Infection with wild-type SARS-CoV-2 elicits broadly neutralizing and protective antibodies against omicron subvariants.

The omicron variants of SARS-CoV-2 have substantial ability to escape infection- and vaccine-elicited antibody immunity. Here, we investigated the extent of such escape in nine convalescent patients infected with the wild-type SARS-CoV-2 during the first wave of the pandemic. Among the total of 476 monoclonal antibodies (mAbs) isolated from peripheral memory B cells, we identified seven mAbs with broad neutralizing activity to all variants tested, including various omicron subvariants. Biochemical and structural analysis indicated the majority of these mAbs bound to the receptor-binding domain, mimicked the receptor ACE2 and were able to accommodate or inadvertently improve recognition of omicron substitutions. Passive delivery of representative antibodies protected K18-hACE2 mice from infection with omicron and beta SARS-CoV-2. A deeper understanding of how the memory B cells that produce these antibodies could be selectively boosted or recalled can augment antibody immunity against SARS-CoV-2 variants.

Single-shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad, durable and protective systemic and mucosal immunity in mice.

Current coronavirus disease 2019 vaccines face limitations including waning immunity, immune escape by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, limited cellular response, and poor mucosal immunity. We engineered a Clec9A-receptor binding domain (RBD) antibody construct that delivers the SARS-CoV-2 RBD to conventional type 1 dendritic cells. Compared with non-targeting approaches, single dose immunization in mice with Clec9A-RBD induced far higher RBD-specific antibody titers that were sustained for up to 21 months after vaccination. Uniquely, increasing neutralizing and antibody-dependent cytotoxicity activities across the sarbecovirus family was observed, suggesting antibody affinity maturation over time. Consistently and remarkably, RBD-specific follicular T helper cells and germinal center B cells persisted up to 12 months after immunization. Furthermore, Clec9A-RBD immunization induced a durable mono- and poly-functional T-helper 1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants of concern, including Omicron subvariants, and with a robust CD8+ T cell signature. Uniquely, Clec9A-RBD single-shot systemic immunization effectively primed RBD-specific cellular and humoral immunity in lung and resulted in significant protection against homologous SARS-CoV-2 challenge as evidenced by limited body weight loss and approximately 2 log10 decrease in lung viral loads compared with non-immunized controls. Therefore, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal protective immunity against rapidly evolving SARS-CoV2 variants.

Attenuation of neurovirulence of chikungunya virus by a single amino acid mutation in viral E2 envelope protein.

BACKGROUND: Chikungunya virus (CHIKV) has reemerged as a major public health concern, causing chikungunya fever with increasing cases and neurological complications. METHODS: In the present study, we investigated a low-passage human isolate of the East/ Central/South African (ECSA) lineage of CHIKV strain LK(EH)CH6708, which exhibited a mix of small and large viral plaques. The small and large plaque variants were isolated and designated as CHIKV-SP and CHIKV-BP, respectively. CHIKV-SP and CHIKV-BP were characterized in vitro and in vivo to compare their virus production and virulence. Additionally, whole viral genome analysis and reverse genetics were employed to identify genomic virulence factors. RESULTS: CHIKV-SP demonstrated lower virus production in mammalian cells and attenuated virulence in a murine model. On the other hand, CHIKV-BP induced higher pro-inflammatory cytokine levels, compromised the integrity of the blood-brain barrier, and led to astrocyte infection in mouse brains. Furthermore, the CHIKV-SP variant had limited transmission potential in Aedes albopictus mosquitoes, likely due to restricted dissemination. Whole viral genome analysis revealed multiple genetic mutations in the CHIKV-SP variant, including a Glycine (G) to Arginine (R) mutation at position 55 in the viral E2 glycoprotein. Reverse genetics experiments confirmed that the E2-G55R mutation alone was sufficient to reduce virus production in vitro and virulence in mice. CONCLUSIONS: These findings highlight the attenuating effects of the E2-G55R mutation on CHIKV pathogenicity and neurovirulence and emphasize the importance of monitoring this mutation in natural infections.

Clinical usefulness of metagenomic next-generation sequencing for Talaromyces marneffei diagnosis in China: a retrospective study.

