XANES study of the electronic structure of molten germanium.
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Journal Article↗
Biomedical subjects
C Li
Publications and source records attributed to C Li.
Ex vivo expansion and genetic marking of primitive human and baboon hematopoietic cells.
The achievement of positive outcomes in many clinical protocols involving hematopoietic stem cells (HSCs) has been handicapped by the limited numbers of marrow repopulating cells available to actually bring about therapy. This insufficiency has been especially problematic in stem cell transplantation and gene therapy. A number of studies have been initiated to attempt expansion of HSCs, mainly by manipulation of key cytokines in cell suspension cultures. Unfortunately, these expansion methods usually lead to altered properties in the amplified cells, mainly by reducing their self-renewal and multi-lineage differentiative potentials. Here we discuss our ongoing work, utilizing a unique endothelial cell line that supports primitive hematopoiesis, to attempt to generate expansion of primate HSCs that retain their elementary properties. Genetic marking of early hematopoietic cells to facilitate tracking will be mentioned as will the development and employment of assay systems designed to evaluate the long-term functional attributes of the expanded cells.
Animals↗
E75 expression in mosquito ovary and fat body suggests reiterative use of ecdysone-regulated hierarchies in development and reproduction.
The steroid hormone ecdysone controls genetic regulatory hierarchies underlying insect molting, metamorphosis and, in some insects, reproduction. Cytogenetic and molecular analysis of ecdysone response in Drosophila larval salivary glands has revealed regulatory hierarchies including early genes which encode transcription factors controlling late ecdysone response. In order to determine whether similar hierarchies control reproductive ecdysone response, we have investigated ecdysone-regulated gene expression in vitellogenic mosquito ovaries and fat bodies. Here, we identify the homologue of the Drosophila E75 early ecdysone inducible gene in the yellow fever mosquito Aedes aegypti, and show that, as in Drosophila, the mosquito homologue, AaE75, consists of three overlapping transcription units with three mRNA isoforms, AaE75A, AaE75B, and AaE75C, originating as a result of alternative splicing. All three AaE75 isoforms are induced at the onset of vitellogenesis by a blood meal-activated hormonal cascade, and highly expressed in the mosquito ovary and fat body, suggesting their involvement in the regulation of oogenesis and vitellogenesis, respectively. Furthermore, in vitro fat body culture experiments demonstrate that AaE75 isoforms are induced by 20-hydroxyecdysone, an active ecdysteroid in the mosquito. These findings suggest that related ecdysone-triggered regulatory hierarchies may be used reiteratively during developmental and reproductive ecdysone responses.
Aedes↗
TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis.
A serious complication of radiotherapy in the treatment of cancer patients is the late onset of fibrosis in normal tissues. Transforming growth factor beta (TGF-beta) is emerging as a key mediator of the fibrotic process through its effects on stimulation of fibroblast proliferation, migration and extracellular matrix (ECM) synthesis. The fact that radiation-induced vascular injury tends to precede the development of fibrosis has led to the suggestion that vascular damage is crucial in its pathogenesis. CD105, the specific type III vascular receptor for TGF-beta1 and -beta3, modulates cell proliferation and ECM production in response to TGF-beta in vitro. In this study, we have quantified the levels of TGF-beta1 and soluble CD105-TGF-beta1 complex in 91 pre-radiotherapy plasma samples from early-stage (T1 or T2) breast cancer patients utilising an enhanced chemiluminescence ELISA system. During the follow-up period, 24 patients had developed moderate and one severe fibrosis of the breast. The mean TGF-beta1 level in these 25 patients was 203.2 +/- 37.3 pg/ml, which was significantly elevated above the level for those with no fibrosis. Furthermore, a significantly lower CD105-TGF-beta1 complex level was observed in the former compared to the latter. Spearman's correlation analysis showed that TGF-beta1 was positively correlated and the CD1O5-TGF-beta1 complex inversely correlated with the occurrence of breast fibrosis. Using a cut-off value of 96 pg/ml, the sensitivity and specificity of TGF-beta1 levels in predicting breast fibrosis were 76% and 74%, respectively. Our results indicate that TGF-beta1 and the receptor-ligand complex appear to be of clinical value in identifying patients at risk of developing post-radiotherapy fibrosis.
Adult↗
Trafficking of the Igalpha/Igbeta heterodimer with membrane Ig and bound antigen to the major histocompatibility complex class II peptide-loading compartment.
