BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology.

BACE1 is essential for the generation of amyloid-ß (Aß) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aß accumulation.

Histology, ultrastructure, and differential gene expression in relation to seasonal sperm storage in the oviduct of the Chinese alligator, Alligator sinensis.

Although oviductal sperm storage are essential steps in reproduction for female animals with internal fertilisation, no systematic study on the identification of genes involving sperm storage has been performed in crocodilian species. In the present research, the relationship between morphological variation related to sperm storage in the oviduct and gene expression patterns derived from RNA sequencing analyses between active period (AP), breeding period (BP), and hibernation period (HP) were investigated. The corresponding results indicated that sperm were observed not only in the ciliated cells within infundibulum and mucosal layer of uterus during BP, but also been detected in the spermatosperm storage tube (SST) in the anterior uterus at HP stage. The further transmission electron microscopy analysis indicated that the differences in the number and activity of the secretory cells likely to attributed to the seasonal variation of microenvironment related to the sperm storage. Based on the RNA-sequecing, 13147 DEGs related to the Peroxisome proliferator-activated receptors (PPARs) and FOXO signalling were identified, including these, the down-regulated ATG12 and BCL2L11 in the HP group may thus constitute an important point of convergence between autophagy and apoptosis involving the FOXO1 pathway. The genes involved in the PPARs pathway might modulate the immune response and thereby contribute to prolong the life span of stored spermatozoa in Alligator sinensis . The outcomes of this study provide fundamental insights into the mechanism of sperm storage in A. sinensis .

F-box proteins Pof3 and Pof1 regulate Wee1 degradation and mitotic entry in fission yeast.

The key cyclin-dependent kinase Cdk1 (Cdc2) promotes irreversible mitotic entry, mainly by activating the phosphatase Cdc25 while suppressing the tyrosine kinase Wee1. Wee1 needs to be downregulated at the onset of mitosis to ensure rapid activation of Cdk1. In human somatic cells, one mechanism of suppressing Wee1 activity is mediated by ubiquitylation-dependent proteolysis through the Skp1/Cul1/F-box protein (SCF) ubiquitin E3 ligase complex. This mechanism is believed to be conserved from yeasts to humans. So far, the best-characterized human F-box proteins involved in recognition of Wee1 are ß-TrCP (BTRCP) and Tome-1 (CDCA3). Although fission yeast Wee1 was the first identified member of its conserved kinase family, the F-box proteins involved in recognition and ubiquitylation of Wee1 have not been identified in this organism. In this study, our screen using Wee1-Renilla luciferase as the reporter revealed that two F-box proteins, Pof1 and Pof3, are required for downregulating Wee1 and are possibly responsible for recruiting Wee1 to SCF. Our genetic analyses supported a functional relevance between Pof1 and Pof3 and the rate of mitotic entry, and Pof3 might play a major role in this process.

Panning anti-LPS nanobody as a capture target to enrich Vibrio fluvialis.

Vibrio fluvialis is considered as a human pathogen in developing countries. This bacterium is widely distributed in seawater and harbors that contains traces of salt. V. fluvialis can cause human enteritis and diarrhea, which has broken out at a global scale. Lipopolysaccharide (LPS) is a key bacterial antigen used to classify V. fluvialis serogroups. In this research, phage display technology was adopted to isolate nanobodies from a naïve phage library by using LPS as the target antigen. The isolated nanobody was tested in LPS ELISA and bacterial enzyme-linked immunosorbent assay Nanobody V23 had a high affinity toward the pathogen and was utilized to synthesize immunomagnetic beads for the enrichment of V. fluvialis. The capture efficiency of the immunomagnetic beads against V. fluvialis was 90.7 ±â€¯3.2% (N = 3) through the plate-counting method. We generated a high-affinity nanobody against LPS from V. fluvialis and developed a rapid method of enriching V. fluvialis by using immunomagnetic beads.

Intravenous injection of l-aspartic acid ß-hydroxamate attenuates choroidal neovascularization via anti-VEGF and anti-inflammation.