PURPOSE: Metagenomic next-generation sequencing (mNGS) has been widely used in the diagnosis of infectious diseases. However, studies on Talaromyces marneffei detection using mNGS remain scarce. Therefore, this study aimed to explore the diagnostic performance of mNGS in T. marneffei. METHODS: Between March 2021 and June 2023, patients who were discharged with a final diagnosis of talaromycosis, or confirmed T. marneffei infection by mNGS, culture or pathological examination were included in the study. Culture and mNGS were performed simultaneously for all patients. Clinical data were retrieved for analysis. RESULTS: A total of 78 patients were enrolled, with 40 in the talaromycosis group and 38 in the suspected-talaromycosis group. In the talaromycosis group, mNGS showed a higher positivity rate(40/40, 100.0%) compared to culture(34/40, 85.0%)(P = 0.111). All patients in the suspected-talaromycosis group tested negative via culture, while mNGS yielded positive results. The T. marneffei reads in the talaromycosis group were significantly higher than in the suspected-talaromycosis group (4399 vs. 28, P < 0.001). In the suspected-talaromycosis group, of the four patients with low reads who did not receive antifungal therapy, one died and one lung lesion progressed; most patients(31/34, 91.2%) recovered after receiving appropriate antifungal therapy. CONCLUSION: mNGS proves to be a rapid and highly sensitive method for detecting T. marneffei. Higher reads of T. marneffei correspond to a higher likelihood of infection. However, cases with low reads necessitate a comprehensive approach, integrating clinical manifestations, laboratory tests, and imaging examinations to confirm T. marneffei infection.

General Entropy Approach Toward Ultratough Sustainable Plastics.

Entropy is a universal concept across the physics of mixtures. While the role of entropy in other multicomponent materials has been appreciated, its effects in polymers and plastics have not. In this work, it is demonstrated that the seemingly small mixing entropy contributes to the miscibility and performance of polymer alloys. Experimental and modeling studies on over 30 polymer pairs reveal a strong correlation between entropy, morphology, and mechanical properties, while elucidating the mechanism behind: in polymer blends with weak interactions, entropy leads to homogeneously dispersed nanosized domains stabilized by highly entangled chains. This unique microstructure promotes uniform plastic deformation at the interface, thus improving the toughness of conventional brittle polymers by 1-2 orders of magnitude without sacrificing other properties, analogous to high-entropy metallic alloys. The proposed strategy also applies to ternary polymer systems and copolymers, offering a new pathway toward the development of sustainable polymers.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Sensitive and Specific Loop-Mediated Isothermal Amplification Assays for Detection of Salmonella, CTX-M-1 Group Genes, mph(A), and ermB in Stool and Blood Samples Based on Orange to Green Visible Dye.

Salmonella is a globally prevalent foodborne bacterium, and ceftriaxone and azithromycin have been regarded as drugs of choice for treating Salmonella infections, particularly in children. With the growing incidence of ceftriaxone and azithromycin resistance in Salmonella, there is an urgent requirement for a rapid and dependable gene testing approach to enhance the efficacy of treating Salmonella infections. Utilizing the orange to green visible dye approach, this study developed loop-mediated isothermal amplification (LAMP) assays for the sensitive and specific detection of Salmonella, ceftriaxone and azithromycin resistance genes (including CTX-M-1 group, mph(A), and ermB genes) in stool and blood samples. The specificity and sensitivity of primers during the LAMP assays for detection of Salmonella, CTX-M-1 group, mph(A), and ermB genes were determined in this study. The detection threshold for Salmonella was found to be 1.5 × 103 colony-forming units (CFU)/mL, while it was 1.5 × 102 CFU/mL for CTX-M-1 group genes (including blaCTX-M-3, blaCTX-M-15, and blaCTX-M-55), 1.5 × 102 CFU/mL for mph(A), and 1.5 × 102 CFU/mL for ermB, showing 10-103-fold, 103-fold, and 105-fold increased sensitivity compared with the polymerase chain reaction assay, respectively. Results indicated that the LAMP primers designed for Salmonella, CTX-M-1 group, mph(A), and ermB genes possess high specificity (100%) and sensitivity (over 94%). This novel approach advocates its application in detecting Salmonella, CTX-M-1 group, mph(A), and ermB genes.

Functional analysis of hepatic long non-coding ribonucleic acids during liver transplantation in humans.

