Enhanced NMDA receptor pathway and glutamate transmission in the hippocampal dentate gyrus mediate the spatial learning and memory impairment of obese rats.

Obesity has been linked with the impairment of spatial memory and synaptic plasticity but the molecular mechanisms remained unidentified. Since glutamatergic transmission and NMDA receptor neural pathways in hippocampal dentate gyrus (DG) are essential in the learning and memory, we aimed to investigate glutamate (Glu) and NMDA receptor signaling of DG in spatial learning and memory in diet-induced obesity (DIO) rats. Spatial learning and memory were assessed via Morris water maze (MWM) test on control (Ctr) and DIO rats. Extracellular concentration of Glu in the DG was determined using in vivo microdialysis and HPLC. The protein expressions of NMDA receptor subunit 2B (NR2B), brain-derived neurotrophic factor (BDNF), the activation of calcium/calmodulin-dependent kinase II (CaMKII) and cAMP-response-element-binding protein (CREB) in the DG were observed by western blot. Spatial learning and memory were impaired in DIO rats compared to those of Ctr. NR2B expression was increased, while BDNF expression and CaMKII and CREB activation were decreased in DG of DIO rats. Extracellular concentration of Glu was increased in Ctr on the 3rd and 4th days of the MWM test, but significant further increment was observed in DIO rats. Microinjection of an NMDA antagonist (MK-801) into the DG reversed spatial learning and memory impairment. Such effects were accompanied by greater BDNF expression and CaMKII/CREB activation in the DG of DIO rats. In conclusion, the enhancement of Glu-NMDA receptor transmission in the hippocampal DG contributes to the impairment of spatial learning and memory in DIO rats, maybe via the modulation of CaMKII-CREB-BDNF signaling pathway.

High-Curie-Temperature Elastic Polymer Ferroelectric by Carbene Cross-Linking.

With the emergence of wearable electronics, ferroelectrics are poised to serve as key components for numerous potential applications. Currently, intrinsically elastic ferroelectrics featuring a network structure through a precise "slight cross-linking" approach have been realized. The resulting elastic ferroelectrics demonstrate a combination of stable ferroelectric properties and remarkable resilience under various strains. However, challenges arose as the cross-linking temperature was too high when integrating ferroelectrics with other functional materials, and the Curie temperature of this elastic ferroelectric was comparatively low. Addressing these challenges, we strategically chose a poly(vinylidene fluoride)-based copolymer with high vinylidene fluoride content to obtain a high Curie temperature while synthesizing a cross-linker with carbene intermediate for high reactivity to reduce the cross-linking temperature. At a relatively low temperature, we successfully fabricated elastic ferroelectrics through carbene cross-linking. The resulting elastic polymer ferroelectrics exhibit a higher Curie temperature and show a stable ferroelectric response under strains up to 50%. These materials hold significant potential for integration into wearable electronics.

Sex difference in nocturnal blood pressure dipping in adolescents with varying degrees of adiposity.

BACKGROUND: For adolescents, abnormal dipping patterns in blood pressure (BP) are associated with early-onset organ damage and a higher risk of cardiovascular disorders in adulthood. Obesity is one of the most common reasons for abnormal BP dipping in young people. However, it is unknown whether the severity of obesity is associated with BP dipping status and whether this association is sex-dependent. METHODS: 499 participants between 12 and 17 years old with overweight or obesity underwent ambulatory blood pressure monitoring (ABPM) between April 2018 and January 2019 in Beijing and Baoding. Participants were grouped by body mass index (BMI) into overweight (BMI 85th-95th percentile), obese (BMI ≥ 95th percentile) and severely obese (BMI ≥ 120% of 95th percentile or ≥ 35 kg/m2) groups. Non-dipping was defined as a < 10% reduction in BP from day to night. The interaction effect between sex and obesity degree was also analyzed. RESULTS: 326 boys and 173 girls were included, of whom 130 were overweight, 189 were obese, and 180 were severely obese. Girls with severe obesity had a higher prevalence of non-dipping, but boys showed no significant differences in BP dipping status between obesity categories. In addition, as obesity severity went up, a more evident increase in night-time SBP was observed in girls than in boys. CONCLUSIONS: Severely obese is associated with a higher prevalence of non-BP dipping patterns in girls than in boys, which suggests that the relationship between the severity of obesity and BP dipping status might be sex-specific.

