A male germ-cell-specific ribosome controls male fertility.

Ribosomes are highly sophisticated translation machines that have been demonstrated to be heterogeneous in the regulation of protein synthesis1,2. Male germ cell development involves complex translational regulation during sperm formation3. However, it remains unclear whether translation during sperm formation is performed by a specific ribosome. Here we report a ribosome with a specialized nascent polypeptide exit tunnel, RibosomeST, that is assembled with the male germ-cell-specific protein RPL39L, the paralogue of core ribosome (RibosomeCore) protein RPL39. Deletion of RibosomeST in mice causes defective sperm formation, resulting in substantially reduced fertility. Our comparison of single-particle cryo-electron microscopy structures of ribosomes from mouse kidneys and testes indicates that RibosomeST features a ribosomal polypeptide exit tunnel of distinct size and charge states compared with RibosomeCore. RibosomeST predominantly cotranslationally regulates the folding of a subset of male germ-cell-specific proteins that are essential for the formation of sperm. Moreover, we found that specialized functions of RibosomeST were not replaceable by RibosomeCore. Taken together, identification of this sperm-specific ribosome should greatly expand our understanding of ribosome function and tissue-specific regulation of protein expression pattern in mammals.

STK33 Phosphorylates Fibrous Sheath Protein AKAP3/4 to Regulate Sperm Flagella Assembly in Spermiogenesis.

Spermatogenesis defects are important for male infertility; however, the etiology and pathogenesis are still unknown. Herein, we identified two loss-of-function mutations of STK33 in seven individuals with non-obstructive azoospermia. Further functional studies of these frameshift and nonsense mutations revealed that Stk33-/KI male mice were sterile, and Stk33-/KI sperm were abnormal with defects in the mitochondrial sheath, fibrous sheath, outer dense fiber, and axoneme. Stk33KI/KI male mice were subfertile and had oligoasthenozoospermia. Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components A-kinase anchoring protein 3 and A-kinase anchoring protein 4, whose expression levels decreased in testis after deletion of Stk33. STK33 regulated the phosphorylation of A-kinase anchoring protein 3/4, affected the assembly of fibrous sheath in the sperm, and played an essential role in spermiogenesis and male infertility.

Maternal RNF114-mediated target substrate degradation regulates zygotic genome activation in mouse embryos.

Zygotic genomic activation (ZGA) is a landmark event in the maternal-to-zygotic transition (MZT), and the regulation of ZGA by maternal factors remains to be elucidated. In this study, the depletion of maternal ring finger protein 114 (RNF114), a ubiquitin E3 ligase, led to developmental arrest of two-cell mouse embryos. Using immunofluorescence and transcriptome analysis, RNF114 was proven to play a crucial role in major ZGA. To study the underlying mechanism, we performed protein profiling in mature oocytes and found a potential substrate for RNF114, chromobox 5 (CBX5), ubiquitylation and degradation of which was regulated by RNF114. The overexpression of CBX5 prevented embryonic development and impeded major ZGA. Furthermore, TAB1 was abnormally accumulated in mutant two-cell embryos, which was consistent with the result of in vitro knockdown of Rnf114. Knockdown of Cbx5 or Tab1 in maternal RNF114-depleted embryos partially rescued developmental arrest and the defect of major ZGA. In summary, our study reveals that maternal RNF114 plays a precise role in degrading some important substrates during the MZT, the misregulation of which may impede the appropriate activation of major ZGA in mouse embryos.

A Novel Mechanism Linking Melatonin, Ferroptosis and Microglia Polarization via the Circodz3/HuR Axis in Subarachnoid Hemorrhage.

A subarachnoid hemorrhage (SAH) is life-threatening bleeding into the subarachnoid space that causes brain damage. Growing evidence has suggested that melatonin provides neuroprotection following SAH. Exploring the mechanisms underlying melatonin-mediated neuroprotection contributes to its clinical application in SAH. The plasma and cerebrospinal fluid (CSF) were collected from SAH patients, and SAH mice were established via pre-chiasmatic injection. Circodz3 expression, levels of IL-1ß and TNF-α, brain water content, neurological and beam-waling scores were determined. Ferroptosis was evaluated by analyzing levels of iron, lipid ROS, MDA, and GSH. The colocalization of circodz3 and Iba-1 was analyzed by immunofluorescence staining. Interaction of circodz3 and HuR was determined with RNA pull-down and RNA immunoprecipitation assays. Herein, we found that circodz3 was highly abundant in SAH patients and mice. Colocalization of circodz3 and Iba-1 in the left hemisphere of SAH mice suggested the implication of circodz3 in regulating microglia activation following SAH. Melatonin alleviated brain edema, neurological impairment, and microglia activation and inhibited circodz3 expression in SAH mice. Moreover, melatonin inhibited M1 polarization, oxidative stress and ferroptosis and restrained circodz3 expression in primary microglia following SAH. These effects were abrogated by circodz3 overexpression. Circodz3 knockdown inhibited ferroptosis and M1 polarization of BV2 microglia after SAH. Circodz3 interacted with HuR to facilitate ß-Trcp1-mediated ubiquitination and degradation, thus restraining the expression of SLC7A11 and GPX4. Collectively, melatonin exerted neuroprotection following SAH via inhibiting ferroptosis and M1 polarization through the circodz3/HuR axis. Our study suggests potential application of melatonin in the treatment of SAH.