BACKGROUND: The potential function of long non-coding RNAs (lncRNAs) in human hepatic ischemia-reperfusion injury (HIRI) remains to be clarified. METHODS: Clinical samples of transplanted liver tissues from 26 patients undergoing liver transplantation (LT) and normal liver tissues from seven patients undergoing hepatic hemangiomactomy (Con) were collected. Typical samples were subjected to whole transcriptome sequencing (RNA-seq). Differentially expressed genes between groups were identified by DEGseq and were analyzed by enrichment analysis including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis. Transcription of five lncRNAs including NONHSAG039942, NONHSAG071405, NONHSAG027516, LXLOC_058190, and LXLOC_024376 that presented significant difference in RNA-sequencing were validated by a quantitative real-time PCR (qRT-PCR), for which the subcellular localization and the binding ability to known human RNA-binding proteins (RBPs) were respectively predicted by LncLocator and catRAPID genomics v2.1. RESULTS: We identified 2917 lncRNAs and 2811 mRNAs that were differentially expressed (p < 0.05 and log2 fold change > 1 or < -1) between groups (LT vs. Con). NONHSAG039942, NONHSAG071405, LXLOC_058190, and LXLOC_024376 were validated by qRT-PCR to be significantly increased in the LT group, and were all predicted to be localized in cytoplasm or cytosol. NONHSAG039942, NONHSAG071405, and LXLOC_058190 held an RBP interaction propensity score of 98.07%, 76.95%, and 152.99%, respectively, with heterogeneous-nuclear ribonucleoprotein U (HNRNPU). Pathways significantly activated in transplant livers that involved HNRNPU as a core enrichment gene included hypoxia, ACE2 expression, apoptosis, spliceosome formation, etc. CONCLUSIONS: NONHSAG039942, NONHSAG071405, and LXLOC_058190 were significantly increased in transplant livers after reperfusion and their role in HIRI may be associated with HNRNPU, a core protein that participates in hypoxia and chromatin accessibility.

Circ_0058063 regulates the development of esophageal cancer through miR-377-3p/HOXA1 axis.

Esophageal cancer is one of the deadliest cancers. Circular RNA (CircRNA) can be used as a tumor marker. Therefore, this provides an important idea for our research. Real-time quantitative PCR (RT-qPCR) was used to analyze the expression of circ_0058063, miR-377-3p and homeobox protein Hox-A1 (HOXA1), western blot was used to analyze the protein levels of HOXA1 and cyclinD1, B cell leukemia/lymphoma 2 associated X (Bax). Cell Counting Kit-8 (CCK-8) assay, colony formation assay and wound healing assay were used to analyze cell proliferation and migration; apoptosis was analyzed by flow cytometry. Dual-luciferase reporter assays were performed to analyze the luciferase activities. Transwell assay was used to analyze the cell invasion. A glycolysis metabolism assay was used to analyze cell glycolysis ability. Xenograft models were used to validate the effect of circ_0009035 in the growth of esophageal cancer in vivo . Circ_0009035 and HOXA1 were upregulated, while miR-377 was downregulated in esophageal cancer.. Circ_0058063 targeted miR-377-3p, and HOX4 was a target of miR-377-3p. Knockdown of circ_0058063 inhibited migration, invasion and proliferation and promoted apoptosis of esophageal cancer cells. MiR-377-3p inhibition or HOXA1 overexpression could restore the effect of si-circ_0058063 on esophageal cancer cells. Knockdown of circ_0058063 repressed the growth of esophageal cancer tumors in vivo. Our study found that circ_0058063 could regulate the expression of HOXA1 by targeting miR-377-3p, thereby affecting the progress of esophageal cancer.

Clinical usefulness of metagenomic next-generation sequencing for Rickettsia and Coxiella burnetii diagnosis.

Rickettsia and Coxiella burnetii are zoonotic tick-borne pathogens that cause febrile illnesses in humans. Metagenomic next-generation sequencing (mNGS) is a new technology used to diagnose infectious diseases. However, clinical experience with applying the test to rickettsioses and Q fever is relatively limited. Therefore, this study aimed to explore the diagnostic performance of mNGS in detecting Rickettsia and C. burnetii. We retrospectively studied patients with rickettsioses or Q fever between August 2021 and July 2022. Peripheral blood mNGS and polymerase chain reaction (PCR) were performed for all patients. Clinical data were retrieved for analysis. Thirteen patients were included in this study (eleven confirmed cases and two suspected cases). Signs and symptoms included fever (13, 100%), rash (7, 53.8%), muscle soreness (5, 38.5%), headache (4, 30.8%), skin eschar (3, 23.1%), and disturbance of consciousness (2, 15.4%). In addition, eight patients (61.6%) had thrombocytopenia, ten (76.9%) had liver function impairment, and two (15.4%) had renal function impairment. The results of mNGS revealed seven patients with R. japonica (53.8%), five with C. burneti (38.5%), two with R. heilongjiangensis (15.4%), and one with R. honei (7.7%). PCR results were positive in 11 patients (84.6%). After receiving doxycycline-based treatment, 12 (92.3%) patients returned to a normal temperature within 72 h. All patients were discharged in better health. Therefore, mNGS can help diagnose Rickettsia and C. burnetii and shorten the diagnosis time, especially for patients with atypical clinical manifestations and unclear epidemiologic evidence of a tick bite or exposure.