Elastic Relaxor Ferroelectric by Thiol-ene Click Reaction.

As ferroelectrics hold significance and application prospects in wearable devices, the elastification of ferroelectrics becomes more and more important. Nevertheless, achieving elastic ferroelectrics requires stringent synthesis conditions, while the elastification of relaxor ferroelectric materials remains unexplored, presenting an untapped potential for utilization in energy storage and actuation for wearable electronics. The thiol-ene click reaction offers a mild and rapid reaction platform to prepare functional polymers. Therefore, we employed this approach to obtain an elastic relaxor ferroelectric by crosslinking an intramolecular carbon-carbon double bonds (CF=CH) polymer matrix with multiple thiol groups via a thiol-ene click reaction. The resulting elastic relaxor ferroelectric demonstrates pronounced relaxor-type ferroelectric behaviour. This material exhibits low modulus, excellent resilience, and fatigue resistance, maintaining a stable ferroelectric response even under strains up to 70 %. This study introduces a straightforward and efficient approach for the construction of elastic relaxor ferroelectrics, thereby expanding the application possibilities in wearable electronics.

PDZD8-mediated endoplasmic reticulum-mitochondria associations regulate sympathetic drive and blood pressure through the intervention of neuronal mitochondrial homeostasis in stress-induced hypertension.

Neuronal hyperexcitation in the rostral ventrolateral medulla (RVLM) drives heightened sympathetic nerve activity and contributes to the etiology of stress-induced hypertension (SIH). Maintenance of mitochondrial functions is central to neuronal homeostasis. PDZD8, an endoplasmic reticulum (ER) transmembrane protein, tethers ER to mitochondria. However, the mechanisms of PDZD8-mediated ER-mitochondria associations regulating neuronal mitochondrial functions and thereby mediating blood pressure (BP) in the RVLM of SIH were largely unknown. SIH rats were subjected to intermittent electric foot shocks plus noise for 2 h twice daily for 15 consecutive days. The underlying mechanisms of PDZD8 were investigated through in vitro experiments by using small interfering RNA and through in vivo experiments, such as intra-RVLM microinjection and Western blot analysis. The function of PDZD8 on BP regulation in the RVLM was determined in vivo via the intra-RVLM microinjection of adeno-associated virus (AAV)2-r-Pdzd8. We found that the c-Fos-positive RVLM tyrosine hydroxylase (TH) neurons, renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE) level, BP, and heart rate (HR) were elevated in SIH rats. ER-mitochondria associations in RVLM neurons were significantly reduced in SIH rats. PDZD8 was mainly expressed in RVLM neurons, and mRNA and protein levels were markedly decreased in SIH rats. In N2a cells, PDZD8 knockdown disrupted ER-mitochondria associations and mitochondrial structure, decreased mitochondrial membrane potential (MMP) and respiratory metabolism, enhanced ROS levels, and reduced catalase (CAT) activity. These effects suggested that PDZD8 dysregulation induced mitochondrial malfunction. By contrast, PDZD8 upregulation in the RVLM of SIH rats could rescue neuronal mitochondrial function, thereby suppressing c-Fos expression in TH neurons and decreasing RSNA, plasma NE, BP, and HR. Our results indicated that the dysregulation of PDZD8-mediated ER-mitochondria associations led to the loss of the activity homeostasis of RVLM neurons by disrupting mitochondrial functions, thereby participating in the regulation of SIH pathology.

Microglia-derived TNF-α contributes to RVLM neuronal mitochondrial dysfunction via blocking the AMPK-Sirt3 pathway in stress-induced hypertension.

BACKGROUND: Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown. METHODS: The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor-α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050. RESULTS: The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF-α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α-treated N2a cells. AMPK activator A769662 upregulated AMPK-Sirt3 signaling pathway and consequently reversed TNF-α-induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p-AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP. CONCLUSIONS: This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK-Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.