Choroidal neovascularization (CNV) is a hallmark of exudative age-related macular degeneration (exAMD) and a major cause of visual loss in AMD. Despite the widespread use of anti-VEGF therapy, serious adverse effects arise from repeated intravitreal injection of anti-VEGF antibodies, which warrant alternative strategy. We report herein that in a CNV murine model created by krypton red laser, intravenous injection of a serine racemase inhibitor, l-Aspartic acid ß-hydroxamate (L-ABH), significantly reduced CNV at the dose 6 mg/kg on the first day before and followed by 3 mg/kg on the third day after laser injury. The CNV volumes were analyzed with isolectin GS-IB4 staining on choroidal/RPE flat mounts on the seventh day after laser injury. Injection of L-ABH did not produce negative effects on retinal function and visual behavior. To dissect the mechanism in vitro, pretreatment with L-ABH in primary RPE cultures significantly reduced production of vascular endothelial growth factor (VEGF) and macrophage chemotactic protein 1 (MCP-1) by TNFα-primed RPEs. Consistent with these observations, L-ABH pretreatment significantly attenuated macrophage migration mediated by TNFα-primed RPE. Collectively, intravenous injection of L-ABH significantly reduced CNV volumes via reducing production of VEGF and MCP-1 by inflammation-primed RPEs.

Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice.

Consistent results suggest the promoting roles of serine racemase (SR)/D-serine in retinal neurodegeneration in diabetic retinopathy (DR). However, the direct evidence connecting SR deficiency with retinal neuroprotection in genetic model of diabetes mellitus has not been reported. In this investigation, we explore the effect of absence of functional SR on the degeneration of retinal ganglion cells (RGCs) with a diabetic murine model, Ins2Akita mice. We established a murine strain with double mutation, termed Ins2Akita-Srr, by mating heterozygous Ins2Akita mice with homozygous Srrochre269 mice. Ins2Akita retained less RGC in posterior, middle, and peripheral retinae than the counterpart from non-diabetic sibling mice at the age of five or seven months. Ins2Akita-Srr mice retained more RGC in middle and peripheral--but not in posterior-- retinae than the counterpart from Ins2Akita sibling mice at the age of five months. By contrast, at the age of seven months, Ins2Akita-Srr mice contained more RGC in peripheral, middle, and posterior retinae than the counterpart from Ins2Akita. RGCs were identified with retrograde labeling in vivo or with immunolabeling against a RGC-specific transcription factor, Brn3a, in retinal flat mounts. Correspondingly, the aqueous humor of Ins2Akita-Srr contained less amount of D-serine than sibling Ins2Akita mice. Thus, SR deficiency significantly prevented RGC loss in diabetic mice. We conclude that D-serine is a critical factor in the degeneration of RGC in DR. Targeting SR expression or activity may be a strategy for ameliorating RGC loss in DR.

Potential deficit from decreased cerebellar granule cell migration in serine racemase-deficient mice is reversed by increased expression of GluN2B and elevated levels of NMDAR agonists.

Inward migration of cerebellar granule cells (CGCs) after birth is critical for lamination in the cerebellar cortex. N-methyl-d-aspartate (NMDA) subtype of glutamate receptor (NMDAR) tethering CGCs into Bergmann glial fibers mediates the inward movement during the glial-dependent migratory phase. Activation of NMDAR depends on simultaneous binding of the GluN2 subunit by glutamate, and of the GluN1 subunit by d-serine or glycine; d-serine is believed to be an endogenous ligand of NMDAR. We hypothesized that lamination of the cerebellar cortex may be compromised in Srr (the gene for serine racemase (SR)) mutated mice (Srrnull) because of significantly low levels of d-serine per se. Indeed, the external germinal cell layer (EGL) in Srrnull was thicker than in sibling wild-type (WT) mice on postnatal day7 (P7), which accords with decreased CGC migration in Srrnull mice. However, the cerebellar laminar structure in Srrnull mice was normal on P12 and later. Feeding d-serine to pregnant mice abrogated the increased EGL thickness in Srrnull mice on P7. To determine the underlying mechanism of abnormal laminar structure during cerebellar development in Srrnull mice, we examined NMDAR subunits and their ligands. We found increased GluN2B on P10 and increased glycine during P7-12 in the cerebellar homogenates from Srrnull mice compared with the corresponding values from sibling WT mice. In summary, the study revealed how the potential defect in early cerebellar development caused by Srr mutation is circumvented by a compensatory mechanism. This knowledge advances understanding of the adaptation of cerebellar development under the condition of Srr mutation.

Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells.

Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor. Activation of the receptor results in production of nitric oxide (. NO), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV. With laser-injured CNV mice, we found that inactivation of SR-coding gene (Srrnull ) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo. RPE from wild-type (WT) mice expressed SR. To explore the possible downstream target of SR inactivation, we showed that choroid/RPE homogenates extracted from laser-injured Srrnull mice contained less inducible nitric oxide synthase and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation-primed WT RPEs expressed more inducible NOS, produced more. NO and VEGF than did inflammation-primed Srrnull RPEs. When co-cultured with inflammation-primed Srrnull RPE, significantly fewer RF/6A-a cell line of choroidal endothelial cell, migrated to the opposite side of the insert membrane than did cells co-cultured with pre-treated WT RPE. Altogether, SR deficiency reduces RPE response to laser-induced inflammatory stimuli, resulting in decreased production of a cascade of pro-angiogenic cytokines, including. NO and VEGF, and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis.

Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study.

BACKGROUND: Recently genome-wide association studies identified that NCAN rs2228603 polymorphism was associated with non-alcoholic fatty liver disease (NAFLD) mainly in subjects of European ancestry. While no research have been conducted to demonstrate the relationship between NCAN rs2228603 and NAFLD in Chinese Han adults. The aim of this study was to investigate whether NCAN rs2228603 is associated with NAFLD in Chinese population. METHODS: Gene NCAN rs2228603 was genotyped in 182 patients with NAFLD and 195 healthy controls. The expression of NCAN was tested according to polymerase chain reaction analysis (PCR) and serum lipids were performed by biology techniques. RESULTS: No significant difference was found in genotype and allele frequencies of NCAN rs2228603 between the NAFLD group and the controls (P > 0.05). Subjects with the NCAN rs2228603 CT genotype showed a higher level of alkaline phosphatase (AKP) (P = 0.017) and a higher high-density lipoprotein (HDL) (P < 0.05). CONCLUSIONS: Our study for the first time identified that the gene NCAN rs2228603 is not a risk factor for the incidence of NAFLD in Chinese population. Also we found the dual and opposite role of T variant in protecting liver with a higher level of HDL and conferring risk for liver damage with a higher level of AKP. TRIAL REGISTRATION: Chinese Clinical Trial Register.gov Identifier: ChiCTR-ROC-15006447 .

Assessing of case-cohort design: a case study for breast cancer patients in Xinjiang, China.

Objective: To assess the effectiveness and clinical value of case-cohort design and determine prognostic factors of breast cancer patients in Xinjiang on the basis of case-cohort design. Methods: The survival data with different sample characteristics were simulated by using Cox proportional risk models. To evaluate the effectiveness for the case-cohort, entire cohort, and simple random sampling design by comparing the mean, coefficient of variation, etc., of covariate parameters. Furthermore, the prognostic factors of breast cancer patients in Xinjiang were determined based on case-cohort sampling designs. The models were comprehensively evaluated by likelihood ratio test, the area under the receiver operating characteristic curve (AUC), and Akaike Information Criterion (AIC). Results: In a simulations study, the case-cohort design shows better stability and improves the estimation efficiency when the censored rate is high. In the breast cancer data, molecular subtypes, T-stage, N-stage, M-stage, types of surgery, and postoperative chemotherapy were identified as the prognostic factors of patients in Xinjiang. These models based on the different sampling designs both passed the likelihood ratio test (p<0.05). Moreover, the model constructed under the case-cohort design had better fitting effect (AIC=3,999.96) and better discrimination (AUC=0.807). Conclusion: Simulations study confirmed the effectiveness of case-cohort design and further determined the prognostic factors of breast cancer patients in Xinjiang based on this design, which presented the practicality of case-cohort design in actual data.

Modelling of tuberculosis dynamics incorporating indirect transmission of contaminated environment and infectivity of smear-negative individuals: A case study for Xinjiang, China.

