To study the clinical factors affecting the outcomes of repeated assisted reproductive technology (ART) cycles.A retrospective analysis of the clinical data and outcomes was conducted among 160 patients undergoing repeated IVF/ICSI-ET treatment between January 2006 and April 2009.The patients with successful clinical pregnancy after two ART cycles (group A) had a younger age and shorter duration of infertility, and had more antral follicles (AFC), more eggs and good-quality embryos with more transferred embryos available and higher good-quality embryo rate (P<0.05) than those who failed to have pregnancy after the cycles (group B). In the second cycle, the patients in group A had higher doses of short-acting GnRHa, r-HCG and HMG and at the same time more good eggs and embryos than in the first cycle.Female age is one of the most important factors affecting the pregnancy rate after repeated ART cycles. The clinical pregnancy rate can be enhanced by administering short-acting GnRHa, HMG, oral contraceptives and adjusting the dose of Gn as well as changing the culture medium of embryos.
To investigate the regulatory effect of miR-149 on interleukin-6 (IL-6) expression in silica-induced pulmonary fibrosis.A mouse model of pulmonary fibrosis was established using silica dust; the level of miR-149 in the lung tissues of mice with silica-induced pulmonary fibrosis was measured by quantitative real-time polymerase chain reaction (qRT-PCR), while the protein expression of IL-6 was measured by immunohistochemistry and Western blot. Type II alveolar epithelial cells (A549) and bronchial epithelial cells (HBE) were exposed to silica dust to establish a model; the level of miR-149 was measured by qRT-PCR, while the protein expression of IL-6 was measured by Western blot. A549 cells were transfected with miR-149 mimics and inhibitor in vitro, and the cellular expression of IL-6 was measured by Western blot. Serum samples from patients with coal workers' pneumoconiosis were examined by double-antibody sandwich ELISA to measure the protein expression of IL-6.At three time points after silica treatment, the miR-149 expression in lung tissues was significantly down-regulated while an evident increase in IL-6 expression was observed in lung tissues (P < 0.01). Silica-stimulated epithelial cell (A549 and HBE) had up-regulated IL-6 expression and down-regulated miR-149 expression (P < 0.01). Increased levels of miR-149 attenuated IL-6 expression, whereas adverse results were found when miR-149 was inhibited. Compared with that in control group, serum level of IL-6 was significantly increased in patients with stage II and III coal workers' pneumoconiosis (P < 0.01).Down-regulation of miR-149 and up-regulation of IL-6 might be involved in the progression of silica-induced pulmonary fibrosis; miR-149 could negatively regulate IL-6 expression.
As of November, 2023, SARS-CoV-2 XBB variants, including EG.5.1 (XBB.1.9.2.5.1), the currently predominant lineage, have been circulating worldwide, according to Nextstrain datasets. The EG.5.1 strain has a characteristic amino acid substitution in the spike protein (S; S:F456L), which allows the strain to escape humoral immunity (appendix p 16).1Kaku Y Kosugi Y Uriu K et al.Antiviral efficacy of the SARS-CoV-2 XBB breakthrough infection sera against omicron subvariants including EG.5.Lancet Infect Dis. 2023; 23: e395-e396Summary Full Text Full Text PDF PubMed Google Scholar EG.5.1 has further evolved, and its descendant lineage harbouring the S:L455F (ie, EG.5.1+S:L455F) variant has emerged and has been named HK.3 (XBB.1.9.2.5.1.1.3). HK.3 was initially discovered in east Asia and is rapidly spreading worldwide. Notably, the XBB subvariants bearing both S:L455F and S:F456L substitutions, including HK.3, are defined as FLip variants. These FLip variants, including JG.3 (XBB.1.9.2.5.1.3.3), JF.1 (XBB.1.16.6.1), and GK.3 (XBB.1.5.70.3) have emerged concurrently, suggesting that the acquisition of these two substitutions confers a growth advantage to XBB in the human population.2Ito J Suzuki R Uriu K et al.Convergent evolution of SARS-CoV-2 omicron subvariants leading to the emergence of BQ.1.1 variant.Nat Commun. 