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Lei Jin

Publications and source records attributed to Lei Jin.

At least 19 recordsLinked to original sources
PubMed2026

ZBTB16-associated NK cell alterations reveal shared immunometabolic signatures linking primary Sjögren's syndrome and type 1 diabetes mellitus.

BACKGROUND: Primary Sjögren's syndrome (pSS) and type 1 diabetes mellitus (T1DM) share immune-inflammatory features, yet conserved pathogenic signatures linking these autoimmune disorders remain incompletely understood. The present research sought to uncover common molecular markers and dissect the underlying immune-metabolic cross-talk underlying pSS and T1DM. METHODS: Gene expression profiles of patients with pSS and T1DM were retrieved from the Gene Expression Omnibus database, normalized, and corrected for batch effects prior to downstream analyses. Overlapping potential biomarkers were screened by integrating differential expression analysis, weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression. Functional enrichment based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases was implemented to interpret gene biological properties, and a protein-protein interaction network was further established afterwards. Diagnostic performance was evaluated using receiver operating characteristic analysis. Experimental validation was conducted in non-obese diabetic (NOD) mice using quantitative PCR, immunohistochemistry, and flow cytometry. The CIBERSORT algorithm was adopted to quantify immune cell infiltration levels. RESULTS: ZBTB16 was identified as a shared hub biomarker in both pSS and T1DM and exhibited favorable diagnostic performance. Experimental validation confirmed significantly reduced ZBTB16 expression in peripheral blood mononuclear cells, salivary gland tissues, and pancreatic tissues of NOD mice. Gene Set Enrichment Analysis indicated that ZBTB16-associated signatures were enriched in mitochondrial-related processes, neuroactive ligand-receptor interactions, and ribosome-related pathways. Immune infiltration analysis revealed that resting natural killer (NK) cells were positively correlated with ZBTB16 expression in both diseases. Flow cytometric analysis further confirmed a reduced proportion of resting NK cells in peripheral blood of NOD mice, consistent with the CIBERSORT-based prediction. CONCLUSION: This study identifies ZBTB16 as a shared biomarker linking pSS and T1DM. Reduced resting NK-cell abundance was consistently observed in both computational and experimental analyses, and bioinformatic correlation analysis suggested a positive association with ZBTB16 expression. These findings provide evidence for shared molecular and immunological signatures underlying the two autoimmune disorders and support further investigation of the biological role and diagnostic value of ZBTB16 in pSS and T1DM.

Sjogren's Syndrome↗
PubMed2006

Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.

Animals↗
PubMed2006

Characteristics of HIV-1-specific CD8 T-cell responses and their role in loss of viremia in children chronically infected with HIV-1 undergoing highly active antiretroviral therapy.

BACKGROUND: Few studies have examined the properties of human immunodeficiency virus type 1 (HIV-1) epitope-specific cytotoxic T lymphocyte (CTL) responses in children. To address this issue, we characterized epitope-specific CTL responses and analyzed the determinants that may affect CTL responses before and after highly active antiretroviral therapy (HAART) in children with HIV-1 infection. METHODS: A total of 22 HIV-1-infected children and 23 uninfected healthy children as control were enrolled in the study. Circulating CD4 T cells and HIV-1 RNA load in plasma were routinely measured. Peripheral HIV-1-specific CTL frequency and HIV-1 epitope-specific, interferon-gamma (IFN-gamma)-producing T lymphocytes were measured using tetramer staining and enzyme-linked immunospot (ELISPOT) assay, respectively. Circulating dendritic cell (DC) subsets were monitored with FACS analysis. RESULTS: More than 80% of the children with HIV-1 infection exhibited a positive HIV-1-epitope-specific CTL response at baseline, but HIV-specific CTLs and IFN-gamma-producing lymphocytes decreased in patients who responded to HAART in comparison with non-responders and HAART-naive children. The duration of virus suppression resulted from HAART was inversely correlated with CTL frequency. While in HAART-naive children, HIV-1-specific CTL frequency was positively correlated with myeloid DC (mDC) frequency, although the cause and effect relationship between the DCs and CTLs remains unknown. CONCLUSIONS: HIV-1-epitope-specific CTL responses are dependent on antigenic stimulation. The impaired DC subsets in blood might result in a defect in DC-mediated T cell responses. These findings may provide insight into understanding the factors and related mechanisms that influence the outcome of HIV-1 carriers to HAART or future antiviral therapies.

Adolescent↗
PubMed2006

Increased infiltration of intrahepatic DC subsets closely correlate with viral control and liver injury in immune active pediatric patients with chronic hepatitis B.

