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OBJECTIVE: This study aimed to explore the clinical detection and prognosis of coagulation function in patients with liver failure and sepsis. METHODS: The plasma fibrinogen (FIB), factor II, factor VII, factor V, factor IV, antithrombin III (ATIII), platelet (PLT), mean PLT volume (MPV), D-dimer, prothrombin activity (PTA), and fibrin degradation product (FDP) levels and thromboelastogram values were detected in patients with liver failure complicated with sepsis and compared with those in the liver failure and liver cirrhosis groups. The patients with liver failure complicated with sepsis were analyzed by univariate and multivariate logistic regression, and the regression equation was established. RESULTS: The levels of FIB, factor II, factor VII, factor V, ATIII, PLT, MPV, D-dimer, and FDP in the patients with liver failure complicated with sepsis were compared with those in the control group patients, and the differences were statistically significant (p

The high rate of SARS-CoV-2 infection poses a serious threat to public health. Previous studies have suggested that SARS-CoV-2 can infect human ovary, the core organ of the female reproductive system. However, it remains unclear which type of ovarian cells are easily infected by SARS-CoV-2 and whether ovarian infectivity differs from puberty to menopause. In this study, public datasets containing bulk and single-cell RNA-Seq data derived from ovarian tissues were analyzed to demonstrate the mRNA expression and protein distribution of the two key entry receptors for SARS-CoV-2—angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2). Furthermore, an immunohistochemical study of ACE2 and TMPRSS2 in human ovaries of different ages was conducted. Differentially expressed gene (DEG) analysis of ovaries of different ages and with varying ovarian reserves was conducted to explore the potential functions of ACE2 and TMPRSS2 in the ovary. The analysis of the public datasets indicated that the co-expression of ACE2 and TMPRSS2 was observed mostly in oocytes and partially in granulosa cells. However, no marked difference was observed in ACE2 or TMPRSS2 expression between young and old ovaries and ovaries with low and high reserves. Correspondingly, ACE2 and TMPRSS2 were detected in the human ovarian cortex and medulla, especially in oocytes of different stages, with no observed variations in their expression level in ovaries of different ages, which was consistent with the results of bioinformatic analyses. Remarkably, DEG analysis showed that a series of viral infection-related pathways were more enriched in ACE2-positive ovarian cells than in ACE2-negative ovarian cells, suggesting that SARS-CoV-2 may potentially target specific ovarian cells and affect ovarian function. However, further fundamental and clinical research is still needed to monitor the process of SARS-CoV-2 entry into ovarian cells and the long-term effects of SARS-CoV-2 infection on the ovarian function in recovered females.

Objective The current study aimed to further verify the feasibility of ultrasound-guided selective pulsed radiofrequency (PRF) therapy of greater auricular nerve (GAN) in the treatment of head and neck post-herpetic neuralgia (PHN) by observing the efficacy and safety. Methods Under the guidance of high-frequency ultrasound (Frequency: 10 MHz), the GAN was identified by a radiofrequency electrode trocar with a transverse in-plane approach, which was inserted into the GAN, then the inner needle of the trocar was retracted. After adjusting the technical variables (electrode tip temperature: 42°C, output voltage: 60 V, pulse frequency: 2 Hz, pulse width: 22 ms, single duration: 240 s, two times), the radiofrequency electrode placed on the auricle and below the ear for sensory and motor tests began to work. Results The pain in the left head and neck of the patient lasted for more than 1 month, we decided to try selective PRF of GAN guided by ultrasound for the first time. Immediately after the treatment, 11-point pain intensity numerical rating scale (PI-NRS) score ranged from 5 to 1. During his hospitalization, mecobalamine and gabapentin were taken instead of opioids. Seven days after the procedure, PI-NRS score was 2, the degree of numbness the patient he felt by himself in the original lesion area relieved from 100% to 40%, the depression module of the Patient Health Questionnaire-9 (PHQ-9) score was from 7 to 5, the Generalized Anxiety Disorder-7 (GAD-7) score from 8 to 4, the range of pain areas was reduced to external auditory tract, and there were no adverse events occurring. Conclusion The ultrasound-guided selective PRF treatment of GAN was safe and effective in the improvement of PHN in the head and neck, which is worthy of clinical promotion.

Cancer is a major threat to human health worldwide, yet the clinical therapies remain unsatisfactory. In this study, we found that a Tetrastigma hemsleyanum leaves flavone (TLF) intervention could achieve tumor inhibition. Besides, neochlorogenic acid (NA), which had the highest absorbance peak in the HPLC profile of TLF, showed superior anti-proliferation ability over TLF, and could effectively trigger apoptosis, restrain migration, and facilitate cytoskeleton collapse, suggesting its key role in TLF's anticancer property. Molecular docking analysis suggested that NA was capable of binding with mitochondrial Ca2+ uniporter (MCU), and further experiments confirmed that NA upregulated the MCU level to permit excess calcium ion influx, leading to mitochondrial calcium imbalance, dysfunction, structure alteration, and ROS elevation. Moreover, tumor-bearing mice were applied to further confirm the excellent tumor inhibition ability of NA under Ca2+-abundant conditions. Therefore, this study uncovered that NA could effectively trigger robust MCU-mediated calcium overload cancer therapy, which could be utilized in novel strategies for future cancer treatment.

Throat aurora was defined based on the ground observations near local noon and has been suggested to be the ground signature of an indentation on the subsolar magnetopause. A global view of the auroral oval with throat aurora will be critical for inferring global processes at the magnetopause, but it has never been achieved. Using imaging spectrograph observations from Defense Meteorological Satellite Program satellites, for the first time, here we show typical throat auroras in a global view and reveal some important observational facts as follows. (1) The throat auroras can be as long as ~8 degrees in latitudinal direction, which is hardly to be fully seen in the ground-based camera. (2) The plasma flows and field aligned currents associated with throat aurora show consistences with previous radar observations, which have been suggested to be the observational evidence of magnetopause reconnection. (3) Most importantly, we confirmed that the electron and ion precipitations associated with throat aurora are always spatially separated, i.e., electrons in the east and ions in the west. The observational results not only establish a new picture of the aurora oval near local noon, but also provide important support to a conceptual model of throat aurora.

