Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation.

Type 2 diabetes mellitus (T2DM) is a common endocrine disorder which remains a large challenge for clinicians. Previous studies have suggested that mitochondrial dysfunction plays an active role in T2DM progression, but a detailed mechanism is still elusive. In the current study, two Han Chinese families with maternally inherited T2DM were evaluated using clinical, genetic, molecular, and biochemical analyses. The mitochondrial genomes were PCR amplified and sequenced. Phylogenetic and bioinformatic analyses were used to assess the potential pathogenicity of mitochondrial DNA (mtDNA) mutations. Interestingly, the matrilineal relatives of these pedigrees exhibited variable severity of T2DM, in particular, the age at onset of T2DM varied from 26 to 65 years, with an average of 49 years. Sequence analysis revealed the presence of ND4 G11696A mutation, which resulted in the substitution of an isoleucine for valine at amino acid (AA) position 312. Indeed, this mutation was present in homoplasmy only in the maternal lineage, not in other members of these families, as well as 200 controls. Furthermore, the m.C5601T in the tRNAAla and novel m.T5813C in the tRNACys, showing high evolutional conservation, may contribute to the phenotypic expression of ND4 G11696A mutation. In addition, biochemical analysis revealed that cells with ND4 G11696A mutation exhibited higher levels of reactive oxygen species (ROS) productions than the controls. In contrast, the levels of mitochondrial membrane potential (MMP), ATP, mtDNA copy number (mtDNA-CN), Complex I activity, and NAD+/NADH ratio significantly decreased in cell lines carrying the m.G11696A and tRNA mutations, suggesting that these mutations affected the respiratory chain function and led to mitochondrial dysfunction that was involved in T2DM. Thus, our study broadened the clinical phenotypes of m.G11696A mutation.

Traveling Ionospheric Disturbances in the Vicinity of Storm-Enhanced Density at Midlatitudes.

This study provides first storm time observations of the westward-propagating medium-scale traveling ionospheric disturbances (MSTIDs), particularly, associated with characteristic subauroral storm time features, storm-enhanced density (SED), subauroral polarization stream (SAPS), and enhanced thermospheric westward winds over the continental US. In the four recent (2017-2019) geomagnetic storm cases examined in this study (i.e., 2018-08-25/26, 2017-09-07/08, 2017-05-27/28, and 2016-02-02/03 with minimum SYM-H index -206, -146, -142, and -58 nT, respectively), MSTIDs were observed from dusk-to-midnight local times predominately during the intervals of interplanetary magnetic field (IMF) Bz stably southward. Multiple wavefronts of the TIDs were elongated NW-SE, 2°-3° longitude apart, and southwestward propagated at a range of zonal phase speeds between 100 and 300 m/s. These TIDs initiated in the northeastern US and intensified or developed in the central US with either the coincident SED structure (especially the SED basis region) or concurrent small electron density patches adjacent to the SED. Observations also indicate coincident intense storm time electric fields associated with the magnetosphere-ionosphere-thermosphere coupling electrodynamics at subauroral latitudes (such as SAPS) as well as enhanced thermospheric westward winds. We speculate that these electric fields trigger plasma instability (with large growth rates) and MSTIDs. These electrified MSTIDs propagated westward along with the background westward ion flow which resulted from the disturbance westward wind dynamo and/or SAPS.

The role of blood CXCL12 level in prognosis of coronary artery disease: A meta-analysis.

