesis and further leads to the reduced sperm count, eventually causing male infertility, which unveils a new recessive-inheritance pattern of SOHLH1-associated male infertility initially., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Centrosomal proteins are necessary components of the centrosome, a conserved eukaryotic organelle essential to the reproductive process. However, few centrosomal proteins have been genetically linked to fertility. Herein we identify a homozygous missense variant of CEP128 (c.665 G > A [p.R222Q]) in two infertile males. Remarkably, male homozygous knock-in mice harboring the orthologous CEP128 R222Q variant show anomalies in sperm morphology, count, and motility. Moreover, Cep128 knock-out mice manifest male infertility associated with disrupted sperm quality. We observe defective sperm flagella in both homozygous Cep128 KO and KI mice; the cilia development in other organs is normal-suggesting that CEP128 variants predominantly affected the ciliogenesis in the testes. Mechanistically, CEP128 is involved in male reproduction via regulating the expression of genes and/or the phosphorylation of TGF-β/BMP-signalling members during spermatogenesis. Altogether, our findings unveil a crucial role for CEP128 in male fertility and provide important insights into the functions of centrosomal proteins in reproductive biology., (© 2022. The Author(s).)

Purpose: To evaluate the unknown genetic causes of teratozoospermia, and determine the pathogenicity of candidate variants., Methods: A primary infertile patient and his family members were recruited in the West China Second University Hospital of Sichuan University. Whole-exome sequencing was performed to identify causative genes in a man with teratozoospermia. Immunofluorescence staining and western blotting were applied to assess the pathogenicity of the identified variant. Intracytoplasmic sperm injection (ICSI) was used to assist fertilization for the patient with teratozoospermia., Results: We performed whole-exome sequencing (WES) and detected a novel homozygous frameshift mutation of c.335&#95;336del [p.E112Vfs*3] in DNAJB13 on a primary infertile male patient. Intriguingly, we identified abnormal sperm morphology in this patient, with recurrent respiratory infections and chronic cough. Furthermore, we confirmed that this mutation resulted in negative effects on DNAJB13 expression in the spermatozoa of the affected individual, causing ultrastructural defects in his sperm. Remarkably, our staining revealed that DNAJB13 was expressed in the cytoplasm of primary germ cells and in the flagella of spermatids during spermiogenesis in humans and mice. Finally, we are the first group to report a favorable prognosis using ICSI for a patient carrying this DNAJB13 mutation., Conclusion: Our study revealed a novel homozygous frameshift mutation of c.335&#95;336del [p.E112Vfs*3] in DNAJB13 involved in teratozoospermia phenotype. Our study greatly expands the spectrum of limited DNAJB13 mutations, and is expected to provide a better understanding of genetic counseling diagnoses and subsequent treatment of male infertility., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

X-linked hypophosphataemia (XLH) is an X-linked dominant rare disease that refers to the most common hereditary hypophosphatemia (HH) caused by mutations in the phosphate-regulating endopeptidase homolog X-linked gene ( PHEX ; OMIM: * 300550). However, mutations that have already been reported cannot account for all cases of XLH. Extensive genetic analysis can thus be helpful for arriving at the diagnosis of XLH. Herein, we identified a novel heterozygous mutation of PHEX (NM&#95;000444.5: c.1768G > A) in a large Chinese family with XLH by whole-exome sequencing (WES). In addition, the negative effect of this mutation in PHEX was confirmed by both bioinformatics analysis and in vitro experimentation. The three-dimensional protein-model analysis predicted that this mutation might impair normal zinc binding. Immunofluorescence staining, qPCR, and western blotting analysis confirmed that the mutation we detected attenuated PHEX protein expression. The heterozygous mutation of PHEX (NM&#95;000444.5: c.1768G > A) identified in this study by genetic and functional experiments constitutes a novel genetic cause of XLH, but further study will be required to expand its use in clinical and molecular diagnoses of XLH., 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 © 2022 Yang, Wang, Shen, Liu, Dai, Wang and Liu.)