PURPOSE: We aimed to evaluate the safety and effectiveness of radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) guided by multiple imaging modalities for hepatocellular carcinomas (HCCs) in special (i.e., high-risk or unfavorable) locations compared with those in conventional locations. METHODS: A total of 122 HCC patients were enrolled, including 85 patients (69.7%) with HCC in conventional locations and 37 (30.3%) with HCC in special locations. The clinical data, overall survival (OS), progression-free survival (PFS), and procedure-related adverse events were analyzed. RESULTS: RFA combined with TACE was successfully performed in all patients. Three complications (2.5%) occurred, with no significant difference between the conventional (n=1, 1.2%) and special (n=2, 5.4%) locations (P = 0.218). Complete tumor necrosis rate was not significantly different between the conventional (n=73, 85.9%) and special (n=34, 91.9%) locations at one-month imaging (P = 0.353). After a follow-up of 3–48 months, the PFS was 17 months for patients with HCC in conventional locations and 14 months for patients with HCC in special locations; one-year PFS rate was 68.1% in the conventional location group, not significantly (P = 0.741) different from 59.1% in the special location group. The OS was 28 months in the conventional location group while 32 months in the special location group. The cumulative one- and two-year OS rates were 89.9% and 63.3%, respectively, in the conventional location group, not significantly different from 96.3% and 65% in the special location group (P = 0.273). Age (P = 0.043) and tumor size (P < 0.001) were significant prognostic factors for OS, and tumor size (P < 0.001) was the only significant prognostic factor for PFS. CONCLUSION: RFA guided by multiple imaging modalities combined with TACE may be safe and effective for treating HCCs in special locations.

Background: Population-based data on the risk assessment of newly diagnosed cervical cancer patients' bone metastasis (CCBM) are lacking. This study aimed to develop various predictive models to assess the risk of bone metastasis via machine learning algorithms.Materials and Methods: We retrospectively reviewed the CCBM patients from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute to risk factors of the presence of bone metastasis. Clinical usefulness was assessed by Akaike information criteria (AIC) and multiple machine learning algorithms based predictive models. Concordance index (C-index) and receiver operating characteristic (ROC) curve were used to define the predictive and discriminatory capacity of predictive models.Results: A total of 16 candidate variables were included to develop predictive models for bone metastasis by machine learning. The areas under the ROC curve (AUCs) of the random forest model (RF), generalized linear model (GL), support vector machine (SVM), eXtreme Gradient Boosting (XGBoost), artificial neutral network (ANN), decision tree (DT), and naive bayesian model (NBM) ranged from 0.85 to 0.93. The RF model with 10 variables was developed as the optimal predictive model. The weight of variables indicated the top seven factors were organ-site metastasis (liver, brain, and lung), TNM stage and age.Conclusions: Multiple machine learning based predictive models were developed to identify risk of bone metastasis in cervical cancer patients. By incorporating clinical characteristics and other candidate variables showed robust risk stratification for CCBM patients, and the RF predictive model performed best among these predictive models.

Chemotherapy-induced ovarian damage and fertility loss have negative impacts on the quality of life for female cancer patients worldwide. Thus, we aimed to explore the feasibility and safety of gene therapy for prevention of such damage. First, we validated doxorubicin-induced ovarian damage in human and mouse ovarian tissues and identified two key genes (Sirt1 and Tgfbr2). Next, we generated AdV-Sirt1 and AdV-Tgfbr2 after vectors screening (AdV,AAV and LV) for their ability to transduce mouse ovaries. Finally, we conducted in situ ovarian injection of AdV-Sirt1 and AdV-Tgfbr2 in doxorubicin-treated mice and assessed their ovarian functions and reserves. The interventions dramatically alleviated doxorubicin-induced ovarian damage without apparently influencing the health status of their offspring. Together, our results indicate that AdV-Sirt1 and AdV-Tgfbr2 can serve as effective and safe agents for reducing doxorubicin-induced ovarian damage and also suggest that they may be potentially applicable for post-chemotherapy protection in female cancer patients.

As a fundamental aging mechanism, cellular senescence causes chronic inflammation via the senescence-associated secretory phenotype (SASP). Theca-interstitial cells are an essential but little-studied component of follicle development in the ovarian microenvironment. In the present study, we observed significant cellular senescence in theca-interstitial cells and secretion of chemokine (C-C motif) ligand 5 (CCL5) by these cells during aging. Furthermore, we aimed to investigate whether and how senescence-associated secretory phenotype (SASP)-associated CCL5 may be involved in follicle development. Increased levels of CCL5 in the microenvironment of follicles attenuated preantral follicle growth, survival, and estradiol secretion. Oocyte maturation and the expression of zona pellucida 3 and differentiation factor 9 (GDF9) were also inhibited by CCL5. Granulosa cell apoptosis in follicles was promoted by CCL5, accompanied by the phosphorylation of nuclear factor-κB by CCL5 and inhibition of the PI3K/AKT pathway. These results suggest that SASP-associated CCL5 produced by senescent theca-interstitial cells may impair follicle development and maturation during ovarian aging by promoting granulosa cell apoptosis.

