ABSTRACT
BACKGROUND: Both anxiety symptoms and suicide risk are common in schizophrenia. However, previous findings about the association between anxiety and suicide risk in schizophrenia were controversial. This study is the first to examine the prevalence of suicide risk and related demographic, clinical features in a large sample of first episode drug-naïve (FEDN) schizophrenia patients with comorbid severe anxiety. METHODS: In total, 316 patients with FEDN schizophrenia were enrolled in this study. Patients' symptoms were assessed using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS). Serum levels of glucose, insulin, uric acid, and lipids including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), were evaluated. RESULTS: In the current study, 56.3% patients presented comorbid severe anxiety. The rate of suicide risk was higher in the severe anxiety group (55.6%) than in the mild-moderate anxiety group (33.3%). The interactions among severe anxiety, uric acid and HDL-C were associated with suicide risk. Compared with patients with normal uric acid, those with abnormal uric acid exhibited a stronger association between HAMA scores and HAMD-suicide item scores. This enhanced association was also observed for patients with abnormal HDL-C levels. CONCLUSIONS: In FEDN schizophrenia patients with comorbid severe anxiety, our findings suggested a high incidence of suicide risk. Abnormal levels of uric acid and low levels of HDL-C, as well as high depression may be associated with an increased risk of suicide in FEDN schizophrenia patients with comorbid severe anxiety.
Subject(s)
Comorbidity , Schizophrenia , Humans , Schizophrenia/epidemiology , Schizophrenia/blood , Male , Female , Adult , Prevalence , Young Adult , Suicide/statistics & numerical data , Anxiety/epidemiology , Anxiety/blood , Uric Acid/blood , Anxiety Disorders/epidemiology , Anxiety Disorders/blood , Adolescent , Middle Aged , Severity of Illness Index , China/epidemiologyABSTRACT
Flowery-like aroma are positive contributors to green tea. Here, the optimal processing conditions for green tea with flowery-like aroma were designed using spreading time, fixation time and drying temperature as three factors designed by response surface methodology (RSM), and the response value of aroma sensory evaluation score. The volatiles in batches of tea samples were analyzed by GC-MS. The optimal quality was obtained with a flowery-like aroma by RSM under a spreading time of 8.97 h, fixation time of 162.3 s, and drying temperature of 103.32 °C. GC-O and odor activity values further revealed floral-like volatiles, including decanal, linalool oxide, ß-lonone, geraniol, (Z)-jasmone, linalool, nonanal, and benzeneacetaldehyde. The recombination of these floral volatiles confirmed the consistency with the floral green tea. Furthermore, the extending spreading duration (8-10 h), reducing fixation duration (160-190 s), and increasing drying temperature (100-115 °C) promote their accumulation in green tea. This study provides new perspectives for the precise enhancement of floral odorants for green tea.
ABSTRACT
Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.
Subject(s)
Adaptor Proteins, Signal Transducing , Corticosterone , DEAD Box Protein 58 , Ferroptosis , Mitophagy , Neural Stem Cells , Animals , Mice , DEAD Box Protein 58/metabolism , DEAD Box Protein 58/genetics , Corticosterone/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Neural Stem Cells/metabolism , Hippocampus/metabolism , Mitochondria/metabolism , Signal Transduction , Receptors, Cell SurfaceABSTRACT
Mounting evidence indicates that the gut microbiota influences the neurodevelopment and behavior of insects through the gut-brain axis. However, it is currently unclear whether the gut microbiota affect the head profiles and immune pathway in pests. Here, we find that gut bacteria is essential for the immune and neural development of adult Spodoptera frugiperda, which is an extremely destructive agricultural pest worldwide. 16 S rRNA sequencing analysis showed that antibiotics exposure significantly disturbed the composition and diversity of gut bacteria. Further transcriptomic analysis revealed that the adult head transcripts were greatly affected by gut dysbacteriosis, and differently expression genes critical for brain and neural development including A4galt, Tret1, nsun4, Galt, Mitofilin, SLC2A3, snk, GABRB3, Oamb and SLC6A1 were substantially repressed. Interestingly, the dysbacteriosis caused sex-specific differences in immune response. The mRNA levels of pll (serine/threonine protein kinase Pelle), PGRP (peptidoglycan-sensing receptor), CECA (cecropin A) and CECB (cecropin B) involved in Toll and Imd signaling pathway were drastically decreased in treated male adults' heads but not in female adults; however, genes of HIVEP2, ZNF131, inducible zinc finger protein 1-like and zinc finger protein 99-like encoding zinc-finger antiviral protein (ZAP) involved in the interferon (IFNα/ß) pathway were significantly inhibited in treated female adults' heads. Collectively, these results demonstrate that gut microbiota may regulate head transcription and impact the S. frugiperda adults' heads through the immune pathway in a sex-specific manner. Our finding highlights the relationship between the gut microbiota and head immune systems of S. frugiperda adults, which is an astonishing similarity with the discoveries of other animals. Therefore, this is the basis for further research to understand the interactions between hosts and microorganisms via the gut-brain axis in S. frugiperda and other insects.
