Vaccination with a Human Papillomavirus L2 Multimer Provides Broad Protection against 17 Human Papillomavirus Types in the Mouse Cervicovaginal Challenge Model.

Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal cancers affecting both males and females, notably cervical cancer. Cervical cancer is the fourth leading cause of cancer deaths among women globally and is the most impactful in low- and middle-income countries (LMICs), where the costs of screening and licensed L1-based HPV vaccines pose significant barriers to comprehensive administration. Additionally, the licensed L1-based HPV vaccines fail to protect against all oncogenic HPV types. This study generated three independent lots of an L2-based target antigen (LBTA), which was engineered from conserved linear L2-protective epitopes (aa11-88) from five human alphapapillomavirus genotypes in E. coli under cGMP conditions and adjuvanted with aluminum phosphate. Vaccination of rabbits with LBTA generated high neutralizing antibody titers against all 17 HPV types tested, surpassing the nine types covered by Gardasil®9. Passive transfer of naïve mice with LBTA antiserum revealed its capacity to confer protection against vaginal challenge with all 17 αHPV types tested. LBTA shows stability at room temperature over >1 month. Standard in vitro and in vivo toxicology studies suggest a promising safety profile. These findings suggest LBTA's promise as a next-generation vaccine with comprehensive coverage aimed at reducing the economic and healthcare burden of cervical and other HPV+ cancers in LMICs, and it has received regulatory approval for a first-in-human clinical study (NCT05672966).

Circular RNA hsa_circ_0094976 modulates GPR155 to inhibit gastric adenocarcinoma malignant characteristics by targeting miR-223-3p.

BACKGROUND: The abnormal expression of circular RNA (circRNA) has been confirmed to be closely related to the development of many human diseases including gastric adenocarcinoma (GA). This study aimed to elucidate the molecular mechanism and biological function of hsa_circ_0094976 (circ_0094976) in GA. METHODS: The expression of circ_0094976, miR-223-3p, and G protein-coupled receptor 155 (GPR155) mRNA was measured by quantitative real-time polymerase chain reaction. Cell viability, cell proliferation, colony formation, migration, and invasion were estimated by cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, colony formation assay, and transwell assay, respectively. The bioinformatics analysis, dual-luciferase reporter assay, and RNA pull-down assay were used for predicting and verifying the interaction of the circ_0094976/miR-223-3p/GPR155 axis. A xenograft mouse model was performed in nude mice to reveal the role of circ_0094976 in vivo. RESULTS: Circ_0094976 was down-regulated in GA tissues and GA cell lines compared to normal controls. Overexpression of circ_0094976 inhibited the GA cell growth, migration, and invasion in vitro, and tumor growth in vivo. Circ_0094976 directly targeted miR-223-3p, and GPR155 was a direct target of miR-223-3p. Moreover, circ_0094976 sponging miR-223-3p to increase the expression of GPR155. CONCLUSION: We disclosed that circ_0094976 could act as a sponge of miR-223-3p to regulate the expression of GPR155, and further restrain the development of GA, which may provide new insight into the therapy of GA.

Aerosol Inhalation of Chimpanzee Adenovirus Vectors (ChAd68) Expressing Ancestral or Omicron BA.1 Stabilized Pre-Fusion Spike Glycoproteins Protects Non-Human Primates against SARS-CoV-2 Infection.

Current COVID-19 vaccines are effective countermeasures to control the SARS-CoV-2 virus pandemic by inducing systemic immune responses through intramuscular injection. However, respiratory mucosal immunization will be needed to elicit local sterilizing immunity to prevent virus replication in the nasopharynx, shedding, and transmission. In this study, we first compared the immunoprotective ability of a chimpanzee replication-deficient adenovirus-vectored COVID-19 vaccine expressing a stabilized pre-fusion spike glycoprotein from the ancestral SARS-CoV-2 strain Wuhan-Hu-1 (BV-AdCoV-1) administered through either aerosol inhalation, intranasal spray, or intramuscular injection in cynomolgus monkeys and rhesus macaques. Compared with intranasal administration, aerosol inhalation of BV-AdCoV-1 elicited stronger humoral and mucosal immunity that conferred excellent protection against SARS-CoV-2 infection in rhesus macaques. Importantly, aerosol inhalation induced immunity comparable to that obtained by intramuscular injection, although at a significantly lower dose. Furthermore, to address the problem of immune escape variants, we evaluated the merits of heterologous boosting with an adenovirus-based Omicron BA.1 vaccine (C68-COA04). Boosting rhesus macaques vaccinated with two doses of BV-AdCoV-1 with either the homologous or the heterologous C68-COA04 vector resulted in cross-neutralizing immunity against WT, Delta, and Omicron subvariants, including BA.4/5 stronger than that obtained by administering a bivalent BV-AdCoV-1/C68-COA04 vaccine. These results demonstrate that the administration of BV-AdCoV-1 or C68-COA04 via aerosol inhalation is a promising approach to prevent SARS-CoV-2 infection and transmission and curtail the pandemic spread.