To explore the clinical and imaging characteristics and summarize the causes of missed diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS) in eclampsia. We collected the data of a total of 45 patients with RPLS who were misdiagnosed initially (27 cases were confirmed and 18 cases were suspicious) out of 804 patients with severe eclampsia who had presented themselves to the Affiliated Hospital of Xuzhou Medical University from January 2014 to December 2016. We summarized the clinical and imaging characteristics of the patients and analyzed the possible causes of the misdiagnosis. Among the 804 patients with eclampsia, 45 were misdiagnosed the first time. Their clinical manifestations included headache (20 cases), epilepsy (13 cases), blurred vision (11 cases), disturbance of consciousness (2 cases), and drowsiness (3 cases). The parietal lobe was involved in 22 cases, the occipital lobe in 15 cases, the frontal lobe in 20 cases, basal ganglia in 9 cases, and the temporal lobe in 8 cases. Low-density lesions were observed on computed tomography (CT) scans. Head magnetic resonance (MR) scans showed hypo-intense lesions on T1-weighted image (T1WI), hyper-intense lesions on the T2-weighted image (T2WI) and fluid-attenuated inversion recovery (FLAIR), iso-intense or slightly hyper-intense lesion on diffusion-weighted imaging (DWI), and slightly hyper-intense or hypo-intense lesion on apparent diffusion coefficient (ADC). The incidence of reversible posterior leukoencephalopathy syndrome is extremely high. The clinical features include headache, mental disturbance, seizures, blurred vision, and other neurological symptoms. The lesion area is mainly limited to the parietal and occipital lobes; however, the frontal lobe, basal ganglia, temporal lobe, corpus callosum, and cerebellum can also be involved. The prognosis is good with timely and appropriate treatments.

Aging has been regarded as a treatable condition, and delaying aging could prevent some diseases. Ovarian aging, a special type of organ senescence, is the earliest-aging organ, as ovaries exhibit an accelerated rate of aging with characteristics of gradual declines in ovarian follicle quantity and quality since birth, compared to other organs. Ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body. Hence, anti-ovarian aging has become a research topic broadly interesting to both biomedical scientists and pharmaceutical industry. A marked progress has been made in exploration of possible anti-ovarian agents or approaches, such as calorie restriction mimetics, antioxidants, autophagy inducers etc., over the past years. This review is attempted to discuss recent advances in the area of anti-ovarian aging pharmacology and to offer new insights into our better understanding of molecular mechanisms underlying ovarian aging, which might be informative for future prevention and treatment of ovarian aging and its related diseases.

Objectives: Both coronavirus disease 2019 (COVID-19) pneumonia and influenza A (H1N1) pneumonia are highly contagious diseases. We aimed to characterize initial computed tomography (CT) and clinical features and to develop a model for differentiating COVID-19 pneumonia from H1N1 pneumonia.Methods: In total, we enrolled 291 patients with COVID-19 pneumonia from January 20 to February 13, 2020, and 97 patients with H1N1 pneumonia from May 24, 2009, to January 29, 2010 from two hospitals. Patients were randomly grouped into a primary cohort and a validation cohort using a seven-to-three ratio, and their clinicoradiologic data on admission were compared. The clinicoradiologic features were optimized by the least absolute shrinkage and selection operator (LASSO) logistic regression analysis to generate a model for differential diagnosis. Receiver operating characteristic (ROC) curves were plotted for assessing the performance of the model in the primary and validation cohorts.Results: The COVID-19 pneumonia mainly presented a peripheral distribution pattern (262/291, 90.0%); in contrast, H1N1 pneumonia most commonly presented a peribronchovascular distribution pattern (52/97, 53.6%). In LASSO logistic regression, peripheral distribution patterns, older age, low-grade fever, and slightly elevated aspartate aminotransferase (AST) were associated with COVID-19 pneumonia, whereas, a peribronchovascular distribution pattern, centrilobular nodule or tree-in-bud sign, consolidation, bronchial wall thickening or bronchiectasis, younger age, hyperpyrexia, and a higher level of AST were associated with H1N1 pneumonia. For the primary and validation cohorts, the LASSO model containing above eight clinicoradiologic features yielded an area under curve (AUC) of 0.963 and 0.943, with sensitivity of 89.7 and 86.2%, specificity of 89.7 and 89.7%, and accuracy of 89.7 and 87.1%, respectively.Conclusions: Combination of distribution pattern and category of pulmonary opacity on chest CT with clinical features facilitates the differentiation of COVID-19 pneumonia from H1N1 pneumonia.

Long non‑coding RNAs (lncRNAs) are involved in the development and progression of a variety of diseases. However, the role of the lncRNA HLA complex group 11 (HCG11) in non‑small cell lung cancer (NSCLC) remains unclear. The present study showed that the expression levels of HCG11 were reduced in tumor tissues compared with adjacent normal tissues, and similar results were obtained in experiments using lung cancer cell lines. Additionally, patients with high HCG11 expression had an increased survival rate compared with patients with low HCG11 expression. Further studies have shown that overexpression of HCG11 inhibited NSCLC cell proliferation in vitro and in vivo. Interestingly, it was observed that HCG11 expression was negatively associated with the expression levels of oncogenic microRNA‑875 (miR‑875) in patient specimens. Specifically, HCG11 served as a sponge of miR‑875. Notably, it was determined that special AT‑rich sequence‑binding protein 2 (SATB2) was a direct target gene of miR‑875, and overexpression of miR‑875 largely abrogated the effects of HCG11 in NSCLC cells. In conclusion, HCG11 was shown to suppress the malignant properties of NSCLC cells by targeting a miR‑875/SATB2 axis, and may therefore be a promising target for the treatment of NSCLC.

BACKGROUND: To investigate the predictive value of blood ammonia (BLA) quantification in the prognosis of acute liver failure (ALF). METHODS: Seventy-one patients with ALF were enrolled and BLA concentration was measured in all patients. After following up for 28 days, patients were divided into two groups: the surviving group (n = 21) and the deceased group (n = 50). An independent-samples t-test was used to compare BLA concentrations between the two groups, and receiver operating characteristic curves were used to ­evaluate the predictive value of BLA in the prognosis of ALF. A fourfold table analysis was performed with the determined BLA cutoff value. RESULTS: The average concentration of BLA in the deceased group was significantly higher compared with the surviving group (144.50 µmol/L vs. 106 µmol/L, respectively; P = .035). The cutoff BLA concentration for a good ALF prognosis was 122.5 µmol/L. The area under the curve was 0.659. Both the sensitivity and specificity were >0.6. The 95% CIs for sensitivity and specificity were 0.452-0.733 and 0.477-0.878, respectively. The fourfold table analysis revealed a positive predictive value of 83.3%, a negative predictive value of 42.9%, a misdiagnosis rate of 28.6%, and an accuracy of 63.4%. CONCLUSION: With a cutoff BLA concentration of 122.5 µmol/L, the prognosis of ALF could be predicted with high sensitivity and specificity, a positive predictive value, a low misdiagnosis rate, and good accuracy.