Objective: The role of C-X-C motif chemokine 12 (CXCL12) in atherosclerotic cardiovascular diseases (ASCVDs) has emerged as one of the research hotspots in recent years. Studies reported that the higher blood CXCL12 level was associated with increased major adverse cardiovascular events (MACEs), but the results were inconsistent. The objective of this study was to clarify the prognostic value of the blood CXCL12 level in patients with coronary artery disease (CAD) through meta-analysis. Methods: All related studies about the association between the blood CXCL12 level and the prognosis of CAD were comprehensively searched and screened according to inclusion criteria and exclusion criteria. The quality of the included literature was evaluated using the Newcastle-Ottawa Scale (NOS). The heterogeneity test was conducted, and the pooled hazard risk (HR) or the odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed-effect or random-effects model accordingly. Publication bias was evaluated using Begg's funnel plot and Egger's test. Sensitivity analysis and subgroup analysis were also conducted. Results: A total of 12 original studies with 2,959 CAD subjects were included in the final data combination. The pooled data indicated a significant association between higher CXCL12 levels and MACEs both in univariate analysis (HR 5.23, 95% CI 2.48-11.04) and multivariate analysis (HR 2.53, 95% CI 2.03-3.16) in the CXCL12 level as the category variable group. In the CXCL12 level as the continuous variable group, the result also indicated that the higher CXCL12 level significantly predicted future MACEs (multivariate OR 1.55, 95% CI 1.02-2.35). Subgroup analysis of the CXCL12 level as the category variable group found significant associations in all acute coronary syndrome (ACS) (univariate HR 9.72, 95% CI 4.69-20.15; multivariate HR 2.47, 95% CI 1.79-3.40), non-ACS (univariate HR 2.73, 95% CI 1.65-4.54; multivariate HR 3.49, 95% CI 1.66-7.33), Asian (univariate HR 7.43, 95% CI 1.70-32.49; multivariate HR 2.21, 95% CI 1.71-2.85), Caucasian (univariate HR 3.90, 95% CI 2.73-5.57; multivariate HR 3.87, 95% CI 2.48-6.04), short-term (univariate HR 9.36, 95% CI 4.10-21.37; multivariate HR 2.72, 95% CI 1.97-3.76), and long-term (univariate HR 2.86, 95% CI 1.62-5.04; multivariate HR 2.38, 95% CI 1.76-3.22) subgroups. Subgroup analysis of the CXCL12 level as the continuous variable group found significant associations in non-ACS (multivariate OR 1.53, 95% CI 1.23-1.92), Caucasian (multivariate OR 3.83, 95% CI 1.44-10.19), and long-term (multivariate OR 1.62, 95% CI 1.37-1.93) subgroups, but not in ACS (multivariate OR 1.36, 95% CI 0.67-2.75), Asian (multivariate OR 1.40, 95% CI 0.91-2.14), and short-term (multivariate OR 1.16, 95% CI 0.28-4.76) subgroups. No significant publication bias was found in this meta-analysis. Conclusion: The higher blood CXCL12 level is associated with increased MACEs in patients with CAD, and the blood CXCL12 level may serve as an important prognostic index for CAD. Integrating the blood CXCL12 level into CAD risk assessment tools may provide more comprehensive messages for evaluating and managing patients with CAD.

Pronounced Suppression and X-Pattern Merging of Equatorial Ionization Anomalies After the 2022 Tonga Volcano Eruption.

Following the 2022 Tonga Volcano eruption, dramatic suppression and deformation of the equatorial ionization anomaly (EIA) crests occurred in the American sector ∼14,000 km away from the epicenter. The EIA crests variations and associated ionosphere-thermosphere disturbances were investigated using Global Navigation Satellite System total electron content data, Global-scale Observations of the Limb and Disk ultraviolet images, Ionospheric Connection Explorer wind data, and ionosonde observations. The main results are as follows: (a) Following the eastward passage of expected eruption-induced atmospheric disturbances, daytime EIA crests, especially the southern one, showed severe suppression of more than 10 TEC Unit and collapsed equatorward over 10° latitudes, forming a single band of enhanced density near the geomagnetic equator around 14-17 UT, (b) Evening EIA crests experienced a drastic deformation around 22 UT, forming a unique X-pattern in a limited longitudinal area between 20 and 40°W. (c) Thermospheric horizontal winds, especially the zonal winds, showed long-lasting quasi-periodic fluctuations between ±200 m/s for 7-8 hr after the passage of volcano-induced Lamb waves. The EIA suppression and X-pattern merging was consistent with a westward equatorial zonal dynamo electric field induced by the strong zonal wind oscillation with a westward reversal.

Mitochondrial Diabetes is Associated with tRNALeu(UUR) A3243G and ND6 T14502C Mutations.