The roles of functionally impaired dendritic cells (DCs) in natural history of chronic hepatitis B (CHB) are unknown. We therefore characterized circulating DC subsets in 15 immune tolerant (IT) and 31 immune active (IA) HBV-infected children. Additionally, intrahepatic DC subsets were also analyzed in 4 IT and 9 IA individuals. The results showed that circulating DC subset numbers were decreased, but the intrahepatic DC counts were concomitantly increased in IA patients versus IT patients or healthy children. This results in the reduction of overall IFN-alpha but not IL-12 production by peripheral blood mononuclear cells of IA patients, although the capacity of single DC in producing cytokines was unchanged in these children. Moreover, there is a significantly inverse correlation of intrahepatic DC subsets with plasma HBV load and a positive correlation with serum ALT levels. These findings suggest that the increased infiltration of intrahepatic DC subsets may participate in the local antiviral immune response in pediatric patients with CHB.

Adolescent↗
PubMed2006

Activation of adenosine A1 receptor modulates dopamine D1 receptor activity in stably cotransfected human embryonic kidney 293 cells.

The antagonistic interactions between adenosine A1 receptors and dopamine D1 receptors were studied in a human embryonic kidney 293 cell line stably cotransfected with human adenosine A1 receptor and dopamine D1 receptor cDNAs. In the cotransfected cells, but not in control cells only transfected with dopamine D1 receptors, adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA, 10 microM) increased the Kd of dopamine D1 receptor antagonist [N-methyl-3H]R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ([3H]SCH23390) without affecting the Bmax. Moreover, CPA induced a concentration-dependent decrease in the affinity of dopamine D1 receptors for the agonist (+/-)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393) and inhibited dopamine D1 receptor-mediated cyclic AMP response element recruitment. Furthermore, pertussis toxin treatment completely counteracted the effects of low concentrations of CPA but only partially counteracted the effects of high concentrations of CPA. These results suggest that adenosine A1 receptors antagonistically modulate dopamine D1 receptors at the level of receptor binding and the second messenger generation. Furthermore, the antagonistic interactions between these two receptors induced by low concentrations of CPA might have a different manner with those induced by high concentrations of CPA.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B.

CD4+CD25+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self and foreign Ags, but their role in persistent viral infection has not been well-defined. In this study, we investigated whether and where CD4+CD25+ Treg contribute to the development of chronic hepatitis B (CHB). One hundred twenty-one patients were enrolled, including 16 patients with acute hepatitis B, 76 with CHB, and 29 with chronic severe hepatitis B. We demonstrated that in chronic severe hepatitis B patients, the frequencies of CD4+CD25+ Treg in both PBMC and liver-infiltrating lymphocytes were significantly increased and there was a dramatic increase of FoxP3(+)-cell and inflammatory cell infiltration in the liver compared with healthy controls. In CHB patients, circulating CD4+CD25+ Treg frequency significantly correlates with serum viral load. In acute hepatitis B patients, circulating CD4+CD25+ Treg frequency was initially low and with time, the profile reversed to exhibit an increased number of circulating Treg in the convalescent phase and restored to normal levels upon resolution. In PBMC taken from infected patients, depletion of CD4+CD25+ Treg led to an increase of IFN-gamma production by HBV-Ag-stimulated PBMC. In addition, CD4+CD25+ Treg were capable of suppressing proliferation of autologous PBMC mediated by HBV Ags, which probably reflects the generation of HBV-Ag-specific Treg in circulation and in the liver of HBV-infected patients. Together, our findings suggest that CD4+CD25+ Treg play an active role not only in modulating effectors of immune response to HBV infection, but also in influencing the disease prognosis in patients with hepatitis B.

Acute Disease↗
PubMed2006

Differential restoration of myeloid and plasmacytoid dendritic cells in HIV-1-infected children after treatment with highly active antiretroviral therapy.

Numerical and functional deficits in myeloid (mDC) and plasmacytoid dendritic cell (pDC) subsets have been found in both adult and pediatric HIV-1 carriers. Whether these impaired DC subsets can be restored after treatment with highly active antiretroviral therapy (HAART) is currently unknown, especially in HIV-1-infected children. In this report, we characterized mDC and pDC subsets in 18 HIV-1-infected children who received HAART treatment and compared them with those in 6 untreated HIV-1-infected children and 27 HIV-1-uninfected healthy children. Among children treated with HAART, 11 were found to suppress HIV-1 replication successfully below the detection limit (HAART-suppressed group) while the remaining 7 failed (HAART-failure group). In HAART-suppressed children, a gradual and complete restoration of the frequency and function of mDCs was observed while the recovery of pDCs was only partial. However, mDC and pDC subsets in HARRT failure children were indistinguishable from the HAART-naive infected children. We also found that mDC frequency and IFN-alpha-releasing capacity of pDC positively correlated with CD4 T cell percentages in all HIV-1-infected children. In HAART-naive children, the mDC frequency correlated the HIV-1-specific CTL frequency. Our findings suggest that HAART has a differential impact on the restoration of mDC and pDC subsets. These findings may help guide the development of HIV-1-specific immune therapy aimed at fully restoring host immune function in chronically HIV-1-infected children.