Lei Li,1,* Ling Chen,1,* Fang Lin,2 Jinsong Mu,2 Dan Wang,1 Wei Zhang,1 Lai Mi,1 Yuling Qin,1 Yuesu Zhou1 1Department of Emergency, Fifth Medical Center of Chinese PLA Hospital, Beijing, 100039, People’s Republic of China; 2Department of Critical Care Medicine, Fifth Medical Center of Chinese PLA Hospital, Beijing, 100039, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuesu Zhou; Yuling QinDepartment of Emergency, Fifth Medical Center of Chinese PLA Hospital, No. 100 Middle Road of West 4th Ring Road, Fengtai District, Beijing, 100039, People’s Republic of ChinaTel/Fax +86 10 66933202Email yuesu_zhou@163.com; ylqin90@163.comObjective: The present study aims to investigate the cytokines interleukin (IL)-4, IL-6, IL-10, and IL-17 in the peripheral blood of patients with acute-on-chronic liver failure combined with sepsis, patients with acute-on-chronic liver failure, and patients with liver cirrhosis; to investigate the changes in the levels of inflammatory factors in cases of coagulation dysfunction in liver failure combined with sepsis; and to discover more typical inflammatory factors for further evaluation by functional experiments.Methods: In the present study, 41 patients with acute-on-chronic liver failure and sepsis were enrolled as study subjects. These patients were compared with 20 patients with either acute-on-chronic liver failure and liver cirrhosis during the same period. The changes in IL-4, IL-6, IL-10, and IL-17 were detected in each group by enzyme-linked immunosorbent assay, and SPSS 17.0 software was adopted for data analysis.Results: There were no significant changes in the levels of IL-4 in any of the groups. However, the levels of IL-6, IL-10, and IL-17 were significantly higher in the acute-on-chronic liver failure and sepsis group than in the acute-on-chronic liver failure and the liver cirrhosis groups.Conclusion: The present study shows that when liver failure is accompanied by sepsis, the serum levels of inflammatory factors IL-6, IL-10, and IL-17 are significantly increased. This could be closely correlated with the occurrence and development of coagulation dysfunction and sepsis. These findings provide new ideas for delaying the deterioration of patients with liver failure in clinical practice.Keywords: liver failure, coagulation dysfunction, sepsis, inflammatory factor, expression

Avian influenza in human, especially the severe type, progresses rapidly and causes multiple complications, such as acute lung injury, acute respiratory distress syndrome (ARDS), pulmonary hemorrhage, pleural effusion, pancytopenia, heart failure, renal failure, multiple organ failure, sepsis, shock, and Reye syndrome. The patients often die from severe pulmonary failure. Compared with adults, children suffering from avian influenza progress more rapidly and are more vulnerable to pneumothorax and secondary infection.

Embryonic exposure to environmental chemicals may result in specific chronic diseases in adulthood. Parabens, a type of environmental endocrine disruptors widely used in pharmaceuticals and cosmetics, have been shown to cause a decline in women's reproductive function. However, whether exposure to parabens during pregnancy also negatively affect the ovarian function of the female offspring in adulthood remains unclear. This study aims to investigate the effects of prenatal propylparaben (PrP) exposure on the ovarian function of adult mice aged 46 weeks, which is equivalent to the age of 40 years in women. Pregnant ICR mice were intraperitoneally injected with human-relevant doses of PrP (i.e., 0, 7.5, 90, and 450 mg/kg/day) during the fetal sex determination period—from embryonic day E7.5 to E13.5. Our results revealed that ovarian aging was accelerated in PrP-exposed mice at 46 weeks, with altered regularity of the estrous cycle, decreased serum estrogen (E2) and progesterone (P4) levels, reduced size of the primordial follicle pool, and increased number of atretic follicles. It was found that prenatal exposure to human-relevant doses of PrP exacerbated ovarian oxidative stress, inflammation, and fibrosis, which promoted follicular atresia by activating the mitochondrial apoptosis pathway. To compensate, the depletion of primordial follicles was also accelerated by activating the PI3K/AKT/mTOR signaling pathway in PrP-exposed mice. Moreover, PrP induced hypermethylation of CpG sites in the promoter region of Cyp11a1 (a 17.16–64.28% increase) partly led to the disrupted steroidogenesis, and the altered methylation levels of imprinted genes H19 and Peg3 may also contribute to the phenotypes observed. These remarkable findings highlight the embryonic origin of ovarian aging and suggest that a reduced use of PrP during pregnancy should be advocated.