Background: Bromodomain-containing protein 7 (BRD7), a member of the bromodomain-containing protein family, plays important roles in chromatin modification and transcriptional regulation. A recent model of Brd7-knockout mice presented azoospermia and male infertility, implying the potential role of BRD7 in spermatogenic failure in humans. This case-control study aimed to explore the association of the BRD7 gene with spermatogenic efficiency and the risk of spermatogenic defects in humans., Results: A total of six heterozygous variants were detected in the coding and splicing regions of the BRD7 gene in patients with azoospermia. For each of four rare variants predicted to potentially damage BRD7 function, we further identified these four variants in oligozoospermia and normozoospermia as well. However, no difference in the allele and genotype frequencies of rare variants were observed between cases with spermatogenic failure and controls with normozoospermia; the sperm products of variant carriers were similar to those of noncarriers. Moreover, similar distribution of the alleles, genotypes and haplotypes of seven tag single nucleotide polymorphisms (tagSNPs) was observed between the cases with azoospermia and oligozoospermia and controls with normozoospermia; associations of tagSNP-distinguished BRD7 alleles with sperm products were not identified., Conclusions: The lack of an association of BRD7-linked rare and common variants with spermatogenic failure implied a limited contribution of the BRD7 gene to spermatogenic efficiency and susceptibility to male infertility in humans., (© 2021. The Author(s).)

The Open Databases Integration for Materials Design (OPTIMADE) consortium has designed a universal application programming interface (API) to make materials databases accessible and interoperable. We outline the first stable release of the specification, v1.0, which is already supported by many leading databases and several software packages. We illustrate the advantages of the OPTIMADE API through worked examples on each of the public materials databases that support the full API specification., (© 2021. The Author(s).)

Previous studies suggest that a reward-associated salient distractor can induce bottom-up attentional capture. Hitherto, the neurophysiological mechanisms underlying attentional allocation upon reward/loss associated nonsalient stimulus remain hardly investigated. The present study built the association between nonsalient stimuli and value, and tested it with a decision-making task. Consequently, we examined whether and how reward/loss-associated nonsalient stimuli (as distractors) influenced attentional allocation in a rapid serial visual presentation task. Behavioral analysis showed a significantly faster recognition of target in the loss condition compared to performance in the neutral/reward conditions. Electrophysiological results showed that reward-associated distractors induced a significant Pd component, while loss-associated distractors induced a significantly higher theta oscillation. These results demonstrated that subjects could proactively suppress reward-associated distractors. More importantly, we showed that attentional allocation upon reward/loss-associated nonsalient distractors is supported by distinct neural mechanisms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To explore the genetic basis for a couple with recurrent conceptions of fetus with abnormal longbones, and another couple with a history of omphalocele., Methods: Genomic DNA was extracted from the peripheral blood samples from both couples. All exons and flanking regions were analyzed with next generation sequencing. Candidate variants were verified by Sanger sequencing., Results: Couple one was found to be heterozygous for, a c.997+1G>T splice-site variant and a missence c.871G>A(p.Glu291Lys) variant of the ALPL gene. Both variants were predicted to be pathogenic and may result in reduced function or loss of alkaline phosphatase. For couple two, the wife was found to harbor a novel c.637&#95;652 delins CCC variant of the CDKN1C gene. This deletion-insertion variant resulted in frame-shift and loss of function (p.Ala213Profs*55) of the CDKN1C protein. Maternally inherited CDKN1C LOF variant has been found to underlie Beckwith-Wiedemann syndrome (BWS), which may manifest as omphalocele., Conclusion: Dispite the lack the direct proof from the lost fetuses, the variants of ALPL and CDKN1C genes can explain the recurrence of fetal malformations for both couples.