Background: Mutations in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM). In particular, m.A3243G is the most common T2DM-related mtDNA mutation in many families worldwide. However, the clinical features and pathophysiology of m.A3243G-induced T2DM are largely undefined. Methods: Two pedigrees with maternally inherited T2DM were underwent clinical, molecular and biochemical assessments. The mtDNA genes were PCR amplified and sequenced. Mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) were measured in polymononuclear leukocytes derived from three patients with both the m.A3243G and m.T14502C mutations, three patients with only the m.A3243G mutation and three controls without these mutations. Moreover, GJB2, GJB3 and GJB6 mutations were screened by PCR-Sanger sequencing. Results: Members of the two pedigrees manifestated variable clinical phenotypes including diabetes and hearing and vision impairments. The age at onset of T2DM varied from 31 to 66 years, with an average of 41 years. Mutational analysis of mitochondrial genomes indicated the presence of the m.A3243G mutation in both pedigrees. Matrilineal relatives in one of the pedigrees harbored the coexisting of m.A3243G and m.T14502C mutations. Remarkably, the m.T14502C mutation, which causes the substitution of a conserved isoleucine for valine at position 58 in ND6 mRNA, may affect the mitochondrial respiratory chain functions. Biochemical analysis revealed that cell lines bearing both the m.A3243G and m.T14502C mutations exhibited greater reductions in ATP levels and increased ROS production compared with those carrying only the m.A3243G mutation. However, we did not find any mutations in the GJB2, GJB3 and GJB6 genes. Conclusion: Our study indicated that mitochondrial diabetes is associated with the tRNALeu(UUR) A3243G and ND6 T14502C mutations.

Recombinant High-Mobility Group Box 1 (rHMGB1) Promotes NRF2-Independent Mitochondrial Fusion through CXCR4/PSMB5-Mediated Drp1 Degradation in Endothelial Cells.

Mitochondrial dynamics plays an important role in maintaining normal endothelial cell function and in the pathogenesis of cardiovascular disease. It is not identified whether high-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP) molecule, could influence mitochondrial dynamics in endothelial cells. The objective of this study is to clarify the effect of HMGB1 on mitochondrial dynamics in endothelial cells and the underlying mechanism. EA.hy926 human endothelial cells were incubated with recombinant HMGB1 (rHMGB1); mitochondrial morphology was observed with a confocal microscope and transmission electron microscope (TEM). The expression of dynamin-related protein 1 (Drp1), Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), Optic atrophy 1 (Opa1), phosphatase and tensin homolog- (PTEN-) induced kinase 1 (PINK1), NOD-like receptor 3 (NLRP3), caspase 1, cleaved caspase 1, 20S proteasome subunit beta 5 (PSMB5), and antioxidative master nuclear factor E2-related factor 2 (NRF2) and the concentration of interleukin 1ß (IL-1ß) were determined. Specific inhibitors C29, TAK-242, FPS-ZM1, AMD3100, and epoxomicin were used to block toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), receptor for advanced glycation end products (RAGE), C-X-C-chemokine receptor 4 (CXCR4), and PSMB5, respectively. siRNAs were used to silence the expression of NRF2. rHMGB1 promoted mitochondrial fusion in endothelial cells, while no significant proinflammatory effects were found. The expression of mitochondrial fission protein Drp1 and phosphorylated subtypes p-Drp1-S616 and p-Drp1-S637 were all downregulated; no significant expression changes of PINK1 and Mfn1, Mfn2, and Opa1 were found. Inhibition of CXCR4 but not TLR4, RAGE, or TLR2 reversed rHMGB1-induced Drp1 downregulation and mitochondrial fusion. Interestingly, inhibition of TLR4 with TAK-242 promoted Drp1 downregulation and mitochondrial fusion. rHMGB1 increased the expression of NRF2 and PSMB5; inhibition of PSMB5 but not silencing NRF2 abolished rHMGB1-induced Drp1 downregulation and mitochondrial fusion. These results indicate that rHMGB1 promotes NRF2 independent mitochondrial fusion via CXCR4/PSMB5 pathway-mediated Drp1 proteolysis. rHMGB1 may influence mitochondrial and endothelial function through this effect on mitochondrial dynamics.

Impact of September 2019 Antarctic Sudden Stratospheric Warming on Mid-Latitude Ionosphere and Thermosphere Over North America and Europe.