2023; 14: 2671Crossref PubMed Scopus (19) Google Scholar,3Bloom JD Neher RA Fitness effects of mutations to SARS-CoV-2 proteins.Virus Evol. 2023; 9vead055Crossref Scopus (2) Google Scholar We investigated the virological properties of HK.3 as a representative of the FLip variants. We estimated the relative effective reproduction number (Re) of HK.3 on the basis of genome surveillance data obtained from 13 countries reporting the substantial presence of HK.3 with a Bayesian hierarchical multinomial logistic regression model (appendix pp 9–14, 16).4Yamasoba D Kimura I Nasser H et al.Virological characteristics of the SARS-CoV-2 omicron BA.2 spike.Cell. 2022; 185: 2103-2115.e19Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar The global mean Re for HK.3 was 1·29 times higher than that of XBB.1.5 and 1·12 higher than that of EG.5.1, suggesting that HK.3 might soon become the predominant lineage worldwide. As of Oct 15, 2023, the HK.3 variant has outcompeted EG.5.1 in countries such as Australia, China, South Korea, and Singapore (appendix p 16). Next, to identify whether the enhanced infectivity of HK.3 contributes to its higher Re, we constructed lentivirus-based pseudoviruses carrying the S proteins XBB.1.5, EG.5.1, HK.3, and an XBB.1.5 derivative, XBB.1.5+L455F. Although the S:L455F substitution significantly increased the infectivity of XBB.1.5, the infectivity of HK.3 (identical to EG.5.1+S:L455F) was similar to that of EG.5.1 (appendix p 16). The difference in the effect of S:L455F between XBB.1.5 and EG.5.1 might be attributed to the epistatic effects due to the S protein structures of XBB.1.5 and EG.5.1. These results suggest that the increased Re of HK.3 is not owing to the increased infectivity caused by S:L455F. We then performed a neutralisation assay using breakthrough infection serum samples (XBB.1.5 [n=20], XBB.1.9 [n=15], XBB.1.16 [n=20], or EG.5.1 [n=18]) to address whether HK.3 evades the antiviral response of humoral immunity induced by breakthrough infection of these variants. The 50% neutralisation titre (NT50) for all breakthrough infection serum samples tested against XBB.1.5+S:L455F was significantly lower than that observed against the parental XBB.1.5 strain (appendix p 16). Notably, the NT50 for EG.5.1 breakthrough infection serum samples against HK.3 was significantly lower (1·6 times, p=0·0003) than that observed against EG.5.1 (appendix p 16). Thus, the increased Re of HK.3 might be partly attributed to the enhanced immune evasion from humoral immunity elicited by breakthrough infection subvariants of XBB, including EG.5.1, its ancestor. S:L455F is a key mutation leading to this immune evasion. JI has received consulting fees and honoraria for lectures from Takeda Pharmaceutical. KSat has received consulting fees from Moderna Japan and Takeda Pharmaceutical and has received honoraria for lectures from Gilead Sciences, Moderna Japan, and Shionogi & Co. All other authors declare no competing interests. YKo, AP, and OP contributed equally. This work was supported in part by the Japan Agency for Medical Research and Development (AMED) Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA (JP223fa627001, to KSat), AMED SCARDA Programme on R&D of New Generation Vaccine including New Modality Application (JP223fa727002, to KSat); AMED Research Programme on Emerging and Re-emerging Infectious Diseases (JP22fk0108146, to KSat; JP21fk0108494, to G2P-Japan Consortium and KSat; JP21fk0108425, to KSat; JP21fk0108432, to KSat; JP22fk0108511, to G2P-Japan Consortium