Exosomal miRNAs contribute to coal dust particle-induced pulmonary fibrosis in rats.

Coal workers' pneumoconiosis (CWP) is a fatal occupational disease caused by inhalation of coal dust particles, which leads to progressive pulmonary fibrosis. Recently, as new signal carriers for intercellular communication, exosomal miRNAs have been validated in the pathogenesis of multiple diseases. However, the research on exosomal miRNAs in CWP is still in the preliminary stage. Here, using miRNA sequencing, exosomal miRNA profiles in bronchoalveolar lavage fluid (BALF) from rats with pulmonary fibrosis induced by coal dust particles were analyzed, and the underlying biological function of putative target genes was explored by GO term analysis and KEGG pathway enrichment analysis. According to the results, intratracheal instillation of coal dust particles can alter the exosomal miRNAs expression in the BALF of rats. Further bioinformatics analysis provided some clues to reveal their function in pathological process of pneumoconiosis. More importantly, we identified 4 differentially expressed exosomal miRNAs (miRNA-21-5p, miRNA-29a-3p, miRNA-26a-5p, and miRNA-34a-5p) by qRT­PCR and further verified the temporal changes in the expression of these exosomal miRNAs in animal models from 2 weeks to 16 weeks postexposure. In addition, we conducted a preliminary study on Smad7 as a potential target of miRNA-21-5p and found that exosomal miRNA 21-5p/Smad7 may contribute to the pulmonary fibrosis induced by coal dust particles. Our study confirmed the contribution of exosomal miRNAs to coal dust particle-induced pulmonary fibrosis and provided new insights into the pathogenesis of CWP.

Ultrathin Niobium Carbide MXenzyme for Remedying Hypertension by Antioxidative and Neuroprotective Actions.

Hypertension, as a leading risk factor for cardiovascular diseases, is associated with oxidative stress and impairment of endogenous antioxidant mechanisms, but there is still a tremendous knowledge gap between hypertension treatment and nanomedicines. Herein, we report a specific nanozyme based on ultrathin two-dimensional (2D) niobium carbide (Nb2 C) MXene, termed Nb2 C MXenzyme, to fight against hypertension by achieving highly efficient reactive oxygen species elimination and inflammatory factors inhibition. The biocompatible Nb2 C MXenzyme displays multiple enzyme-mimicking activities, involving superoxide dismutase, catalase, glutathione peroxidase, and peroxidase, inducing cytoprotective effects by resisting oxidative stress, thereby alleviating inflammatory response and reducing blood pressure, which is systematically demonstrated in a stress-induced hypertension rat model. This strategy not only opens new opportunities for nanozymes to treat hypertension but also expands the potential biomedical applications of 2D MXene nanosystems.

In Vitro Identification and In Vivo Confirmation of Inhibitors for Sweet Potato Chlorotic Stunt Virus RNA Silencing Suppressor, a Viral RNase III.

Sweet potato virus disease (SPVD), caused by synergistic infection of Sweet potato chlorotic stunt virus (SPCSV) and Sweet potato feathery mottle virus (SPFMV), is responsible for substantial yield losses all over the world. However, there are currently no approved treatments for this severe disease. The crucial role played by RNase III of SPCSV (CSR3) as an RNA silencing suppressor during the viruses' synergistic interaction in sweetpotato makes it an ideal drug target for developing antiviral treatment. In this study, high-throughput screening (HTS) of small molecular libraries targeting CSR3 was initiated by a virtual screen using Glide docking, allowing the selection of 6,400 compounds out of 136,353. We subsequently developed and carried out kinetic-based HTS using fluorescence resonance energy transfer technology, which isolated 112 compounds. These compounds were validated with dose-response assays including kinetic-based HTS and binding affinity assays using surface plasmon resonance and microscale thermophoresis. Finally, the interference of the selected compounds with viral accumulation was verified in planta In summary, we identified five compounds belonging to two structural classes that inhibited CSR3 activity and reduced viral accumulation in plants. These results provide the foundation for developing antiviral agents targeting CSR3 to provide new strategies for controlling sweetpotato virus diseases.IMPORTANCE We report here a high-throughput inhibitor identification method that targets a severe sweetpotato virus disease caused by coinfection with two viruses (SPCSV and SPFMV). The disease is responsible for up to 90% yield losses. Specifically, we targeted the RNase III enzyme encoded by SPCSV, which plays an important role in suppressing the RNA silencing defense system of sweetpotato plants. Based on virtual screening, laboratory assays, and confirmation in planta, we identified five compounds that could be used to develop antiviral drugs to combat the most severe sweetpotato virus disease.

