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Articles by Y He
Total Records ( 12 ) for Y He
  Y He , A Dagher , Z Chen , A Charil , A Zijdenbos , K Worsley and A. Evans
 

White matter tracts, which play a crucial role in the coordination of information flow between different regions of grey matter, are particularly vulnerable to multiple sclerosis. Many studies have shown that the white matter lesions in multiple sclerosis are associated with focal abnormalities of grey matter, but little is known about the alterations in the coordinated patterns of cortical morphology among regions in the disease. Here, we used cortical thickness measurements from structural magnetic resonance imaging to investigate the relationship between the white matter lesion load and the topological efficiency of structural cortical networks in multiple sclerosis. Network efficiency was defined using a ‘small-world’ network model that quantifies the effectiveness of information transfer within brain networks. In this study, we first classified patients (n = 330) into six subgroups according to their total white matter lesion loads, and identified structural brain networks for each multiple sclerosis group by thresholding the corresponding inter-regional cortical thickness correlation matrix, followed by a network efficiency analysis with graph theoretical approaches. The structural cortical networks in multiple sclerosis demonstrated efficient small-world architecture regardless of the lesion load, an organization that maximizes the information processing at a relatively low wiring cost. However, we found that the overall small-world network efficiency in multiple sclerosis was significantly disrupted in a manner proportional to the extent of total white matter lesions. Moreover, regional efficiency was also significantly decreased in specific brain regions, including the insula and precentral gyrus as well as regions of prefrontal and temporal association cortices. Finally, we showed that the lesions also altered many cortical thickness correlations in the frontal, temporal and parietal lobes. Our results suggest that the white matter lesions in multiple sclerosis might be associated with aberrant neuronal connectivity among widely distributed brain regions, and provide structural (morphological) evidence for the notion of multiple sclerosis as a disconnection syndrome.

  L Wang , C Yu , H Chen , W Qin , Y He , F Fan , Y Zhang , M Wang , K Li , Y Zang , T. S Woodward and C. Zhu
 

Numerous studies argue that cortical reorganization may contribute to the restoration of motor function following stroke. However, the evolution of changes during the post-stroke reorganization has been little studied. This study sought to identify dynamic changes in the functional organization, particularly topological characteristics, of the motor execution network during the stroke recovery process. Ten patients (nine male and one female) with subcortical infarctions were assessed by neurological examination and scanned with resting-state functional magnetic resonance imaging across five consecutive time points in a single year. The motor execution network of each subject was constructed using a functional connectivity matrix between 21 brain regions and subsequently analysed using graph theoretical approaches. Dynamic changes in topological configuration of the network during the process of recovery were evaluated by a mixed model. We found that the motor execution network gradually shifted towards a random mode during the recovery process, which suggests that a less optimized reorganization is involved in regaining function in the affected limbs. Significantly increased regional centralities within the network were observed in the ipsilesional primary motor area and contralesional cerebellum, whereas the ipsilesional cerebellum showed decreased regional centrality. Functional connectivity to these brain regions demonstrated consistent alterations over time. Notably, these measures correlated with different clinical variables, which provided support that the findings may reflect the adaptive reorganization of the motor execution network in stroke patients. In conclusion, the study expands our understanding of the spectrum of changes occurring in the brain after stroke and provides a new avenue for investigating lesion-induced network plasticity.

  Y He , H Zhang , J Yin , J Xie , X Tan , S Liu , Q Zhang , C Li , J Zhao , H Wang and G. Cao
 

Genetic predisposition of nuclear factor-kappa B (NF-B)-signaling pathways linking inflammation to hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unresolved. We conducted a case–control study to determine the associations of the polymorphisms within the promoter regions of NFKB1 encoding NF-B1 and NFKBIA encoding IkappaBalpha with the development of HCC. A total of 404 healthy controls, 482 non-HCC subjects with HBV infection and 202 patients with HCC were included. NFKB1 –94ATTG2 allele and GG allele in the 3'-untranslated region of NFKBIA were more prevalent in HCC patients than in the healthy controls. NFKBIA –826CT and NFKBIA –881AG allelic carriages were more prevalent in HCC patients than in the non-HCC subjects with HBV infection. The estimated haplotype frequency of NFKBIA promoter –881G–826T–519C was significantly higher in the patients with HCC than in the HBV-infected subjects without HCC (odds ratio = 3.142, P = 0.002). As compared with the HBV-infected subjects without HCC, NFKBIA –826 T and NFKBIA –881AG allelic carriages were only associated with HCC risk in the subjects with HBV genotype C. The association of NFKBIA –881AG allelic carriage with HCC risk was not affected by liver cirrhosis (LC) status, alanine aminotransferase level and hepatitis B e antigen status. By multivariate regression analysis, NFKB1 –94ATTG2, NFKBIA –826T, NFKBIA –881AG and HBV genotype C were independently associated with an increased risk of HCC. In conclusion, NFKB1 –94ATTG2 allele and haplotype –881G–826T–519C in NFKBIA promoter were associated with hepatocarcinogenesis. NFKBIA –826T and –881AG were associated with the risk of HCC in the subjects infected with HBV genotype C.