Adolescent↗
PubMed2006

Characterization and application of a new optical probe for membrane lipid domains.

In this article, we characterize the fluorescence of an environmentally sensitive probe for lipid membranes, di-4-ANEPPDHQ. In large unilamellar lipid vesicles (LUVs), its emission spectrum shifts up to 30 nm to the blue with increasing cholesterol concentration. Independently, it displays a comparable blue shift in liquid-ordered relative to liquid-disordered phases. The cumulative effect is a 60-nm difference in emission spectra for cholesterol containing LUVs in the liquid-ordered state versus cholesterol-free LUVs in the liquid-disordered phase. Given these optical properties, we use di-4-ANEPPDHQ to image the phase separation in giant unilamellar vesicles with both linear and nonlinear optical microscopy. The dye shows green and red fluorescence in liquid-ordered and -disordered domains, respectively. We propose that this reflects the relative rigidity of the molecular packing around the dye molecules in the two phases. We also observe a sevenfold stronger second harmonic generation signal in the liquid-disordered domains, consistent with a higher concentration of the dye resulting from preferential partitioning into the disordered phase. The efficacy of the dye for reporting lipid domains in cell membranes is demonstrated in polarized migrating neutrophils.

Animals↗
PubMed2006

Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds.

The tyrosine kinase pp60src (Src) is the prototypical member of a family of proteins that participate in a broad array of cellular signal transduction processes, including cell growth, differentiation, survival, adhesion, and migration. Abnormal Src family kinase (SFK) signaling has been linked to several disease states, including osteoporosis and cancer metastases. Src has thus emerged as a molecular target for the discovery of small-molecule inhibitors that regulate Src kinase activity by binding to the ATP pocket within the catalytic domain. Here, we present crystal structures of the kinase domain of Src in complex with two purine-based inhibitors: AP23451, a small-molecule inhibitor designed to inhibit Src-dependent bone resorption, and AP23464, a small-molecule inhibitor designed to inhibit the Src-dependent metastatic spread of cancer. In each case, a trisubstituted purine template core was elaborated using structure-based drug design to yield a potent Src kinase inhibitor. These structures represent early examples of high affinity purine-based Src family kinase-inhibitor complexes, and they provide a detailed view of the specific protein-ligand interactions that lead to potent inhibition of Src. In particular, the 3-hydroxyphenethyl N9 substituent of AP23464 forms unique interactions with the protein that are critical to the picomolar affinity of this compound for Src. The comparison of these new structures with two relevant kinase-inhibitor complexes provides a structural basis for the observed kinase inhibitory selectivity. Further comparisons reveal a concerted induced-fit movement between the N- and C-terminal lobes of the kinase that correlates with the affinity of the ligand. Binding of the most potent inhibitor, AP23464, results in the largest induced-fit movement, which can be directly linked to interactions of the hydrophenethyl N9 substituent with a region at the interface between the two lobes. A less pronounced induced-fit movement is also observed in the Src-AP23451 complex. These new structures illustrate how the combination of structural, computational, and medicinal chemistry can be used to rationalize the process of developing high affinity, selective tyrosine kinase inhibitors as potential therapeutic agents.

Adenine↗
PubMed2006

Providers' assessment of barriers to effective management of hypertension and hyperlipidemia in community health centers.

We explored 251 providers' (47% licensed practical nurses, 27% registered nurses, 10% physicians, 10% physician assistants, 6% other) perceptions of barriers to effective management of hypertension and hyperlipidemia from 72 Midwest community health centers (CHCs). Optimal care for these diseases is difficult in any setting; little is known about the specific barriers CHCs face. Community health centers often have a multidisciplinary team that participates in patient care. Current models of quality improvement and chronic care management require virtually all CHC providers to know clinical guidelines. Providers in this study generally chose hypertension and hyperlipidemia target levels that met or were more stringent than national guidelines, but lacked confidence to address behavioral change and reported obstacles to modifying patient lifestyle. Community health centers should strengthen providers' skills in facilitating lifestyle change. Improving quality of care requires supporting providers' efforts to take patients' psychosocial and financial challenges into account, and revised policies to eliminate financial and cultural barriers to care.

