Hypoconnectivity within the cingulo-opercular network in patients with mild cognitive impairment in Chinese communities.

INTRODUCTION: At rest, the brain's higher cognitive systems engage in correlated activity patterns, forming networks. With mild cognitive impairment (MCI), it is essential to understand how functional connectivity within and between resting-state networks changes. This study used resting-state functional connectivity to identify significant differences within and between the cingulo-opercular network (CON) and default mode network (DMN). METHODS: We assessed cognitive function in patients using the Chinese version of the Alzheimer's disease assessment scale-Cognitive subscale (ADAS-Cog). A group of MCI subjects (ages 60-83 years, n = 45) was compared to age-matched healthy controls (n = 70). Resting-state functional connectivity was used to determine functional connectivity strength within and between the CON and DMN. RESULTS: Compared to healthy controls, the MCI group showed significantly lower functional connectivity within the CON (F = 10.76, df = 1, p = 0.001, FDR adjusted p = 0.003). Additionally, the MCI group displayed no distinct differences in functional connectivity within DMN (F = 0.162, df = 1, p = 0.688, FDR adjusted p = 0.688) and between CON and DMN (F = 2.270, df = 1, p = 0.135, FDR adjusted p = 0.262). Moreover, we found no correlation between ADAS-Cog and within- or between-connectivity metrics among subjects with MCI. CONCLUSIONS: Our findings indicate that specific patterns of hypoconnectivity within CON circuitry may characterize MCI relative to healthy controls. This work improves our understanding of network dysfunction underlying MCI and could inform more targeted treatment.

Preliminary Analysis of Volume-Based Resting-State Functional MRI Characteristics of Successful Aging in China.

BACKGROUND: Resting-state function MRI (rs-fMRI) research on successful aging can provide insight into the mechanism of aging with a different perspective from aging-related disease. OBJECTIVE: rs-fMRI research was used to analyze the brain function characteristics of successful aging. METHODS: A total of 47 usual aging individuals and 26 successful aging (SA) individuals underwent rs-fMRI scans and neuropsychological tests. Volume-based rs-fMRI data analysis was performed with DPASF to obtain ALFF, ReHo, DC, and VMHC. RESULTS: The SA group showed increased ALFF in right opercular part of inferior frontal gyrus (Frontal_Inf_Oper_R) and right supramarginal gyrus; increased ReHo in right middle temporal pole gyrus and decreased ReHo in left superior frontal gyrus and middle occipital gyrus; increased DC in right medial orbitofrontal gyrus and pulvinar part of thalamus; decreased DC in left fusiform gyrus and right medial frontal gyrus; increased VMHC in right medial orbitofrontal gyrus; and decreased VMHC in the right superior temporal gyrus, right and left middle temporal gyrus, right and left triangular part of inferior frontal gyrus. ALFF in Frontal_Inf_Oper_R were found to be significantly correlated with MMSE scores (r = 0.301, p = 0.014) and ages (r = -0.264, p = 0.032) in all subjects, which could be used to distinguish the SA (AUC = 0.733, 95% CI: 0.604-0.863) by ROC analysis. CONCLUSION: The brain regions with altered fMRI characteristics in SA group were concentrated in frontal (6 brain regions) and temporal (4 brain regions) lobes. ALFF in Frontal_Inf_Oper_R was significantly correlated to cognitive function and ages, which might be used to distinguish the SA.

Association Analysis of Polymorphisms in BIN1, MC1R, STARD6 and PVRL2 with Mild Cognitive Impairment in Elderly Carrying APOE ε4 Allele.