The binding of antigen to the B cell antigen receptor (BCR) initiates two major cellular events. First, upon cross-linking by antigen, the BCR induces signal transduction cascades leading to the transcription of a number of genes associated with B cell activation. Second, the BCR internalizes and delivers antigens to processing compartments, where processed antigenic peptides are loaded onto major histocompatibility complex (MHC) class II molecules for presentation to T helper cells. The BCR consists of membrane Ig (mIg) and Igalpha/Igbeta heterodimer (Igalpha/Igbeta). The Igalpha/Igbeta, the signal transducing component of the BCR, has been indicated to play a role in antigen processing. In order to understand the function of the Igalpha/Igbeta in antigen transport, we studied the intracellular trafficking pathway of the Igalpha/Igbeta. We show that in the absence of antigen binding, the Igalpha/Igbeta constitutively traffics with mIg from the plasma membrane, through the early endosomes, to the MHC class II peptide-loading compartment. Cross-linking the BCR does not alter the trafficking pathway; however, it accelerates the transport of the Igalpha/Igbeta to the MHC class II peptide-loading compartment. This suggests that the Igalpha/Igbeta heterodimer is involved in BCR-mediated antigen transport through the entire antigen transport pathway.
Dimerization↗
Murine fibroblast growth factor receptor 1alpha isoforms mediate node regression and are essential for posterior mesoderm development.
Alternative splicing in the fibroblast growth factor receptor 1 (Fgfr1) locus generates a variety of splicing isoforms, including FGFR1alpha isoforms, which contain three immunoglobulin-like loops in the extracellular domain of the receptor. It has been previously shown that embryos carrying targeted disruptions of all major isoforms die during gastrulation, displaying severe growth retardation and defective mesodermal structures. Here we selectively disrupted the FGFR1alpha isoforms and found that they play an essential role in posterior mesoderm formation during gastrulation. We show that the mutant embryos lack caudal somites, develop spina bifida, and die at 9.5-12.5 days of embryonic development because they are unable to establish embryonic circulation. The primary defect is a failure of axial mesoderm cell migration toward the posterior portions of the embryos during gastrulation, as revealed by regional marker analysis and DiI labeling. In contrast, the anterior migration of the notochord is unaffected and the embryonic structures rostral to the forelimb are relatively normal. These data demonstrate that FGF/FGFR1alpha signals are posteriorizing factors that control node regression and posterior embryonic development.
Abnormalities, Multiple↗
Identification of neuronal input to the arcuate nucleus (ARH) activated during lactation: implications in the activation of neuropeptide Y neurons.
Activation of the neuropeptide Y (NPY) neuronal system in the arcuate nucleus of the hypothalamus (ARH) during lactation in the rat is likely due to the neural impulses arising from the suckling stimulus. However, the afferent neuronal input to the ARH that is activated during lactation and is responsible for activation of NPY neurons is currently unknown. Previously, using cFos as a marker for neuronal activation, we identified several brain areas in the lactating animals that were activated by the suckling stimulus. Thus, the objective of the present study was to determine if these activated areas observed in the lactating animals project directly into the ARH. The retrograde tracer, fluorogold (FG), was injected into the ARH on day 4 postpartum. Chronically suckled rats were then deprived of their eight-pup litters on day 9 postpartum, and 48 h later, the pups were returned to the females to reinitiate the suckling stimulus for 90 min to induce cFos expression. The animals were then perfused and the brains were subjected to double-label immunohistochemistry to visualize both FG- and cFos-positive cells. Substantial FG/cFos double-labeled cells were found in forebrain regions, including the medial preoptic area, periventricular preoptic area, bed nucleus of the stria terminalis, and the medial amygdala, and in brainstem regions including the lateral parabrachial nucleus, peripeduncular area and ventrolateral medulla. The results of the present study demonstrate that specific areas in the brain are activated during lactation and send direct projections to the ARH. Thus, these areas are potentially important candidates for mediating the activation of the NPY neuronal system in the ARH during lactation.
Animals↗
Distinct ATP-activated currents in different types of neurons dissociated from rat dorsal root ganglion.
Rat dorsal root ganglion neurons can be classified into at least three distinct groups based on cell size, afferent fiber diameter, electrophysiological properties, sensitivity to vanilloid agonists such as capsaicin, and function. In the present study, ATP-activated current in these neurons was characterized using whole-cell patch-clamp recording. Small diameter (<30 microm) cells had high capsaicin sensitivity, high affinity for ATP, and rapidly desensitizing ATP-activated current. Medium diameter (30-50 microm) cells had no capsaicin sensitivity, lower affinity for ATP and slowly desensitizing ATP-activated current. Large diameter (>50 microm) cells were insensitive to both capsaicin and ATP. These findings suggest that distinct types of ATP receptor-ion channels are expressed in different types of dorsal root ganglion neurons, and may contribute to the functional differences among these types of neurons.
