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Biomedical subjects

L Feng

Publications and source records attributed to L Feng.

At least 37 records · Page 2Linked to original sources
PubMed2002

Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores.

Central core disease (CCD) is a congenital myopathy due to dominant mutations in the skeletal muscle ryanodine receptor gene (RYR1). The authors report three patients from two consanguineous families with symptoms of a congenital myopathy, cores on muscle biopsy, and confirmed linkage to the RYR1 locus. Molecular genetic studies in one family identified a V4849I homozygous missense mutation in the RYR1 gene. This report suggests a congenital myopathy associated with recessive RYR1 mutations.

Biopsy↗
PubMed2002

Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study.

BACKGROUND: Ullrich congenital muscular dystrophy (UCMD) is a form of merosin-positive congenital muscular dystrophy characterized by proximal contractures, distal laxity, rigidity of the spine, and respiratory complications. Recently, a deficiency of collagen VI on muscle and skin biopsy together with recessive mutations in the collagen 6A2 gene were reported in three families with UCMD. However, the clinical spectrum, frequency, and level of heterogeneity of this disorder are not known. SUBJECTS AND METHODS: The authors studied 15 patients (aged 3 to 23.6 years) with a clinical diagnosis of UCMD. Linkage analysis to the three collagen VI genes was performed in all informative families (n = 7), whereas immunohistochemical analysis of collagen VI expression in muscle was performed in the remaining cases. RESULTS: An immunocytochemical reduction of collagen VI was observed in six patients. Three of the six patients belonged to informative families, and haplotype analysis clearly suggested linkage to the COL6A1/2 locus in two cases and to the COL6A3 loci in the third case. In the remaining nine patients, primary collagen VI involvement was excluded based on either the linkage analysis (four families) or considered unlikely based on normal immunolabeling of collagen VI. Age and presentation at onset, the distribution and severity of weakness and contractures, and the frequency of nonambulant patients were similar in the patients with and without collagen VI involvement. Distal laxity, rigidity of the spine, scoliosis, failure to thrive, and early and severe respiratory impairment were found in all patients by the end of the first decade of life, irrespective of their maximum motor functional ability or their collagen status. CONCLUSIONS: These results suggest that collagen VI involvement is relatively common in UCMD (40%); however, the role of this molecule was excluded in a number of cases, suggesting genetic heterogeneity of this condition.

Adolescent↗
PubMed2002

Genetically engineered analogs of ascomycin for nerve regeneration.

The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/520-calcineurin ternary complex. They also have calcineurin-independent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13- and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13- and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.

Acetyltransferases↗
PubMed2001

Interaction of p53 and DNA-PK in response to nucleoside analogues: potential role as a sensor complex for DNA damage.

Therapeutic nucleoside analogues such as ara-C, gemcitabine, and fludarabine exert their cytotoxic activity against cancer cells mainly by incorporation into DNA and disruption of further DNA synthesis, resulting in the triggering of apoptosis. However, the molecules that recognize the incorporated analogues in DNA and subsequently initiate the downstream cellular responses remain to be identified. Here, we report that the DNA-dependent protein kinase (DNA-PK) and p53 are able to form a protein complex that interacts with the gemcitabine-containing DNA and plays a role in signaling to apoptotic pathways. DNA-PK/Ku and p53 were copurified in a protein fraction that binds to gemcitabine-containing DNA in preference to normal DNA. Immunoprecipitation experiments revealed that the two proteins physically associate in a complex. Treatment with gemcitabine resulted in an increase of DNA-PK and p53 protein and an increase in the phosphorylation of p53 at Ser15. Furthermore, confocal microscopy demonstrated a colocalization of DNA-PK and p53 to the nucleus in cells treated with gemcitabine. The nuclear localization of the DNA-PK/p53 complex was coincident with the induction of apoptosis in these cells. Although the wild-type p53 present in the protein complex exhibited 3'-5' exonuclease activity, it was incapable of excising the incorporated gemcitabine from DNA. The binding of the p53/DNA-PK complex to DNA substantially blocked further DNA synthesis by DNA polymerases alpha and epsilon in vitro, indicating a stalling of this complex at the site of drug incorporation. These data suggest that DNA-PK and p53 may form a sensor complex that detects the disruption of DNA replication caused by nucleoside analogue incorporation and may subsequently signal for apoptosis.

Antigens, Nuclear↗
PubMed2001

Correlation properties of binary spatiotemporal chaotic sequences and their application to multiple access communication.