Diagnostic Values of miR-221-3p in Serum and Cerebrospinal Fluid for Post-Stroke Depression and Analysis of Risk Factors.

BACKGROUND: We aimed to explore the diagnostic values of miR-221-3p in serum and cerebrospinal fluid (CSF) for post-stroke depression (PSD) and to analyze the risk factors of the disease. METHODS: Admitted to the Second Affiliated Hospital of Harbin Medical University, Harbin, China from May 2013 to May 2020, 136 stroke patients were enrolled, among which 76 PSD patients were taken as a PSD group and 60 non-depressed patients were taken as a Non-PSD group. miR-221-3p expression in serum and CSF and concentrations of inflammatory cytokines (IL-6, TNF-α) in serum were detected, to analyze the diagnostic and prognostic values of the indicators for PSD. Correlations of miR-221-3p in serum with that in CSF, with the National Institute of Health Stroke Scale (NIHSS) score and the Hamilton Depression Rating Scale (HAMD) score, and with inflammatory cytokines were analyzed, so as to analyze the risk factors affecting the occurrence of PSD. RESULTS: Compared with the Non-PSD group, miR-221-3p remarkably upregulated in serum and CSF in the PSD group, and its areas under the curves (AUCs) for PSD identification were 0.900 and 0.925, respectively. According to the correlation analysis, miR-221-3p in serum was remarkably positively correlated with that in CSF, NIHSS score, HAMD score, IL-6 and TNF-α. In addition, a history of mental illness, NIHSS score, HAMD score, IL-6, TNF-α and miR-221-3p were risk factors of PSD. CONCLUSION: miR-221-3p in serum and CSF can be used as the diagnostic and risk warning indicators of PSD.

Esophagitis dissecans superficialis associated with acute transoral paraquat poisoning: Clinical study of 15 cases.

To analyze the clinical characteristics and therapeutic effects of transoral paraquat poisoning combined with Esophagitis dissecans superficialis (EDS). A retrospective observational study was conducted on paraquat poisoning patients between January 1, 2011 and August 30, 2016 in Qilu hospital. Fifteen patients with EDS were enrolled in this study. The clinical characteristics, prognosis, and pathological features of esophageal necrosis mucosa of these patients were retrospectively analyzed and summarized. Esophageal mucosal dissection occurs mainly within 3-8 days after transoral paraquat poisoning in 15 patients. Dosage of paraquat is range from 50 to 100 ml. Most patients have physical problems with swallowing before the intramural esophageal dissection occurred. And there are other symptoms, including sore throat or dysphagia (100%), nausea and vomiting (86.7%), heartburn or upper abdominal pain (73.3%), hematemesis (60%), abdominal distension (20%) and cough frequently (6.7%). In death group, most patients demonstrate features of the multiple organ failure when the esophageal mucosal stripping happened, including lung injury, renal failure, and hepatic failure. The shape of esophageal dissection was tubular in 60%, irregular in 40%, and they vary in size. Pathological examination showed extensive injury, necrosis and hemorrhage of digestive tract epithelium, and obvious inflammatory reaction of epithelial tissue. Transoral paraquat poisoning has certain damage to the patient's esophageal mucosa, and some may be complicated with EDS, and the prognosis is poor, especially when combined with multiple organ dysfunction. Esophageal damage is mainly located in the esophageal mucosa and have different degrees. Special attention should be paid on such patients.

The status and comparison of ovarian reserve between fertile and infertile healthy Chinese women of reproductive age.

ABSTRACT: We aimed to investigate ovarian reserve status, and explore differences in ovarian reserve between fertile and infertile healthy Chinese women of reproductive age.We recruited 442 fertile women aged 23 to 49 years (mean: 35.22 ±â€Š4.91 years) as subjects, and 196 infertile women aged 23 to 46 years (mean: 32.34 ±â€Š4.34 years) as controls. For all participants, a number of parameters were tested on days 2 to 4 of a spontaneous cycle, including basal serum follicle-stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH), total testosterone, anti-Müllerian hormone (AMH), ovarian response prediction index (ORPI), and antral follicle count (AFC).There were significant differences in terms of AFC, serum AMH levels, and ORPI among subject subgroups (10.58 ±â€Š5.80; 2.533 ±â€Š2.146 ng/mL; 1.28 ±â€Š1.87; respectively), and among control subgroups (12.44 ±â€Š5.69; 3.189 ±â€Š2.551 ng/mL; 1.88 ±â€Š2.68; respectively) (P < .01 for all). For both subjects and controls, AFC, AMH levels, and ORPI decreased gradually with increasing age, and presented with similar age-related trends; there were positive correlations between AMH and AFC (P < .001), and negative correlations between age and AFC, AMH, ORPI (P < .05 for all). There was a significant difference in age (P < .001), serum E2 (P < .01), and AMH (P < .01) levels between subjects and controls; however, when controlling for confounding factors (age, body mass index, total testosterone, and LH), we found no differences between the 2 groups with regards to the serum levels of AMH, FSH, E2, and AFC (P > .05 for all). Moreover, receiver operating characteristic curve analysis indicated that the significant variables of subjects and controls for evaluating ovarian reserve included age, AMH and ORPI, and ORPI was more valuable than other variables.A diminished ovarian reserve was one of the manifestations caused by female aging. When confounding factors were controlled for, we found no differences in ovarian reserve when compared between fertile and infertile women, and no correlation with infertility.