Anti-apoptosis effect of recombinant human interleukin-11 in neonatal hypoxic-ischemic rats through activating the IL-11Rα/STAT3 signaling pathway.

Hypoxia-ischemia (HI) is one of the most common causes of death and disability in neonates. Apoptosis contributes to HI development. Interleukin-11(IL-11) has been shown to protect mice from cerebral ischemia/reperfusion injury. However, whether IL-11 exerts the anti-apoptotic effect on HI injury is unclear. In this study, we demonstrated that recombinant human IL-11 (rhIL-11) prevented apoptosis of rat neonates with HI through activating IL-11Rα/STAT3 signaling. Sprague-Dawley rat pups on the 7th day after birth were used to establish an HI injury model. The expression levels of IL-11Rα and GP130 were increased first and then decreased after HI. In contrast, IL-11 expression was first decreased and then increased. Immunofluorescence staining showed that IL-11Rα was localized in neurons and oligodendrocytes. RhIL-11 treatment alleviated hippocampal and cortical damages, significantly reduced cerebral infarction volumes, cerebral edema, and loss of the Nissl body and nerve cells, and also ameliorated the outcomes of HI injury and long-term neurological deficits. In addition, rhIL-11 treatment upregulated the expressions levels of Bcl-2 and p-STAT3/STAT3, and downregulated the protein concentrations of the lytic protease, and cleaved-caspase-3. Furthermore, GP130 inhibitor and JAK1 inhibitor reversed the protective effects of rhIL-11. Overall, rhIL-11 showed an anti-apoptosis effect on the brain after HI injury. Our results indicated that rhIL-11 reduced neuronal apoptosis by activating the brain IL-11Rα/STAT3 pathway.

Feasibility of quantification based on novel evaluation with stool DNA and fecal immunochemical test for colorectal cancer detection.

BACKGROUND: Stool DNA (sDNA) tests and fecal immunochemical test (FIT) are used for the detection of colorectal cancer (CRC). Here we performed a novel evaluation using sDNA and FIT to assess their performance in CRC screening and monitoring in Hubei, China. METHODS: Stool samples were collected from a high-risk population in Hubei, China (n = 359). sDNA tests and FIT were performed to test for KRAS mutations, NDRG4 and BMP3 methylation, and check hemoglobin levels. The methylation in BMP3 and NDRG4 genes was detected by TaqMan PCR method from human fecal samples. KRAS gene mutation in human fecal DNA was tested using TaqMan probe and amplification-refractory mutation system method. The colloid gold method was used for detection of hemoglobin in fecal samples. Finally, a novel evaluation by software was used to calculate the comprehensive value of the combined results for CRC detection and monitoring. RESULTS: The sensitivity and specificity of the novel evaluation for early CRC (stage I and II), advanced adenoma (AA), and non-colon cancer neoplasm (NA) detection were 95.45% and 81.6%, 29.63% and 75.9%, and 23.08% and 75.17%, respectively. The receiver operating characteristic (ROC) curves of the combined value for the above diseases were 0.945 ± 0.015, 0.543 ± 0.055, and 0.547 ± 0.038, respectively. The levels of the novel evaluation were not significantly associated with the pathology and stage (P > 0.05). In 20 out of 22 CRC patients, the novel evaluation of sDNA and FIT had decreased below threshold (< 165) at after surgery. DISCUSSION: The novel evaluation with sDNA test and FIT has increased sensitivity for screening of CRC and AA. The novel evaluation may have potential importance as an indicator of early CRC. Additionally, the dynamic changes of the comprehensive value after surgery were correlated with CRC treatment.

Analgesia and patient comfort after enhanced recovery after surgery in uvulopalatopharyngoplasty: a randomised controlled pilot study.