This paper studies the correlation property and the spectral density of the binary spatiotemporal chaotic sequences that are generated by the one-way coupled map lattice. The results show that this kind of chaotic sequences possesses excellent randomlike property and could be used directly in the spread spectrum multiple access (SSMA) communications. The multiple access interference in the additional white Gaussian noise background is then analyzed, and the corresponding formulas are presented. The simulation and computation results indicate that the communication system adopting such spreading sequences possesses as good performance as the one employing Gold sequences. But the former has larger capacity and higher complexity. Therefore, the binary spatiotemporal chaotic sequences are good candidates for the spreading sequences in SSMA communications.

Journal Article↗
PubMed2001

Glutamate 47 in 1-aminocyclopropane-1-carboxylate synthase is a major specificity determinant.

Glutamate 47 is conserved in 1-aminocyclopropane-1-carboxylate (ACC) synthases and is positioned near the sulfonium pole of (S,S)-S-adenosyl-L-methionine (SAM) in the modeled pyridoxal phosphate quinonoid complex with SAM. E47Q and E47D constructs of ACC synthase were made to investigate a putative ionic interaction between Glu47 and SAM. The k(cat)/K(m) values for the conversion of (S,S)-SAM to ACC and methylthioadenosine (MTA) are depressed 630- and 25-fold for the E47Q and E47D enzymes, respectively. The decreases in the specificity constants are due to reductions in k(cat) for both mutant enzymes, and a 5-fold increase in K(m) for the E47Q enzyme. Importantly, much smaller effects were observed for the kinetic parameters of reactions with the alternate substrates L-vinylglycine (L-VG) (deamination to form alpha-ketobutyrate and ammonia) and L-alanine (transamination to form pyruvate), which have uncharged side chains. L-VG is both a substrate and a mechanism-based inactivator of the enzyme [Feng, L., and Kirsch, J. F. (2000) Biochemistry 39, 2436-2444], but the partition ratio, k(cat)/k(inact), is unaffected by the Glu47 mutations. ACC synthase primarily catalyzes the beta,gamma-elimination of MTA from the (R,S) diastereomer of SAM to produce L-VG [Satoh, S., and Yang, S. F. (1989) Arch.Biochem. Biophys. 271, 107-112], but catalyzes the formation of ACC to a lesser extent via alpha,gamma-elimination of MTA. The partition ratios for (alpha,gamma/beta,gamma)-elimination on (R,S)-SAM are 0.4, < or =0.014, and < or =0.08 for the wild-type, E47Q, and E47D enzymes, respectively. The results of these experiments strongly support a role for Glu47 as an anchor for the sulfonium pole of (S,S)-SAM, and consequently a role as an active site determinant of reaction specificity.

Catalytic Domain↗
PubMed2001

Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study.

The FLT3 gene is mutated by an internal tandem duplication (ITD) in 20-25% of adults with acute myeloid leukemia (AML). We studied 82 adults <60 years of age with primary AML and normal cytogenetics, who received uniform high-dose therapy and found FLT3 ITD in 23 (28%) patients. When the 23 FLT3 ITD+ cases were compared with the 59 cases with wild-type (WT) FLT3, disease-free survival (DFS) was inferior (P = 0.03), yet overall survival (OS) was not different (P = 0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacked a FLT3 WT allele (FLT3(ITD-R)) as determined by PCR and loss of heterozygosity. Thus, three genotypic groups were identified: normal FLT3(WT/WT), heterozygous FLT3(ITD/WT), and hemizygous FLT3(ITD/-). DFS and OS were significantly inferior for patients with FLT3(ITD/-) (P = 0.0017 and P = 0.0014, respectively). Although DFS and OS for FLT3(WT/WT) and FLT3(ITD/WT) groups did not differ (P = 0.32 and P = 0.98, respectively), OS of the FLT3(ITD/-) group was worse than the FLT3(WT/WT) (P = 0.0005) and FLT3(ITD/WT) (P = 0.008) groups. We propose a model in which FLT3(ITD/-) represents a dominant positive, gain-of-function mutation providing AML cells with a greater growth advantage compared with cells having the FLT3(WT/WT) or FLT3(ITD/WT) genotypes. In conclusion, we have identified the FLT3(ITD/-) genotype as an adverse prognostic factor in de novo AML with normal cytogenetics. A poor prognosis of the relatively young FLT3(ITD/-) adults (median age, 37 years), despite treatment with current dose-intensive regimens, suggests that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.

Acute Disease↗
PubMed2001

A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene.