Endoscopic vs. microscopic transsphenoidal surgery outcomes in 514 nonfunctioning pituitary adenoma cases.

Transsphenoidal surgery remains the preference choice for patients with nonfunctioning pituitary tumors at present, but the superiority of surgical modalities is still debated. Moreover, the efficacy of microscopic and endoscopic transsphenoidal surgery has not been fully studied. Therefore, the present study was designed to compare the postoperative outcomes of the two widely used approaches worldwide. This retrospective study included 514 patients with the first transsphenoidal pituitary adenoma resection in Shandong Provincial Hospital from January 2015 to July 2020 and compared the outcomes of microscope transsphenoidal surgery (MTSS) and endoscopy transsphenoidal surgery (ETSS). A total of 514 patients were included in this study, of whom 210 received the ETSS and 304 received the MTSS. The patients in two groups were similar in terms of postoperative hyponatremia (p = 0.229), diabetes insipidus (p = 0.264), the recovery of hormonal axis (p < 0.05), and extent of resection (EOR) (p = 0.067). ETSS was more likely to cause cerebrospinal fluid leakage than MTSS (p = 0.017, 3.6% vs. 8.6%). CSF leakage might be related to tumor size (95% CI = 1.305-2.766, p = 0.001), and the surgeon's transsphenoidal surgery volume < 300 was also a risk factor (95% CI = 1.396-9.067, p = 0.008). The effect of different surgeries on postoperative vision improvement was statistically difference in univariate analysis (p = 0.048) but not after adjustment for confounders (p = 0.112). Furthermore, there were statistical difference in EOR between MTSS and ETSS when adenomas were performed suprasellar extension (p = 0.037) or optic chiasm compression (p = 0.045). Both techniques are valid for the treatment of nonfunctional adenomas. But CSF leakage is more likely after ETSS. In addition, ETSS is more conducive to resection of nonfunctional adenomas with suprasellar extension or optic chiasm compression.

Development of a recombinase-aided amplification assay for rapid detection of human norovirus GII.4.

BACKGROUND: Human noroviruses are one of the main causes of foodborne illnesses and represent a serious public health concern. Rapid and sensitive assays for human norovirus detection are undoubtedly necessary for clinical diagnosis, especially in regions without more sophisticated equipment. METHOD: The rapid reverse transcription recombinase-aided amplification (RT-RAA) is a fast, robust and isothermal nucleic acid detection method based on enzyme reaction. This method can complete the sample detection at 39 °C in 30 min. In this study, we successfully established a rapid reverse transcription recombinase-aided amplification (RT-RAA) assay for the detection of human norovirus GII.4 and applied this assay to clinical samples, as well as comparison with commercial reverse transcription real-time fluorescence quantitative PCR (RT-qPCR). RESULTS: At 95% probability, the detection sensitivity of RT-RAA was 3.425 log10 genomic copies (LGC)/reaction. Moreover, no cross-reaction was observed with other norovirus genogroups and other common foodborne viruses. Stool samples were examined by RT-RAA and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Compared of RT-qPCR, kappa values for human norovirus detection with RT-RAA were 0.894 (p < 0.001), indicating that both assays were in agreement. CONCLUSION: This RT-RAA assay provides a rapid, specific, and sensitive assay for human norovirus detection and is suitable for clinical testing.

Effect of acute exposure of saxitoxin on development of zebrafish embryos (Danio rerio).