Limited observational evidence indicates that ionospheric changes caused by Arctic sudden stratospheric warmings (SSWs) occur at middle latitudes in the Southern Hemisphere. However, it is not known if a similar interhemispheric linkage is produced by Antarctic SSWs. Here we examine thermospheric and ionospheric anomalies observed in September 2019 at middle latitudes in the Northern Hemisphere. We report persistent (at least 30 days) and strong (up to 80%-100%) positive anomalies in the daytime total electron content (TEC) and increases in the thermospheric O/N2 ratio in the western region of North America. However, central and eastern regions of North America experience moderate suppression of TEC reaching 20%-40% of the baseline. Different positive and negative anomalies are observed over the European sector. We hypothesize that regional differences in the TEC response could be related to modulation of thermospheric winds during SSWs, changes in thermospheric composition, and differences in declination angle.

Mitochondrial ND1 T4216C and ND2 C5178A mutations are associated with maternally transmitted diabetes mellitus.

Mutations in mitochondrial DNA (mtDNA) are important causes for type 2 diabetes mellitus (T2DM). To investigate the association between mtDNA mutations/variants and diabetes, we reported here clinical, genetic and biochemical characterization of a Chinese pedigree with maternally transmitted T2DM. Using PCR and direct sequencing analysis of mitochondrial genomes from the matrilineal relatives, we identified two potential pathogenic mutations, m.T4216C (p.Y304H) and m.C5178A (p.L237M) in the ND1 and ND2 genes, respectively, together with a set of genetic polymorphisms belonging to the human mitochondrial haplogroup D4b. Moreover, by isolating and analyzing polymononuclear leukocytes generated from the T2DM patients and controls, we identified lower levels of mitochondrial membrane potential and ATP production in T2DM patients than in the controls, in contrast, a significantly higher level of reactive oxygen species was observed in the T2DM patients carrying both of the m.T4216C and m.C5178A mutations (p < 0.05 for all). In addition, the plasma levels of malondialdehyde and 8-hydroxydeoxyguanosine in the T2DM patients markedly increased, while the level of superoxide dismutase decreased (p < 0.05 for all). Taken together, our data indicated that the ND1 T4216C and ND2 C5178A mutations may lead to oxidative stress and impair the mitochondrial function, and this, in turn, might have been involved in the pathogenesis and progression of T2DM in this pedigree. Thus, our study provides novel insight into the pathophysiology of T2DM that is manifested by mitochondrial dysfunction.

Expression and prognostic potential of GPX1 in human cancers based on data mining.

BACKGROUND: Glutathione peroxidase-1 (GPX1) is a member of the GPX family, which considered an enzyme that interacts with oxidative stress. GPX1 differential expression is closely correlated with carcinogenesis and disease progression. In this study, we used bioinformatics analysis to investigate GPX1 expression level and explore the prognostic information in different human cancers. METHODS: Expression was analyzed via the Oncomine database and Gene Expression Profiling Interactive Analysis tool, and potential prognostic analysis was evaluated using the UALCAN, GEPIA, and DriverDBv3 databases. Then, the UALCAN database was used to find the promoter methylation of GPX1 in defied cancer types. While GPX1 related functional networks were found within the GeneMANIA interactive tool and Cytoscape software. Moreover, Metascape online website was used to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: We found that GPX1 was commonly overexpressed in most human cancers. High expression of GPX1 could lead to poor outcomes in Brain Lower Grade Glioma, while GPX1 over expression was correlated with better prognosis in Kidney renal papillary cell carcinoma (KIPP). High GPX1 expression was marginally associated with poor prognosis in acute myeloid leukemia (AML). Gene regulation network suggested that GPX1 mainly involved in pathways including the glutathione metabolism, ferroptosis, TP53 regulates metabolic genes, reactive oxygen species (ROS) metabolic process, and several other signaling pathways. CONCLUSIONS: Our findings revealed that GPX1 showed significant expression differences among cancers and served as a prognostic biomarker for defined cancer types. The data mining effectively revealed useful information about GPX1 expression, prognostic values, and potential functional networks in cancers, thus providing researchers with an available way to further explore the mechanism underlying carcinogenesis of genes of interest in different cancers.