Chromosomal fusion of the N-terminal region of the Ewings Sarcoma Oncogene (EWS-activation-domain, EAD) to the DNA-binding domains of a variety of cellular transcription factors produce oncogenic proteins (EWS-fusion proteins (EFPs)) that cause distinct malignancies. In EFPs, the EAD acts as a potent transcriptional activation domain and this ability is repressed in the context of normal, non-tumorigenic, EWS. Trans-activation by the EAD is therefore a specific characteristic of EFPs and it is thought that EFPs induce tumorigenesis via improper transcriptional activation of cellular genes. Functional elements required for transcriptional activation are dispersed throughout the EAD, as are thirty-one copies of a Degenerate Hexapeptide Repeat (DHR, consensus SYGQQS). This suggests that the EAD contains a highly reiterated functional element related to DHRs. Here we show that in the context of EWS/ATF1, the EFP that causes malignant melanoma of soft parts, trans-cooperation by small regions of the EAD ( approximately 30 residues) results in potent transcriptional activation dependent on the conserved tyrosine residues present in DHRs. These findings provide the first evidence for a role of DHRs in EAD-mediated trans-activation and demonstrate that the EAD represents a novel tyrosine-dependent transcriptional activation domain.

Amino Acid Sequence↗
PubMed2001

The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors.

Migration is a basic feature of many cell types in a wide range of species. Since the 1800s, cell migration has been proposed to occur in the nervous and immune systems, and distinct molecular cues for mammalian neurons and leukocytes have been identified. Here we report that Slit, a secreted protein previously known for its role of repulsion in axon guidance and neuronal migration, can also inhibit leukocyte chemotaxis induced by chemotactic factors. Slit inhibition of the chemokine-induced chemotaxis can be reconstituted by the co-expression of a chemokine receptor containing seven transmembrane domains and Roundabout (Robo), a Slit receptor containing a single transmembrane domain. Thus, there is a functional interaction between single and seven transmembrane receptors. Our results reveal the activity of a neuronal guidance cue in regulating leukocyte migration and indicate that there may be a general conservation of guidance mechanisms underlying metazoan cell migration. In addition, we have uncovered an inhibitor of leukocyte chemotaxis, and propose a new therapeutic approach to treat diseases involving leukocyte migration and chemotactic factors.

Animals↗
PubMed2001

Phosphorylation of neurofibromin by cAMP-dependent protein kinase is regulated via a cellular association of N(G),N(G)-dimethylarginine dimethylaminohydrolase.

The neurofibromatosis type 1 (NF1) tumor suppressor (neurofibromin) is thought to play crucial roles in cellular Ras- and cAMP-dependent kinase (PKA)-associated signals. In this study, we identified a cellular neurofibromin-associating protein, N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) that is known as a cellular NO/NOS regulator. The interaction of DDAH was mainly directed to the C-terminal domain (CTD) and to the cysteine/serine-rich domain (CSRD) of neurofibromin, coinciding with the regions containing specific PKA phosphorylation sites. DDAH increased PKA phosphorylation of native neurofibromin in a dose-dependent manner, especially affecting the phosphorylation of CSRD. These findings suggest that the PKA accessibility of neurofibromin was regulated via DDAH interaction, and this regulation may modulate the cellular function of neurofibromin that is implicated in NF1-related pathogenesis.

Amidohydrolases↗
PubMed2001

Full-contact domain labeling: identification of a novel phosphoinositide binding site on gelsolin that requires the complete protein.

Gelsolin, an actin and phosphoinositide binding protein, was photoaffinity labeled using a variety of benzophenone-containing phosphoinositide polyphosphate analogues. The N-terminal half and the C-terminal half of gelsolin showed synergy in the binding of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. Competitive displacement experiments with dibutyryl, dioctanoyl, or dipalmitoyl derivatives of PtdIns(4,5)P(2) suggested that, in addition to the inositol headgroup, a diacylglyceryl moiety was important for binding; these analogues also inhibited the gelsolin-severing activity of F-actin. In addition to the previously identified PtdIns(4,5)P2 binding site in the N-terminal half of gelsolin, a new binding site was identified in the C-terminal half by mapping the photocovalently modified peptide fragments. Moreover, increasing concentrations of Ca(2+) decreased the binding of the photolabile analogues to the C-terminal phosphoinositide binding site on gelsolin. A molecular model of the binding of PtdIns(4,5)P2 within two folded repeats of gelsolin has been calculated using these data.

Actins↗
PubMed2001

The effect of hydroxyapatite ultrofine powder on the immunity function of tumor-bearing mice.

The inhibitory effect of hydroxyapatite ultrofine powder (HAUFP) on tumor and the effect on the immunity function of body were investigated. The levels of IL-2 in the spleen cells and serum TNF levels in the tumor-bearing mice at the 7th day and 14th after peritoneal injection of HAUFP were detected by using the methods of colorimetric analysis of MTT and crystal purple decoration, respectively. The disappearance of the ascites of the mice was observed. The results showed that the levels of IL-2 and TNF in the tumor-bearing mice were higher obviously in the drug-treated group than in the control group (P < 0.01), the ascites growth was inhibited. It was suggested that HAUFP could increase the levels of IL-2 and TNF of the tumor-bearing mice and improve the immune function of body.