BACKGROUND: Apolipoprotein (APOE) ε4 is recognized as an independent risk factor for mild cognitive impairment (MCI). However, not everyone with the ε4 allele develops MCI, suggesting that other susceptibility genes exist. This study aimed to identify MCI susceptibility genes, including BIN1, MC1R, STARD6, and PVRL2, in elderly Han Chinese and to verify their association with APOE ε4 allele in MCI onset. METHODS: To determine whether polymorphisms in BIN1 (rs6733839, rs7561528), MC1R (rs2228479), STARD6 (rs10164112), and PVRL2 (rs6859) occurred in elderly MCI patients carrying APOE ε4 allele, we carried out a case-control study including 285 MCI patients and 326 healthy controls. RESULTS: Statistically significant differences in the proportion of APOE ε4 carriers, and BESCI, ADAS-cog, and CNT scores existed between the NC and MCI groups (all P < 0.01). Frequencies of the rs10164112 T and rs6859 A alleles were significantly higher in the latter than in the former (P = 0.01; 0.029). However, no significant differences in allele and genotype distribution of BIN1 (rs6733839, rs7561528) and MC1R (rs2228479) existed between samples in our two groups (all P > 0.05). When stratified by APOE ε4 status (carriers/non-carriers), genotype frequencies of BIN1 rs7561528, STARD6 rs10164112, and PVRL2 rs6859 among the four groups (NCε4+, NCε4-, MCIε4+, MCIε4-) were significantly different. Additionally, our results suggest a significant association between MCI and BIN1 rs7561528, STARD6 rs10164112, and PVRL2 rs6859 (all P<0.05) in elderly carriers. CONCLUSION: This suggests that among the Han Chinese, MCI in elderly APOE ε4 carriers may be related to the BIN1 (rs7561528), STARD6 (rs10164112) and PVRL2 (rs6859). Genotype AA of rs7561528 and TT of rs10164112 might be protective factors against MCI in elderly APOE ε4 carriers.

A study of regional homogeneity of resting-state Functional Magnetic Resonance Imaging in mild cognitive impairment.

Mild cognitive impairment (MCI) is considered to be the early stage of Alzheimer's disease (AD), but the diagnostic predictive markers for MCI patients are still unclear. Here we have identified the brain function activity changes in MCI patients by using the resting-state functional magnetic resonance imaging (rs-fMRI). A total of 28 MCI patients and 38 age- and gender-matched healthy controls from the Wuxi Mental Health Center were recruited, and their abnormal spontaneous brain activities in the MCI were examined. The results showed that, compared with the healthy controls, MCI patients exhibited reduced regional homogeneity (ReHo) in the right superior temporal gyrus, right middle temporal gyrus, left angular gyrus and superior marginal gyrus. In addition, the correlation analysis revealed that ReHo in these regions were not correlated with the AD Assessment Scale-Cognitive score in MCI. We concluded abnormalities in the right superior temporal gyrus, right middle temporal gyrus, left angular gyrus and superior marginal gyrus with MCI, suggesting that the right language network may be impaired in MCI, which may provide a better understanding of dementia progression and potentially comprehensive treatment in MCI.

Abnormal Default-Mode Network Homogeneity in Patients With Mild Cognitive Impairment in Chinese Communities.

Background and Objective: Current evidence suggests that abnormalities within the default-mode network (DMN) play a key role in the broad-scale cognitive problems that characterize mild cognitive impairment (MCI). However, little is known about the alterations of DMN network homogeneity (NH) in MCI. Methods: Resting-state functional magnetic resonance imaging scans (rs-fMRI) were collected from 38 MCI patients and 69 healthy controls matched for age, gender, and education. NH approach was employed to analyze the imaging dataset. Cognitive performance was measured with the Chinese version of Alzheimer's disease assessment scale-Cognitive subscale (ADAS-Cog). Results: Two groups have no significant differences between demographic factors. And mean ADAS-Cog score in MCI was 12.02. MCI patients had significantly lower NH values than controls in the right anterior cingulate cortex and significantly higher NH values in the ventral medial prefrontal cortex(vmPFC) than those in healthy controls. No significant correlations were found between abnormal NH values and ADAS-Cog in the patients. Conclusions: These findings provide further evidence that abnormal NH of the DMN exists in MCI, and highlight the significance of DMN in the pathophysiology of cognitive problems occurring in MCI.