Xinjiang has been one of the high incidence areas of pulmonary tuberculosis (PTB) in China. Besides being infected by direct contacting with active PTB individuals (direct infection), the susceptible would be infected because of the exposure to the environment contaminated by Mycobacterium tuberculosis (indirect infection). Active PTB individuals include not only the smear-positive PTB (PTB+) but also the smear-negative PTB (PTB-) who are infectious due to their ability to release tiny Mycobacterium tuberculosis particles even in the absence of visible Mycobacterium tuberculosis in sputum. By taking account of direct/indirect infection and the difference between PTB+ and PTB- individuals in transmission capability, a periodic dynamical PTB transmission model is proposed. The model is fitted to the newly monthly PTB+ and PTB- cases in Xinjiang from 2008 to 2017 by Markov Chain Monte Carlo algorithm. Moreover, global sensitivity analysis is constructed to address the uncertainty of some key parameters by using Latin hypercube sampling and partial rank correlation coefficient methods. Basic reproduction number R0 for PTB transmission in Xinjiang is estimated to be 2.447 (95% CrI:(1.203, 3.844)), indicating that PTB has been prevalent in Xinjiang over the study period. Our results suggest that reducing the direct/indirect transmission rates, early screening, isolating and treating the latent, PTB+ and PTB- individuals, and enhancing the clearance of Mycobacterium tuberculosis in the environment could more effectively control PTB transmission in Xinjiang. The model fits the reported PTB data well and achieves acceptable prediction accuracy. We believe that our model can provide heuristic support for controlling PTB transmission in Xinjiang.

Exercised-enriched blood plasma rescues hippocampal impairments and cognitive deficits in an Alzheimer's disease model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and moderate exercise holds promise in ameliorating the ongoing neurodegeneration and cognitive decline. Here, we investigated whether exercise-enriched blood plasm could yield a beneficial therapeutic effect on AD pathologies and cognitive decline in transgenic AD (P301S) mice. In this investigation, a cohort of 2-month-old C57BL/6 mice were granted continuous access to either a running wheel or a fixed wheel for 6 weeks. After that, their plasmas were extracted and subsequently injected intravenously into 4.5-month-old P301S mice biweekly over a 6-week period. A comprehensive methodology was then employed, integrating behavioral tests, pathology assessments, and biochemical analyses to unveil the potential anti-dementia implications of exercise-enriched blood plasma in P301S mice. Upon systemic administration, the findings revealed a noteworthy attenuation of hippocampus-dependent behavioral impairments in P301S mice. Conversely, blood plasma from sedentary counterparts exhibited no discernible impact. These effects were intricately associated with the mitigation of neuroinflammation, the augmentation of hippocampal adult neurogenesis, and a reduction of synaptic impairments following the administration of exercise-enriched blood plasma. These findings advance the proposition that administering exercise-enriched blood plasma may serve as an effective prophylactic measure against AD, opening avenues for further exploration and potential therapeutic interventions.

Microporous metallic scaffolds supported liquid infused icephobic construction.

HYPOTHESIS: Ice accretion on component surfaces often causes severe impacts or accidents. Liquid-infused surfaces (LIS) have drawn much attention as icephobic materials for ice mitigation in recent years due to their outstanding icephobicity. However, the durability of LIS constructions remains a big challenge, including mechanical vulnerability and rapid depletion of lubricants. The practical applications of LIS materials are significantly restrained, and the full potential of LIS for ice prevention has yet to be demonstrated. EXPERIMENTS: A universal approach was proposed to introduce microporous metallic scaffolds in the LIS construction to increase the applicability and durability, and to prompt the potential of LIS for ice mitigation. Microporous Ni scaffolds were chosen to integrate with polydimethylsiloxane modified by silicone oil addition. FINDINGS: The new LIS construction demonstrated significantly improved durability in icing/de-icing cyclic test, and it also offered a solution for the rapid oil depletion by restraining the deformation of the matrix material. Low ice adhesion strength could be maintained via a micro-crack initiation mechanism. The results indicated that the multi-phase LIS construction consisting of microporous Ni scaffolds effectively addressed the shackles of the icephobicity deterioration of LIS materials, confirming a new design strategy for the R&D of icephobic surfaces.