Objective: This study was intended to investigate the relationship between COVID-19 disease and ovarian function in reproductive-aged women.Methods: Female COVID-19 patients of reproductive age were recruited between January 28 and March 8, 2020 from Tongji Hospital in Wuhan. Their baseline and clinical characteristics, as well as menstrual conditions, were recorded. Differentials in ovarian reserve markers and sex hormones (including anti-Müllerian hormone [AMH], follicle-stimulating hormone [FSH], the ratio of FSH to luteinizing hormone [LH], estradiol [E2], progesterone [P], testosterone [T], and prolactin [PRL] were compared to those of healthy women who were randomly selected and individually matched for age, region, and menstrual status. Uni- and multi-variable hierarchical linear regression analyses were performed to identify risk factors associated with ovarian function in COVID-19 women.Results: Seventy eight patients agreed to be tested for serum hormone, of whom 17 (21.79%) were diagnosed as the severe group and 39 (50%) were in the basal level group. Menstrual status (P = 0.55), menstrual volumes (P = 0.066), phase of menstrual cycle (P = 0.58), and dysmenorrhea history (P = 0.12) were similar without significant differences between non-severe and severe COVID-19 women. Significant lower serum AMH level/proportion (0.19/0.28 vs. 1.12 ng/ml, P = 0.003/0.027; AMH ≤ 1.1 ng/ml: 75/70.4 vs. 49.7%, P = 0.009/0.004), higher serum T (0.38/0.39 vs. 0.22 ng/ml, P < 0.001/0.001) and PRL (25.43/24.10 vs. 12.12 ng/ml, P < 0.001/0.001) levels were observed in basal level and the all-COVID-19 group compared with healthy age-matched control. When adjusted for age, menstrual status and parity variations in multivariate hierarchical linear regression analysis, COVID-19 disease was significantly associated with serum AMH (β = −0.191; 95% CI: −1.177–0.327; P = 0.001), T (β = 0.411; 95% CI: 11.154–22.709; P < 0.001), and PRL (β = 0.497; 95% CI: 10.787–20.266; P < 0.001), suggesting an independent risk factor for ovarian function, which accounted for 3.2% of the decline in AMH, 14.3% of the increase in T, and 20.7% of the increase in PRL.Conclusion: Ovarian injury, including declined ovarian reserve and reproductive endocrine disorder, can be observed in women with COVID-19. More attention should be paid to their ovarian function under this pandemic, especially regarding reproductive-aged women.Clinical Trial Number: ChiCTR2000030015.

Fertility and ovarian protection against chemotherapy-associated ovarian damage has formed a new field called oncofertility, which is driven by the pursuit of fertility protection as well as good life quality for numerous female cancer survivors. However, the choice of fertility and ovarian protection method is a difficult problem during chemotherapy and there is no uniform guideline at present. To alleviate ovarian toxicity caused by anticancer drugs, effective methods combined with an individualized treatment plan that integrates an optimal strategy for preserving and restoring reproductive function should be offered from well-established to experimental stages before, during, and after chemotherapy. Although embryo, oocyte, and ovarian tissue cryopreservation are the major methods that have been proven effective and feasible for fertility protection, they are also subject to many limitations. Therefore, this paper mainly discusses the future potential methods and corresponding mechanisms for fertility protection in chemotherapy-associated ovarian damage.

Background Neoadjuvant chemotherapy has been used for treatment of cervical cancer for a long time; however, the role of early non-response on prognosis is still confusing. This study was designed to assess its impact on disease-free survival (DFS). Methods Databases "PubMed", "Embase" and the "Cochrane Library" were searched out through May 2020, and both random effects model and fixed effect model were employed to calculate the main pooled results. I2 and Cochrane Q test were used to test the heterogeneity among the studies. Funnel plot with Begg's and Egger's tests was used to assess the publication bias that may exist in the study. Sensitivity analysis was performed to detect the origin of the heterogeneity. Results A total of 1,349 articles were found at first; then, after several rounds of exclusion, we identified 8 articles with 9 studies which were accordant with the standards of the inclusion. A combined analysis was performed among the 1,462 responders and 490 non-responders. For 1-year DFS, sub-analysis showed hazard ratio (HR) was 0.25 (95% CI: 0.14-0.43) using RECIST criteria; and HR was 0.52 (95% CI: 0.36- 0.75) using WHO criteria; Egger's test showed that P=0.35 for RECIST criteria and P=0.57 for WHO criteria; Begg's test showed P=0.34 for RECIST criteria and P=0.60 for WHO criteria. For 3-year DFS, HR was 0.26 (95% CI: 0.16-0.43) using RECIST criteria and was 0.47 (95% CI: 0.30-0.73) using WHO criteria. For 5-year DFS, HR was 0.26 (95% CI: 0.16-0.42) using RECIST criteria and was 0.49 (95% CI: 0.33-0.71) using WHO criteria. Conclusions Early non-response to neoadjuvant chemotherapy was significantly associated with higher recurrence of cervical cancer. Prospective randomized studies are warranted to validate this finding.

Throat aurora is a special discrete auroral form often observed at the ionospheric convection throat region near magnetic local noon. Some observational properties of throat aurora have been established, but the geomagnetic response is not yet explored. Using geomagnetic observations from a chain of stations in the Norwegian sector and auroral observations from an all‐sky imager and the DMSP satellites, for the first time, we identify geomagnetic responses associated with the occurrence of throat aurora. These variations are well explained by combining the models of flux transfer events and throat aurora. The estimated increase in ionospheric equivalent current confirms the association of throat aurora with ground observations. The results provide further evidence for throat aurora being associated with magnetopause reconnection. Based on the observational features, a new association of geomagnetic variations with throat aurora may be defined to reflect their occurrence at high latitudes near local noon.

Background Recent studies have indicated that females with coronavirus disease 2019 (COVID-19) have a lower morbidity, severe case rate, and mortality and better outcome than those of male individuals. However, the reasons remained to be addressed. Methods To find the factors that potentially protect females from COVID-19, we recruited all confirmed patients hospitalized at 3 branches of Tongji Hospital (N = 1902), and analyzed the correlation between menstrual status (n = 509, including 68 from Mobile Cabin Hospital), female hormones (n = 78), and cytokines related to immunity and inflammation (n = 263), and the severity/clinical outcomes in female patients, Nonmenopausal females with COVID-19 had milder severity, better outcome, and shorter hospital stays than menopausal patients. E2 might be a potential protective factor against COVID-19, partly through its regulation of cytokines, which significantly correlated with severity of infection.