Multiple morphological abnormalities of the sperm flagella (MMAF) is defined as deformities that cause sperm motility disorders, further resulting in male infertility. However, the reported genes related to sperm flagellar defects can only explain approximately 60% of human MMAF cases. Here, we report two novel compound heterozygous mutations, c.16246&#95;16247insCCCAAATATCACC (p. T5416fs*7) and c.17323C > T (p.Q5774*), in the fibrous sheath-interacting protein 2 gene (FSIP2; OMIM: 615796) in an infertile patient by whole-exome sequencing (WES). Western blotting and immunofluorescence staining confirmed that the compound heterozygous mutations abrogated FSIP2 protein expression. Notably, our staining revealed that FSIP2 is expressed in the cytoplasm of primary germ cell and flagella of spermatids during the spermiogenesis. Moreover, intracytoplasmic sperm injection (ICSI) was carried out using sperm from this patient; however, pregnancy failed after embryo transfer through one cycle. Our findings may be helpful in establishing a genetic diagnosis for MMAF, as well as provide additional beneficial knowledge for genetic counseling and infertility treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Supramolecular peptide hydrogel has shown promising potential in vaccine development largely because of its ability to function both as antigen depot and immune adjuvant. Nap-G d F d F d Y, a tetrapeptide hydrogel that has been previously reported to exhibit adjuvant effect, is inadvertently found to contain conserved peptide sequence for insulin, proinsulin, and glutamic acid decarboxylase, 3 major autoantigens for the autoimmune type 1 diabetes (T1D). At present, despite being managed clinically with insulin replacement therapy, T1D remains a major health threat with rapidly increasing incidences, especially in children and young adults, and antigen-specific immune tolerance induction has been proposed as a feasible approach to prevent or delay T1D progression at an early stage. Here, it is reported that innoculation of Nap-G d F d F d Y leads to complete protection of nonobese diabetic (NOD) mice from T1D development till the age of 36 weeks. Better maintenance of pancreatic islet morphology with minimal immune cell infiltration is also observed from mice exposed to Nap-G d F d F d Y. This beneficial impact is mainly due to its facilitative role on enhancing peripheral T regulatory cell (Treg) population, shown as increased splenic Treg percentage, and function, demonstrated by maintenance of circulating TGF- β 1 level. Serum cytokine microarray data further implicate a "buffering" role of Nap-G d F d F d Y on systemic inflammatory tone in NOD mice. Thus, with its versatility, applicability, and excellent potency, Nap-G d F d F d Y is posited as a novel therapeutic intervention for T1D., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Type 1 diabetes (T1D) is an autoimmune subtype of diabetes, mainly caused by the immune attack of self-insulin-producing cells. Immune modulation that delays the onset of T1D is able to reduce diabetic complications and mortality. We have previously reported that mannosylated sodium alginate nanoparticles (MAN-ALG) exhibited excellent dendritic cell targeting and in vivo antigen delivery efficacy. To investigate the role of MAN-ALG in an autoimmune context, we loaded the MAN-ALG with Ins2 9-23 , a T1D autoantigen [MAN-ALG(PEP)], for T1D immune tolerance induction in nonobese diabetic (NOD) mice. We observed the delayed onset of T1D occurrence and some degree of blood glucose reduction accompanied by a larger islet area, attributable to augmented T-regulatory cell proportion in mice treated with MAN-ALG(PEP). However, MAN-ALG was also found to elicit lysosomal escape and cross-presentation of Ins2 9-23 in bone marrow-derived dendritic cells, leading to the immune activation of Ins2 9-23 -recognizing T cells and destruction of Ins2 9-23 -expressing islet cells. This dual impact resulted in delayed but a nonpreventive effect of MAN-ALG(PEP) on the T1D onset in NOD mice. Considering the potent immune stimulatory property of MAN-ALG, cautions should be implemented when using alginate-based biomaterials in an autoimmune context. Moreover, it is also noted that regarding the in vivo outcome of immune therapies, biomaterial-based delivery systems and their detailed role on immune regulation need to be examined.