and KSat; JP22fk0108516, to KSat; JP22fk0108506, to KSat); AMED Research Programme on HIV/AIDS (JP22fk0410039, to KSat); JST PRESTO (JPMJPR22R1, to JI); JST CREST (JPMJCR20H4, to KSat); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (23K14526, to JI); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to KSat); JSPS Research Fellow DC2 (22J11578, to KU); JSPS Research Fellow DC1 (23KJ0710, to YKo); The Tokyo Biochemical Research Foundation (to KSat); and The Mitsubishi Foundation (to KSat). Members of the G2P-Japan Consortium are listed in the appendix (p 18). Download .pdf (.63 MB) Help with pdf files Supplementary appendix
Abstract Recently, it was found that in the gynogenetic haploid and diploid embryos of goldfish, which have exactly the same genome, the haploid condition results in obstruction of gene expression and abnormal development while the diploid embryos have normal gene expression and development. A diploid‐dependent regulatory apparatus was proposed to regulate gene expression. To study the difference at the protein expression level of the embryos of haploid and diploid in development, we extracted the total proteins of both the gynogenetic haploid and diploid embryos of goldfish in the same eye formation stage. Two‐dimensional polyacrylamide gel electrophoresis was used to separate proteins. The stained gel images were analyzed with the PDQUEST software. A part of protein spots that were differentially expressed in haploid and diploid embryos were identified by matrix assisted laser desorption/ionisation‐time of flight‐mass spectrometry and database analysis. Sixteen protein spots that were absolutely different (only expressed in diploid embryos but not in haploid embryos or vice versa ) and 16 protein spots that were up‐ and downregulated were identified unambiguously, which include some proteins that are correlative with eyes development, nerve development, developing regulation, cell differentiation, and signal transduction. The different significantly gene expression during embryos developing between diploid and haploid is demonstrated.
Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization.
Abstract Purpose In this study, we aim to explore the efficacy of paxlovid on reducing mortality of COVID-19 patients in clinical setting, especially whether paxlovid modifies the risk of death in these severe and critical patients. Methods Our retrospective cohort study was conducted on the medical records of patients, consecutively admitted for COVID-19 to five hospitals in Chongqing, China from Dec 8, 2022 to Jan 20, 2023. Based on whether patients received paxlovid during their hospitalization, patients were grouped as paxlovid group and non-paxlovid group. We used 1:1 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between groups. Statistical analysis were performed by SPSS 23.0. The differences in 28-day mortality between these two groups and its influencing factors were the main results we focused on. Results There were 1018 patients included in our study cohort. With 1:1 ratio PSM, each of the paxlovid group and non-paxlovid group included 237 patients. The results showed that patients using paxlovid have a lower 28-day mortality in overall population either before PSM (OR 0.594, 95% CI 0.385–0.917, p = 0.019) or after PSM (OR 0.458, 95% CI 0.272–0.774, p = 0.003) with multivariable adjusted logistic regression models. Meanwhile, in severe subgroup, it showed similar findings.With paxlovid treatment, it showed a significantly lower 28-day mortality in severe subgroup both before PSM (28% vs.41%, p = 0.008) and after PSM (19% vs.32%, p = 0.007). Conclusion Paxlovid can significantly reduce the risk of 28-day mortality in overall population and severe subgroup patients.This study distinguished the severe subgroup patients with COVID-19 who benefit more from paxlovid treatment.