ImportanceHow to explain the better prognosis of female coronavirus disease 2019 (COVID-19) patients than that of males?ObjectiveTo determine the correlation between menstruation status/sex hormones and prognosis of COVID-19, and to identify potential protective factors for female patients.Design, Setting, and ParticipantsA cross-sectional study of COVID-19 patients who were hospitalized at Tongji and Mobile Cabin Hospitals from Jan 28, 2020 to March 8, 2020.ExposuresConfirmed SARS-CoV-2 infection.Main Outcomes and MeasuresSex differences in severity and composite endpoints (admission to intensive care unit (ICU), use of mechanical ventilation, or death) of COVID-19 patients were compared. The correlation analysis and cox/logistic regression modeling of menstruation status/sex hormones and prognosis were conducted. Correlation between cytokines related to immunity and inflammation and disease severity or estradiol (E2) was revealed.ResultsChi square test indicated significant differences in distribution of composite endpoints (pp=0.029). E2 showed protective effect against disease severity (HR= 0.335, 95%CI = (0.105-1.070), p= 0.046). In the Mann-Whitney U test, the higher levels of IL6 and IL8 were found in severe group (p= 0.040, 0.033). The higher levels of IL2R, IL6, IL8 and IL10 were also observed in patients with composite end points (p). E2 levels were negatively correlated with IL2R, IL6, IL8 and TNFα in luteal phase (Pearson Correlation=−0.592, −0.558, −0.545, −0.623; p=0.033, 0.048, 0.054, 0.023) and with C3 in follicular phase (Pearson Correlation=-0.651; p=0.030).Conclusions and RelevanceMenopause is an independent risk factor for COVID-19. E2 and AMH are negatively correlated with COVID-19’s severity probably due to their regulation of cytokines related to immunity and inflammation.Key PointsQuestionAny differences in the outcomes between hospitalized female and male COVID-19 patients? If so, why?FindingsFemale patients display better prognosis than male patients. Non-menopausal women have shorter length of hospital stays, and AMH and E2 are negatively correlated with COVID-19’s severity. There is a negative correlation between E2 and the levels of IL6, IL8, IL2R and TNF-α, which are significantly correlated with disease severity or composite endpoint.MeaningNon-menopause and female sex hormones, especially E2 and AMH, are potential protective factors for females COVID-19 patients. E2 supplements could be potentially used for COVID-19 patients.

Type 2 diabetes (T2D) is a chronic metabolic disease related to glucose metabolism disorders. Increasing evidences indicate that flavonoids obtained from plants have beneficial effects on T2D. Apios americana Medik, originally cultivated in North America, is rich in flavonoids. In this study, A. americana flower extract (AFE) was purified and flavonoids were identified. The beneficial effects of AFE on glucose metabolism disorders were investigated. Results showed that AFE protected hepatic cells from oxidative stress caused by hyperglycemia and increased glucose consumption and glucose uptake. The AKT pathway was involved in AFE-mediated hypoglycemic action in LO2 cells, accompanied by phosphorylation of FoxO1, Gsk-3β and AMPK. In vivo, AFE protected Caenorhabditis elegans (C. elegans) from oxidative stress under hyperglycemia and restored the expressions of PMK-1 and SKN-1. Furthermore, AFE decreased excessive glucose and lipid accumulation and extended the lifespans of high glucose (HG) treated C. elegans. AFE might be beneficial to decrease glucose metabolism disorders and T2D.

Background Hepatitis B virus (HBV) is considered highly prevalent in West Africa. However, major gaps in surveillance exist in Sierra Leone. Although healthcare workers (HCWs) are at high risk for HBV infection, little is known about the prevalence and knowledge of hepatitis B among HCWs in Sierra Leone. Methods A cross-sectional study of all HCWs at the No. 34 Military Hospital located in Freetown, Sierra Leone, was conducted from March 20 to April 10, 2017. Whole blood was collected and screened for HBV markers using a one-step rapid immunochromatographic test with positive samples tested for HBV DNA. Additionally, questionnaires assessing self-reported knowledge of HBV infections were administered to all participants. Data were processed and analyzed using SPSS (version 17.0) software. Results A total of 211 HCWs were included in this study with a median age of 39.0 years (range: 18–59). Of the participating HCWs, 172 (81.5%) participants were susceptible (all markers negative), 21(10.0%) were current HBV (HBsAg positive) and nine (4.3%) were considered immune because of past infection (HBsAg negative and anti-HBc positive; anti-HBs positive). Additionally, nine (4.3%) participants displayed immunity to the virus as a result of prior hepatitis B vaccination (only anti-HBs positive). Of the 21 HCWs with positive HBsAg, 13 (61.9%) had detectable HBV DNA. There was a significantly lower risk for current HBV infection among HCWs older than 39 years (OR 0.337, p = 0.046). In addition, only 14 (6.6%), 73 (34.6%) and 82 (38.9%) participants in this survey had adequate knowledge about the clinical outcome, routes of transmission, and correct preventive measures of HBV infection, respectively. Conclusions HCWs in Sierra Leone lacked adequate knowledge of the hepatitis B virus. Additionally, the low coverage rate of hepatitis B vaccination among HCWs fails to meet WHO recommendations, leaving many of the sampled HCWs susceptible to infection. This study reaffirms the need for more intensive training for HCWs in addition to strengthening vaccination programmes to protect HCWs against HBV in Sierra Leone. Electronic supplementary material The online version of this article (10.1186/s12879-018-3235-1) contains supplementary material, which is available to authorized users.

High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. However, its effect on cervical cancer remains largely indistinct. In this study, we found that HMGA1 was generally overexpressed in cervical cancer tissues and was positively correlated with lymph node metastasis and advanced clinical stage. Via exogenously increasing or decreasing the expression of HMGA1, we showed that HMGA1 affected the proliferation, colony formation, migration and invasion of cervical cancer cells in vitro. Rescue experiments suggested that miR-221/222 could partly reverse HMGA1-mediated migration and invasion processes. Mechanistically, we discovered that HMGA1 accelerated the G1/S phase transition by regulating the expression of cyclin D1 and cyclin E1, which was consistent with the results of the in vivo experiment. Furthermore, we found that HMGA1 regulated the expression of the miR-221/222 cluster at the transcriptional level and that miR-221/222 targeted the 3′UTR of tissue inhibitor of metalloproteinases 3(TIMP3). We propose a fresh perspective that HMGA1 participates in the migration and invasion process via the miR-221/222-TIMP3-MMP2/MMP9 axis in cervical cancer. In summary, our study identified a critical role played by HMGA1 in the progression of cervical cancer and the potential mechanisms by which exerts its effects, suggesting that targeting HMGA1-related pathways could be conducive to the therapies for cervical cancer.