As a type of cyanobacterial toxins, saxitoxin (STX) is receiving great interest due to its increasing presence in waterbodies. However, the underlying mechanism of STX-induced adverse effect is poorly understood. Here, we examined the developmental toxicity and molecular mechanism induced by STX using zebrafish embryos as an animal model. The embryonic toxicity induced by STX was demonstrated by inhibition of embryo hatching, increase in mortality rate, abnormal heart rate, abnormalities in embryo morphology as well as defects in angiogenesis and common cardinal vein remodeling. STX induced embryonic DNA damage and cell apoptosis, which would be alleviated by antioxidant N-acetyl-L-cysteine. Additionally, STX significantly increased reactive oxygen species level, catalase activity and malondialdehyde content and decreased the activity of superoxide dismutase and glutathione content. STX also promoted the expression of vascular development-related genes DLL4 and VEGFC, and inhibited VEGFA expression. Furthermore, STX altered the transcriptional regulation of apoptosis-related genes (BAX, BCL-2, P53 and CASPASE 3). Taken together, STX induced adverse effect on development of zebrafish embryos, which might be associated with oxidative stress-induced apoptosis.

Cylindrospermopsin induces abnormal vascular development through impairing cytoskeleton and promoting vascular endothelial cell apoptosis by the Rho/ROCK signaling pathway.

Cylindrospermopsin (CYN) is a widely distributed cyanobacterial toxin in water bodies and is considered to pose growing threats to human and environmental health. Although its potential toxicity has been reported, its effects on the vascular system are poorly understood. In this study, we examined the toxic effects of CYN on vascular development and the possible mechanism of vascular toxicity induced by CYN using zebrafish embryos and human umbilical vein endothelial cells (HUVECs). CYN exposure induced abnormal vascular development and led to an increase in the growth of common cardinal vein (CCV), in which CCV remodeling was delayed as reflected by the larger CCV area and wider ventral diameter. CYN decreased HUVECs viability, inhibited HUVECs migration, promoted HUVECs apoptosis, destroyed cytoskeleton, and increased intracellular ROS levels. Additionally, CYN could promote the expression of Bax, Bcl-2, and MLC-1 and inhibit the expression of ITGB1, Rho, ROCK, and VIM-1. Taken together, CYN may induce cytoskeleton damage and promote vascular endothelial cell apoptosis by the Rho/ROCK signaling pathway, leading to abnormal vascular development. The current results provide potential insight into the mechanism of CYN toxicity in angiocardiopathy and are beneficial for understanding the environmental risks of CYN for aquatic organisms and human health.

Nodularin induced oxidative stress contributes to developmental toxicity in zebrafish embryos.

Nodularin (NOD) is a kind of cyanobacterial toxins. It is of concern due to elicit severe genotoxicity in humans and animals. The comprehensive evaluation of NOD-induced adverse effects in living organisms is urgently needed. This study is aimed to report the developmental toxicity and molecular mechanism using zebrafish embryos exposed to NOD. The embryonic toxicity induced by NOD is demonstrated by inhibition of embryo hatching, increase in mortality rate, abnormal heart rate, embryonic malformation as well as defects in angiogenesis and common cardinal vein remodeling. NOD triggered a decreased rate of angiogenesis through inhibiting endothelial cells migration. NOD induced embryonic cell apoptosis and DNA damage, which can be alleviated by antioxidant N-acetyl-L-cysteine. NOD significantly caused oxidative damage as indicated by changes in reactive oxygen species, superoxide dismutase, catalase, glutathione and malondialdehyde. NOD also altered the expression of vascular development-genes (DLL4, CDH5, VEGFA, VEGFC) and apoptosis-related genes (BAX, BCL-2, P53, CASPASE 3). Taken together, NOD induced adverse effect on zebrafish embryos development, which may be associated with oxidative stress and apoptosis through the activation of P53-BAX/BCL-2-CASPASE 3-mediated pathway.

Clinical results of Intraductal Meibomian gland probing combined with intense pulsed light in treating patients with refractory obstructive Meibomian gland dysfunction: a randomized controlled trial.