Subject(s)
Dysbiosis , Transcriptome , Male , Animals , Female , Spodoptera/microbiology , Dysbiosis/veterinary , Gene Expression Profiling , Immunity , LarvaABSTRACT
Introduction: Spodoptera frugiperda is a serious world-wide agricultural pest. Gut microorganisms play crucial roles in growth, development, immunity and behavior of host insects. Methods: Here, we reported the composition of gut microbiota in a laboratory-reared strain of S. frugiperda using 16S rDNA sequencing and the effects of gut microbiota on the reproduction. Results: Proteobacteria and Firmicutes were the predominant bacteria and the taxonomic composition varied during the life cycle. Alpha diversity indices indicated that the eggs had higher bacterial diversity than larvae, pupae and adults. Furthermore, eggs harbored a higher abundance of Ralstonia, Sediminibacterium and microbes of unclassified taxonomy. The dynamics changes in bacterial communities resulted in differences in the metabolic functions of the gut microbiota during development. Interestingly, the laid eggs in antibiotic treatment groups did not hatch much due to the gut dysbacteriosis, the results showed gut microbiota had a significant impact on the male reproduction. Discussion: Our findings provide new perspectives to understand the intricate associations between microbiota and host, and have value for the development of S. frugiperda management strategies focusing on the pest gut microbiota.
ABSTRACT
BACKGROUND: Lactate is an important metabolite derived from glycolysis under physiological and pathological conditions. The Warburg effect reveals the vital role of lactate in cancer progression. Numerous studies have reported crucial roles for lactate in cancer progression and cell fate determination. Lactylation, a novel posttranslational modification (PTM), has provided a new opportunity to investigate metabolic epigenetic regulation, and studies of this process have been initiated in a wide range of cancer cells, cancer-associated immune cells, and embryonic stem cells. CONCLUSION: Lactylation is a novel and interesting mechanism of lactate metabolism linked to metabolic rewiring and epigenetic remodeling. It is a potential and hopeful target for cancer therapy. Here, we summarize the discovery of lactylation, the mechanisms of site modification, and progress in research on nonhistone lactylation. We focus on the potential roles of lactylation in cancer progression and cell fate determination and the possible therapeutic strategies for targeting lysine lactylation. Finally, we suggest some future research topics on lactylation to inspire some interesting ideas.
Subject(s)
Lysine , Neoplasms , Humans , Lysine/metabolism , Epigenesis, Genetic , Neoplasms/pathology , Glycolysis/physiology , Lactic AcidABSTRACT
Biomass burning is an important source of polycyclic aromatic hydrocarbons (PAHs) and elemental carbon (EC), but the formation mechanisms are still unclear. Cellulose, hemicellulose, and lignin are the three major components of biomass. In this study, the three-components extracted from three typical biomass raw materials were used for laboratory combustion experiments, to investigate the differences in the emission factors and chemical compositions of PAHs and EC. The average emission factors of the 16 kinds of PAHs were showing as lignin (135 ± 180 mg/kg) > cellulose (97.8 ± 124 mg/kg) > hemicellulose (48.9 ± 65.2 mg/kg), and the average emission factors of EC presented in the descending order of cellulose (1.65 ± 3.02 g/kg), lignin (1.30 ± 1.04 g/kg), and hemicellulose (0.450 ± 0.480 g/kg), respectively. The proportion of naphthalene emitted from cellulose and hemicellulose combustion is higher, while fluoranthene and pyrene accounted significantly higher proportion for lignin. Moreover, the influence of ignition temperature and oxygen content on the emission characteristics of PAHs and EC were also discussed. The influence of ignition temperature on the emission of EC and PAHs is more significant compared to oxygen content, because it obviously promoted the PAHs and EC formations through resonance-stabilized hydrocarbon-radical chain reaction (RSR) pathway. However, correlation analysis combined with cluster analysis showed that the RSR-pathway probably had different effects on PAH growth for the three-components, as the indene-involved RSR-pathway were mainly related to 4-6 ring PAHs for cellulose and lignin (except fluoranthene and pyrene), but 2-4 ring PAHs for hemicellulose. We also found that the fitted results according to the proportion of three-components were significantly higher than the measured values of raw materials for indene, medium-molecular-weight PAHs, and soot-EC. These results presented the different formation pathways for medium-molecular-weight PAHs and the two EC components emitted by biomass combustion, which are worthy of further studies in exploring the generation mechanisms of PAHs and EC.
