Phenolic Acid Derivatives from Ficus esquiroliana Levl. and Their Anti-Inflammatory Effects.

One new mesomer, ficusnaph A (1), two new phenolic acid derivatives, ficusnaphs B and C (2 and 3) together with three known biogenetically related polysubstituted naphthalene derivatives (4-6) were isolated from the stems of Ficus esquiroliana Levl. The structures of these compounds were elucidated using comprehensive spectroscopic methods. Compounds 1-6 were evaluated the inhibitory activities against the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in mouse macrophage RAW264.7 cells in vitro. Compounds 1 and 2 showed significant inhibitory activity with the IC50 value of 3.12±0.14 and 7.66±0.18 µM, respectively.

Marginal donor liver versus standard donor liver: A single-center observational study.

BACKGROUND: The effectiveness and safety of marginal donor livers remain controversial. This study aimed to investigate the clinical efficacy of marginal donor livers in patients with liver transplantation (LT). METHODS: This study included 199 liver donors (including 16 split donors) and 206 liver recipients from January 1, 2018 to January 27, 2020, with case follow-up until July 31, 2021. Clinical data of donors and recipients were retrospectively analyzed and were divided into the marginal donor and standard donor groups according to the criteria of marginal donor livers. Indices of liver and kidney functions, complications, and survival curves of the two groups were compared. RESULTS: Compared with the standard donor group, the blood creatinine levels were significantly higher in the marginal donor group in the first week after operation (P < 0.05); there were no significant differences in alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels after LT (all P > 0.05); there was no significant difference in the incidence of complications after LT (P > 0.05); there was also no significant difference in the survival curve (P = 0.335). CONCLUSIONS: There were no significant differences in liver and kidney function and survival curve between the standard donor and marginal donor groups. The marginal donor liver appears safe and reliable for LT and may be an important strategy to expand the donor pool and solve the shortage of organs.

Three new long-chain polyenes from the mangrove-derived fungus Penicillium herquei JX4.

One new epimer pair of long-chain polyenes penicilqueis E (1) and F (2), and one new long-chain polyene pinophol G (3), along with one known compound (4), were obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4. Their structures were elucidated by detailed analysis of comprehensive spectroscopic data. The inhibitory activities of all compounds against the nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro were evaluated.

[Pharmacokinetic study of Polydopamine Guttate Pills loaded with active components of Sarcandrae Herba in rats].

An ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method was established for the determination of active components of Sarcandrae Herba, and applied to the pharmacokinetics study of multiple dosage forms. After SD rats were administered by gavage with three dosage forms [Sarcandrae Herba extract, commercial Sarcandrae Herba Guttate Pills, and polydopamine guttate pills loaded with active components of Sarcandrae Herba(PDA-Sg Guttate Pills)], blood samples were collected from the inner canthus at different time points. After protein precipitation, plasma samples were separated on ACQUITY UPLC C_(18) column(2.1 mm×100 mm, 1.7 µm). The mobile phase consisted of water containing 0.2% formic acid and acetonitrile in gradient elution. The negative ions were measured simultaneously in the multi-reaction monitoring(MRM) mode. The pharmacokinetic parameters were calculated and fitted by DAS 2.0. All four components could be detected in the plasma of rats in each group at each time point except the neochlorogenic acid and cryptochlorogenic acid in the Sarcandrae Herba extract group. The guttate pills group showed a significant increase in drug content at each time point. The exposure of the main components of Sarcandrae Herba in blood was effectively increased by PDA-drug loading effect in PDA-Sg Guttate Pills(The AUC_(0-24 h) of neochlorogenic acid, cryptochlorogenic acid, isaziridin and rosmarinic acid reached 2.45, 32.90, 1.54, 4.81 times that of the commercial guttate pills). This study proves the measurability of the above-mentioned multi-component in vitro-in vivo delivery process. The pharmacokinetic study has shown that PDA-Sg Guttate Pills can effectively delay the elimination time and improve the bioavailability of the four components, which can provide theoretical data for the production of the drug.