Experimental Study on the Effect of a Weifufang on Human Gastric Adenocarcinoma Cell Line BGC-823 Xenografts and PTEN Gene Expression in Nude Mice.

Background: This study aims at investigating the effect of the Weifufang, an effective prescription for the treatment of gastric cancer developed by the Traditional Chinese Medicine (TCM)/Combination of TCM and Western Medicine Department of the Hunan Cancer Hospital, on gastric cancer xenografts in nude mice and its effect on the PTEN gene; it also aims at exploring the possible tumor suppression mechanism. Methods: Nude mice with xenografts were treated with different concentrations of the Weifufang for 2 weeks, and changes in tumor volume were observed. The histopathology of the tumor was detected by hematoxylin and eosin staining; PTEN gene expression in tumor tissues was detected by immunohistochemistry (IHC) and western blot. Results: After 2 weeks of treatment, tumor inhibition rates in the 5-flourouracil (5-FU) group, and in the Weifufang low-, middle-, and high-dose groups were 30.67%, 19%, 49.52%, and 29.36%, respectively. The IOD of the PTEN gene was detected by IHC. The values in the water group, the 5-FU group, and the Weifufang low-, middle-, and high-dose groups were 0.013 ± 0.004, 0.085 ± 0.062, 0.041 ± 0.024, 0.128 ± 0.032, and 0.061 ± 0.052, respectively. Except for the 5-FU group, the differences between the gastric compound middle dose-group and the other groups were statistically significant (p < 0.05). Results of PTEN expression detection by western blot: The expression levels in the water group, 5-FU group, and the Weifufang low-, middle-, and high-dose groups were 0.2240 ± 0.0172, 0.4200 ± 0.0228, 0.2760 ± 0.0163, 0.3840 ± 0.0133, and 0.3040 ± 0.0211, respectively. Except for the 5-FU group, differences between the Weifufang middle-dose group and the other groups were statistically significant (p < 0.05). Conclusion: The Weifufang may inhibit the growth of gastric cancer xenografts by upregulating PTEN gene expression. The middle-dose group had the best effect.

Interleukin-8 Gene -251 A/T (rs4073) Polymorphism and Coronary Artery Disease Risk: A Meta-Analysis.

BACKGROUND Inflammation plays an important role in the pathogenesis of coronary artery disease (CAD). Studies have reported that inflammatory cytokine interleukin-8 (IL-8) gene -251 A/T (rs4073) polymorphism is correlated with CAD susceptibility, but the result remains controversial. The objective of this study was to clarify the association between IL-8 gene -251 A/T polymorphism and CAD risk. MATERIAL AND METHODS A meta-analysis included 8244 patients from 9 individual studies with 10 populations was conducted. Heterogeneity test was conducted, and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated used fixed-effect or random-effects model accordingly. Publication bias was evaluated with the Begg's funnel plot and Egger's test. Sensitivity analysis was also conducted. RESULTS A significant association between IL-8 gene -251 A/T polymorphism and CAD risk was found in the dominant model (OR 1.42, 95% CI 1.16-1.76, P<0.001), recessive model (OR 1.30, 95% CI 1.12-1.52, P<0.001), allelic model (OR 1.28, 95% CI 1.12-1.47, P<0.001), homozygote model (OR 1.59, 95% CI 1.21-2.08, P<0.001), and heterozygote model (OR 1.35, 95% CI 1.11-1.64, P=0.002). Subgroup analysis by ethnicity found significant associations in the Chinese population in the dominant model(OR 1.43, 95% CI 1.26-1.61, P<0.001), recessive model (OR 1.39, 95% CI 1.21-1.59, P<0.001), allelic model (OR 1.31, 95% CI 1.21-1.42, P<0.001), homozygote model (OR 1.66, 95% CI 1.41-1.95, P<0.001), and heterozygote model (OR 1.34, 95% CI 1.18-1.52, P<0.001), but no significant association was found in the Caucasian population. No significant publication bias was found. CONCLUSIONS The IL-8 gene -251 A/T polymorphism was significantly associated with CAD risk in the Chinese population but not in the Caucasian population, -251 A allele carrier had an increased risk of CAD in the Chinese population.

Observations of the step-like accelerating processes of cold ions in the reconnection layer at the dayside magnetopause.