P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke Mice.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) develops in approximately one-third of stroke survivors and is associated with ingravescence. Nonetheless, the biochemical mechanisms underlying PSCI remain unclear. The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions (MCAOs) and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5 (CDK5)-mediated tau hyperphosphorylation on the PSCI behavior. METHODS: Cognitive behavior was investigated, followed by the detection of tau hyperphosphorylation, mobilization, activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice. Finally, we treated HEK293/tau cells with oxygen-glucose deprivation (OGD) and a CDK5 inhibitor (Roscovitine) or a GSK3ß inhibitor (LiCl) to the roles of CDK5 and GSK3ß in mediating ischemia-reperfusion-induced tau phosphorylation. RESULTS: Ischemia induced cognitive impairments within 2 months, as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra. Furthermore, p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation (control) group, while the expression levels of protein phosphatase 2 (PP2A) and the phosphorylation level at Tyr307 were comparable between the two groups. In addition, the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD. CONCLUSION: These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra, contributing to the pathogenesis of PSCI.

Mineralized and osteoid tissue from dental pulp stem cells on micro-arc oxidation titanium in vitro.

The presence of insufficient bone volume affects the implant healing and success. The aim of this study was to evaluate osteogenic capacity of dental pulp stem cells (DPSCs) on micro-arc oxidation (MAO) titanium surface. DPSCs were challenged at MAO and smooth titanium surface separately for different durations, and the bone marrow mesenchymal stem cells (BMSCs) served as the positive controls. The osteogenic capacity of DPSCs on MAO titanium surface was assessed by using scanning electron microscopy, energy dispersive spectroscopy, biochemical tests and real-time quantitative PCR. Data showed that DPSCs differentiated into osteoblasts and expressed bone morphogenetic genes on MAO titanium surface. The results of this study revealed that DPSCs had good potential to generate mineralized tissue on MAO titanium plates. The differential potential of DPSCs may be regulated by MAO titanium surface. The osteogenesis potential of DPSCs on the MAO titanium was similar with BMSCs.

The total synthesis of (-)-strempeliopine via palladium-catalyzed decarboxylative asymmetric allylic alkylation.

In the work reported herein, the concise and enantioselective total synthesis of the Schizozygine alkaloid (-)-strempeliopine was developed. This synthetic strategy featured the palladium-catalyzed decarboxylative asymmetric allylic alkylation of N-benzoyl lactam to set up the absolute configuration at the C20 position, a highly diastereoselective one-pot Bischler-Napieralski/lactamization and iminium reduction sequence for the construction of the pentacyclic core structure, and the late-stage dearomative addition of indole, leading to the otherwise difficult-to-achieve hexacyclic indoline framework with complete control of four neighbouring stereocenters.

Stereoselective Total Syntheses of C18-Oxo Eburnamine-Vincamine Alkaloids.

Here, we disclose the divergent total syntheses of representative C18-oxo eburnamine-vincamine alkaloids (+)-eburnaminol, (-)-larutenine, and (-)-cuanzine. Key to the approach is a substrate-controlled iridium-catalyzed asymmetric hydrogenation/lactamization cascade that leads to the formation of the common tetracyclic skeleton with essential cis-C20/C21 stereochemistry (93% yield, 98% ee, >20:1 dr, gram scale). Access to the targeted alkaloids is effected late in the synthesis by implementation of a number of diversity-oriented transformations and late-stage modifications.

Prognostic analysis of breast cancer in Xinjiang based on Cox proportional hazards model and two-step cluster method.

Objective: To examine the factors that affect the prognosis and survival of breast cancer patients who were diagnosed at the Affiliated Cancer Hospital of Xinjiang Medical University between 2015 and 2021, forecast the overall survival (OS), and assess the clinicopathological traits and risk level of prognosis of patients in various subgroups. Method: First, nomogram model was constructed using the Cox proportional hazards models to identify the independent prognostic factors of breast cancer patients. In order to assess the discrimination, calibration, and clinical utility of the model, additional tools such as the receiver operating characteristic (ROC) curve, calibration curve, and clinical decision curve analysis (DCA) were used. Finally, using two-step cluster analysis (TCA), the patients were grouped in accordance with the independent prognostic factors. Kaplan-Meier survival analysis was employed to compare prognostic risk among various subgroups. Result: T-stage, N-stage, M-stage, molecular subtyping, type of operation, and involvement in postoperative chemotherapy were identified as the independent prognostic factors. The nomogram was subsequently constructed and confirmed. The area under the ROC curve used to predict 1-, 3-, 5- and 7-year OS were 0.848, 0.820, 0.813, and 0.791 in the training group and 0.970, 0.898, 0.863, and 0.798 in the validation group, respectively. The calibration curves of both groups were relatively near to the 45° reference line. And the DCA curve further demonstrated that the nomogram has a higher clinical utility. Furthermore, using the TCA, the patients were divided into two subgroups. Additionally, the two groups' survival curves were substantially different. In particular, in the group with the worse prognosis (the majority of patients did not undergo surgical therapy or postoperative chemotherapy treatment), the T-, N-, and M-stage were more prevalent in the advanced, and the total points were likewise distributed in the high score side. Conclusion: For the survival and prognosis of breast cancer patients in Xinjiang, the nomogram constructed in this paper has a good prediction value, and the clustering results further demonstrated that the selected factors were important. This conclusion can give a scientific basis for tailored treatment and is conducive to the formulation of focused treatment regimens for patients in practical practice.