Attitude of Health Personnel↗
PubMed2006

The impact of patient preferences on the cost-effectiveness of intensive glucose control in older patients with new-onset diabetes.

OBJECTIVE: Cost-effectiveness analyses have reported that intensive glucose control is not cost-effective in older patients with new-onset diabetes. However, these analyses have had limited data on patient preferences concerning diabetic health states. We examined how the cost- effectiveness of intensive glucose control changes with the incorporation of patient preferences. RESEARCH DESIGN AND METHODS: We collected health state preferences/utilities from 519 older diabetic patients. We incorporated these utilities into an established cost-effectiveness model of intensive glucose control and compared incremental cost-effectiveness analyses ratios (ICERs) (cost divided by quality-adjusted life-year [QALY]) when using the original and patient-derived utilities for complications and treatments. RESULTS: The mean utilities were approximately 0.40 for major complications, 0.76 (95% CI 0.74-0.78) for conventional glucose control, 0.77 (0.75-0.80) for intensive therapy with oral medications, and 0.64 (0.61-0.67) for intensive therapy with insulin. Incorporating our patient-derived complication utilities alone improved ICERs for intensive glucose control (e.g., patients aged 60-65 years at diagnosis, 136,000 dollars/QALY-->78,000 dollars/QALY), but intensive therapy was still not cost-effective at older ages. When patient-derived treatment utilities were also incorporated, the cost-effectiveness of intensive treatment depended on the method of glucose control. Intensive control with insulin generated fewer QALYs than conventional control. However, intensive control with oral medications was beneficial on average at all ages and had an ICER < or =100,000 dollars to age 70. CONCLUSIONS: The cost-effectiveness of intensive glucose control in older patients with new-onset diabetes is highly sensitive to assumptions regarding quality of life with treatments. Cost-effectiveness analyses of diabetes care should consider the sensitivity of results to alternative utility assumptions.

Aged↗
PubMed2006

[Comparison between the results of ICSI with fresh and with frozen-thawed sperm obtained by PESA to treat azoospermia].

OBJECTIVE: Retrospective study of the results of ICSI (intracytoplasmic sperm insemination) with frozen sperm obtained by PESA (percutaneous epididymal sperm aspiration) was performed in 27 patients. METHODS: With conventional freezing method, sperm from diagnosing PESA and the remaining motile sperm after treating cycle were frozen. After frozen-thawed and ICSI process, fertilization rate, implantation rate, clinical pregnancy rate were compared and other outcomes including pregnant combinations and parameters of newborns of experimental group (which used frozen-thawed sperm) and control group (which used fresh PESA sperm) were analyzed respectively. RESULTS: One hundred and sixty three and 1 157 oocytes of stage M II were injected respectively in the experimental group (15 cycles) and control group (100 cycles), and fertilization rate of experimental group was prominently higher than that of control group (84.05% vs 73.29%, P < 0.05), while implantation rate and clinical pregnancy rate were of no difference from the control, respectively (23.07% vs 15.73%; 53.33% vs 37.00%, P > 0.05). The differences in newborn's weights between two groups were of no statistical significance (P > 0.05). In the experimental group, eight clinical pregnancies were achieved including 5 live deliveries and 3 ongoing pregnancies, 37 clinical pregnancies including 30 deliveries with only 1 fetal death, 3 ongoing pregnancies and 4 abortions in the control group. Neither vital pregnant combinations nor neonate malformations were found in both groups. CONCLUSION: ICSI using frozen-thawed sperm obtained by PESA is an economic effective and safe method to treat azoospermia. Recovering rates of frozen sperm form PESA should be further increased.

Azoospermia↗
PubMed2006

[The phenotype and function of CD4+ CD25+ regulatory T cells in hepatitis B patients].