Subject(s)
Polycyclic Aromatic Hydrocarbons , Polycyclic Aromatic Hydrocarbons/analysis , Lignin , Cellulose , Carbon/chemistry , Oxygen/analysisABSTRACT
A new piezoelectric inchworm actuator with screw clamping mechanisms has been developed recently for the wing folding mechanism of a small unmanned aircraft where the actuator power density is a great concern. Considering that the prototype actuator was designed just with engineering intuition and the performance optimization through experimental developments would take a vast amount of cost and time, a mathematical model was developed to investigate the actuator's critical design parameters and optimize its presently undesirable performance. Based on the lumped parameter method reported previously, and taking full account of the detailed modeling of the complex actuator housing and the actual nonlinear behaviors from the high-force contact and friction occurring at the screw-nut interface, as well as the output performance of the main drive elements including the piezoelectric stack and hollow ultrasonic motors (HUSMs), this model was built and then was experimentally verified for its accuracy and availability. Finally, nine design parameters were studied for their individual effect on the actuator's output using the proposed model. The simulation results indicate that the performance can be considerably improved by performing a slight modification to the prototype, and the dynamic modeling and parameter optimization methods used in this study can also serve as a useful reference for the design of similar piezoelectric inchworm actuators with intermittent clamping behaviors.
ABSTRACT
The use of robot swarms for odor source localization (OSL) can better adapt to the reality of unstable turbulence and find chemical contamination or hazard sources faster. Inspired by the collective behavior in nature, swarm intelligence (SI) is recognized as an appropriate algorithm framework for multi-robot system due to its parallelism, scalability and robustness. Applications of SI-based multi-robots for OSL problems have attracted great interest over the last two decades. In this review, we firstly summarize the trending issues in general robot OSL field through comparing some basic counterpart concepts, and then provide a detailed survey of various representative SI algorithms in multi-robot system for odor source localization. The research field originates from the first introduction of the standard particle swarm optimization (PSO) and flourishes in applying ever-increasing quantity of its variants as modified PSOs and hybrid PSOs. Moreover, other nature-inspired SI algorithms have also demonstrated the diversity and exploration of this field. The computer simulations and real-world applications reported in the literatures show that those algorithms could well solve the main problems of odor source localization but still retain the potential for further development. Lastly, we provide an outlook on possible future research directions.
ABSTRACT
Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood-brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.
Subject(s)
Blood-Brain Barrier , Fructose , Animals , Blood-Brain Barrier/metabolism , Depression/etiology , Fatty Acids, Volatile/metabolism , Fructose/adverse effects , Fructose/metabolism , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , NeurogenesisABSTRACT
Fungal infections cause ~1.5 million deaths each year worldwide, and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria. The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species. Therefore, a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies. Here, we report that DOCK2 (dedicator of cytokinesis 2) promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages. DOCK2-deficient macrophages exhibit decreased RAC GTPase (Rac family small GTPase) activation and ROS (reactive oxygen species) production, which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways. Mechanistically, after fungal stimulation, activated SYK (spleen-associated tyrosine kinase) phosphorylates DOCK2 at tyrosine 985 and 1405, which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation. Importantly, nanoparticle-mediated delivery of in vitro transcribed (IVT) Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo. Taken together, this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.
Subject(s)
Candidiasis , GTPase-Activating Proteins , Guanine Nucleotide Exchange Factors , Immunity, Innate , rac GTP-Binding Proteins , Animals , Candidiasis/immunology , GTPase-Activating Proteins/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Humans , Mice , Mice, Inbred C57BL , RNA, Messenger , Reactive Oxygen Species/metabolism , rac GTP-Binding Proteins/metabolismABSTRACT
Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N-acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9 Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow-derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections.