Purpose: There are limited genes known to cause primary ciliary dyskinesia (PCD)-associated asthenozoospermia. In the present study, we aimed to expand the spectrum of mutations in PCD and to provide new information for genetic counseling diagnoses and the treatment of male infertility in PCD., Methods: One sterile patient with typical situs inversus was recruited to our center, and semen sample was collected. We performed whole-exome sequencing (WES) on the patient to identify the pathogenic mutations associated with PCD and used transmission electron microscopy to investigate spermatozoal ultrastructure. In addition, western blotting and immunofluorescence staining were used to confirm the untoward impact of the variant on the expression of LRRC6, as well as on the dynein arm proteins in the patient's spermatozoa., Results: We identified a homozygous nonsense variant c.749G>A (p.W250*) of LRRC6 in the PCD patient. This variant severely impaired LRRC6 expression and further led to negative effects on dynein arm protein expression in the spermatozoa of the affected individual, which eventually caused defects in sperm ultrastructure and motility. Moreover, we are the first to report a positive prognosis using intracytoplasmic sperm injection (ICSI) for LRRC6-associated male infertility., Conclusions: Our findings strongly implicated the homozygous mutation of c.749G>A (p.W250*) in LRRC6 as a new genetic cause of PCD, uncovering its involvement in defective sperm flagella and poor sperm motility. Furthermore, we posit that patients with LRRC6 mutations may have good outcomes with ICSI treatment. These findings add to the literature on the genetic diagnoses and treatment of male infertility associated with PCD.

Background: We examined the genetic variants of a Chinese family with a 22-month-old infant with sporadic non-syndromic sensorineural hearing loss (NSHL). Methods: The whole-exome sequence data in the family, especially the de novo variants presented in the patient, were analyzed and the effect of the disease-causing genetic variants on the protein expression level and cellular localization were examined by cell-based functional assay. Results: The infant had no known NSHL-causing variants, except two compound heterozygous variants in connexin26 gene GJB2 ; one was the c.79G>A, c.341A>G haplotype from the asymptomatic mother who was benign, and the other was a de novo pathogenic c.262G>C (p.A88P). In vitro , GJB2 with c.262G>C was weakly expressed and displayed a punctate distribution in the cytoplasm and cytomembrane, while wild type GJB2 was robustly expressed in the cytomembrane. We deduced that the de novo pathogenic GJB2 c.262G>C exacerbated loss-of-function in the context of leaky variants c.79G>A, c.341A>G in the patient. Interestingly, further analysis of exome sequences revealed that the occurrence of de novo pathogenic variants in the infant was frequent. Among the total~47,000 variants, 143 were de novo in the patient, whereas among all 74 variants predicted to be pathogenic/likely pathogenic, 21 were heterozygous and two were homozygous de novo . The occurrence rate of de novo deleterious variants was much higher (31.1%, 23/74) than that in total (0.34%, 143/47,000). It is notable that most genes with de novo deleterious variants were environment-sensitive, such as GJB2 , MNK1 , MNK2, MUC4 , RAD21 and DNA copy number variations. Conclusions: The full picture of genetic variants in the exome might help us to interpret the NSHL-causing variants. More research is needed into the causes of de novo deleterious variants and gene-environment interactions in congenital NSHL., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hu S et al.)

Background: We examined the genetic variants of a Chinese family with a 22-month-old infant with sporadic non-syndromic sensorineural hearing loss (NSHL). Methods: The whole-exome sequence data in the family, especially the de novo variants presented in the patient, were analyzed and the effect of the disease-causing genetic variants on the protein expression level and cellular localization were examined by cell-based functional assay. Results: The infant had no known NSHL-causing variants, except two compound heterozygous variants in connexin26 gene GJB2 ; one was the c.79G>A, c.341A>G haplotype from the asymptomatic mother which was benign, and the other was a de novo pathogenic c.262G>C (p.A88P). In vitro , GJB2 with c.262G>C was weakly expressed and displayed a punctate distribution in the cytoplasm and cytomembrane, while wild type GJB2 was robustly expressed in the cytomembrane. We deduced that the de novo pathogenic GJB2 c.262G>C exacerbated loss-of-function in the context of leaky variants c.79G>A, c.341A>G in the patient. Interestingly, further analysis of exome sequences revealed that the occurrence of de novo pathogenic variants in the infant was frequent. Among the total~47,000 variants, 143 were de novo in the patient, whereas among all 74 variants predicted to be pathogenic/likely pathogenic, 21 were heterozygous and two were homozygous de novo . The occurrence rate of de novo deleterious variants was much higher (31.1%, 23/74) than that in total (0.34%, 143/47,000). It is notable that most genes with de novo deleterious variants were environment-sensitive, such as GJB2 , MNK1 , MNK2, MUC4 , RAD21 and DNA copy number variations. Conclusions: The full picture of genetic variants in the exome might help us to interpret the NSHL-causing variants. More research is needed into the causes of de novo deleterious variants and gene-environment interactions in congenital NSHL., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hu S et al.)