A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma.

BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

Argirein alleviates stress-induced and diabetic hypogonadism in rats via normalizing testis endothelin receptor A and connexin 43.

AIM: Argirein (rhein-arginine) is a derivative of rhein isolated from Chinese rhubarb (Rheum Officinale Baill.) that exhibits antioxidant and anti-inflammatory activities. In the present study we investigated the effects of argirein on stress-induced (hypergonadotrophic) and diabetic (hypogonadotrophic) hypogonadism in male rats. METHODS: Stress-induced and diabetic hypogonadism was induced in male rats via injection of isoproterenol (ISO) or streptozotocin (STZ). ISO-injected rats were treated with argirein (30 mg·kg(-1)·d(-1), po) or testosterone replacement (0.5 mg·kg(-1)·d(-1), sc) for 5 days, and STZ-injected rats were treated with argirein (40-120 mg·kg(-1)·d(-1), po) or aminoguanidine (100 mg·kg(-1)·d(-1), po) for 4 weeks. After the rats were euthanized, blood samples and testes were collected. Serum hormone levels were measured, and the expression of endothelin receptor A (ETA), connexin 43 (Cx43) and other proteins in testes was detected. For in vitro experiments, testis homogenate was prepared from normal male rats, and incubated with ISO (1 µmol/L) or high glucose (27 mmol/L). RESULTS: ISO injection induced hyper-gonadotrophic hypogonadism characterized by low testosterone and high FSH and LH levels in the serum, whereas STZ injection induced hypogonadotrophic hypogonadism as evidenced by low testosterone and low FSH and LH levels in the serum. In the testes of ISO- and STZ-injected rats, the expression of ETA, MMP-9, NADPH oxidase and pPKCε was significantly increased, and the expression of Cx43 was decreased. Administration of argirein attenuated both the abnormal serum hormone levels and the testis changes in ISO- and STZ-injected rats, and aminoguanidine produced similar actions in STZ-injected rats; testosterone replacement reversed the abnormal serum hormone levels, but did not affect the testis changes in ISO-injected rats. Argirein (0.3-3 µmol/L) exerted similar effects in testis homogenate incubated with ISO or high glucose in vitro. CONCLUSION: Two types of hypogonadism of male rats exhibit increased expression of ETA and depressed expression of Cx43 in testes, despite different patterns of serum FSH and LH. Argirein alleviates the two types of male hypogonadism via normalizing ETA and Cx43 in testes.

Protective Effect of Salvia Przewalskii Extract on Puromycin-Induced Podocyte Injury.

BACKGROUND: To determine the effect of Salvia przewalskii extract (SPE) from total phenolic acids on puromycin aminonucleoside (PAN)-induced rat podocyte injury. METHODS: The rats were divided into groups that were treated with either PAN only or PAN followed by tacrolimus or SPE. We evaluated the effects of SPE on podocyte injury 5, 10, 15 and 21 days following treatment. RESULTS: (1) Proteinuria was observed starting on day 5 in all groups. The peak levels of proteinuria differed among the groups with tacrolimus and high-dose SPE, which significantly decreased proteinuria relative to the PAN and low- and medium-dose SPE groups. The proteinuria in each group decreased by day 15 and returned to a normal level by day 21. (2) H&E and PAS staining revealed no abnormality in glomerular morphology. With electron microscopy, we observed foot process effacement in the rats of all groups starting on day 5, but rats in the tacrolimus and high-dose SPE groups exhibited a lower degree. (3) IHC staining of nephrin and podocin revealed unaffected expression and better linear distributions in the high-dose SPE and tacrolimus groups. Western blot analysis confirmed that SPE could improve the expression of proteins. (4) The mRNA levels of nephrin and podocin in the tacrolimus and high-dose SPE groups were significantly higher than that in the others. CONCLUSION: In our study, we first demonstrated the ability of SPE to reduce proteinuria, preserve the morphology and structure of podocytes and retain the levels of slit diaphragm proteins on PAN-induced rat podocytes injury.