The SPARC is a crucial matricellular protein and may influence the course of various diseases like tumor metastasis and fibrosis. In the present study, we investigated the association between the potential functional polymorphisms in SPARC and coal workers' pneumoconiosis (CWP) risk in a Chinese population.Five potentially functional polymorphisms (rs1059279, rs1059829, rs1053411, rs2304052 and rs4958281) in SPARC were genotyped and analyzed in a case-control study including 697 CWP cases and 694 controls. The genotyping was used by the TaqMan method with the ABI 7900HT Real Time PCR system.Our results revealed that three SNPs (rs1059279, rs1059829, rs1053411) were significantly associated with increased risk of CWP under an additive model (OR = 1.35, 95%CI = 1.06-1.71, P = 0.015 for rs1059279; OR = 1.20, 95%CI = 1.03-1.39, P = 0.021 for rs1059829; OR = 1.31, 95%CI = 1.03-1.65, P = 0.025 for rs1053411). In the stratification analysis, significant associations were observed between each of these three SNPs and patients with 0-20 pack-years of smoking (OR = 1.73, 95%CI = 1.21-2.45 for rs1059279; OR = 1.48, 95%CI = 1.07-2.05 for rs105982; OR = 1.58, 95%CI = 1.13-2.22 for rs1053411). Furthermore, the association between rs1059279 and CWP risk remained significant among subjects with over 27 years of exposure (OR = 1.27, 95%CI = 1.03-1.56, P = 0.023). In the combined analysis of these five polymorphisms, individuals with multiple risk alleles had a higher risk of CWP (Ptrend = 0.015).Our results indicate that three functional SPARC SNPs are associated with an increased risk of CWP in a Chinese population. Further functional research and validation studies with diverse populations are warranted to confirm our findings.
Coal workers' pneumoconiosis (CWP) is characterized by chronic pulmonary inflammation and fibrotic nodular lesions that usually lead to progressive fibrosis. Inflammation is the first step in the development of CWP. E-selectin, an adhesion molecule, is involved in the development of various inflammatory diseases.We investigated the association between the functional polymorphisms in SELE and the risk of CWP in Han Chinese population. Three polymorphisms (T1880C/rs5355, T1559C/rs5368, A16089G/rs4786) in SELE were genotyped and analyzed in a case-control study with 697 CWP cases and 694 controls. The genotyping was based on the TaqMan method with the ABI 7900HT Real Time PCR system.The SELE rs5368 CT genotype was associated with a significantly increased risk of CWP (OR = 1.28, 95% CI = 1.02-1.60, P = 0.03) relative to the CC genotype. The statistical analysis of classification and regression tree (CART) and multifactor dimensionality reduction (MDR) were used to predict the interactions among risk factors of CWP. The MDR analysis found that the best interaction model was the two-factor model that contains pack-years smoked and SELE rs5368 genotypes. For non-smokers, the CART analysis showed an increased risk of CWP for carriers of the SELE rs_5368 variant genotype compared with the common genotype (OR = 1.51; 95% CI = 1.11-2.05, P = 0.0069).The results suggest that the T1559C/rs5368 polymorphism and smoking are involved in the susceptibility to CWP. Further studies are warranted to validate these findings.
Patients with extremely severe oligozoospermia (ESO) and cryptozoospermia (CO) are suitable using intracytoplasmic sperm injection (ICSI) as an infertility treatment. However, some andrologists are confused to distinguish ESO and CO in clinic diagnose. This study was designed for the first time to evaluate and compare patients with ESO and CO to determine whether these are useful clinical distinctions. A total of 270 infertile men in our center were classified into four groups as Group nonobstruction azoospermia (NOA, n = 44), Group ESO (n = 78), Group CO (n = 40), and Group obstruction azoospermia (OA, n = 108). Comparisons of the volume of bilateral testes, the level of follicle stimulating hormone (FSH) and inhibin B were obtained in four groups. Then comparisons of fertilization rates, cleavage rate, and excellent embryos rate were obtained when couples performed ICSI. All indexes (volume of bilateral testis, level of FSH and inhibin B) in Groups ESO and CO were no difference, while Groups OA versus NOA, OA versus ESO, and OA versus CO were significant differences (P < 0.05). The rates of fertilization were no differences in Groups ESO and CO while Groups OA versus ESO, OA versus CO were significant differences (P < 0.05). Therefore, the spermatogenic functions in patients with CO and ESO were similar, better than NOA but worse than OA. However, it would be helpful to evaluate their spermatogenesis using testicular biopsies, especially accompanied azoospermia in clinical practice.
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