Animals↗
PubMed2001

Stearyl poly(ethylene oxide) grafted surfaces for preferential adsorption of albumin.

An ideal surface for many biomedical applications would resist non-specific protein adsorption while at the same time triggering a specific biological pathway. Based on the approach of selectively binding albumin to free fatty acids, stearyl groups were immobilized onto poly(styrene) backbone via poly(ethylene oxide) side chains. X-ray photoelectron spectroscopy (XPS) analysis indicates substantial surface enrichment of the stearyl poly(ethylene oxide) (SPEO). In an aqueous environment, the surface rearrangement is limited, as proved by dynamic contact angle tests. The comb-like copolymer presents a special hydrophobic surface with high SPEO surface density, which may be due to the 'tail like' SPEO architecture at the copolymer/water interface. Protein adsorption tests confirm that the comb-like surfaces adsorb high levels of albumin and resist fibrinogen adsorption very significantly. The surfaces prepared in this research attract and reversibly bind albumin due to the synergistic action of the PEO chains and the stearyl end groups.

Adsorption↗
PubMed2001

Treatment compliance in the trajectory of treatment progress among offenders.

Research on drug treatment process has been limited, with most studies centering on individual and program factors associated with successful treatment completion. Recent literature has begun highlighting the salience of treatment engagement in reducing drug dependence among criminal offenders. This study descriptively analyzes incidents of treatment noncompliance identified in monthly progress reports for 150 criminal justice-mandated clients in residential treatment. We identify seven problem types and seven dimensions of noncompliance in the trajectory of treatment engagement. The latter are prevalence, frequency, types, specialization, temporal distribution, paths, and correlates. It is found that incidents of rule violations are common among criminal justice participants of residential treatment. Although for most clients these troubles do not appear to evolve into serious obstacles to recovery, a few clients with a high frequency of noncompliant behavior never engage in treatment. Clinical implications for improving treatment engagement and retention are discussed.

Adult↗
PubMed2001

Competitive pathways via nonadiabatic transitions in photodissociation.

Photodissociation processes of molecules and radicals involving multiple pathways and nonadiabatic crossings are studied using the photofragment imaging technique and the core-sampling version of time-of-flight spectroscopy. Capabilities and challenges are illustrated by two systems. The isocyanic acid system demonstrates how interactions among potential energy surfaces can change during dissociation. The hydroxymethyl photodecomposition system highlights Rydberg-valence interactions common in free radicals. The cross-fertilization between theory and experiment is emphasized.

Journal Article↗
PubMed2001

Surface modification of polyurethane for promotion of cell adhesion and growth 1: surface photo-grafting with N,N-dimethylaminoethyl methacrylate and cytocompatibility of the modified surface.

Functional polyurethane (PU) surface was prepared by photo-grafting N,N-dimethylaminoethyl methacrylate (DMAEM) onto the membrane surface. Grafting copolymerization was conducted by the combined use of the photo-oxidation and irradiation grafting. PU membrane was photo-oxidized to introduce the hydroperoxide groups onto the surface, then the membrane previously immersed in monomer solution was irradiated by UV light. The X-ray photoelectron spectroscopy and water contact angle characterized the grafted copolymers and verified the occurrence of graft copolymerization. The results showed that UV irradiation could realize the graft copolymerization effectively. The grafted membrane showed minimal surface morphology. Human umbilical vein endothelium (HUVE) cells were seeded on the grafted surfaces. The performance of the surface in cell attachment correlated with the content of oxygen and nitrogen. Cells were spread more extensive and grown faster on the surface with lower degree of grafting.

Journal Article↗
PubMed2001

PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation.

Signaling mechanisms underlying neurotrophic regulation of synaptic transmission are not fully understood. Here we show that neurotrophin-3 (NT3)-induced potentiation of synaptic transmission at the neuromuscular synapses is blocked by inhibition of phosphoinositide-3 kinase, phospholipase C-gamma or the downstream IP3 receptors of phospholipase C-gamma, but not by inhibition of MAP kinase. However, neither stimulation of Ca2+ release from intracellular stores by photolysis of caged IP3, nor expression of a constitutively active phosphoinositide-3 kinase (PI3K*) in presynaptic motoneurons alone is sufficient to enhance transmission. Photo-uncaging of IP3 in neurons expressing PI3K* elicits a marked synaptic potentiation, mimicking the NT3 effect. These results reveal an involvement of PI3 kinase in transmitter release, and suggest that concomitant activation of PI3 kinase and IP3 receptors is both necessary and sufficient to mediate the NT3-induced synaptic potentiation.

Animals↗