  Y Gao , Y He , J Ding , K Wu , B Hu , Y Liu , Y Wu , B Guo , Y Shen , D Landi , S Landi , Y Zhou and H. Liu
 

Hepatocellular carcinoma (HCC) is the fifth most common malignancy caused by environmental and genetic factors. MicroRNAs (miRNAs) are a class of short non-coding RNAs with posttranscriptional regulatory functions. They participate in diverse biological pathways and function as gene regulators. Genetic polymorphisms in 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding, with consequences on regulation of target genes thereby affecting the individual's cancer risk. We have previously predicted polymorphisms falling in miRNA-binding regions of cancer genes. We selected an insertion/deletion (Indel) polymorphism (rs3783553) in the 3' UTR of interleukin (IL)-1 (IL1A) for a case–control study in a Chinese population. With samples from 403 HCC patients and 434 healthy control individuals, strong evidence of association was observed for the variant homozygote. This association was validated in a second independent case–control study with 1074 HCC patients and 1239 healthy control individuals (odds ratio = 0.62; 95% confidence interval = 0.49–0.78). We further show that the ‘TTCA’ insertion allele for rs3783553 disrupts a binding site for miR-122 and miR-378, thereby increasing transcription of IL-1 in vitro and in vivo. These findings suggest that functional polymorphism rs3783553 in IL1A could contribute to HCC susceptibility. Considering IL-1 affects not only various phases of the malignant process, such as carcinogenesis, tumor growth and invasiveness, but also patterns of interactions between malignant cells and the host's immune system, our results indicated that IL-1 may be a promising target for immunotherapy, early diagnosis and intervention of HCC.

  Z Hu , X Li , X Qu , Y He , B. Z Ring , E Song and L. Su
 

A few genetic polymorphisms of TP53 are known to have a significant effect on cancer susceptibility. Intron 3 16 bp duplication polymorphism of TP53 has been reported to be associated with breast cancer, colorectal cancer, lung cancer and other cancers, but the reported results remain inconclusive. The present study, a meta-analysis including a total of 9801 cases and 10 391 controls from 26 studies, revealed that the 16 bp insertion (Ins) allele is significantly associated with an increased cancer risk in overall analysis [Ins/Ins + deletion (Del)/Ins versus Del/Del: odds ratio (OR) = 1.14, 95% confidence interval (CI) = 1.02–1.27, P = 0.02; Ins/Ins versus Del/Del: OR = 1.35, 95% CI = 1.11–1.63, P = 0.002; Del/Ins versus Del/Del: OR = 1.10, 95% CI = 0.98–1.23, P = 0.11.), particularly in breast cancer subgroup (Ins/Ins + Del/Ins versus Del/Del: OR = 1.16, 95% CI = 1.03–1.31, P = 0.02; Ins/Ins versus Del/Del: OR = 1.81, 95% CI = 1.30–2.52, P < 0.001; Del/Ins versus Del/Del: OR = 1.10, 95% CI = 0.97–1.25, P = 0.13). The relative risks to the colorectal and lung cancers increased but their association power was relatively weak, which may result from a limited number of studies of these two cancer types. These results suggest that intron 3 16 bp duplication polymorphism of TP53 is potentially an important and clinically relevant genetic marker contributing to cancer susceptibility.

  X Li , Y He , C. H Ruiz , M Koenig and M. D. Cameron
 

Dasatinib was approved in 2006 for the treatment of imatinib-resistant chronic myelogenous leukemia and functions primarily through the inhibition of BCR-ABL and Src kinase. Dasatinib is extensively metabolized in humans by CYP3A4. In this study, we report that the bioactivation of dasatinib by CYP3A4 proceeds through a reactive intermediate that leads to CYP3A4 inactivation with KI = 6.3 µM and kinact = 0.034 min–1. The major mechanism of inactivation proceeds through hydroxylation at the para-position of the 2-chloro-6-methylphenyl ring followed by further oxidation, forming a reactive quinone-imine, similar to the reactive intermediates formed by acetaminophen and diclofenac. Formation of a reactive imine-methide was also detected but appears to be a minor pathway. When glutathione was added to human liver microsomal incubations, dasatinib-glutathione adducts were detected. Numerous dasatinib analogs were synthesized in an effort to understand what modifications would block the formation of reactive intermediates during dasatinib metabolism. It is interesting to note that blocking the site of hydroxylation with a methyl group was not effective because a reactive imine-methide was formed, nor was blocking the site with fluorine because the fluorine was removed through an oxidative defluorination mechanism and the reactive quinone-imine was still formed. Numerous analogs are presented that did effectively block the formation of glutathione adducts and prevent the inactivation of CYP3A4.