Testis-specific protein Y-encoded 1 (TSPY1), a Y chromosome-linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl-histone H4 and trimethylated histone H3-lysine 4, two post-translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1-CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen-AR axis-regulated oncogene, suggesting a novel and potential target for PCa therapy., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

This pot experiment aimed to investigate the influence of rice straw biochar (BC 0, 1, and 3%, w/w) and organic manure (OM 0, 1, and 2%, w/w) addition on the growth, nutrient and cadmium (Cd) uptake of forage soybean in 10 mg Cd kg -1 contaminated soils. Compared with non-biochar treatments, biochar decreased shoot biomass, height and nitrogen (N) contents. Organic manure markedly increased the shoot biomass, shoot phosphorus (P), potassium (K), calcium (Ca) and magnesium (Mg) concentration, and root N, P, Ca contents without biochar addition treatments, while in the case of 3% biochar, there were no significant effects on N, K, Ca, and Mg contents of shoot and root among organic manure treatments. In comparison with other treatments, the minimum Cd content of shoots and roots both occurred in the treatment of BC3%+OM2%, while shoot Cd content reached the maximum value in OM2% treatment. Thus, these results suggested that organic manure addition can elevate forage soybean yield and nutrient content, while biochar had no positive effects. High biochar (3%) addition in combination with highest dose of organic manure (2%) can decline the Cd content of soybean and contribute to the agricultural product safety.

Purpose: This study aims to develop and validate a nomogram to predict lymph node (LN) metastasis preoperatively in patients with T1 high-grade urothelial carcinoma., Methods: We retrospectively evaluated the data of 2,689 patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC) and bilateral lymphadenectomy in two medical centers. Eventually, 412 patients with T1 high-grade urothelial carcinoma were enrolled in the primary cohort to develop a prognostic nomogram designed to predict LN status. An independent validation cohort (containing 783 consecutive patients during the same period) was subjected to validate the predicting model. Binary regression analysis was used to develop the predicting nomogram. We assessed the performance of the nomogram concerning its clinical usefulness, calibration, and discrimination., Results: Overall, 69 (16.75%), and 135 (17.24%) patients had LN metastasis in the primary cohort and external validation cohort, respectively. The final nomogram included information on tumor number, tumor size, lymphovascular invasion (LVI), fibrinogen, and monocyte-to-lymphocyte ratio (MLR). The nomogram showed good predictive accuracy and calibration with a concordance index in the primary cohort of 0.853. The application of the nomogram in the external validation cohort still gave good discrimination (C-index, 0.845) and good calibration. The analysis of the decision curve shows that the nomogram has clinical application value., Conclusion: The nomogram that incorporated the tumor number, tumor size, LVI, fibrinogen, and MLR showed favorable predictive accuracy for LN metastasis. It may be conveniently used to predict LN metastasis in patients with T1 high-grade urothelial carcinoma and be helpful in guiding treatment decisions., (Copyright © 2020 Ou, Song, Liu, Zhu, Yang and Liu.)

Poly[lactic- co -(glycolic acid)] (PLGA) is arguably one of the most versatile synthetic copolymers used for biomedical applications. In vivo delivery of multiple substances including cells, pharmaceutical compounds, and antigens has been achieved by using PLGA-based micro-/nanoparticles although, presently, the exact biological impact of PLGA particles on the immune system remains controversial. Type 1 diabetes (T1D) is one subtype of diabetes characterized by the attack of immune cells against self-insulin-producing pancreatic islet cells. Considering the autoimmune etiology of T1D and the recent use of PLGA particles for eliciting desired immune responses in various aspects of immunotherapy, for the present study, a combination of Ins2 9-23 peptide (a known autoantigen of T1D) and PLGA microparticles was selected for T1D prevention assessment in nonobese diabetic (NOD) mice, a well-known animal model with spontaneous development of T1D. Thus, inoculation of PLGA microparticles + Ins2 9-23 completely prevented T1D development, significantly better than untreated controls and mice treated by either PLGA microparticles or Ins2 9-23 per se. Subsequent mechanistic investigation further revealed a facilitative role of PLGA microparticles in immune tolerance induction. In summary, our data demonstrate an adjuvant potential of PLGA microparticles in tolerance induction and immune remodulation for effective prevention of autoimmune diseases such as T1D.