Effect of the Biofilm Age and Starvation on Acid Tolerance of Biofilm Formed by Streptococcus mutans Isolated from Caries-Active and Caries-Free Adults.

Streptococcus mutans (S. mutans) is considered a leading cause of dental caries. The capability of S. mutans to tolerate low pH is essential for its cariogenicity. Aciduricity of S. mutans is linked to its adaptation to environmental stress in oral cavity. This study aimed to investigate the effect of biofilm age and starvation condition on acid tolerance of biofilm formed by S. mutans clinical isolates. S. mutans clinical strains isolated from caries-active (SM593) and caries-free (SM18) adults and a reference strain (ATCC25175) were used for biofilm formation. (1) Both young and mature biofilms were formed and then exposed to pH 3.0 for 30 min with (acid-adapted group) or without (non-adapted group) pre-exposure to pH 5.5 for three hours. (2) The mature biofilms were cultured with phosphate-buffered saline (PBS) (starved group) or TPY (polypeptone-yeast extract) medium (non-starved group) at pH 7.0 for 24 h and then immersed in medium of pH 3.0 for 30 min. Biofilms were analyzed through viability staining and confocal laser scanning microscopy. In all three strains, mature, acid-adapted and starved biofilms showed significantly less destructive structure and more viable bacteria after acid shock than young, non-adapted and non-starved biofilms, respectively (all p < 0.05). Furthermore, in each condition, SM593 biofilm was denser, with a significantly larger number of viable bacteria than that of SM18 and ATCC25175 (all p < 0.05). Findings demonstrated that mature, acid-adapted and starvation might protect biofilms of all three S. mutans strains against acid shock. Additionally, SM593 exhibited greater aciduricity compared to SM18 and ATCC25175, which indicated that the colonization of high cariogenicity of clinical strains may lead to high caries risk in individuals.

Association between MKL1 rs6001946 and schizophrenia in a Han Chinese population.

Megakaryoblastic leukemia 1 (MKL1) is highly expressed in the nervous system and plays a potentially principal role in neuronal migration and morphology. A recent study showed that some genetic loci within the MKL1 gene, especially single nucleotide polymorphism (SNP) rs6001946, may increase schizophrenia susceptibility. Here, we sought to determine whether the polymorphism rs6001946 was associated with schizophrenia in a Han Chinese population using the ligase detection reaction-polymerase chain reaction method to genotype SNP rs6001946 in the MKL1 gene. We observed that there was a marginally significant association between SNP rs6001946 and the risk of schizophrenia (P=0.077). Our results indicated that SNP rs6001946 of the MKL1 gene is likely a risk factor for schizophrenia, but the role of SNP rs6001946 in the development of schizophrenia in Han Chinese should be interpreted cautiously. Further studies with larger sample sizes are needed to determine the involvement of the MKL1 polymorphism in schizophrenia susceptibility.

Effects of Exposure to Domestic Physical Violence on Children's Behavior: A Chinese Community-based Sample.

Domestic physical violence (DPV) is common in China due to its long history of slavery and feudalism. This study aimed to examine the effects of exposure to DPV on children's behavior in a Chinese community. Ninety-three 12- to 16-year-old adolescents exposed to DPV were compared to 54 adolescents with no exposure to DPV. We found that DPV exposure was associated with adverse behaviors in children, especially among boys. Children witnessing DPV alone had similar behavioral scores as the abused children. We recommend that both abused and DPV witness-only adolescents in Chinese communities need treatment to mitigate the effects on maladjusted behaviors. The intervention programs for children who witness domestic violence are also important.

Single Cell Chemical Proteomics with Membrane-Permeable Activity-Based Probe for Identification of Functional Proteins in Lysosome of Tumors.

