Stylized transcript map of chromosome 4q35 encompassing the locus for a bipolar disorder susceptibility gene.
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Bipolar Disorder↗
Biomedical subjects
L Ma
Publications and source records attributed to L Ma.
Depth dose enhancement of electron beams subject to external uniform longitudinal magnetic fields: a Monte Carlo study.
We studied the dose distributions from electron beams subjected to a longitudinal magnetic field applied to them before they reach the phantom. We found that specific combinations of the length and intensity of the magnetic field produced enhancement of the peaks of the central-axis depth-dose distributions. The EGS4 Monte Carlo system was used in this study. In the simulations, a uniform axial magnetic field parallel to the electron beam direction was applied to the air gap between the collimation and the phantom. We extensively studied the simplified case of an 18 MeV electron beam point source. Dose deposition was calculated for various magnetic field strengths, distances through which the magnetic field was applied, collimation sizes, and source to collimation distances. The magnetic field strengths varied from 0 to 3 T, the source-to-collimation distances studied were 50 and 95 cm, the collimation sizes studied were 10 x 10 and 20 x 20 cm2, and the distance through which the field was applied ranged from 10 to 20 cm. Specific combinations of these variables resulted in as much as a 70% enhancement of the peak dose relative to the surface dose. Finally, to determine how the geometry of a real accelerator affects the resulting dose distribution, we performed a full simulation of an Elekta SL20 linear accelerator and compared the results with the ideal case.
Electromagnetic Fields↗
CTX-M-14, a plasmid-mediated CTX-M type extended-spectrum beta-lactamase isolated from Escherichia coli.
Four Escherichia coli isolates harboring CTX-M-14, with a single Ala231-->Val substitution compared to CTX-M-9, had three different ribotypes. Cefotaxime resistance was plasmid encoded and conjugatively transferable. Three isolates had the same plasmid restriction enzyme digestion profile, suggesting clonal spread of a resistant plasmid. A high k(cat)/K(m) value for cefotaxime (20.3 microM(-1) s(-1)) but low values for ceftazidime and aztreonam (< 0.02 microM(-1) s(-1)) were observed in hydrolysis assays, indicating resistance to cefotaxime (MIC > or = 64 microg/ml) but susceptibility to ceftazidime (MIC < or = 2 microg/ml).
Amino Acid Substitution↗
Optimized intensity-modulated arc therapy for prostate cancer treatment.
We recently implemented intensity-modulated arc therapy (IMAT) at our institution. In this study, we evaluate the dosimetric merits of the application of this technique to the treatment of prostate cancer. Each IMAT treatment plan incorporated bilateral overlapping arcs. The dose from each beam segment was computed using the three-dimensional dose model of a clinical treatment planning system (Render Plan 3.5, Precision Therapy). The weights assigned to the individual arc segments were optimized using a gradient search method. For 12 patients, comparisons were made between the IMAT treatment plans and corresponding plans using fixed cone-beam intensity-modulated radiotherapy (IMRT) from a commercial inverse planning system (CORVUS, NOMOS Corp.). We found that the optimized IMAT treatments produced similar dose distributions to the IMRT deliveries. Compared with the IMRT treatments, the IMAT treatments produced slightly less target dose homogeneity with consistently greater sparing of the rectum in regions of lower dose. The trade-off between target dose conformity and rectum sparing can be adjusted in both optimization procedures. Because the total beam-on time for IMAT delivery is 1 to 2 minutes with approximately 5-6 minutes of patient setup time, the delivery efficiency of the IMAT treatment was significantly better than the multiple-beam IMRT treatment.
Humans↗
Whisker-related neural patterns develop normally despite severe whisker defects in Msx2 knockout mice.
In mice, whiskers on the snout form a highly specialized tactile organ with exquisitely patterned neural representations in the brain. Targeted deletion of the Msx2 gene leads to severe craniofacial defects, and stubby, curly whiskers. We examined the whisker pad histology, innervation, and whisker-related pattern formation along the trigeminal pathway in Msx2 -/- mice. Although the whiskers are severely deformed, whisker follicle structure, pattern and density of innervation, as well as central neural patterns in the brainstem, thalamus, and cortex appeared normal. We conclude that whisker-related neural patterns can form in the absence of normal whiskers, as long as whisker follicle innervation is intact.
Animals↗
The nonhelical tail domain of keratin 14 promotes filament bundling and enhances the mechanical properties of keratin intermediate filaments in vitro.
Keratin filaments arise from the copolymerization of type I and II sequences, and form a pancytoplasmic network that provides vital mechanical support to epithelial cells. Keratins 5 and 14 are expressed as a pair in basal cells of stratified epithelia, where they occur as bundled arrays of filaments. In vitro, bundles of K5-K14 filaments can be induced in the absence of cross-linkers, and exhibit enhanced resistance to mechanical strain. This property is not exhibited by copolymers of K5 and tailless K14, in which the nonhelical tail domain has been removed, or copolymers of K5 and K19, a type I keratin featuring a short tail domain. The purified K14 tail domain binds keratin filaments in vitro with specificity (kD approximately 2 microM). When transiently expressed in cultured cells, the K14 tail domain associates with endogenous keratin filaments. Utilization of the K14 tail domain as a bait in a yeast two-hybrid screen pulls out type I keratin sequences from a skin cDNA library. These data suggest that the tail domain of K14 contributes to the ability of K5-K14 filaments to self-organize into large bundles showing enhanced mechanical resilience in vitro.
