Postoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. However, the mechanism of POCD remains ...largely unknown. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is located in the mitochondria and regulates mitochondrial function. SIRT3 is the only sirtuin that specifically plays a role in extending lifespan in humans and is associated with neurodegenerative diseases. Therefore, the aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice.
SIRT3 expression levels were decreased after surgery. For the interventional study, an adeno-associated virus (AAV)-SIRT3 vector or an empty vector was microinjected into hippocampal CA1 region before anesthesia/surgery. Western blotting, immunofluorescence staining, and enzyme-linked immune-sorbent assay (ELISA) were used to measure the oxidative stress response and downstream microglial activation and proinflammatory cytokines, and Golgi staining and long-term potentiation (LTP) recording were applied to evaluate synaptic plasticity.
Overexpression of SIRT3 in the CA1 region attenuated anesthesia/surgery-induced learning and memory dysfunction as well as synaptic plasticity dysfunction and the oxidative stress response (superoxide dismutase SOD and malondialdehyde MDA) in aged mice with POCD. In addition, microglia activation (ionized calcium binding adapter molecule 1 Iba1) and neuroinflammatory cytokine levels (tumor necrosis factor-alpha TNF-α, interleukin IL-1β and IL-6) were regulated after anesthesia/surgery in a SIRT3-dependent manner.
The results of the current study demonstrate that SIRT3 has a critical effect in the mechanism of POCD in aged mice by suppressing hippocampal neuroinflammation and reveal that SIRT3 may be a promising therapeutic and diagnostic target for POCD.
Pulmonary fibrosis (PF) is a senescence‐associated disease with poor prognosis. Currently, there is no effective therapeutic strategy for preventing and treating the disease process. Mounting ...evidence suggests that arachidonic acid (ARA) metabolites are involved in the pathogenesis of various fibrosis. However, the relationship between the metabolism of ARA and PF is still elusive. In this study, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of ARA in the lungs of PF mice induced by bleomycin (BLM). Therefore, we aimed to explore the role of COX‐2/CYP‐derived ARA metabolic disorders in PF. PTUPB, a dual COX‐2 and soluble epoxide hydrolase (sEH) inhibitor, was used to restore the balance of COX‐2/CYP metabolism. sEH is an enzyme hydrolyzing epoxyeicosatrienoic acids derived from ARA by CYP. We found that PTUPB alleviated the pathological changes in lung tissue and collagen deposition, as well as reduced senescence marker molecules (p16Ink4a and p53‐p21Waf1/Cip1) in the lungs of mice treated by BLM. In vitro, we found that PTUPB pretreatment remarkably reduced the expression of senescence‐related molecules in the alveolar epithelial cells (AECs) induced by BLM. In conclusion, our study supports the notion that the COX‐2/CYP‐derived ARA metabolic disorders may be a potential therapeutic target for PF via inhibiting the cellular senescence in AECs.
Here, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of arachidonic acid in the lungs of mice with pulmonary fibrosis (PF) induced by bleomycin. PTUPB, a dual COX‐2 and soluble epoxide hydrolase inhibitor, was used to restore the balance of COX‐2/CYP metabolism. Our findings showed that PTUPB alleviated bleomycin‐induced PF via inhibiting the cellular senescence in alveolar epithelial cells, indicating a potential therapeutic target for PF.
There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as ...a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.
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•Development of LNP-encapsulated mRNA vaccine (ARCoV) targeting the RBD of SARS-CoV-2•ARCoV induces neutralizing antibodies and T cell immunity in mice and NHPs•ARCoV vaccination confers full protection against SARS-CoV-2 challenge in mice•ARCoV is a thermostable vaccine candidate for phase I studies
ARCoV is an LNP-encapsulated mRNA vaccine platform that is highly immunogenic and safe in mice and non-human primates, conferring protection against challenge with a SARS-CoV-2 mouse-adapted strain.