Isoproterenol induced stressful reactions in the brain are characterized by inflammation due to activation of NADPH oxidase and ER stress: attenuated by Apocynin, Rehmannia complex and Triterpene acids.

Inflammatory changes in the cerebral network are present in early mechanisms involved in neurodegenerative disease, Alzheimer disease (AD), and aging brain. We intended to verify that these are likely due to an activation of NADPH oxidase (NOX) and endoplasmic reticulum (ER) stress. Apocynin (APO) an inhibitor of NOX is potential to ameliorate these changes. Rehmannia complex (Reh) a famous prescription in China and the triterpene acids (TTA) isolated from Reh may relieve the isoproterenol (ISO) induced chronic inflammation in the brain, compared with APO. Rats were administered with ISO for 10 days and astrocytes were incubated with ISO for 24 h. Changes in neural MMP (matrix metalloproteinase), Cx43, AQP4 (aquaporin 4), NFκB, IκBß, and p-PERK (PKB like kinase) were conducted and intervened with APO, Reh and TTA, in vivo and in vitro, respectively. An increased MDA and upregulated NOX subunit p47phox, ETA, PERK in association with abnormal MMP-2/9 and Cx40/43 were found in cerebral tissue of ISO-injected rats. Astrocytes incubated with ISO exhibited upregulated APQ4, IκBß, NFκB and p-PERK/PERK and downregulated Cx43. These were significantly abrogated by APO and Reh, in vivo, and APO and TTA in vitro. In conclusion, neural damages induced by ISO were characterized by inflammatory changes in cerebral tissue and astrocytes, which were blunted significantly by APO, Reh and TTA, respectively. Reh and TTA are potential in alleviating the early pathogenesis in neurodegenerative changes in AD in the clinical settings through suppressing NOX and ER stress in the brain.

[Resources and application of She's nationality wild medicinal plants].

To make a thorough investigation of the common She's nationality wild medicinal plants resources in our country, including the species, the distribution, the folk application and the endemic medicinal plant species, Field surveyed was conducted with 25 She people mainly lived area (county, district or city) throughout the country, the folk prescription and treatment cases provided by She's medical personnel, the drug usage and dosage, the commonly used traditional She's medicine and drug samples were collected. And the distribution, growing environment of these plants were investigated, their characteristics, photographs, GPS data and track were record , and the fresh wax leaf or plants specimens were collected. In total 1 600 varieties of folk medicine of She's nationality, 450 disease names and 1 016 prescriptions were collected. 520 kinds of these medicinal plants were commonly used, growing mainly distributed in the southeastern China, about 200 meters above sea level to 1 500 meters. There are 5 First-Grade State protection wild plants (medicinal), 15 second-Grade State protection wild plants (medicinal), and 11 She characteristic medicinal plants in our study, they belong to 144 families, 312 genera 494 species, 2 subspecies, 17 varieties, 3 forms and 1 cultivated varieties of She's nationality. Folk medicine usage is different from the traditional Chinese medicine and ethnic medicine. This survey finds out the common She's nationality wild medicinal plants resources in China, including the species, the distribution, the folk application and commonly used drugs, and found the rare and endangered medicinal plants and the She's nationality endemic medicinal plants, which provides a basis for further development and use the traditional She's medicine resources.

Prospects of Pseudomonas in Microbial Fuel, Bioremediation, and Sustainability.

Microbial applications in agriculture and industry have gained significant attention due to their potential to address environmental challenges and promote sustainable development. Among these, the genus Pseudomonas stands out as a promising candidate for various biotechnological uses, thanks to its metabolic flexibility, resilience, and adaptability to diverse environments. This review provides a comprehensive overview of the current state and future prospects of microbial fuel production, bioremediation, and sustainable development, focusing on the pivotal role of Pseudomonas species. We emphasize the importance of microbial fuel as a renewable energy source and discuss recent advancements in enhancing biofuel generation using Pseudomonas strains. Additionally, we explore the critical role of Pseudomonas in bioremediation processes, highlighting its ability to degrade a wide spectrum of pollutants, including hydrocarbons, pesticides, and heavy metals, thereby reducing environmental contamination. Despite significant progress, several challenges remain. These include refining microbial strains for optimal process efficiency and addressing ecological considerations. Nonetheless, the diverse capabilities of Pseudomonas offer promising avenues for innovative solutions to pressing environmental issues, supporting the transition to a more sustainable future.