Cold ions of plasmaspheric origin have been observed to abundantly appear in the magnetospheric side of the Earth's magnetopause. These cold ions could affect the magnetic reconnection processes at the magnetopause by changing the Alfvén velocity and the reconnection rate, while they could also be heated in the reconnection layer during the ongoing reconnections. We report in situ observations from a partially crossing of a reconnection layer near the subsolar magnetopause. During this crossing, step-like accelerating processes of the cold ions were clearly observed, suggesting that the inflow cold ions may be separately accelerated by the rotation discontinuity and slow shock inside the reconnection layer.

Advanced glycation end products influence mitochondrial fusion-fission dynamics through RAGE in human aortic endothelial cells.

Mitochondrial dynamics plays a critical role in maintaining healthy endothelial function, but whether the atherogenic advanced glycation end products (AGEs) can influence mitochondrial dynamics of endothelial cell remains unclear. AGE modified bovine serum albumin (AGE-BSA) was used as AGEs, primary human aortic endothelial cell line was multiplied, and divided into groups incubated with AGEs of different concentrations for different time. The expression of phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) was silenced with specific siRNA. Mitochondrial morphology of HAECs in each group was determined with transmission electron microscopy. Real time PCR method was used to detect the mRNA expression levels of mitochondrial dynamics regulatory genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy 1 (Opa1), and dynamin-related protein 1 (Drp1) of HAECs, and western blot method was used to detect the protein expression levels of these regulatory genes. Specific antibody was used to block receptor for advanced glycation end products (RAGE). Treatment of different concentrations of AGEs, HAECs presented more granular mitochondrion, indicating AGEs promoted mitochondrial fission of HAECs remarkably. Silencing PINK1 induced mitochondrial fission in HAECs, and AGEs further promoted mitochondrial fragmentation in HAECs of PINK1 silenced. Different concentrations of AGEs down-regulated the mRNA and protein expression of mitochondrial pro-fusional genes Mfn1, Mfn2, Opa1, up-regulated the expression of mitochondrial pro-fissional gene Drp1, and both of the two phosphorylated Drp1 (p-ser-Drp1-616 and p-ser-Drp1-637) were increased. Time-dependent dynamic alterations of the expression levels of Mfn1, Mfn2, Opa1, and Drp1 were also found in HAECs stimulated with AGEs. Blocking RAGE with anti-RAGE inhibited AGEs induced mitochondrial fission and reversed AGEs induced expression changes of mitochondrial regulatory genes Drp1, Mfn1, Mfn2, and Opa1, indicating AGEs induced mitochondrial fission through RAGE in HAECs. In conclusion, AGEs may promote mitochondrial fission of HAECs through its receptor RAGE, silencing PINK1 induces mitochondrial fission, and AGEs further promote mitochondrial fragmentation in HAECs of PINK1 silenced. AGEs up-regulate the expression of mitochondrial pro-fissional gene Drp1 and down-regulate the expression of mitochondrial pro-fusional genes Mfn1, Mfn2, and Opa1 in HAECs.

Advanced glycation endproducts trigger autophagy in cadiomyocyte via RAGE/PI3K/AKT/mTOR pathway.

UNLABELLED: Previous studies showed that the accumulation of advanced glycation end products (AGEs) induce cardiomyocyte apoptoisis, leading to heart dysfunction. However, the effect of AGEs on another cell death pathway, autophagy, in cardiomyocytes remains unknown. METHODS: Rat neonate cardiomyocytes were cultured and treated with AGEs at different concentration. Two classic autophagy markers, microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1, were detected by western blot assay. The inhibition of RAGE and phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mTOR pathway were applied to cells, respectively. RESULTS: AGEs administration enhanced the expression of Beclin-1 and LC3 II in cardiomyocytes, increased the number of autophagic vacuoles and impaired the cell viability in dose-dependant manners. Also, AGEs inhibited the PI3K/Akt/mTOR pathway via RAGE. Inhibition of RAGE with RAGE antibody reduced expression of Beclin-1 and LC3 II/I and inhibited the cellular autophagy, accompanied by the reactivation of PI3K/Akt/mTOR pathway in cultured cells. Notably, the presence of inhibition of PI3K/Akt/mTOR pathway abolished the protective effect of RAGE inhibition on cardiomyocytes. CONCLUSION: This study provides evidence that AGEs induces cardiomyocyte autophagy by, at least in part, inhibiting the PI3K/Akt/mTOR pathway via RAGE.