  X Li , Y He , C. H Ruiz , M Koenig and M. D. Cameron
 

Dasatinib was approved in 2006 for the treatment of imatinib-resistant chronic myelogenous leukemia and functions primarily through the inhibition of BCR-ABL and Src kinase. Dasatinib is extensively metabolized in humans by CYP3A4. In this study, we report that the bioactivation of dasatinib by CYP3A4 proceeds through a reactive intermediate that leads to CYP3A4 inactivation with KI = 6.3 µM and kinact = 0.034 min–1. The major mechanism of inactivation proceeds through hydroxylation at the para-position of the 2-chloro-6-methylphenyl ring followed by further oxidation, forming a reactive quinone-imine, similar to the reactive intermediates formed by acetaminophen and diclofenac. Formation of a reactive imine-methide was also detected but appears to be a minor pathway. When glutathione was added to human liver microsomal incubations, dasatinib-glutathione adducts were detected. Numerous dasatinib analogs were synthesized in an effort to understand what modifications would block the formation of reactive intermediates during dasatinib metabolism. It is interesting to note that blocking the site of hydroxylation with a methyl group was not effective because a reactive imine-methide was formed, nor was blocking the site with fluorine because the fluorine was removed through an oxidative defluorination mechanism and the reactive quinone-imine was still formed. Numerous analogs are presented that did effectively block the formation of glutathione adducts and prevent the inactivation of CYP3A4.

  Y Yashiro Ohtani , Y He , T Ohtani , M. E Jones , O Shestova , L Xu , T. C Fang , M. Y Chiang , A. M Intlekofer , S. C Blacklow , Y Zhuang and W. S. Pear
 

Precise control of the timing and magnitude of Notch signaling is essential for the normal development of many tissues, but the feedback loops that regulate Notch are poorly understood. Developing T cells provide an excellent context to address this issue. Notch1 signals initiate T-cell development and increase in intensity during maturation of early T-cell progenitors (ETP) to the DN3 stage. As DN3 cells undergo β-selection, during which cells expressing functionally rearranged TCRβ proliferate and differentiate into CD4+CD8+ progeny, Notch1 signaling is abruptly down-regulated. In this report, we investigate the mechanisms that control Notch1 expression during thymopoiesis. We show that Notch1 and E2A directly regulate Notch1 transcription in pre-β-selected thymocytes. Following successful β-selection, pre-TCR signaling rapidly inhibits Notch1 transcription via signals that up-regulate Id3, an E2A inhibitor. Consistent with a regulatory role for Id3 in Notch1 down-regulation, post-β-selected Id3-deficient thymocytes maintain Notch1 transcription, whereas enforced Id3 expression decreases Notch1 expression and abrogates Notch1-dependent T-cell survival. These data provide new insights into Notch1 regulation in T-cell progenitors and reveal a direct link between pre-TCR signaling and Notch1 expression during thymocyte development. Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions.

  Y He , Y Li , Z Peng , H Yu , X Zhang , L Chen , Q Ji , W Chen and R. Wang
 

A prominent feature of the rodent Muc3 SEA module is the precursor cleavage event that segregates the O-glycosylated N-terminal fragment and transmembrane domain into the noncovalently attached heterodimer. There are seven potential N-glycosylation sites that occur in a cluster in the SEA module of Muc3. However, it is unknown if these sites are modified or what the function of these N-glycans may be in the SEA module. Our data show that the proteolytic cleavage of the rodent Muc3 SEA module was partially prevented by treatment with tunicamycin, an inhibitor of N-glycosylation. Each single mutant of the seven N-glycosylation sites (N1A, N2A, N3A, N4A, N5A, N6A, and N7A) and multiple mutants, including double (N34A) and triple (N345A) mutants, and mutants with four (N3457A), five (N34567A), six (N134567A and N234567A), seven (N1234567A) mutations, confirmed that all seven of these potential sites are N-glycosylated simultaneously. The proteolytic cleavage of the SEA module was not affected when it lacked only one, two, or three N-glycans, but was partially inhibited when lacking four, five, and six N-glycans. In all, 2%, 48%, 85%, and 73% of the products from N3457A, N34567A, N134567A, and N234567A transfectants, respectively, remained uncleaved. The proteolytic cleavage was completely prevented in the N1234567A transfectant, which eliminated all seven N-glycans in the SEA module. The interaction of the heterodimer was independent of the N-glycans within the rodent Muc3 SEA module. Thus, the N-glycosylation pattern constituted a control point for the modulation of the proteolytic cleavage of the SEA module.

  S Liu , H Zhang , C Gu , J Yin , Y He , J Xie and G. Cao
  Background

The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC).

Methods

We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided.

Results

Of the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (Ptrend < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype.

Conclusions

HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.

  G Fu , Y Chen , M Yu , A Podd , J Schuman , Y He , L Di , M Yassai , D Haribhai , P. E North , J Gorski , C. B Williams , D Wang and R. Wen
 

Phospholipase C1 (PLC1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLC1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLC1. We demonstrate that PLC1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-B. Importantly, PLC1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLC1 is essential for T cell development, activation, and tolerance.

 
 
 
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