Three new indole alkaloid derivatives from Fissistigma oldhamii Levl. and their anti-inflammatory effects.

Three new indole alkaloid derivatives, fissindoalkas A-C (1-3) together with one known biogenetically related polysubstituted indole alkaloid (4) were isolated from the roots of Fissistigma oldhamii (Hemsl.) Merr. The structures of compounds 1-4 were elucidated using comprehensive spectroscopic methods. The inhibitory activities of compounds 1-4 against nitric oxide (NO) production induced by lipopolysaccharide (LPS) were evaluated in vitro using mouse macrophage RAW264.7 cells. Compounds 2 and 3 showed potent inhibitory activities on NO production with IC50 values of 2.52 ± 0.18 and 2.33 ± 0.16 µM. These results indicate that the discovery of indole alkaloid derivatives, from the roots of F. oldhamii, which show significant anti-inflammatory properties, could be of great importance to the research and for the development of novel natural anti-inflammatory agents.

Clinical value of oral contrast-enhanced ultrasonography in diagnosis of gastric tumors.

BACKGROUND: The incidence of gastric cancer remains high, and it is the sixth most common cancer and the fourth leading cause of cancer deaths worldwide. Oral contrast-enhanced ultrasonography is a simple, non-invasive, and painless method for the diagnosis of gastric tumors. AIM: To explore the diagnostic value of oral contrast-enhanced ultrasonography for the detection of gastric tumors. METHODS: The screening results based on oral contrast-enhanced ultrasonography and electronic gastroscopy were compared with those of the postoperative pathological examination. RESULTS: Among 42 patients with gastric tumors enrolled in the study, the diagnostic accordance rate was 95.2% for oral contrast-enhanced ultrasonography (n = 40) and 90.5% for electronic gastroscopy (n = 38) compared with postoperative pathological examination. The Kappa value of consistency test with pathological findings was 0.812 for oral contrast-enhanced ultrasonography and 0.718 for electronic gastroscopy, and there was no significant difference between them (P = 0.397). For the TNM staging of gastric tumors, the accuracy rate of oral contrast-enhanced ultrasonography was 81.9% for the overall T staging and 50%, 77.8%, 100%, and 100% for T1, T2, T3, and T4 staging, respectively. The sensitivity and specificity were both 100% for stages T3 and T4. The diagnostic accuracy rate of oral contrast-enhanced ultrasonography was 93.8%, 80%, 100%, and 100% for stages N0, N1-N3, M0, and M1, respectively. CONCLUSION: The accordance rate of qualitative diagnosis by oral contrast-enhanced ultrasonography is comparable to that of gastroscopy, and it could be used as the preferred method for the early screening of gastric tumors.

Two new anthraquinone derivatives from Saprosma crassipes H. S. Lo.

Two new anthraquinone derivatives sapranquinones A and B (1 and 2) together with two known biogenetically related anthraquinone derivatives (3 and 4) were isolated from the stems of Saprosma crassipes H. S. Lo. The structures of these compounds were elucidated using comprehensive spectroscopic methods. Compounds 1-4 were evaluated for their antibacterial activities and compounds 1 and 3 had a broad spectrum antibacterial activity against Staphylococcus albus, Escherichia coli, Bacillus cereus, Micrococcus tetragenus, and Micrococcus luteus with MIC values ranging from 1.25 to 5 µg/mL.

1-Selector 1-Memristor Configuration with Multifunctional a-IGZO Memristive Devices Fabricated at Room Temperature.