Animals↗
Delayed treatment with polynitroxyl albumin reduces infarct size after stroke in rats.
Nitroxides are antioxidants that are known to protect cells from oxidative damage. Polynitroxyl albumin (PNA) is a compound of human serum albumin covalently labeled with nitroxides that exhibits a prolonged half-life and an enhanced antioxidant activity. Adult male Sprague-Dawley rats were subjected to 90 min intraluminal middle cerebral artery occlusion and the drug was administered intravenously immediately or 2 h after reperfusion. The effects of the drug were evaluated 24 h after reperfusion. Infarct volume was significantly reduced in immediate (79% reduction) and delayed (53% reduction) PNA-treated groups. The efficacy of a single, delayed i.v. injection of PNA suggests that PNA has great promise in the treatment of acute human stroke.
Albumins↗
Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract.
Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17beta-estradiol or diethylstilbestrol (DES), a synthetic estrogen. However, the exact role and extent to which each pathway contributes to the resulting pathology remain unknown. We employed the alphaERKO mouse, which lacks estrogen receptor-alpha (ERalpha), to discern the role of ERalpha and estrogen signaling in mediating the effects of neonatal DES exposure. The alphaERKO provides the potential to expose DES actions mediated by the second known ER, ERbeta, and those that are ER-independent. Wild-type and alphaERKO females were treated with vehicle or DES (2 microg/pup/day for Days 1-5) and terminated after 5 days and 2, 4, 8, 12, and 20 months for biochemical and histomorphological analyses. Assays for uterine expression of the genes Hoxa10, Hoxa11, and Wnt7a shortly after treatment indicated significant decreases in DES-treated wild-type but no effect in the alphaERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ERbeta. Adult alphaERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure exhibited in treated wild-type animals, including atrophy, decreased weight, smooth muscle disorganization, and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent vaginal cornification. Therefore, the lack of DES effects on gene expression and tissue differentiation in the alphaERKO provides unequivocal evidence of an obligatory role for ERalpha in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.
Abnormalities, Drug-Induced↗
Genetic divergence of the dihydrofolate reductase and dihydropteroate synthase genes in Pneumocystis carinii from 7 different host species.
To investigate the phylogenetic and therapeutic implications of the genetic divergence in the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes among different Pneumocystis carinii strains, these 2 genes in P. carinii obtained from 7 different host species were sequenced. Pairwise comparison of the DHPS sequences demonstrated 6%-24% and 6%-30% divergence in the nucleotide and deduced amino acid sequences, respectively. The DHFR gene was even more divergent, with differences of 15%-34% and 18%-42% in the nucleotide and deduced amino acid sequences, respectively. Phylogenetic analysis of DHFR and DHPS sequences revealed that all P. carinii strains were confined within a distinct group that was closely related to ascomycete fungi and that human-derived P. carinii was most closely related to monkey-derived P. carinii. Recognizing the substantial differences in the DHFR and DHPS genes among P. carinii from different host species has important implications for drug discovery and the development of new diagnostic methods.
Animals↗
Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects.
Cytosolic sulphotransferases transfer the sulpho moiety from the cofactor 5'-phosphoadenosine-3'-phosphosulphate (PAPS) to nucleophilic groups of xenobiotics and small endogenous compounds (such as hormones and neurotransmitters). This reaction often leads to products that can be excreted readily. However, other sulpho conjugates are strong electrophiles and may covalently bind with DNA and proteins. All known cytosolic sulphotransferases are members of an enzyme/gene superfamily termed SULT. In humans, 10 SULT genes are known. One of these genes encodes two different enzyme forms due to the use of alternative first exons. Different SULT forms substantially differ in their substrate specificity and tissue distribution. Genetic polymorphisms have been described for three human SULTs. Several allelic variants differ in functional properties, including the activation of promutagens. Only initial results are available from the analysis of SULT allele frequencies in different population groups, e.g. subjects suffering from specific diseases and corresponding controls.
Arylsulfotransferase↗
CR16 forms a complex with N-WASP in brain and is a novel member of a conserved proline-rich actin-binding protein family.