Background Cyclophosphamide (CTX), which has been used to treat common female cancers for several years, often causes ovarian damage, early menopause and infertility. However, strategies for the effective prevention and treatment of CTX-induced ovarian damage are still lacking. Epigallocatechin gallate (EGCG) and theaflavins (TFs), key molecules derived from green tea or black tea, have been shown to exert preventive effects on many ageing-related diseases. Purpose We aimed to explore the potential preventive and protective effects of EGCG and TFs on CTX-induced ovarian damage and compare the two compounds. Study Design Six-week-old female mice were administered a low or high dose of EGCG or TFs. The low dose was equivalent to the average daily amount of tea consumed by a drinker. Methods We determined the oestrous cycle and serum hormone levels to evaluate ovarian endocrine function, and we performed mating tests for reproductivity. We also assessed the follicle count and AMH level to evaluate ovarian reserve, and we performed Masson's trichrome and Sirius red staining to evaluate ovarian fibrosis. We conducted γ-H2AX and TUNEL analyses to evaluate DNA damage, and we also measured the relevant indicators of oxidative stress and follicular activation, including NRF2, HO-1, SOD2, AKT, mTOR and RPS6. Results EGCG and TFs treatment independently improved the ovarian endocrine function and reproductivity of mice that were administered CTX. EGCG and TFs also increased the ovarian reserve of these animals. Furthermore, EGCG and TFs alleviated oxidation-induced damage to ovarian DNA in mice by activating the NRF2/HO-1 and SOD2 pathways and reducing the apoptosis of growing follicles. At the same time, EGCG and TFs reduced the overactivation of primordial follicles by inhibiting the AKT/mTOR/RPS6 pathway. Conclusion The present study showed that EGCG and TFs independently improved ovarian function in mice with CTX-induced ovarian damage, thereby providing useful information for designing a potential clinical strategy that will protect against chemotherapy-induced ovarian damage.

Regeneration of the architecturally complex alveolar niche of the lung requires precise temporal and spatial control of epithelial cell behavior. Injury can lead to a permanent reduction in gas exchange surface area and respiratory function. Using mouse models, we show that alveolar type 1 (AT1) cell plasticity is a major and unappreciated mechanism that drives regeneration, beginning in the early postnatal period during alveolar maturation. Upon acute neonatal lung injury, AT1 cells reprogram into alveolar type 2 (AT2) cells, promoting alveolar regeneration. In contrast, the ability of AT2 cells to regenerate AT1 cells is restricted to the mature lung. Unbiased genomic assessment reveals that this previously unappreciated level of plasticity is governed by the preferential activity of Hippo signaling in the AT1 cell lineage. Thus, cellular plasticity is a temporally acquired trait of the alveolar epithelium and presents an alternative mode of tissue regeneration in the postnatal lung.

Calcium overload therapy has attracted widespread attention in oncological field, whereas its efficacy has been limited due to insufficient calcium ions in tumor site and poor efficiency of calcium entering tumor, resulting in dissatisfied therapeutic effect. Kaempferol-3-O-rutinoside (KAE), a biosafe flavone with excellent anti-cancer ability, can effectively disrupt calcium homeostasis regulation and facilitate calcium influx, while calcium carbonate (CaCO3) serves as an ideal calcium ions supplier. Inspired by these concepts, KAE loaded into CaCO3 nanoparticles and incorporated with the cancer cell membrane (M) for synergistic tumor therapy. In this therapeutic platform (M@CaCO3@KAE), membrane coating ensures targeted delivery of CaCO3@KAE. Upon reaching tumor, CaCO3@KAE specifically responds to tumor microenvironment, consequently releases KAE and calcium ions. KAE effectively breaks the calcium balance, while calcium ions remarkably aggravate and magnify KAE-mediated calcium overload. Accordingly, mitochondrial structure and functions are destructed, causing cytoskeleton collapse and oxidative stress, leading to cancerous cellular apoptosis. With the combined and cascaded efficacy, considerable in vitro and in vivo tumor inhibition was achieved by M@CaCO3@KAE. This study provides an alternative nano-system, acting as a biomimetic calcium bomb, to ensure targeted, synergistic, efficient and biosafe calcium overload tumor therapy.

The primordial follicle assembly, activation and the subsequent development are critical processes for female reproduction. A limited number of primordial follicles are activated to enter the growing follicle pool each wave, and the primordial follicle pool progressively diminishes over a woman's life‐time. The number of remaining primordial follicles represents the ovarian reserve. Identification and functional investigation of the factors involved in follicular initial recruitment will be of great significance to the understanding of the female reproduction process and ovarian ageing. In this study, we aimed to study whether and how semaphorin 6C (Sema6c) regulated the primordial follicle activation in the neonatal mouse ovary. The attenuation of SEMA6C expression by SiRNA accelerated the primordial follicle activation in the in vitro ovary culture system. PI3K‐AKT‐rpS6 pathway was activated when SEMA6C expression was down‐regulated. And the LY294002 could reverse the effect of low SEMA6C expression on primordial follicle activation. Our findings revealed that Sema6c was involved in the activation of primordial follicles, and the down‐regulation of SEMA6C led to massive primordial follicle activation by interacting with the PI3K‐AKT‐rpS6 pathway, which might also provide valuable information for understanding premature ovarian failure and ovarian ageing.

Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress.