Serving as neuromorphic hardware accelerators, memristors play a crucial role in large-scale neuromorphic computing. Herein, two-terminal memristors utilizing amorphous indium-gallium-zinc oxide (a-IGZO) are fabricated through room-temperature sputtering. The electrical characteristics of these memristors are effectively modulated by varying the oxygen flow during the deposition process. The optimized a-IGZO memristor, fabricated under 3 sccm oxygen flow, presents a 5 × 103 ratio between its high- and low-resistance states, which can be maintained over 1 × 104 s with minimal degradation. Meanwhile, desirable properties such as electroforming-free and self-compliance, crucial for low-energy consumption, are also obtained in the a-IGZO memristor. Moreover, analog conductance switching is observed, demonstrating an interface-type behavior, as evidenced by its device-size-dependent performance. The coexistence of negative differential resistance with analog switching is attributed to the migration of oxygen vacancies and the trapping/detrapping of charges. Furthermore, the device demonstrates optical storage capabilities by exploiting the optical properties of a-IGZO, which can stably operate for up to 50 sweep cycles. Various synaptic functions have been demonstrated, including paired-pulse facilitation and spike-timing-dependent plasticity. These functionalities contribute to a simulated recognition accuracy of 90% for handwritten digits. Importantly, a one-selector one-memristor (1S1M) architecture is successfully constructed at room temperature by integrating a-IGZO memristor on a TaOx-based selector. This architecture exhibits a 107 on/off ratio, demonstrating its potential to suppress sneak currents among adjacent units in a memristor crossbar.

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH oxidase activation.

AIM: Hypoxia/oxidative stress can alter the pharmacokinetics (PK) of CPU86017-RS, a novel antiarrhythmic agent. The aim of this study was to investigate the mechanisms underlying the alteration of PK of CPU86017-RS by hypoxia/oxidative stress. METHODS: Male SD rats exposed to normal or intermittent hypoxia (10% O2) were administered CPU86017-RS (20, 40 or 80 mg/kg, ig) for 8 consecutive days. The PK parameters of CPU86017-RS were examined on d 8. In a separate set of experiments, female SD rats were injected with isoproterenol (ISO) for 5 consecutive days to induce a stress-related status, then CPU86017-RS (80 mg/kg, ig) was administered, and the tissue distributions were examined. The levels of Mn-SOD (manganese containing superoxide dismutase), endoplasmic reticulum (ER) stress sensor proteins (ATF-6, activating transcription factor 6 and PERK, PRK-like ER kinase) and activation of NADPH oxidase (NOX) were detected with Western blotting. Rat liver microsomes were incubated under N2 for in vitro study. RESULTS: The Cmax, t1/2, MRT (mean residence time) and AUC (area under the curve) of CPU86017-RS were significantly increased in the hypoxic rats receiving the 3 different doses of CPU86017-RS. The hypoxia-induced alteration of PK was associated with significantly reduced Mn-SOD level, and increased ATF-6, PERK and NOX levels. In ISO-treated rats, the distributions of CPU86017-RS in plasma, heart, kidney, and liver were markedly increased, and NOX levels in heart, kidney, and liver were significantly upregulated. Co-administration of the NOX blocker apocynin eliminated the abnormalities in the PK and tissue distributions of CPU86017-RS induced by hypoxia/oxidative stress. The metabolism of CPU86017-RS in the N2-treated liver microsomes was significantly reduced, addition of N-acetylcysteine (NAC), but not vitamin C, effectively reversed this change. CONCLUSION: The altered PK and metabolism of CPU86017-RS induced by hypoxia/oxidative stress are produced by mitochondrial abnormalities, NOX activation and ER stress; these abnormalities are significantly alleviated by apocynin or NAC.

Safety and immunogenicity of heterologous boosting with orally aerosolised or intramuscular Ad5-nCoV vaccine and homologous boosting with inactivated vaccines (BBIBP-CorV or CoronaVac) in children and adolescents: a randomised, open-label, parallel-controlled, non-inferiority, single-centre study.