Subject(s)
Candida albicans/physiology , Candidiasis/immunology , Immunity, Innate/immunology , Leukocytes, Mononuclear/immunology , Microtubules/immunology , Myosin Type I/metabolism , Myosin Type I/physiology , Acetylation , Animals , Antifungal Agents/pharmacology , Candidiasis/drug therapy , Candidiasis/metabolism , Candidiasis/microbiology , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microtubules/drug effects , Microtubules/metabolism , Microtubules/microbiology , Myosin Type I/genetics , Signal TransductionABSTRACT
BACKGROUND: Primary familial brain calcification (PFBC) is a rare inheritable neurodegenerative disease characterized by bilateral calcification in different brain regions and by a range of neuropsychiatric symptoms. Six causative genes of PFBC (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified. METHODS: Sanger sequencing was used to identify the causative genes associated with PFBC in this study. RESULTS: We describe the first PFBC case with both SLC20A2 and PDGFRB heterozygous mutations. Notably, this patient with the digenic mutation (who was only 5 years old) showed severe brain calcification and migraine, whereas the patient's parents, who each carried a heterozygous mutation in SLC20A2 or PDGFRB, exhibited varying degrees of brain calcification but were clinically asymptomatic. CONCLUSION: This case highlights the digenic influences on the characteristics of PFBC patients.
Subject(s)
Brain/pathology , Calcinosis/genetics , Migraine Disorders/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Sodium-Phosphate Cotransporter Proteins, Type III/genetics , Brain/diagnostic imaging , Calcinosis/pathology , Child , Female , Heterozygote , Humans , Migraine Disorders/pathology , MutationABSTRACT
The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.
Subject(s)
Antifungal Agents/immunology , Candidiasis/immunology , Cell Differentiation , GTPase-Activating Proteins/chemistry , GTPase-Activating Proteins/metabolism , Receptor, EphB2/metabolism , Signal Transduction/drug effects , Th17 Cells/metabolism , Animals , Antifungal Agents/pharmacology , CARD Signaling Adaptor Proteins/metabolism , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/microbiology , Female , GTPase-Activating Proteins/genetics , Humans , Lectins, C-Type/metabolism , Male , Mice, Knockout , Multiple Sclerosis/complications , Multiple Sclerosis/immunology , Phosphorylation , Receptor, EphB2/immunology , Receptors, Immunologic , Receptors, Pattern Recognition/metabolism , Th17 Cells/immunologyABSTRACT
Atrial septal defect (ASD) is a common acyanotic congenital cardiac disorder associated with genetic mutations. The objective of this study was to identify the genetic factors in a Chinese family with ASD patients by a whole exome sequencing approach. Causative ASD gene mutations were examined in 16 members from a three-generation family, among which 6 individuals were diagnosed as having ASD. One hundred and eighty-three unrelated healthy Chinese were recruited as a normal control group. Peripheral venous blood was collected from every subject for genetic analysis. Exome sequencing was performed in the ASD patients. Potential causal mutations were detected in non-ASD family members and normal controls by polymerase chain reaction and sequencing analysis. The results showed that all affected family members carried two novel compound mutations, c.1187delT of PCDHGA4 and c.2557insC of SLFN14, and these two mutations were considered to have synergetic function on ASD. In conclusion, the mutations of c.1187delT of PCDHGA4 and c.2557insC of SLFN14 may be pathogenic factors contributing to the development of ASD.
Subject(s)
Endoribonucleases/genetics , Heart Septal Defects, Atrial/genetics , Mutation/genetics , Adult , Amino Acid Sequence , Asian People/genetics , Exome/genetics , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Young AdultABSTRACT
BACKGROUND: The serum level of osteoprotegerin (encoded by OPG or TNFRSF11B) was previously shown to be increased in patients with ischemic stroke. A single nucleotide polymorphism rs3134069 in the TNFRSF11B gene was previously associated with ischemic stroke in a population of diabetic patients in Italy. It remains to be determined whether rs3134069 is associated with ischemic stroke in the general population or populations without diabetes. MATERIALS AND METHODS: We genotyped rs3134069 and performed a case-control association study to test whether rs3134069 is associated with ischemic stroke in 2 independent Chinese Han populations, including a China-Central population with 1629 cases and 1504 controls and a China-Northern population with 1206 cases and 720 controls. RESULTS: rs3134069 showed significant association with ischemic stroke in the China-Central population (P = 9.24 × 10-3, odds ratio [OR] = 1.50). The association was replicated in the independent China-Northern population (P = 2.45 × 10-4, OR = 1.53). The association became more significant in the combined population (P = 7.09 × 10-6, OR = 1.41). The associations remained significant in the male population, female population, and population without type 2 diabetes. Our expression quantitative trait loci analysis found that the minor allele C of rs3134069 was significantly associated with a decreasedexpression level of TNFRSF11B (P = .002). CONCLUSIONS: This study demonstrates that rs3134069 in TNFRSF11B increases risk of ischemic stroke by decreasing TNFRSF11B expression.