A Natural Bioactive Peptide from Pinctada fucata Pearls Can Be Used as a Potential Inhibitor of the Interaction between SARS-CoV-2 and ACE2 against COVID-19.

The frequent occurrence of viral infections poses a serious threat to human life. Identifying effective antiviral components is urgent. In China, pearls have been important traditional medicinal ingredients since ancient times, exhibiting various therapeutic properties, including detoxification properties. In this study, a peptide, KKCH, which acts against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was derived from Pinctada fucata pearls. Molecular docking showed that it bound to the same pocket of the SARS-CoV-2 S protein and cell surface target angiotensin-converting enzyme II (ACE2). The function of KKCH was analyzed through surface plasmon resonance (SPR), Enzyme-Linked Immunosorbent Assays, immunofluorescence, and simulation methods using the SARS-CoV-2 pseudovirus and live virus. The results showed that KKCH had a good affinity for ACE2 (KD = 6.24 × 10-7 M) and could inhibit the binding of the S1 protein to ACE2 via competitive binding. As a natural peptide, KKCH inhibited the binding of the SARS-CoV-2 S1 protein to the surface of human BEAS-2B and HEK293T cells. Moreover, viral experiments confirmed the antiviral activity of KKCH against both the SARS-CoV-2 spike pseudovirus and SARS-CoV-2 live virus, with half-maximal inhibitory concentration (IC50) values of 398.1 µM and 462.4 µM, respectively. This study provides new insights and potential avenues for the prevention and treatment of SARS-CoV-2 infections.

Prediction model for successful induction of labor by cervical strain elastography diagnosed at late-term pregnancy in nulliparous women: a prospective cohort study.

BACKGROUND: The use of cervical strain elastography for nulliparous women during late-term pregnancy remains unclear. This study assesses the predictive value of late-term cervical strain elastography for successful induction of labor (IOL) in nulliparous women. METHODS: This single-centered, prospective study included 86 patients undergoing IOL between January 2020 and March 2022. Univariate and multivariate analyses were conducted to identify predictive factors for successful IOL. The predictive values were assessed using the area under receiver operating characteristic (ROC) curves. RESULTS: IOL was successful in 58 patients. The hardness ratio and cervical length were significantly associated with successful late-term IOL in nulliparous women. The predictive value of the combination of hardness ratio and cervical length was higher than that of cervical length alone. CONCLUSIONS: The hardness ratio and cervical length assessed by cervical strain elastography during late-term pregnancy are predictors of the success of IOL in nulliparous women. The predictive value of the combination of hardness ratio and cervical length was higher than that of cervical length alone.

Global phosphoproteomic analysis identified key kinases regulating male meiosis in mouse.

Meiosis, a highly conserved process in organisms from fungi to mammals, is subjected to protein phosphorylation regulation. Due to the low abundance of phosphorylation, there is a lack of systemic characterization of phosphorylation regulation of meiosis in mammals. Using the phosphoproteomic approach, we profiled large-scale phosphoproteome of purified primary spermatocytes undergoing meiosis I, and identified 14,660 phosphorylation sites in 4419 phosphoproteins. Kinase-substrate phosphorylation network analysis followed by in vitro meiosis study showed that CDK9 was essential for meiosis progression to metaphase I and had enriched substrate phosphorylation sites in proteins involved in meiotic cell cycle. In addition, histones and epigenetic factors were found to be widely phosphorylated. Among those, HASPIN was found to be essential for male fertility. Haspin knockout led to misalignment of chromosomes, apoptosis of metaphase spermatocytes and a decreased number of sperm by deregulation of H3T3ph, chromosomal passenger complex (CPC) and spindle assembly checkpoint (SAC). The complicated protein phosphorylation and its important regulatory functions in meiosis indicated that in-depth studies of phosphorylation-mediated signaling could help us elucidate the mechanisms of meiosis.

[Alterations in the intestinal microbiota of preterm infants with neurodevelopmental impairments: a prospective cohort study]. / ç¥žç»å‘è‚²æŸå®³æ—©äº§å„¿è‚ é“èŒç¾¤å˜åŒ–çš„å‰çž»æ€§é˜Ÿåˆ—ç ”ç©¶.