To investigate the characteristics of cytokines in patients with different HBV infection status and their correlation with HBV DNA, HBsAg, and HBeAg levels. Peripheral blood samples were collected ...from patients with chronic HBV infection in immune tolerance phase (IT), HBeAg‐positive chronic hepatitis B (CHB), and acute hepatitis B (AHB) groups, and levels of cytokines were detected by Luminex technique, and analyzed by FLEXMAP 3D analyzer. The correlation between cytokines and HBV DNA load, HBsAg, HBeAg, and alanine aminotransferase (ALT) level in patients with chronic HBV infection was analyzed. In total 312 subjects (184 males and 128 females) were enrolled in the study. There were significant differences among IT, CHB, and AHB groups in Flt‐3L value (P = .003; H = 12.312), IFN‐γ (P = .001; H = 11.723), IL‐10 (P = .001; H = 18.736), IL‐17A ((P = .001; H = 12.735), and TGF‐β1 (P = .001; Z = 48.571). IFN‐α2 levels in CHB group were significantly higher than those in IT and AHB groups (15.24 vs 35.78 pg/mL, P = .000; Z = 3.727; 13.88 vs 35.78 pg/mL, P = .024; Z = −2.258. In CHB group, the levels of HBsAg and ALT were positively correlated with the levels of IL‐10 (r = .173; P = .006; r = 0.176; P = .006, respectively), while HBeAg level was positively correlated with the IFN‐α2 level (r = .153; P = .016). In AHB group, the HBsAg level was positively correlated with Flt‐3L, IFN‐α2, IL‐10, and IL‐6 (r = .402; P = .023; r = .436; P = .016; r = .524, P = .002; r = .405; P = .022, respectively). HBeAg level was positively correlated with IFN‐γ and IL‐17A levels (r = .400; P = .023; r = .373; P = .036, respectively), and ALT level was positively correlated with IL‐6 levels (r = .367; P = .039). In either AHB or CHB group, HBV DNA load was only related to TGF‐β level (r = .493; P = .004; r = −.218, P = 0.009 respectively). The correlation between Flt‐3L and HBsAg (F = 7.422; P = .007); IL‐17, IL‐6, and HBeAg (F = 5.757; P = .017; F = 6.156; P = .014) were statistically significant. There was significant correlation between TGF‐β2 and HBV DNA (F = 11.795; P = .001), and between ALT and HBsAg, HBV DNA (F = 26.089; P = .000; F = 4.724; P = .031). HBsAg, HBeAg, and HBV DNA were correlated with cytokines and ALT in patients with HBV infection. The level of IFN‐α2 was significantly higher in patients with CHB. HBV DNA load was only correlated with the level of TGF‐β in acute or CHB.
Highlights
Recover from acute HBV infection or the onset of hepatitis in patients with chronic HBV infection depend on host immune response. Immune cells and relevant cytokines are closely related to the pathogenesis and chronicity of hepatitis B, as well as efficiency of treatments. This study focused on the relation of serum cytokines levels to the HBV load, HBV antigens levels in patients with chronic hepatitis B and patients with acute hepatitis B. It was demonstrated that levels of HBsAg, HBeAg, and HBV DNA load were correlated with serum concentration of cytokines and ALT levels, also to provide the basis for identifying the treatment opportunity of chronic HBV infection in clinical practice.