BACKGROUND: Heterologous booster immunisation with orally administered aerosolised Ad5-nCoV vaccine (AAd5) has been shown to be safe and highly immunogenic in adults. Here, we aimed to assess the safety and immunogenicity of heterologous booster immunisation with orally administered AAd5 in children and adolescents aged 6-17 years who had received two doses of inactivated vaccine (BBIBP-CorV or CoronaVac). METHODS: We did a randomised, open-label, parallel-controlled, non-inferiority study to assess the safety and immunogenicity of heterologous booster immunisation with AAd5 (0·1 mL) or intramuscular Ad5-nCoV vaccine (IMAd5; 0·3 mL) and homologous booster immunisation with inactivated vaccine (BBIBP-CorV or CoronaVac; 0·5 mL) in children (aged 6-12 years) and adolescents (aged 13-17 years) who had received two doses of inactivated vaccine at least 3 months earlier in Hunan, China. Children and adolescents who were previously immunised with two-dose BBIBP-CorV or CoronaVac were recruited for eligibility screening at least 3 months after the second dose. A stratified block method was used for randomisation, and participants were stratified by age and randomly assigned (3:1:1) to receive AAd5, IMAd5, or inactivated vaccine. The study staff and participants were not masked to treatment allocation. Laboratory and statistical staff were masked during the study. In this interim analysis, adverse events within 14 days and geometric mean titre (GMT) of serum neutralising antibodies on day 28 after the booster vaccination, based on the per-protocol population, were used as the primary outcomes. The analysis of non-inferiority was based on comparison using a one-sided 97·5% CI with a non-inferiority margin of 0·67. This study was registered at ClinicalTrials.gov, NCT05330871, and is ongoing. FINDINGS: Between April 17 and May 28, 2022, 436 participants were screened and 360 were enrolled: 220 received AAd5, 70 received IMAd5, and 70 received inactivated vaccine. Within 14 days after booster vaccination, vaccine-related adverse reactions were reported: 35 adverse events (in 13 [12%] of 110 children and 22 [20%] of 110 adolescents) in 220 individuals in the AAd5 group, 35 (in 18 [51%] of 35 children and 17 [49%] of 35 adolescents) in 70 individuals in the IMAd5 group, and 13 (in five [14%] of 35 children and eight [23%] of 35 adolescents) in 70 individuals in the inactivated vaccine group. Solicited adverse reactions were also reported: 34 (13 [12%] of 110 children and 21 [10%] of 110 adolescents) in 220 individuals in the AAd5 group, 34 (17 [49%] of 35 children and 17 [49%] of 35 adolescents) in 70 individuals in the IMAd5 group, and 12 (five [14%] of 35 children and seven [20%] of 35 adolescents) in 70 individuals in the inactivated vaccine group. The GMTs of neutralising antibodies against ancestral SARS-CoV-2 Wuhan-Hu-1 (Pango lineage B) in the AAd5 group were significantly higher than the GMTs in the inactivated vaccine group (adjusted GMT ratio 10·2 [95% CI 8·0-13·1]; p<0·0001). INTERPRETATION: Our study shows that a heterologous booster with AAd5 is safe and highly immunogenic against ancestral SARS-CoV-2 Wuhan-Hu-1 in children and adolescents. FUNDING: National Key R&D Program of China.

Using quasars as standard clocks for measuring cosmological redshift.

We report hitherto unnoticed patterns in quasar light curves. We characterize segments of the quasar's light curves with the slopes of the straight lines fit through them. These slopes appear to be directly related to the quasars' redshifts. Alternatively, using only global shifts in time and flux, we are able to find significant overlaps between the light curves of different pairs of quasars by fitting the ratio of their redshifts. We are then able to reliably determine the redshift of one quasar from another. This implies that one can use quasars as standard clocks, as we explicitly demonstrate by constructing two independent methods of finding the redshift of a quasar from its light curve.

Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine.