Direct observations of the evolution of polar cap ionization patches.

Patches of ionization are common in the polar ionosphere, where their motion and associated density gradients give variable disturbances to high-frequency (HF) radio communications, over-the-horizon radar location errors, and disruption and errors to satellite navigation and communication. Their formation and evolution are poorly understood, particularly under disturbed space weather conditions. We report direct observations of the full evolution of patches during a geomagnetic storm, including formation, polar cap entry, transpolar evolution, polar cap exit, and sunward return flow. Our observations show that modulation of nightside reconnection in the substorm cycle of the magnetosphere helps form the gaps between patches where steady convection would give a "tongue" of ionization (TOI).

Effect of oxidized LDL on the expression of connexins in cultured human umbilical-vein endothelial cells.

The role of connexins in atherogenesis has attracted increasing attention in recent years; however, whether oxidized LDL (low density lipoprotein) is one of the pro-atherosclerotic factors that can influence the expression of endothelial connexins remains unclear. To investigate the effect of oxidized LDL on the gene expression of the gap junction proteins connexin37, connexin40 and connexin43 in cultured HUVEC (human umbilical-vein endothelial cells) in vitro, HUVEC were cultured and divided into groups before being stimulated with various concentrations of oxidized LDL for different times. mRNA expression of connexin37, connexin40 and connexin43 in each group were determined semi-quantitatively by RT-PCR (reverse transcription-PCR), while protein expression of the three connexins was investigated by immunocytochemical staining. Various concentrations of oxidized LDL down-regulated mRNA and protein expression of connexin37, and up-regulated the expression of connexin40 and connexin43. Time-dependent dynamic alterations of the mRNA expression levels of connexin37, connexin40 and connexin43 were also found in HUVEC stimulated by oxidized LDL. We conclude that oxidized LDL can change the expression of connexin genes in cultured HUVEC within a short period, and thus may be involved in the pro-atherosclerotic effect of oxidized LDL.

[Application of the national diagnostic criteria of occupational mercury poisoning].

OBJECTIVE: To investigate the clinical manifestation of patients with renal injury induced by chronic mercury intoxication and the application of the diagnostic criteria of occupational mercury poisoning. METHODS: The clinical data of 8 patients with chronic occupational mercury intoxication were analysed and evaluated. RESULTS: All the observed clinical signs of chronic mercury intoxication correspond with the items of the diagnostic criteria of occupational mercury poisoning. The increasing beta2-MG was one of the clinical manifestations of renal injury induced by chronical mercury intoxication. The renal injury obviously was dose-dependent and reversible. CONCLUSIONS: The national diagnostic criteria of occupational mercury poisoning is practically valuable. The renal injury induced by chronic mercury intoxication should not be neglected.

[The correlation between ICAM-1 gene K469E polymorphism and coronary heart disease].

OBJECTIVE: To investigate the correlation between intercellular adhesion molecule1 (ICAM1) gene K469E polymorphism and coronary heart disease(CHD) in Han Chinese population. METHODS: Using the methods of polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP), 173 CHD patients and 141 controls were analyzed for the polymorphism, genotype and allele distribution of ICAM1 gene K469E. RESULTS: The distribution of ICAM1 genotypes was in Hardy-Weinberg equilibrium. The frequency of KK genotype in CHD group was significantly higher than that in control (64.2% vs 48.9%, P<0.01). Similarly, the frequency of K allele in CHD group was significantly higher than that in control (79.2% vs 69.9%, P<0.01). With Logistic Regression Analysis ruling out the influences of age, gender and other CHD risk factor, the homozygous individual with KK genotype was 2.35 folds of KE or EE genotype one suffering from CHD (OR: 2.35, 95%CI: 1.03-5.36, P<0.05). CONCLUSION: ICAM1 gene K469E polymorphism is associated with CHD risk of Han Chinese population, the K allele may serve as a genetic risk factor of coronary heart disease.