OBJECTIVE: Our aim was to investigate the frequency, phenotype and function of CD4+ CD25 high regulatory T cells (Treg) in patients with acute and chronic hepatitis B (AHB, CHB). METHODS: Peripheral blood mononuclear cells (PBMCs) from 16 AHB patients at acute phase (week 1 of illness), 72 CHB patients, and 32 health subjects were analyzed for Treg frequency and CD45RO, CD45RA, CD95 and HLA-DR phenotype by flow cytometry. Intracellular expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) was examined by intracellular cytokines staining. Forkhead/winged helix transcription factor (FoxP3) mRNA was detected by a real-time RT-PCR assay. The effects of MACS magnetic beads-purified Treg cells on the proliferation of PBMCs were examined by a [3H]-thymidine incorporation assay. The effect of Treg cells on IFN gamma secretion of autologous PBMCs was examined by ELISA. RESULTS: CHB patients presented a higher fraction of circulating CD4+ CD25 high Treg frequency than AHB patients (P < 0.05), but had no significant difference compared with healthy controls. CD4+ CD25 high Treg expressed high levels of CD45RO, HLA-DR and CTLA-4, low level of CD45RA, and expressed FoxP3 mRNA specifically. We also observed that Treg cells could suppress the expansion and IFN gamma secretion of autologous PBMCs when stimulated with HBV antigen or anti-CD3 antibody, and the suppressive effect was stronger when HBV antigen was used as stimulator. CONCLUSIONS: CHB patients presented a higher fraction of circulating Treg frequency than AHB patients at acute phase, but had no significant difference compared with healthy controls. FoxP3 mRNA was specifically expressed in CD4+ CD25+ cell population. Treg could suppress HBV antigen-specific T cell response in vitro. The study furthers our understanding of Treg's role in immunopathogenesis of hepatitis B.

Antigens, CD↗
PubMed2005

Synthesis, spectra, delivery and potentiometric responses of new styryl dyes with extended spectral ranges.

Styryl dyes have been among the most widely used probes for mapping membrane potential changes in excitable cells. However, their utility has been somewhat limited because their excitation wavelengths have been restricted to the 450-550 nm range. Longer wavelength probes can minimize interference from endogenous chromophores and, because of decreased light scattering, improve recording from deep within tissue. In this paper we report on our efforts to develop new potentiometric styryl dyes that have excitation wavelengths ranging above 700 nm and emission spectra out to 900 nm. We have prepared and characterized dyes based on 47 variants of the styryl chromophores. Voltage-dependent spectral changes have been recorded for these dyes in a model lipid bilayer and from lobster nerves. The voltage sensitivities of the fluorescence of many of these new potentiometric indicators are as good as those of the widely used ANEP series of probes. In addition, because some of the dyes are often poorly water soluble, we have developed cyclodextrin complexes of the dyes to serve as efficient delivery vehicles. These dyes promise to enable new experimental paradigms for in vivo imaging of membrane potential.

Action Potentials↗
PubMed2005

Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors.

Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs on the market. In a previous report, the crystal structures of the catalytic domain of FXIa (rhFXI(370-607)) in complex with various ecotin mutants have been described. However, ecotin forms a matrix-like interaction with rhFXI(370-607) and is impossible to displace with small-molecule inhibitors; ecotin crystals are therefore not suitable for iterative structure-based ligand design. In addition, rhFXI(370-607) did not crystallize in the presence of small-molecule ligands. In order to obtain the crystal structure of rhFXI(370-607) with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were implemented to promote crystal formation of rhFXI(370-607). A quadruple mutant of rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily crystallized in the presence of benzamidine. The benzamidine in the preformed crystals was easily exchanged with other FXIa small-molecule inhibitors. These crystals have facilitated the structure-based design of small-molecule FXIa inhibitors.

Benzamidines↗
PubMed2005

High-resolution association mapping of quantitative trait loci: a population-based approach.

In this article, population-based regression models are proposed for high-resolution linkage disequilibrium mapping of quantitative trait loci (QTL). Two regression models, the "genotype effect model" and the "additive effect model," are proposed to model the association between the markers and the trait locus. The marker can be either diallelic or multiallelic. If only one marker is used, the method is similar to a classical setting by Nielsen and Weir, and the additive effect model is equivalent to the haplotype trend regression (HTR) method by Zaykin et al. If two/multiple marker data with phase ambiguity are used in the analysis, the proposed models can be used to analyze the data directly. By analytical formulas, we show that the genotype effect model can be used to model the additive and dominance effects simultaneously; the additive effect model takes care of the additive effect only. On the basis of the two models, F-test statistics are proposed to test association between the QTL and markers. By a simulation study, we show that the two models have reasonable type I error rates for a data set of moderate sample size. The noncentrality parameter approximations of F-test statistics are derived to make power calculation and comparison. By a simulation study, it is found that the noncentrality parameter approximations of F-test statistics work very well. Using the noncentrality parameter approximations, we compare the power of the two models with that of the HTR. In addition, a simulation study is performed to make a comparison on the basis of the haplotype frequencies of 10 SNPs of angiotensin-1 converting enzyme (ACE) genes.

Alleles↗