OBJECTIVES: To investigate the difference in intestinal microbiota between preterm infants with neurodevelopmental impairment (NDI) and those without NDI. METHODS: In this prospective cohort study, the preterm infants who were admitted to the neonatal intensive care unit of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from September 1, 2019 to September 30, 2021 were enrolled as subjects. According to the assessment results of Gesell Developmental Scale at the corrected gestational age of 1.5-2 years, they were divided into two groups: normal (n=115) and NDI (n=100). Fecal samples were collected one day before discharge, one day before introducing solid food, and at the corrected gestational age of 1 year. High-throughput sequencing was used to compare the composition of intestinal microbiota between groups. RESULTS: Compared with the normal group, the NDI group had a significantly higher Shannon diversity index at the corrected gestational age of 1 year (P<0.05). The principal coordinate analysis showed a significant difference in the composition of intestinal microbiota between the two groups one day before introducing solid food and at the corrected gestational age of 1 year (P<0.05). Compared with the normal group, the NDI group had a significantly higher abundance of Bifidobacterium in the intestine at all three time points, a significantly higher abundance of Enterococcus one day before introducing solid food and at the corrected gestational age of 1 year, and a significantly lower abundance of Akkermansia one day before introducing solid food (P<0.05). CONCLUSIONS: There are significant differences in the composition of intestinal microbiota between preterm infants with NDI and those without NDI. This study enriches the data on the characteristics of intestinal microbiota in preterm infants with NDI and provides reference for the microbiota therapy and intervention for NDI in preterm infants.

Comparative study on sex hormone secretion in peripheral blood of women with common hematological tumors before and after chemotherapy.

This study aimed to explore the secretion of sex hormones in peripheral blood of women with common hematological tumors before and after chemotherapy. From January 2019 to April 2021, 100 female patients with common hematological tumors in our hospital were selected as the observation group, and 50 healthy women in our hospital during the same period were selected as the control group. The serum levels of follicle-stimulating hormone (FSH), estradiol (E2) and luteinizing hormone (LH) were detected and compared between the observation group and the control group before chemotherapy, patients with different disease types in the observation group, postmenopausal patients in the observation group, and postmenopausal patients in the observation group. Results showed that the serum FSH, E2 and LH levels of the observation group had no significant changes before chemotherapy (P > 0.05). Compared with before chemotherapy, the levels of serum FSH and LH in patients with different disease types in the observation group after chemotherapy were significantly higher, while E2 was significantly lower (P < 0.05), and the serum FSH, E2 and LH levels of postmenopausal patients in the observation group did not change significantly after chemotherapy (P > 0.05). The levels of FSH and LH in the observation group after chemotherapy were significantly higher, and E2 was significantly lower (P < 0.05). In general, the levels of sex hormone secretion in peripheral blood of women with common hematological tumors before and after chemotherapy can change significantly, especially in postmenopausal patients, but not in postmenopausal patients, which has a certain reference value for clinical practice.

Emergency Removal of Ingested Foreign Bodies in 586 Adults at a Single Hospital in China According to the European Society of Gastrointestinal Endoscopy (ESGE) Recommendations: A 10-Year Retrospective Study.

BACKGROUND The 2016 European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend that ingested foreign bodies in the upper gastrointestinal (GI) tract are removed as an emergency within 6 hours, with an endoscopic approach that is individualized according to the type of foreign body identified. This retrospective study evaluated the 10-year experience of a single hospital in China performing emergency removal of ingested foreign bodies in 586 adults. MATERIAL AND METHODS Between 2011 and 2020, medical records of 642 adults with a diagnosis of foreign bodies ingestion were retrospectively screened. The timing of endoscopic intervention was classified according to ESGE recommendations. Uni- and multivariate analyses were performed. RESULTS We included 586 patients. The median (range) diameter of foreign bodies was 2.5 (1-24) cm: for sharp ones it was 2.5 (1.5-4.0) cm and for long ones it was 16.9 (10-24) cm. The most common site of foreign body lodgment was the esophagus (n=481; 82.1%); 45.6% (n=252) received emergent removal within 6 hours, while 32.2% (n=178) underwent urgent removal within 24 hours. There were 583 (99.5%) foreign bodies removed successfully and the complication rate was 17.9%. Major complications occurred in 45 patients (7.7%). Female sex and non-emergent endoscopy after 6 hours were significantly associated with a higher overall complications rate. For major complications, older age, time interval >24 hours, and sharper objects were associated with major complications. CONCLUSIONS The findings from this retrospective study support the ESGE statement that endoscopic removal of ingested foreign bodies from the upper GI tract within 6 hours reduces complication rates for adults in the emergency setting.