High anti-Müllerian hormone levels might not reflect the likelihood of clinical pregnancy rate in IVF/ICSI treatment.

OBJECTIVE: To investigate if high anti-Müllerian hormone (AMH) concentration is a useful tool to predict the outcome of assisted reproductive treatment. METHODS: Retrospective cohort study involving 520 patients who underwent IVF/ICSI procedures in a university hospital. We measured the serum AMH level on day 3 of the menstrual cycle. Based on AMH levels, we divided the patients into three groups as follows: low (<25th percentile) AMH group, average (25th to 75th percentile) AMH group and high (>75th percentile) AMH group. We recorded the fertilization rate (FR), the number of oocytes retrieved, the number of good quality embryos (GQEs) and the clinical pregnancy rate (CPR). RESULTS: There was no difference between the three AMH groups in terms of maternal age, body mass index (BMI), follicle-stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH) and testosterone (T) in the IVF/ICSI cycles. The women in the high serum AMH group had a higher number of retrieved oocytes than those in the low or average AMH groups (p < 0.01) in the IVF/ICSI cycles. Compared with the low or average AMH groups, the women with high AMH levels had a higher number of good quality embryos (GQEs) in the IVF/ICSI cycles (p < 0.01). However, high AMH women had no significantly higher clinical pregnancy rate (CPR) compared to the women in the low or average AMH groups. In addition, for the prediction of CPR, the AMH levels alone were not an independent predictor of CPR for IVF and ICSI cycles in the ROC curve analysis. CONCLUSIONS: High anti-Müllerian hormone levels are an independent predictor of the number of retrieved oocytes and good quality embryos (GQEs), but might not reflect the likelihood of higher clinical pregnancy rates (CPR) in IVF/ICSI treatment.

Role of the Hippo signaling pathway in safflower yellow pigment treatment of paraquat-induced pulmonary fibrosis.

OBJECTIVE: To elucidate the molecular mechanisms by which safflower yellow (SY) mediates therapeutic effects in rats with paraquat intoxication-induced pulmonary fibrosis. METHODS: Rats received combinations of paraquat, SY, and SB431542, a transforming growth factor (TGF)-ß1 receptor antagonist. Survival over 28 days was assessed by Kaplan-Meier analysis. Rat tissue and serum samples were assessed by hematoxylin and eosin staining, Masson's Trichrome staining, immunoblotting, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and transmission electron microscopy. RESULTS: Survival rates were higher in SY and SB431542 groups (treatment and paraquat) than in the exposure group (paraquat alone). In the exposure group, serum TGF-ß1 levels increased between days 3 and 14; mammalian STE20-like (MST) levels increased between days 3 and 7; TGF-ß1 and Smad3 levels increased between days 3 and 14; and Yap and connective tissue growth factor levels increased between days 3 and 28. TGF-ß1 levels were lower in SY and SB431542 groups than in the exposure group. Pathology scores were higher in exposure, SY, and SB431542 groups than in the control group throughout the experiment. CONCLUSIONS: In rats with paraquat intoxication-induced pulmonary fibrosis, Hippo signaling could be activated by the MST-Yap pathway; SY and SB431542 could alleviate pulmonary fibrosis via Hippo signaling.

Specific activity of a Bacillus thuringiensis strain against Locusta migratoria manilensis.

Bacillus thuringiensis (Bt) has played an important role in biocontrol of pests. However, insecticidal activity of B. thuringiensis against locusts has been rarely reported. Bt strain BTH-13 exhibiting specific activity to locusts was isolated from a soil sample in China and characterized. Its bipyramidal parasporal crystal is mainly composed of a protein of 129kDa, and produces a mature toxin of 64kDa after activation. The pattern of total DNA from BTH-13 showed a large and three small plasmid bands. Known delta-endotoxin genes, cry1Aa, cry1Ab, cry1Ac, cry1C, cry3, cry4 and cry7Aa were not found from strain BTH-13 by PCR amplification. The sequence analysis of a DNA fragment produced by PCR amplification with degenerate cry-selective primers revealed that the fragment encoded a delta-endotoxin segment, which exhibited some similarity to several Cry proteins (41% of the highest similarity to Cry7Ba1). Toxicity tests were performed against Locusta migratoria manilensis, and the results demonstrated that trypsin-treated sporulated cultures and crystal proteins had high toxicity to larval and adult locusts. Cry toxin of BTH-13 was detected on the midguts of treated locusts using immunofluorescent technology, which confirmed the site of action of the crystal proteins in their toxicity for locusts.