Summary
Fungi, as eukaryotic organisms, contain two genomes, the mitochondrial genome and the nuclear genome, in their cells. How the two genomes evolve and correlate to each other is debated. ...Herein, taking the gourmet pine mushroom Tricholoma matsutake as an example, we performed comparative mitogenomic analysis using samples collected from diverse locations and compared the evolution of the two genomes. The T. matsutake mitogenome encodes 49 genes and is rich of repetitive and non‐coding DNAs. Six genes were invaded by up to 11 group I introns, with one cox1 intron cox1P372 showing presence/absence dynamics among different samples. Bioinformatic analyses suggested limited or no evidence of mitochondrial heteroplasmy. Interestingly, hundreds of mitochondrial DNA fragments were found in the nuclear genome, with several larger than 500 nt confirmed by PCR assays and read count comparisons, indicating clear evidence of transfer of mitochondrial DNA into the nuclear genome. Nuclear DNA of T. matsutake showed a higher mutation rate than mitochondrial DNA. Furthermore, we found evidence of incongruence between phylogenetic trees derived from mitogenome and nuclear DNA sequences. Together, our results reveal the dynamic genome evolution of the gourmet pine mushroom.
This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis ...of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up.
This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18–45 years, with intact cervix and 1–4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18–26 and 27–45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006.
Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2–100·0) against high-grade genital lesions (0 0% of 3310 participants in the vaccine group and 13 0·4% of 3302 participants in the control group) and 97·3% (89·9–99·7) against persistent infection (2 0·1% of 3262 participants in the vaccine group and 73 2·2% of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 7·2% of 3691 participants) and control groups (290 7·9% of 3681); none were considered related to vaccination.
The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention.
National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.
Organic field‐effect transistors (OFETs) are the central building blocks of organic electronics, but still suffer from low performance and manufacturing difficulties. This is due in part to the ...absence of doping, which is mostly excluded from OFET applications for the concern about uncontrollable dopant diffusion. Doping enabled the modern semiconductor industry to build essential components like Ohmic contacts and P–N junctions, empowering devices to function as designed. Recent breakthroughs in organic semiconductors and doping techniques demonstrated that doping can also be a key enabler for high‐performance OFETs. However, the knowledge of organic doping remains limited particularly for OFET use. Therefore, this review addresses OFET doping from a device perspective. The paper overviews doping basics and roles in advanced complementary technologies. These fundamentals help to understand why and how doping provides the desired transistor characteristics. Typical OFETs without doping are discussed, with consideration for operating principle and problems caused by the absence of doping. Achievements for channel, contact, and overall doping are also examined to clarify the corresponding doping roles. Finally, doping mechanisms, techniques, and dopants associated with OFET applications are reviewed. This paper promotes fundamental understanding of OFET doping for the development of high‐performance OFETs with doped components.
Doping specifically for organic transistor applications from a device perspective is reviewed. Doping fundamentals, various doping roles in transistors, different operating principles, relevant issues caused by the absence of doping in typical organic transistors, organic transistor doping achievements to date, doping mechanisms, techniques, and dopants are systematically discussed.
Recently, we reported that some dairy cows could produce high amounts of milk with high amounts of protein (defined as milk protein yield MPY) when a population was raised under the same nutritional ...and management condition, a potential new trait that can be used to increase high-quality milk production. It is unknown to what extent the rumen microbiome and its metabolites, as well as the host metabolism, contribute to MPY. Here, analysis of rumen metagenomics and metabolomics, together with serum metabolomics was performed to identify potential regulatory mechanisms of MPY at both the rumen microbiome and host levels.
Metagenomics analysis revealed that several Prevotella species were significantly more abundant in the rumen of high-MPY cows, contributing to improved functions related to branched-chain amino acid biosynthesis. In addition, the rumen microbiome of high-MPY cows had lower relative abundances of organisms with methanogen and methanogenesis functions, suggesting that these cows may produce less methane. Metabolomics analysis revealed that the relative concentrations of rumen microbial metabolites (mainly amino acids, carboxylic acids, and fatty acids) and the absolute concentrations of volatile fatty acids were higher in the high-MPY cows. By associating the rumen microbiome with the rumen metabolome, we found that specific microbial taxa (mainly Prevotella species) were positively correlated with ruminal microbial metabolites, including the amino acids and carbohydrates involved in glutathione, phenylalanine, starch, sucrose, and galactose metabolism. To detect the interactions between the rumen microbiome and host metabolism, we associated the rumen microbiome with the host serum metabolome and found that Prevotella species may affect the host's metabolism of amino acids (including glycine, serine, threonine, alanine, aspartate, glutamate, cysteine, and methionine). Further analysis using the linear mixed effect model estimated contributions to the variation in MPY based on different omics and revealed that the rumen microbial composition, functions, and metabolites, and the serum metabolites contributed 17.81, 21.56, 29.76, and 26.78%, respectively, to the host MPY.