Proteomics at single-cell resolution can help to identify the heterogeneity among cell populations, shows more and more significance in current chemistry and biology. In this work, we demonstrated a new single cell chemical proteomic (SCCP) strategy with a membrane-permeable activity-based probe (ABP) to characterize the functional proteins in lysosome located in the cytosol. The ABP targeted to the cysteine cathepsin family protein, CpFABP-G, was designed for cysteine cathepsins labeling. The labeled HeLa cell of a cancer cell line was injected into a capillary and was lysed by SDS solution with heating. The lysate was then online readout by capillary electrophoresis-laser-induced fluorescence method. Due to the employment of highly specified ABP kicking out the uncorrelated proteins, the expression of cysteine cathepsins in individual HeLa cells was easily detected, and heterogeneity among those HeLa cells was readily discriminated. Further work was concentrated on SCCP analysis of the mouse leukemia cell of monocyte macrophage (RAW264.7). It was for the first time identifying two expression modes of cysteine cathepsins in RAW264.7, which could be undermined by the analysis of cell populations. We believed that SCCP would be one of the powerful alternatives for proteomics at single-cell resolution.

An exploratory study of the association between SORL1 polymorphisms and sporadic Alzheimer's disease in the Han Chinese population.

In previous studies, we reported that the sortilin-related receptor, L (DLR class) A repeats containing (SORL1) gene single nucleotide polymorphisms (SNPs) are associated with the risk of sporadic Alzheimer's disease (SAD) in the Han Chinese population. To further explore the relationships between SORL1 genetic variants and SAD, we conducted a two-step study. Sequencing analysis in 50 case samples identified 14 SNPs within the promoter and untranslated region of the SORL1 gene. Subsequent genotyping analysis in 106 patients with SAD and 179 healthy controls detected a significant association between the "G" allele of SNP rs1133174 in the 3' untranslated region of the SORL1 gene and SAD risk (odds ratio =1.92, 95% confidence interval [95% CI] =1.28-2.90, adjusted P=0.028). In addition, "G" allele carriers of rs1133174 (GA + GG) have a 2.15-fold increased risk of SAD compared to noncarriers (AA) (adjusted P=0.042). However, no significant positive associations were observed in the other 13 SNPs within the SORL1 gene. These preliminary findings suggest that the SORL1 SNP rs1133174 may be a potential risk locus for SAD in the Han Chinese population.

Methylation of the tryptophan hydroxylase­2 gene is associated with mRNA expression in patients with major depression with suicide attempts.

Tryptophan hydroxylase-2 (TPH2) contributes to alterations in the function of neuronal serotonin (5-HT), which are associated with various psychopathologies, including major depressive disorder (MDD) or suicidal behavior. The methylation of a single CpG site in the promoter region of TPH2 affects gene expression. Suicide and MDD are strongly associated and genetic factors are at least partially responsible for the variability in suicide risk. The aim of the present study was to investigate whether variations in TPH2 methylation in peripheral blood samples may predispose patients with MDD to suicide attempts. TPH2 mRNA expression levels differed significantly between 50 patients with MDD who had attempted suicide (MDD + suicide group) and 75 control patients with MDD (MDD group); TPH2 expression levels were significantly decreased (P=0.0005) in the patients who had attempted suicide. Furthermore, the frequency of TPH2 methylation was 36.0% in the MDD + suicide group, while it was 13.0% in the MDD group. The results of the present study demonstrated that methylation in the promoter region of TPH2 significantly affected the mRNA expression levels of TPH2, thus suggesting that methylation of the TPH2 promoter may silence TPH2 mRNA expression in MDD patients with or without suicidal behavior. In addition, there was a significant correlation between the methylation status of the TPH2 promoter and depression, hopelessness and cognitive impairment in the MDD + suicide group. In conclusion, the present study demonstrated that TPH2 expression was regulated by DNA methylation of the TPH2 promoter region in patients with MDD.