BACKGROUND: This study aims to optimize the therapeutic regimen for refractory obstructive meibomian gland dysfunction (o-MGD) patients by combining intraductal meibomian gland probing (MGP) and intense pulsed light (IPL) to enhance their positive effects and reduce their limitations. METHODS: This randomized, assessor blind study includes 45 patients (90 eyes) with refractory o-MGD who were divided into 3 groups via allocation concealment: IPL (group I, received an IPL treatment course: 3 times at 3-week intervals), MGP (group II, received MGP one time), and combined MGP-IPL (group III, MGP first followed by an IPL treatment course). Standard Patient Evaluation of Eye Dryness score (SPEED), tear break-up time (TBUT), corneal fluorescein staining (CFS), meibum grade, and lid margin finding results were assessed at baseline, 3 weeks after final treatment for groups I and III, 3 and 12 weeks after MGP for group II. Six months after final treatment, the SPEED and willingness to receive any treatment again were also collected for all groups. Paired Wilcoxon, Mann-Whitney U with Bonferroni correction, and Kruskal-Wallis tests were used for data analysis. RESULTS: For all 3 groups, all previously mentioned indexes improved significantly following treatment (P<0.01). MGP-IPL was better than IPL and MGP in terms of post-treatment SPEED, TBUT, meibum grade, and lid telangiectasia (P<0.05/3). Furthermore, the MGP-IPL was better than IPL in terms of lid tenderness and better than MGP in terms of orifice abnormality (P< 0.05/3). Six months later, the SPEED for the MGP-IPL was also significantly lower than other groups (P<0.05/3). Moreover, no patients in the MGP-IPL group expressed the need to be treated again compared to 35.7% or 20% of patients in the IPL or MGP groups, respectively. CONCLUSIONS: Compared with IPL or MGP alone, the combination MGP-IPL produced best results in relieving all signs and symptoms and helping patients attain long-lasting symptom relief. TRIAL REGISTRATION: http://clinicaltrials.gov , ChiCTR1900021273 (retrospectively registered February 9, 2019).

Transcriptome analysis of Paecilomyces hepiali at different growth stages and culture additives to reveal putative genes in cordycepin biosynthesis.

Paecilomyces hepialid (PH) is an endoparasitic fungus of Cordyceps sinensis (CS) and has become a substitute for CS due to their similar pharmacological activities. Because the market demand for CS is difficult to satisfy, and cordycepin, the effective compound of CS, is difficult to industrially produce, we produced 5 samples of PH by culturing for different durations and adding different additives to the culture broth, and detected their cordycepin content with UPLC ESI MS/MS. Then we grouped these cultures into five transcriptome comparisons containing 3 time variable groups and 2 additive variable groups. We used next-generation (NG) sequencing methods to acquire transcriptomic information and investigated the response of gene expression to the additives and the influence of different growth stages. This work will contribute to a better understanding of purine metabolism in PH, and possibly in other Cordyceps species. It will provide a useful resource to further advance transcriptomics studies in Cordyceps species.

Entry and Deposit of Aluminum in the Brain.

Aluminum, as a known neurotoxicant, contributes to cognitive dysfunction and may contribute to Alzheimer's disease. The important reason is that aluminum can enter and be deposited in the brain. There have been three routes by which aluminum could enter the brain from systemic circulation or the site of absorption. Aluminum fluxes into brain across the blood-brain barrier (BBB), the choroid plexuses and the nasal cavity. Some factors, such as the increasing of the blood-brain barrier permeability, citric acid and parathyroid hormone (PTH), and vitamin D, can promote aluminum to enter the brain. But the redistribution of aluminum out of the brain is slow, so aluminum can be deposited in the brain for a long time.

Lack of association between polymorphisms in interleukin (IL)-12, IL-12R, IL-23, IL-23R genes and Takayasu arteritis in a Chinese population.