Adenosine Triphosphate↗
Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque.
BACKGROUND: Tenascin is a large extracellular matrix glycoprotein generally found in adult tissues undergoing active remodeling such as healing wounds and tumors. To determine the potential role of tenascin-C (TN-C) in the pathophysiology of atherosclerosis, we investigated the pattern of expression of TN-C in human coronary atherosclerotic plaques. METHODS AND RESULTS: Immunohistochemical staining and in situ hybridization demonstrated minimal and random expression of TN-C in fibrotic but lipid-poor atherosclerotic plaques. In contrast, all plaques with an organized lipid core or ruptured intimal surface strongly expressed TN-C, which was preferentially concentrated around the lipid core, shoulder regions, and ruptured area of the plaques but not in the fibrous cap. TN-C was not detected in normal arterial tissue. To identify the cellular source of TN-C, the plaques were stained with smooth muscle cell- and macrophage-specific antibodies. TN-C expression correlated with the infiltration of macrophages. Northern blot and immunoprecipitation analysis showed that macrophages expressed 7. 0-kb TN-C mRNA and 220-kDa protein. Reverse transcription-polymerase chain reaction of total RNA derived from macrophages showed that they express the small isoform of TN-C. Zymogram analysis revealed that macrophages markedly increased MMP-9 expression. CONCLUSIONS: This study demonstrates that the level of TN-C expression correlates with the degree of inflammation present, not with plaque size. In addition, cultured macrophages have the capacity to express the TN-C gene. These findings suggest the significance of macrophages in the remodeling of atherosclerotic plaque matrix composition.
Adult↗
Quality of life in endometrial cancer survivors.
OBJECTIVE: The aim of this study was to evaluate the health-related quality of life in survivors of endometrial cancer (EC); and to identify common problems that they may encounter, in the hope of paving the way to improving their quality of life. STUDY DESIGN: We investigated and compared the health conditions and quality of life between EC survivors and the general population as a control group. There were 61 EC patients who were at clinical stage I-III and survived for 5-7 years after the primary treatments. The control group was composed of 527 healthy postmenopausal women. All of them completed a self-evaluated questionnaire pertaining to personal conditions, medical surveillance, individual well-being and quality of life. RESULTS: The EC survivors were divided into two groups: an older group (n = 34) and a younger group (n = 27). The latter was compared with the controls. In general, most of the EC survivors were old, low-educated women. The majority of them were in a poor condition. They were inactive, received medical surveillance and had regular medication. The distribution of various complications was higher in the older EC group while the climacteric symptoms were more common in the younger EC group. In both EC groups, the quality of life was lower than in the controls. The prevalence of somatic symptoms was higher in the older EC survivors and psychological problems were a common complaint of the younger EC survivors. CONCLUSION: The quality of life was poor in the EC survivors. To improve their life quality, earlier psychological counseling should be offered to EC survivors, in particular to younger and single women, and hormone replacement therapy (HRT) should be recommended, but on a selective basis, to those patients at low risk of cancer recurrence.
Aged↗
Induction of low density lipoprotein receptor (LDLR) transcription by oncostatin M is mediated by the extracellular signal-regulated kinase signaling pathway and the repeat 3 element of the LDLR promoter.
Oncostatin M (OM) activates the transcription of the human low density lipoprotein receptor (LDLR) in HepG2 cells through a sterol-independent mechanism. Our previous studies showed that mutations within the repeat 3 sequence of the LDLR promoter significantly decreased OM activity on LDLR promoter luciferase reporter constructs that contain the sterol responsive element-1 (repeat 2) and Sp1 binding sites (repeats 1 and 3). In this study, we investigated the signal transduction pathways that are involved in OM-induced LDLR transcription. In HepG2 cells, OM induced a rapid increase in LDLR mRNA expression, with increases detected at 30 min and maximal induction at 1 h. This OM effect was not blocked by protein synthesis inhibitors, inhibitors of p38 kinase, phosphatidylinositol 3-kinase, or c-Jun N-terminal kinase, but OM activity was completely abolished by pretreating cells with inhibitors of the extracellular signal-regulated kinase (ERK) kinase (mitogen/ERK kinase (MEK)). To investigate whether the repeat 3 sequence of the LDLR promoter is the OM-responsive element that converts ERK activation at the promoter level, three luciferase reporters, pLDLR-TATA containing only the TATA-like elements of the promoter, pLDLR-R3 containing repeat 3 and the TATA-like elements, and pLDLR-234 containing repeats 1, 2, 3 and the TATA-like elements were constructed and transiently transfected into HepG2 cells. OM had no effect on the basal promoter construct pLDLR-TATA; however, including a single copy of repeat 3 sequence in the TATA vector (pLDLR-R3) resulted in a full OM response. The activity of OM on pLDLR-R3 was identical to that of pLDLR-234. Importantly, the ability of OM to increase luciferase activities in both pLDLR-R3- and pLDLR-234-transfected cells was blocked in a dose-dependent manner by inhibition of MEK. These results demonstrate that the mitogen-activated protein kinase MEK/ERK cascade is the essential signaling pathway by which OM activates LDLR gene transcription and provide the first evidence that the repeat 3 element is a new downstream target of ERK activation.