Subject(s)
Brain Ischemia/genetics , Osteoprotegerin/genetics , Polymorphism, Single Nucleotide , Stroke/genetics , Adult , Aged , Asian People/genetics , Brain Ischemia/diagnosis , Brain Ischemia/ethnology , Case-Control Studies , Chi-Square Distribution , China/epidemiology , Diabetes Mellitus, Type 2/ethnology , Diabetes Mellitus, Type 2/genetics , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Odds Ratio , Phenotype , Quantitative Trait Loci , Risk Assessment , Risk Factors , Stroke/diagnosis , Stroke/ethnologyABSTRACT
The tissue factor pathway inhibitor (TFPI) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels (P = 0.017 under a recessive model), but not with PT, APTT or TT (P > 0.05). Using a large case-control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P = 0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD.
Subject(s)
Blood Coagulation/genetics , Coronary Artery Disease/genetics , Fibrinogen/genetics , Genetic Association Studies , Lipoproteins/genetics , Coronary Artery Disease/blood , Coronary Artery Disease/pathology , Female , Humans , Male , Partial Thromboplastin Time , Polymorphism, Single Nucleotide/genetics , Prothrombin Time , Risk Factors , Thrombin TimeABSTRACT
BACKGROUND: The CAV1 gene encodes caveolin-1 expressed in cell types relevant to atherosclerosis. Cav-1-null mice showed a protective effect on atherosclerosis under the ApoE(-/-) background. However, it is unknown whether CAV1 is linked to CAD and MI in humans. In this study we analyzed a tagSNP for CAV1 in intron 2, rs3807989, for potential association with CAD. METHODS AND RESULTS: We performed case-control association studies in three independent Chinese Han populations from GeneID, including 1249 CAD cases and 841 controls in Population I, 1260 cases and 833 controls in Population II and 790 cases and 1212 controls in Population III (a total of 3299 cases and 2886 controls). We identified significant association between rs3807989 and CAD in three independent populations and in the combined population (Padj = 2.18 × 10(-5), OR = 1.19 for minor allele A). We also detected significant association between rs3807989 and MI (Padj = 5.43 × 10(-5), OR = 1.23 for allele A). Allele A of SNP rs3807989 was also associated with a decreased level of LDL cholesterol. Although rs3807989 is a tagSNP for both CAV1 and nearby CAV2, allele A of SNP rs3807989 was associated with an increased expression level of CAV1 (both mRNA and protein), but not CAV2. CONCLUSIONS: The data in this study demonstrated that rs3807989 at the CAV1/CAV2 locus was associated with significant risk of CAD and MI by increasing expression of CAV1 (but not CAV2). Thus, CAV1 becomes a strong candidate susceptibility gene for CAD/MI in humans.
Subject(s)
Caveolin 1/genetics , Coronary Artery Disease/genetics , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide , Aged , Asian People/genetics , Case-Control Studies , Caveolin 1/blood , Caveolin 2/genetics , China/epidemiology , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Coronary Artery Disease/ethnology , Databases, Genetic , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/diagnosis , Myocardial Infarction/ethnology , Phenotype , Risk Factors , Up-RegulationABSTRACT
Zinc complexes constructed from the amino-modified benzotriazole phenol pro-ligand, 2-(2H-benzotriazol-2-yl)-6-((diisopropylamino)methyl)-4-(2,4,4-trimethylpentan-2-yl)phenol ((C8DIA)BTP-H, 1), were synthesized stepwise and structurally characterized. The reaction of (C8DIA)BTP-H (1) with one equivalent of diethyl zinc (ZnEt2) generates a dimeric and four-coordinated zinc complex, [(µ-(C8DIA)BTP)ZnEt]2 (2), which is doubly bridged by two phenolate groups of C8DIABTP ligands. Further reaction of 2 with benzyl alcohol (BnOH) in stoichiometric proportions affords a tetranuclear zinc benzylalkoxide complex [(µ-OBn)((C8DIA)BTP)Zn]4 (3) that possesses a saddle-shaped core with four µ2-bridging benzylalkoxy groups upon four Zn centres. Interestingly, the di-nuclear Zn alkoxide [(µ-OBn)((C8DIA)BTP)Zn(DMAP)]2 (4) could be prepared by treatment of 3 with a stoichiometric amount of 4-(dimethylamino)pyridine (DMAP). ZnEt2 reacts with two equivalents of 1 in the presence of DMAP (1.0 mol equiv.) to yield a five-coordinated mononuclear zinc complex, [((C8DIA)BTP)2Zn(DMAP)] (5). All complexes adopt an N,O-bidentate coordination mode from the phenoxy oxygen atom and benzotriazole nitrogen atom, in which the nitrogen atom of the pendent arm substituent is not coordinated to the zinc centre. Ring-opening polymerization of ε-caprolactone and ß-butyrolactone catalysed by 2 and 3 was investigated.