BACKGROUND: Uvulopalatopharyngoplasty(UPPP) is the most prevalent surgical treatment of obstructive sleep apnea, but postoperative pharyngeal pain may affect patient comfort. The enhanced recovery after surgery pathway has been proved beneficial to many types of surgery but not to UPPP yet. The aim of this pilot study was to preliminarily standrize an enhanced recovery after surgery protocol for UPPP, to assess whether it has positive effects on reducing postoperative pharyngeal pain and improving patient comfort, and to test its feasibility for an international multicentre study. METHODS: This randomised controlled study analysed 116 patients with obstructive sleep apnoea (OSA) who were undergoing UPPP in a single tertiary care hospital. They were randomly divided according to treatment: the ERAS group (those who received ERAS treatment) and the control group (those who received traditional treatment). Ninety-five patients completed the assessment (ERAS group, 59 patients; control group, 36 patients). Pharyngeal pain and patient comfort were evaluated using a visual analogue scale (VAS) at 30 min and at 6, 12, 24 and 48 h after UPPP. Complications, hospitalisation duration, and hospital cost were recorded. RESULTS: The VAS scores for resting pain and swallowing pain were significantly lower in the ERAS group than those in the control group at 30 min and at 6, 12, 24 and 48 h after surgery. Patient comfort was improved in the ERAS group. The hospitalisation duration and cost were comparable between the groups. The incidence of complications showed an increasing trend in the ERAS group. CONCLUSION: The ERAS protocol significantly relieved pharyngeal pain after UPPP and improved comfort in patients with OSA, which showed the prospect for an larger study. Meanwhile a potential increase of post-operative complications in the ERAS group should be noticed. TRIAL REGISTRATION: Chinese Clinical Trial Registry (23/09/2018, ChiCTR1800018537 ).

Assessment of thyroid function in children, adults and pregnant and lactating women after long-term salt iodisation measurements.

Universal salt iodisation (USI) has been successfully implemented in China for more than 15 years. Recent evidence suggests that the definition of 'adequate iodine' (100-199 µg/l) be revised to 'sufficient iodine' (100-299 µg/l) based on the median urinary iodine concentration (MUI) in school-age children. The objective of this study was to determine the prevalence of thyroid dysfunction in populations after long-term salt iodisation and examine whether the definition of adequate iodine can be broadened to sufficient iodine based on the thyroid function in four population groups. A cross-sectional survey was conducted in six provinces in the northern, central and southern regions of China. Four population groups consisting of 657 children, 755 adults, 347 pregnant women and 348 lactating women were recruited. Three spot urinary samples were collected over a 10-d period and blood samples were collected on the 1st day. In the study, among the adults, pregnant women and lactating women, the prevalence rates of elevated thyroglobulin antibody and thyroid microsomal antibody levels were 12·4, 8·5 and 7·8 %, and 12·1, 9·1 and 9·1 %, respectively. Abnormally high thyroid dysfunction prevalence was not observed after more than 15 years of USI in China because the thyroid dysfunction rates were all <5 %. The recommended range should be cautiously broadened from adequate iodine to sufficient iodine according to the MUI of school-age children considering the high levels of hormones and antibodies in the other populations. Adults, particularly pregnant women positive for thyroid antibodies, should be closely monitored.

Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice.

Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC50 of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer's disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.

Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice.

To explore the effects of propofol post-conditioning (PPC) on hepatic ischaemia/reperfusion injury (HIRI) and the potential mechanisms that might be involved in the interaction of Brahma-related gene1(BRG1) and Nuclear-related factor 2(Nrf2). Patients were randomized into PPC(n = 16) and non-PPC(NPC)( n = 21) groups. Propofol(2 mg/kg) was infused within 10 min. of the onset of liver reperfusion during liver transplantation in the PPC group. Liver function tests, as well as Brg1, Nrf2, Heme oxygenase-1(HO-1) and NADPH:quinone oxidoreductase1(NQO1) expression levels were evaluated. CMV-Brg1 mice were designed to investigate the role of Brg1 overexpression during HIRI. Brg1 and Nrf2 siRNA were used to examine the relationship between Brg1 and Nrf2/HO-1 pathways in propofol-mediated effects in a human hepatocyte(L02) hypoxia/reoxygenation(H/R) model. In patients, PPC attenuated both donor liver pathological and function injury, and reducing oxidative stress markers, compared to the NPC group, 24 hrs after surgery. PPC increased liver Brg1, Nrf2, HO-1 and NQO1 expression. In mice, PPC reduced HIRI by decreasing liver oxidative stress and activating Nrf2/HO-1 pathway, accompanied by up-regulation of BRG1 expression. BRG1 overexpression activated Nrf2/HO-1 transcription in CMV-BRG1 mice during HIRI. In vitro, PPC significantly elevated expression of Nrf2, HO-1 and NQO1, resulting in a reduction of cell DCFH-DA and 8-isoprostane levels and decreased lactate dehydrogenase levels, leading to an overall increase in cell viability. Moreover, the protective effects of propofol were partially abrogated in Nrf2-knock-down or BRG1-knock-down hepatocytes. Nrf2-knock-down drastically reduced protein expression of HO-1 and NQO1, while Brg1-knock-down decreased HO-1 expression. Propofol post-conditioning alleviates HIRI through BRG1-mediated Nrf2/HO-1 transcriptional activation.