BACKGROUND: Hypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as StAR (steroidogenic acute regulatory protein) and 3-beta-HSD (3-beta-hydroxysteroid dehydrogenase) in the testis. It was hypothesized that these abnormalities in the testis by hypoxia are associated with oxidative stress and an increase in chaperones of endoplasmic reticulum stress (ER stress) and ER stress could be modulated by a reduction in calcium influx. Therefore, we verify that if an application of CPU86017-RS (simplified as RS, a derivative to berberine) could alleviate the ER stress and depressed gene expressions of StAR and 3-beta-HSD, and low plasma testosterone in hypoxic rats, these were compared with those of nifedipine. METHODS: Adult male Sprague-Dawley rats were randomly divided into control, hypoxia for 28 days, and hypoxia treated (mg/kg, p.o.) during the last 14 days with nifedipine (Nif, 10) and three doses of RS (20, 40, 80), and normal rats treated with RS isomer (80). Serum testosterone (T) and luteinizing hormone (LH) were measured. The testicular expressions of biomarkers including StAR, 3-beta-HSD, immunoglobulin heavy chain binding protein (Bip), double-strand RNA-activated protein kinase-like ER kinase (PERK) and pro-apoptotic transcription factor C/EBP homologous protein (CHOP) were measured. RESULTS: In hypoxic rats, serum testosterone levels decreased and mRNA and protein expressions of the testosterone biosynthesis related genes, StAR and 3-beta-HSD were downregulated. These changes were linked to an increase in oxidants and upregulated ER stress chaperones: Bip, PERK, CHOP and distorted histological structure of the seminiferous tubules in the testis. These abnormalities were attenuated significantly by CPU86017-RS and nifedipine. CONCLUSION: Downregulated StAR and 3-beta-HSD significantly contribute to low testosterone in hypoxic rats and is associated with ER stress which mediates testis damage caused by oxygen deprivation. CPU86017-RS is potential in ameliorating hypoxia-induced testicular injuries, possibly by its calcium antagonist effects on the testis.

CPU86017-RS attenuate hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and pro-inflammatory cytokines.

AIM: Downregulation of androgen biosynthesis genes StAR (steroidogenic acute regulatory) and 3ß-HSD (3ß-hydroxysteroid dehydrogenase) contributes to low testosterone levels in hypoxic mice and is possibly related to increased expression of pro-inflammatory cytokines in the testis. The aim of this study is to investigate the effects of CPU86017-RS that block Ca(2+) influx on hypoxia-induced testis insult in mice. METHODS: Male ICR mice were divided into 5 groups: control group, hypoxia group, hypoxia group treated with nifedipine (10 mg/kg), hypoxia groups treated with CPU86017-RS (60 or 80 mg/kg). Hypoxia was induced by placing the mice in a chamber under 10%±0.5% O2 for 28 d (8 h per day). The mice were orally administered with drug in the last 14 d. At the end of experiment the testes of the mice were harvested. The mRNA and protein levels of StAR, 3ß-HSD, connexin 43 (Cx43), matrix metalloprotease 9 (MMP9), endothelin receptor A (ET(A)R) and leptin receptor (OBRb) were analyzed using RT-PCR and Western blotting, respectively. The malondialdehyde (MDA), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) levels were measured using biochemical kits. Serum testosterone concentration was measured with radioimmunoassay. RESULTS: Hypoxia significantly increased the MDA level, and decreased the LDH, ACP and SDH activities in testes. Meanwhile, hypoxia induced significant downregulation of StAR and 3ß-HSD in testes responsible for reduced testosterone biosynthesis. It decreased the expression of Cx43, and increased the expression of MMP9, ETAR and OBRb, leading to abnormal testis function and structure. These changes were effectively diminished by CPU86017-RS (80 mg/kg) or nifedipine (10 mg/kg). CONCLUSION: Low plasma testosterone level caused by hypoxia was due to downregulation of StAR and 3ß-HSD genes, in association with an increased expression of pro-inflammatory cytokines. These changes can be alleviated by CPU86017-RS or nifedipine.