Tangeretin Inhibits BACE1 Activity and Attenuates Cognitive Impairments in AD Model Mice.

Tangeretin (TAN) exhibits many bioactivities, including neuroprotective effects. However, the efficacy of TAN in Alzheimer's disease (AD) has not been sufficiently investigated. In the present study, we integrated behavioral tests, pathology assessment, and biochemical analyses to elucidate the antidementia activity of TAN in APPswe/PSEN1dE9 transgenic (Tg) mice. At supplementation levels of 100 mg/kg body weight per day, TAN significantly attenuated the cognitive impairment of Tg mice in behavioral tests. These effects were associated with less synaptic impairments and fewer ß-amyloid accumulations after TAN administration. Furthermore, our study revealed that TAN possessed powerful inhibitory activity against ß-secretase both in vitro and in vivo, which played a crucial role in the process of Aß generation. These findings indicate that TAN is a potential drug for preventing AD pathology. The key mechanism underlying the antidementia effect of TAN may include its inhibitory activity against ß-secretase.

A Third Dose of an Inactivated Vaccine Dramatically Increased the Levels and Decay Times of Anti-SARS-CoV-2 Antibodies, but Disappointingly Declined Again: A Prospective, Longitudinal, Cohort Study at 18 Serial Time Points Over 368 Days.

Background: Due to anti-SARS-CoV-2 antibody decay and SARS-CoV-2 variants, vaccine booster doses are a constant concern. It was focused on whether the third dose can quickly evoke and activate immunity and produce a sufficient and durable immune protection. Objectives: To evaluate the responses and durations of five subsets of anti-SARS-CoV-2 antibodies and their predictive values for protection after the administration of a three-dose inactivated SARS-CoV-2 vaccines regimens. Methods: A prospective cohort study of five subsets of anti-SARS-CoV-2 antibodies (neutralizing antibody, anti-RBD total antibody, anti-Spike IgG, anti-Spike IgM, and anti-Spike IgA) was carried out to evaluate the efficacies and immune characteristics of a three-dose inactivated SARS-CoV-2 vaccines regimen in 32 volunteers. The dynamic response and immune decay were longitudinally profiled at 18 serial time points over 368 days. Results: The neutralizing antibody, anti-RBD total antibody, anti-Spike IgG and anti-Spike IgA levels rapidly increased to 773.60 (380.90-1273.00) IU/mL, 639.30 (399.60-878.60) AU/mL, 34.48 (16.83-44.68) S/CO and 0.91 (0.35-1.14) S/CO, respectively, after the administration of the third dose. Compared to the peak value after the second dose, these values were increased by 4.22-fold, 3.71-fold, 1.01-fold and 0.92-fold. On the other hand, the half-lives of the neutralizing antibody, anti-RBD total antibody, and anti-Spike IgG were 56.26 (95% CI, 46.81 to 70.49) days, 66.37 (95% CI, 54.90 to 83.88) days, and 82.91 (95% CI, 63.65 to 118.89) days, respectively. Compared to the half-lives after the second dose, these values were increased by 1.71-fold, 2.00-fold, and 2.93-fold, respectively. Nevertheless, the positive conversion rate of anti-Spike IgM was decreased to 9.38% (3/32), which was much lower than that after the second dose (65.63% (21/32)). Conclusions: Compared to the second dose, the third dose dramatically increased the antibody levels and decay times. However, the half-life of neutralizing antibody remained unsatisfactory. Due to decay, a fourth dose, and even annual revaccination, might be considered in the SARS-CoV-2 vaccination management strategy.