Antineoplastic Agents↗
Age of male circumcision and risk of prevalent HIV infection in rural Uganda.
OBJECTIVE: To assess whether circumcision performed on postpubertal men affords the same level of protection from HIV-1 acquisition as circumcisions earlier in childhood. DESIGN: Cross-sectional study of a population-based cohort. SETTING: Rakai district, rural Uganda. METHODS: A total of 6821 men aged 15-59 years were surveyed and venous blood samples were tested for HIV-1 and syphilis. Age at circumcision was dichotomized into men who were circumcised before or at age 12 years (prepubertal) and men circumcised after age 12 years (postpubertal). Postpubertal circumcised men were also subdivided into those reporting circumcision at ages 13-20 years and > or = 21 years. RESULTS: HIV-1 prevalence was 14.1% in uncircumcised men, compared with 16.2% for men circumcised at age > or = 21 years, 10.0% for men circumcised at age 13-20 years, and 6.9% in men circumcised at age < or = 12 years. On bivariate analysis, lower prevalence of HIV-1 associated with prepubertal circumcision was observed in all age, education, ethnic and religious groups. Multivariate adjusted odds ratio of prevalent HIV-1 infection associated with prepubertal circumcision was 0.39 [95% confidence interval (CI), 0.29-0.53]. In the postpubertal group, the adjusted odds ratio for men circumcised at ages 13-20 years was 0.46 (95% CI, 0.28-0.77), and 0.78 (95% CI, 0.43-1.43) for men circumcised after age 20 years. CONCLUSIONS: Prepubertal circumcision is associated with reduced HIV risk, whereas circumcision after age 20 years is not significantly protective against HIV-1 infection. Age at circumcision and reasons for circumcision need to be considered in future studies of circumcision and HIV risk.
Adolescent↗
Alleles that may influence HIV-1 pathogenesis in Chinese subjects.
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Alleles↗
Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis.
Angiogenesis is essential for tumor growth and metastasis. There are conflicting reports as to whether microvessel density (IMD) in breast cancers is associated with prognosis. This could be due to the use of different antibodies to endothelial cell markers, variation in tissue pretreatment protocols, and nonstandardized counting methods. We have assessed the IMD in 106 breast carcinomas using a pan-endothelial marker, CD34, and a recently described mAb to CD105, which preferentially reacts with endothelial cell in angiogenic tissues. IMD values (separated as above or below median) for CD105 expression showed a statistically significant correlation with overall (P = 0.0029) and disease-free survival (P = 0.0362). In contrast, blood vessel counts using a panendothelial marker CD34 did not correlate with overall or disease-free survival (P = 0.2912 and P = 03153, respectively). When IMD values were subdivided into quartiles and assessed for their prognostic values, there was a statistically significant difference in the overall survival across CD105, but not CD34, values (P = 0.0017 and P = 0.7997, respectively) and also disease-free survival (P = 0.0431 and P = 0.5066, respectively). Further analysis of IMD values demonstrated that there were no deaths in the lowest quartile for CD105 and it differed from the other three quartiles. However, examination of clinical details of patients in the lowest quartile failed to reveal clustering of patients known to be associated with low-risk factors. Multivariate analysis confirmed that IMD values using CD105 were an independent prognostic factor. These results suggest that the ability to quantitatively distinguish between tumor neovascularization and preexisting vessels may be important in the assessment of tumor angiogenesis, but requires confirmation in a greater number of patients with a longer follow-up.
Adult↗
Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Rakai Project Study Group.