Background: Brachydactyly (BD) is a rare autosomal dominant inherited disease characterized by shortness of the fingers and/or toes, which has been classified into the subtypes A-E. However, the exact cause and mechanism of BD remain to be illuminated. Here, we aim to reveal the clinical and genetic characteristics of a subtype of BD, brachydactyly-anonychia., Methods: In this study, a large Chinese family with three members affected by brachydactyly-anonychia was investigated. Both whole-exome sequencing and microarray-based comparative genomic hybridization (CGH) were performed on this family and the results of copy number variation (CNV) were verified by quantitative real-time PCR (qPCR)., Results: All the affected individuals showed short fingers and toes as well as missing nails; and the absence of middle phalanges in figure II-V of the upper and lower extremities was observed by X-ray examination. A duplication involving in the region of 17q24.3 was detected by CGH. The results of qPCR also represented this duplication in 17q24.3 in all the patients., Conclusion: In summary, our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly-anonychia in this family, which support the prior report that brachydactyly-anonychia is associated with 17q24.3 duplication, and further indicates the pathogenic correlation between BD and CNVs., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Purpose: Empty follicle syndrome (EFS) refers to the inability to obtain mature oocytes after appropriate ovarian stimulation during the process of in vitro fertilization (IVF). However, the specific cause and mechanism of action underlying EFS remain to be further explored. Herein we aimed to investigate the clinical and genetic characteristics of EFS., Methods: After data were collected in an infertile family, we performed whole-exome sequencing (WES) on the patient and confirmed the pathogenic mutations through Sanger sequencing. Western immunoblotting, immunofluorescence staining, and minigene assay were further used to investigate the negative effects of these mutations., Results: Absence of oocytes was observed over 2 cycles of IVF in the patient, and we evaluated the novel compound heterozygous mutations c.2T>A (p. M1K) and c.1112+1G>T of the zona pellucida glycoprotein 1 gene (ZP1, MIM# 195000) by WES. For the family under study, EFS was classified as an autosomal recessive inheritance pattern. The results of western blotting and immunofluorescence staining analyses confirmed that the missense mutation of c.2T>A [p. M1K] resulted in almost missing protein production. Additionally, using a minigene assay, we demonstrated the deleterious effect on the ZP1 gene of the splice site mutation c.1112+1G>T, which caused truncation of ZP1 protein., Conclusions: The compound heterozygous mutations of ZP1 gene identified in this study by genetic and functional experiments constituted a novel genetic cause of EFS, and further study will expand its use in the clinical and molecular diagnoses of EFS.

The objective of the study was to explore the influences of arbuscular mycorrhizae (AM), phosphorus (P) fertiliser, biochar application (BC) and their interactions on Medicago sativa growth, nutrient, Cd content and AM fungi-plant symbioses. Applications of both P fertiliser and BC significantly increased total biomass and P and potassium (K) uptake, regardless of AM. When no P fertiliser or BC was used, the shoot biomass and nitrogen (N), P, and K contents in the +AM treatments were 1.39, 1.54, 4.53 and 2.06 times higher than those in the -AM treatments, respectively. AM fungi only elevated the total P uptake by 44.03% when P fertiliser was applied at a rate of 30 mg P kg -1 in the absence of BC addition. With BC application or high-P fertiliser input (100 mg P kg -1 ), the soil available P was significantly higher than that in the other treatments, and AM fungi significantly reduced the shoot biomass. The minimum Cd concentration occurred in the shoots of alfalfas treated with BC and high-P fertiliser inputs; this concentration was lower than the maximum permitted concentration in China. Although the BC and high-P inputs could eliminate the positive mycorrhizal response, the results suggested that BC application in combination with high-P fertiliser input could not only increase forage yields but also lower Cd concentrations to meet the forage safety standards by the dilution effect., 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 © 2020 Elsevier Inc. All rights reserved.)