Objective To summarize the current understanding of neuronal intranuclear inclusion disease (NIID) and improve the understanding of the physician about this condition. Methods We searched PubMed with keywords related to NIID and selected publications which seemed appropriate. We analyzed its clinical features, pathogenesis, evaluation methods, treatment options, and research prospectives. Results NIID is a degenerative condition which can affect multiple organ systems especially central nervous system. Its clinical features greatly vary, and making the exact diagnosis is often difficult. There are several genes which have been associated with this disorder. Some specific signs on diffusion-weighted-imaging (DWI) sequence of magnetic resonance (MR) imaging are characteristics to NIID. Conclusion Intranuclear inclusions have been found in various nonneural cells of the body; therefore, the term systemic intranuclear inclusion disease is, perhaps, better suited to explain this disorder. There are several disorders which need to be ruled out before making the diagnosis, and neuroimaging and biopsy analysis should be combined to support the diagnosis.

Monogenic lung diseases that are caused by mutations in surfactant genes of the pulmonary epithelium are marked by perinatal lethal respiratory failure or chronic diffuse parenchymal lung disease with few therapeutic options. Using a CRISPR fluorescent reporter system, we demonstrate that precisely timed in utero intra-amniotic delivery of CRISPR-Cas9 gene editing reagents during fetal development results in targeted and specific gene editing in fetal lungs. Pulmonary epithelial cells are predominantly targeted in this approach, with alveolar type 1, alveolar type 2, and airway secretory cells exhibiting high and persistent gene editing. We then used this in utero technique to evaluate a therapeutic approach to reduce the severity of the lethal interstitial lung disease observed in a mouse model of the human SFTPC(I73T) mutation. Embryonic expression of SftpC(I73T) alleles is characterized by severe diffuse parenchymal lung damage and rapid demise of mutant mice at birth. After in utero CRISPR-Cas9-mediated inactivation of the mutant SftpC(I73T) gene, fetuses and postnatal mice showed improved lung morphology and increased survival. These proof-of-concept studies demonstrate that in utero gene editing is a promising approach for treatment and rescue of monogenic lung diseases that are lethal at birth.

Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of epithelial polarity and proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also disrupts epithelial-mesenchymal crosstalk and leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate.

During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal–distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.

Nitric oxide (NO) plays a pivotal role in the cutaneous healing process and a topical supplement of NO is beneficial for wound repair. In this work, a novel polyethylenimine (PEI) based diazeniumdiolate nitric oxide donor was prepared. The obtained polymer (PEI-PO-NONOate) was characterized by Fourier transform infrared (FTIR) spectroscopy, UV-vis absorption spectra, and nuclear magnetic resonance (NMR). The PEI-PO-NONOate polymer was stable under anhydrous conditions at different temperatures. A total of 0.57 μmol gaseous NO was released from 1.0 mg of the PEI-PO-NONOate polymer in PBS of pH 7.4 and it presented a proton-driven release pattern. Furthermore, the PEI-PO-NONOate polymer exhibited a controlled release profile sustained for over 30 hours within the polyethylene glycol (PEG) mixture system. Cytotoxicity evaluation was performed on L929 cells. Full-thickness excisional cutaneous wound models of mice were prepared and the PEI-PO-NONOate polymer was applied to investigate its effects on wound healing. The results revealed that the PEI-PO-NONOates exhibited good biocompatibility. It was also found that the PEI-PO-NONOate polymer promoted cutaneous wound healing and closure with enhanced granulation tissue formation, collagen deposition, and angiogenesis, as compared to the control. In summary, a novel nitric oxide releasing polymer with high loading efficiency and a controlled release profile was developed which presented the potential for application in the acceleration of cutaneous wound healing.

SUMMARY Alveolar epithelial type 2 (AT2) cells integrate signals from multiple molecular pathways to proliferate and differentiate to drive regeneration of the lung alveolus. Utilizing in vivo genetic and ex vivo organoid models, we investigated the role of Fgfr2 signaling in AT2 cells across the lifespan and during adult regeneration after influenza infection. We show that, although dispensable for adult homeostasis, Fgfr2 restricts AT2 cell fate during postnatal lung development. Using an unbiased computational imaging approach, we demonstrate that Fgfr2 promotes AT2 cell proliferation and restrains differentiation in actively regenerating areas after injury. Organoid assays reveal that Fgfr2-deficient AT2 cells remain competent to respond to multiple parallel proliferative inputs. Moreover, genetic blockade of AT2 cell cytokinesis demonstrates that cell division and differentiation are uncoupled during alveolar regeneration. These data reveal that Fgfr2 maintains AT2 cell fate, balancing proliferation and differentiation during lung alveolar regeneration., In brief Using an unbiased computational imaging approach, Liberti et al. demonstrate that alveolar epithelial type 2 (AT2) cells actively maintain their fate independent of their ability to divide. AT2 cells balance the decision to divide versus differentiate to drive lung regeneration after acute injury., Graphical Abstract

Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2Axin2. The number of AT2Axin2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, invivo clonal analysis, and exvivo lung organoid assays reveal that AT2sAxin2 promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation.

Follicular atresia is the main process responsible for the loss of follicles and oocytes from the ovary, and it is the root cause of ovarian aging. Apoptosis of granulosa cells (GCs) is the cellular mechanism responsible for follicular atresia in mammals. Recent advances have highlighted fundamental roles for EGR1 in age-related diseases via the induction of apoptosis. In the present study, we found that the expression of EGR1 was significantly increased in aged mouse ovaries compared with young ovaries. Immunohistochemical analysis revealed strongly positive EGR1 staining in atretic follicles, especially in apoptotic granulosa cells. We further showed that EGR1 up-regulation in mouse primary granulosa cells inhibited cell proliferation and promoted apoptosis. In addition, the promotion of apoptosis in GCs by EGR1 increases over time and with reactive oxygen species (ROS) stimulation. Our mechanistic study suggested that EGR1 regulates GC apoptosis in a mitochondria-dependent manner and that this mainly occurs through the NF-κB signaling pathway. In conclusion, our results suggested that age-related up-regulation of EGR1 promotes GC apoptosis in follicle atresia during ovarian aging.