BACKGROUND: The study tested the hypothesis that community-level control of sexually transmitted disease (STD) would result in lower incidence of HIV-1 infection in comparison with control communities. METHODS: This randomised, controlled, single-masked, community-based trial of intensive STD control, via home-based mass antibiotic treatment, took place in Rakai District, Uganda. Ten community clusters were randomly assigned to intervention or control groups. All consenting residents aged 15-59 years were enrolled; visited in the home every 10 months; interviewed; asked to provide biological samples for assessment of HIV-1 infection and STDs; and were provided with mass treatment (azithromycin, ciprofloxacin, metronidazole in the intervention group, vitamins/anthelmintic drug in the control). Intention-to-treat analyses used multivariate, paired, cluster-adjusted rate ratios. FINDINGS: The baseline prevalence of HIV-1 infection was 15.9%. 6602 HIV-1-negative individuals were enrolled in the intervention group and 6124 in the control group. 75.0% of intervention-group and 72.6% of control-group participants provided at least one follow-up sample for HIV-1 testing. At enrolment, the two treatment groups were similar in STD prevalence rates. At 20-month follow-up, the prevalences of syphilis (352/6238 [5.6%]) vs 359/5284 [6.8%]; rate ratio 0.80 [95% CI 0.71-0.89]) and trichomoniasis (182/1968 [9.3%] vs 261/1815 [14.4%]; rate ratio 0.59 [0.38-0.91]) were significantly lower in the intervention group than in the control group. The incidence of HIV-1 infection was 1.5 per 100 person-years in both groups (rate ratio 0.97 [0.81-1.16]). In pregnant women, the follow-up prevalences of trichomoniasis, bacterial vaginosis, gonorrhoea, and chlamydia infection were significantly lower in the intervention group than in the control group. No effect of the intervention on incidence of HIV-1 infection was observed in pregnant women or in stratified analyses. INTERPRETATION: We observed no effect of the STD intervention on the incidence of HIV-1 infection. In the Rakai population, a substantial proportion of HIV-1 acquisition appears to occur independently of treatable STD cofactors.
Acquired Immunodeficiency Syndrome↗
Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts.
The abnormally high number of centrosomes found in many human tumor cells can lead directly to aneuploidy and genomic instability through the formation of multipolar mitotic spindles. To facilitate investigation of the mechanisms that control centrosome reproduction, a frog egg extract arrested in S phase of the cell cycle that supported repeated assembly of daughter centrosomes was developed. Multiple rounds of centrosome reproduction were blocked by selective inactivation of cyclin-dependent kinase 2-cyclin E (Cdk2-E) and were restored by addition of purified Cdk2-E. Confocal immunomicroscopy revealed that cyclin E was localized at the centrosome. These results demonstrate that Cdk2-E activity is required for centrosome duplication during S phase and suggest a mechanism that could coordinate centrosome reproduction with cycles of DNA synthesis and mitosis.
Animals↗
Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator).
The cystic fibrosis transmembrane conductance regulator (CFTR) functions as an ATPase and as a chloride channel. It has been hypothesized, on the basis of electrophysiological findings, that the catalytic activity of CFTR is tightly coupled to the opening and closing of the channel gate. In the present study, to determine the structural basis for the ATPase activity of CFTR, we assessed the effect of mutations within the "Walker A" consensus motifs on ATP hydrolysis by the purified, intact protein. Mutation of the lysine residue in the "Walker A" motif of either the first nucleotide binding fold (CFTRK464A) or the second nucleotide binding fold (CFTRK1250A) inhibited the ATPase activity of the purified intact CFTR protein significantly, by greater than 50%. This finding suggests that the two nucleotide binding folds of CFTR are functioning cooperatively in catalysis. However, the rate of channel gating was only significantly inhibited in one of these purified mutants, CFTRK1250A, suggesting that ATPase activity may not be tightly coupled to channel gating as previously hypothesized.
Adenosine Triphosphatases↗
ClC-2 activation modulates regulatory volume decrease.
ClC-2 belongs to a large family of chloride channels and its expression in certain cell types is associated with the appearance of swelling-activated chloride (Cl-) currents. In the present report, we examined the hypothesis that ClC-2 plays a role in regulatory volume decrease by expressing ClC-2 in Sf9 cells using the baculovirus system. First, we showed that ClC-2 protein expression is associated with appearance of a Cl- conductance which is activated by hypo-osmotic shock and can be distinguished from swelling-activated chloride currents endogenous to Sf9 cells on the basis of its pharmacology and specific inhibition by an anti-ClC-2 antibody. Second, we show that the rate of regulatory volume decrease is significantly enhanced in Sf9 cells expressing ClC-2 protein. Hence, our data support the hypothesis that ClC-2 is capable of mediating regulatory volume decrease.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