A two-stage association study suggests BRAP as a susceptibility gene for schizophrenia.

Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P  =  2.31E-6, OR  =  0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P  =  1.43E-6, OR  =  0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P  =  0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.

Microfluidic chip-based C. elegans microinjection system for investigating cell-cell communication in vivo.

The propagation of intercellular calcium wave (ICW) is essential for coordinating cellular activities in multicellular organisms. However, the limitations of existing analytical methods hamper the studies of this biological process in live animals. In this paper, we demonstrated for the first time a novel microfluidic system with an open chamber for on-chip microinjection of C. elegans and investigation of ICW propagations in vivo. Worms were long-term immobilized on the side wall of the open chamber by suction. Using an external micro-manipulator, localized chemical stimulation was delivered to single intestinal cells of the immobilized worms by microinjection. The calcium dynamics in the intestinal cells expressing Ca(2+) indicator YC2.12 was simultaneously monitored by fluorescence imaging. As a result, thapsigargin injection induced ICW was observed in the intestinal cells of C. elegans. Further analysis of the ICW propagation was realized in the presence of heparin (an inhibitor for IP3 receptor), which allowed us to investigate the mechanism underlying intercellular calcium signaling. We expect this novel microfluidic platform to be a useful tool for studying cell-cell communication in multicellular organisms in vivo.

Different endocytic functions of AGEF-1 in C. elegans coelomocytes.

BACKGROUND: ADP-ribosylation factors (ARFs) are a family of small GTP-binding proteins that play roles in membrane dynamics and vesicle trafficking. AGEF-1, which is thought to act as a guanine nucleotide exchange factor of class I ARFs, is required for caveolin-1 body formation and receptor-mediated endocytosis in oocytes of Caenorhabditis elegans. This study explores additional roles of AGEF-1 in endocytic transport. METHODS: agef-1 expression was knocked down by using RNAi in C. elegans. Markers that allow analysis of endocytic transport in scavenger cells were investigated for studying the effect of AGEF-1 on different steps of membrane transport. RESULTS: Knockdown of AGEF-1 levels results in two apparent trafficking defects in coelomocytes of C. elegans. First, there is a delay in the uptake of solutes from the extracellular medium. Second, there is a dramatic enlargement of the sizes of lysosomes, even though lysosomal acidification is normal and degradation still occurs. CONCLUSION: Our results suggest that AGEF-1 regulates endosome/lysosome fusion or fission events, in addition to earlier steps in endocytic transport. GENERAL SIGNIFICANCE: AGEF-1 is the first identified GTPase regulator that functions at the lysosome fusion or fission stage of the endocytic pathway. Our study provides insight into lysosome dynamics in C. elegans.

[Association between aggressive behaviors and COMT Val158Met and 5-HTTLPR polymorphisms in children].

OBJECTIVE: To investigate the association between aggressive behaviors and catechol-O-methyltransferase (COMT) single nucleotide polymorphism at position 158 from a valine to a methionine (Val158Met) as well as serotonin (5-HT) transporter gene linked polymorphic region (5-HTTLPR) in children. METHODS: A total of 68 children who were exposed to domestic violence were recruited. The frequencies of genotypes and alleles of COMT Val158Met and 5-HTTLPR were examined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. A comparison was conducted between 24 children with high scores of aggressive problems and 44 control children with low scores of aggressive problems according to Child Behavior Checklist (for parents).ResultsThere were no significant differences in genotypes of COMT Val158Met (χ2=1.612, P=0.447) and 5-HTTLPR (χ2=1.807, P=0.405) between the two groups. There were also no significant differences in the frequencies of alleles of COMT Val158Met (χ2=1.648, P=0.119) and 5-HTTLPR(χ2=0.403, P=0.527) in the two groups. CONCLUSIONS: COMT Val158Met and 5-HTTLPR might not be the susceptible genes of children's aggression, suggesting that children's aggressive behaviors might be affected by multivariate factors.