These findings provide a fundamental understanding of how the microbiome-dependent and host-dependent mechanisms contribute to varied individualized performance in the milk production quality of dairy cows under the same management condition. This fundamental information is vital for the development of potential manipulation strategies to improve milk quality and production through precision feeding. Video Abstract.
Abstract
Background
The atherogenicity of remnant cholesterol (RC) has been underlined by recent guidelines, which was linked to coronary artery disease (CAD), especially for patients with diabetes ...mellitus (DM). This study aimed to examine the prognostic value of plasma RC in the patients with CAD under different glucose metabolism status.
Methods
Fasting plasma RC were directly calculated or measured in 4331 patients with CAD. Patients were followed for the occurrence of major adverse cardiovascular events (MACEs) and categorized according to both glucose metabolism status DM, pre-DM, normoglycemia (NG) and RC levels. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals.
Results
During a mean follow-up of 5.1 years, 541 (12.5%) MACEs occurred. The risk for MACEs was significantly higher in patients with elevated RC levels after adjustment for potential confounders. No significant difference in MACEs was observed between pre-DM and NG groups (p > 0.05). When stratified by combined status of glucose metabolism and RC, highest levels of calculated and measured RC were significant and independent predictors of developing MACEs in pre-DM (HR: 1.64 and 1.98; both p < 0.05) and DM (HR: 1.62 and 2.05; both p < 0.05). High RC levels were also positively associated with MACEs in patients with uncontrolled DM. .
Conclusions
In this large-scale and long-term follow-up cohort study, data firstly demonstrated that higher RC levels were significantly associated with the worse prognosis in DM and pre-DM patients with CAD, suggesting that RC may be a target for patients with impaired glucose metabolism.
Transcription activator-like effector nucleases (TALENs) are a powerful approach for targeted genome editing and have been proved to be effective in several organisms. In this study, we reported that ...TALENs can induce somatic mutations in Nile tilapia, an important species for worldwide aquaculture, with reliably high efficiency. Six pairs of TALENs were constructed to target genes related to sex differentiation, including dmrt1, foxl2, cyp19a1a, gsdf, igf3, and nrob1b, and all resulted in indel mutations with maximum efficiencies of up to 81% at the targeted loci. Effects of dmrt1 and foxl2 mutation on gonadal phenotype, sex differentiation, and related gene expression were analyzed by histology, immunohistochemistry, and real-time PCR. In Dmrt1-deficient testes, phenotypes of significant testicular regression, including deformed efferent ducts, degenerated spermatogonia or even a complete loss of germ cells, and proliferation of steroidogenic cells, were observed. In addition, disruption of Dmrt1 in XY fish resulted in increased foxl2 and cyp19a1a expression and serum estradiol-17β and 11-ketotestosterone levels. On the contrary, deficiency of Foxl2 in XX fish exhibited varying degrees of oocyte degeneration and significantly decreased aromatase gene expression and serum estradiol-17β levels. Some Foxl2-deficient fish even exhibited complete sex reversal with high expression of Dmrt1 and Cyp11b2. Furthermore, disruption of Cyp19a1a in XX fish led to partial sex reversal with Dmrt1 and Cyp11b2 expression. Taken together, our data demonstrated that TALENs are an effective tool for targeted gene editing in tilapia genome. Foxl2 and Dmrt1 play antagonistic roles in sex differentiation in Nile tilapia via regulating cyp19a1a expression and estrogen production.
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