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Rab11a sustains GSK3ß/Wnt/ß-catenin signaling to enhance cancer progression in pancreatic cancer.

The Rab family GTPases regulate many major biological processes during tumor progression such as cell proliferation, cytoskeleton organization, cell movement, and invasion. The present study aims to examine the clinical significance, biological roles, and molecular mechanism of Rab11a in pancreatic cancer progression. We examined expression pattern of Rab11a in 96 cases of pancreatic cancer specimens using immunohistochemistry and found Rab11a overexpression correlated with tumor-node-metastasis (TNM) stage (p = 0.0111). We depleted Rab11a in Bxpc3 cells using small interfering RNA (siRNA) and overexpressed Rab11a in Capan2 cells. Knockdown of Rab11a inhibited cell growth, invasion, and cell cycle progression while its overexpression facilitated cell growth, invasion, and cell cycle progression. In addition, Rab11a overexpression increased gemcitabine resistance and inhibited gemcitabine-induced apoptosis in Capan2 cells while its depletion reduced drug resistance. We investigated the role of Rab11a in the regulation of Wnt/ß-catenin signaling and we demonstrated that Rab11a overexpression upregulated GSK3ß phosphorylation and nuclear ß-catenin accumulation. Rab11a depletion inhibited while its overexpression enhanced ß-catenin/T-cell factor (TCF) transcriptional activity with corresponding change of Wnt target genes including cyclin D1, cyclin E, MMP7, and c-myc. Wnt inhibitor (FH535) partly attenuated the effects of Rab11a on cell proliferation and Wnt target genes. In conclusion, the present study demonstrated that Rab11a promotes aggressiveness of pancreatic cancer through GSK3ß/Wnt/ß-catenin signaling pathway.

Magnetic circuit design for the performance experiment of shear yield stress enhanced by compression of magnetorheological fluids.

The shear yield stress is an important parameter for the industrial application of magnetorheological (MR) fluids. A test equipment was designed and built to perform investigations on the behaviours of compression and shear after squeeze of MR fluids. Mathematical expression of magnetic flux density was further established. Furthermore, the magnetic field distribution of the test device based on two-coil mode and single-coil mode was simulated and compared using finite element analysis(ANSYS/Multiphysics). An experimental test system was fabricated and modified based on the final conditions and simulation results. The compression and shear after squeeze performances of MR fluids were tested. The results showed that a smaller initial gap distance or a larger compressive strain corresponds to a larger compressive stress under the same external magnetic field strength. The shear yield stress after the squeeze of MR fluids increases quickly with the increasing compression stress and the increasing magnetic flux density. This test equipment was thought to be suitable for studying the compression and shear after squeeze performances of MR fluids.

In-situ texturing hollow carbon host anchored with Fe single atoms accelerating solid-phase redox for Li-Se batteries.

Se-based cathodes have caught tremendous attention owing to their comparable volumetric capacity and better electronic conductivity to S cathodes. However, its low utilization ratio and sluggish redox kinetics due to the high reaction barrier of solid-phase transformation from Se to Li2Se limit its practical application. Herein, an in-situ texturing hollow carbon host by gas-solid interface reaction anchored with Fe single-atomic catalyst is designed and prepared for advanced Li-Se batteries. This Se host presents high pore volume of 1.49 cm3 g-1, Fe single atom content of 1.53 wt%, and its specific structure protects single-atomic catalyst from the destructive reaction environment, thus balancing catalytic activity and durability. After Se loading by reduction of H2SeO3, this homogenous Se-based cathode delivers a superior rate capacity of 431.3 mA h g-1 at 4C, and great discharge capacity of 301.8 mA h g-1 after 1000 cycles at 10C, with high Li-ion diffusion coefficient and capacitance-contributed ratio. The distribution of relaxation times analysis verifies solid-phase transformation mechanism of this cathode and density functional theory calculations confirm the adsorption and bidirectionally catalysis effect of Fe single-atomic catalyst. This work provides a new strategy to prepare high-efficient Se cathode associated with non-noble metal single atoms for high-performance Li-Se batteries.