OBJECTIVE: The goal of this study was to investigate the relationship between polymorphisms in interleukin (IL)-12, IL-12R, IL-23, and IL-23R genes and Takayasu arteritis (TA) in a Chinese population. METHODS: A case-control study was performed to investigate the associations of 19 single nucleotide polymorphisms (SNPs) mapping to IL12A, IL12B, IL12RB1, IL12RB2 and IL23R with susceptibility to TA in 145 Chinese TA patients and 300 healthy controls. Genotype identification was performed with the MassARRAY system from Sequenom. The statistical analysis was conducted by Chi square test and unconditional logistic regression with plink. RESULTS: No significant differences were found for the distribution of allele and genotype frequencies of these SNPs between TA patients and healthy controls. However, a trend for IL12A rs582054 and IL23R rs1004819 in association with the TA phenotype was detected. TA patients carrying the rs582054/rs568408 haplotype (P' = 0.019) appeared less likely to progress to a more severe form of disease. And the C allele (P' = 0.082) of IL23R rs1004819 appeared to be a protective factor to refractory disease. CONCLUSIONS: These findings suggest that the polymorphisms of IL12A, IL12B, IL12RB1, IL12RB2 and IL23R might make no contribution to the susceptibility of TA in the Chinese population.

Identification of Hypertension Predictors and Application to Hypertension Prediction in an Urban Han Chinese Population: A Longitudinal Study, 2005-2010.

INTRODUCTION: Research suggests that targeting high-risk, nonhypertensive patients for preventive intervention may delay the onset of hypertension. We aimed to develop a biomarker-based risk prediction model for assessing hypertension risk in an urban Han Chinese population. METHODS: We analyzed data from 26,496 people with hypertension to extract factors from 11 check-up biomarkers. Then, depending on a 5-year follow-up cohort, a Cox model for predicting hypertension development was built by using extracted factors as predictors. Finally, we created a hypertension synthetic predictor (HSP) by weighting each factor with its risk for hypertension to develop a risk assessment matrix. RESULTS: After factor analysis, 5 risk factors were extracted from data for both men and women. After a 5-year follow-up, the cohort of participants had an area under receiver operating characteristic curve (area under the curve [AUC]) with an odds ratio (OR) of 0.755 (95% confidence interval [CI], 0.746-0.763) for men and an OR of 0.801 (95% CI, 0.792-0.810) for women. After tenfold cross validation, the AUC was still high, with 0.755 (95% CI, 0.746-0.763) for men and 0.800 (95% CI, 0.791-0.810) for women. An HSP-based 5-year risk matrix provided a convenient tool for risk appraisal. CONCLUSION: Hypertension could be explained by 5 factors in a population sample of Chinese urban Han. The HSP may be useful in predicting hypertension.

Effects of aluminium on ß-amyloid (1-42) and secretases (APP-cleaving enzymes) in rat brain.

Chronic administration of aluminium has been proposed as an environmental factor that may affect some pathological changes related to neurotoxicity and Alzheimer's disease (AD). The abnormal generation and deposition of ß-amyloid (Aß) in senile plaques are hallmark features in the brains of AD patients. Furthermore, Aß is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or ß-secretase) and γ-secretase. In the present study, we investigated the modulation of Aß deposition and neurotoxicity in aluminium-maltolate-treated (0, 15, 30, 45 mmol/kg body weight via intraperitoneal injection) in experimental rats. We measured Aß1-40 and Aß1-42 in the cortex and hippocampus in rat brains using ELISA. Subtypes of α-secretase, ß-secretase, and γ-secretase, including ADAM9, ADAM10, ADAM17 (TACE), BACE1, presenilin 1 (PS1) and nicastrin (NCT), were determined using western blotting analyses. These results indicated that aluminium-maltolate induced an AD-like behavioural deficit in rats at 30 and 45 mmol/kg body weight. Moreover, the Aß1-42 content increased significantly, both in the cortex and hippocampus, although no changes were observed in Aß1-40. Furthermore, ADAM9, ADAM10, and ADAM17 decreased significantly; in contrast, BACE1, PS1, and NCT showed significant increase. Taken together, these results suggest that the changes in secretases may correlate to the abnormal deposition of Aß by aluminium in rat brains.