The Neuronal Wiskott-Aldrich syndrome protein (N-WASP) has emerged as a central regulator of the actin cytoskeleton with abilities to integrate multiple upstream signal inputs and transmit them to the Arp2/3 complex. Here, we demonstrate that native N-WASP is present in a tight complex with a proline-rich protein, CR16, which shares approximately 25% identity with WASP interacting protein. CR16 is encoded by a gene previously cloned as a glucocorticoid-regulated mRNA from a rat hippocampal cDNA library. Although N-WASP is expressed ubiquitously, full-length CR16 protein is found predominately in the brain. CR16 and N-WASP colocalize in primary hippocampal neurons and at the tips of their growth cone filopodia. In vitro, CR16 directly binds both monomeric and filamentous actin but does not affect the kinetics of actin polymerization mediated by N-WASP and the Arp2/3 complex. Sequence homologues of CR16 are found not only in other vertebrates but also in the invertebrate Caenorhabditis elegans and in yeast. Thus, CR16 and WASP interacting protein belong to a family of N-WASP-binding proteins.
Amino Acid Sequence↗
[In vitro inhibitive effects of Tripterygium wilforii on NO production, iNOS activity, and iNOS-mRNA expression in chondrocyrtes of patients with rheumatoid arthritis].
OBJECTIVE: To study the mechanism of treatment of rheumatoid arthritis with Tripterygium wilfordii Hook. f. (TWHF). METHODS: Chondrocytes from the resected knee joint cartilage of patients with rheumatoid and TWHF, dexamethasone, or (arthritis were isolated and cultured. IL-1 indomethacin of different concentrations were added into the culture solution overnight. Griess reagent was added to the supernatant to detect the content of NO. Chondrocytes were collected to examine the iNOS activity by detecting the conversion of L-14C-arginine into L-14C-citruline. The total RNA of chondrocyte was extracted and the iNOS-mRNA was examined by Northern blotting. RESULTS: The inhibitory rates of NO production by TWHF of concentrations of 2 mg/L, 4 mg/L, 8 mg/L, and 16 mg/L were 10.8%, 25.48%, 55.17%, and 80.45% respectively. The inhibitory rates of iNOS activity by TWHF of concentrations of 2 mg/L, 4 mg/L, 8 mg/L, and 16 mg/L were 12.29%, 27.67%, 59.04%, and 85.06% respectively. Such inhibitory effects were dosage-dependent. TWHF ffectively inhibited the expression of iNOS-mRNA induced by IL-1 in chondrocyte (r = 0.976 and 0.974). Dexamethasone inhibited NO production, iNOS activity, and expression of iNOS-mRNA significantly but not dosage-dependently. Indomethcin only had weak inhibitory effect. CONCLUSION: TWHF inhibits NO production in chondrocytes by limiting the transcription of iNOS gene, which may be one of the mechanisms of treatment of RA with TWHF.
Arthritis, Rheumatoid↗
The role of AP-1 in the transcriptional regulation of the rat apical sodium-dependent bile acid transporter.
Ileal reclamation of bile salts, a critical determinant of their enterohepatic circulation, is mediated primarily by the apical sodium-dependent bile acid transporter (ASBT=SLC10A2). We have defined mechanisms involved in the transcriptional regulation of ASBT. The ASBT gene extends over 17 kilobases and contains five introns. Primer extension analysis localized two transcription initiation sites 323 and 255 base pairs upstream of the initiator methionine. Strong promoter activity is imparted by both a 2.7- and 0.2-kilobase 5'-flanking region of ASBT. The promoter activity is cell line specific (Caco-2, not Hep-G2, HeLa-S3, or Madin-Darby canine kidney cells). Four distinct specific binding proteins were identified by gel shift and cross-linking studies using Caco-2 or rat ileal nuclear extracts. Two AP-1 consensus sites were identified in the proximal promoter. DNA binding and promoter activity could be abrogated by mutation of the proximal AP-1 site. Supershift analysis revealed binding of c-Jun and c-Fos to this AP-1 element. Co-expression of c-Jun enhanced promoter activity in Caco-2 cells and activated the promoter in Madin-Darby canine kidney cells. Region and developmental stage-specific expression of ASBT in the rat intestine correlated with the presence of one of these DNA-protein complexes and both c-Fos and c-Jun proteins. A specific AP-1 element regulates transcription of the rat ASBT gene.
Animals↗
Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition.
BACKGROUND: Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME). METHODS AND RESULTS: We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1-deficient (PAI-1(-/-)) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141+/-3 mm Hg in WT animals versus 112+/-4 mm Hg in PAI-1(-/-) mice (P<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (P<0.01 versus PAI-1(-/-) mice). Cardiac type I collagen mRNA expression was greater in control (P<0.01) and L-NAME-treated PAI-1(-/-) (P<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. CONCLUSIONS: These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.
Animals↗
Diversity and specificity of actions of Slit2 proteolytic fragments in axon guidance.
The Slits are secreted proteins that bind to Robo receptors and play a role in axon guidance and neuronal migration. In vertebrates, Slit2 is a major chemorepellent for developing axons and is involved in the control of midline crossing. In vivo, Slit2 is cleaved into 140 kDa N-terminal (Slit2-N) and 55-60 kDa C-terminal (Slit2-C) fragments, although the uncleaved/full-length form can also be isolated from brain extract. We explored the functional activities of Slit2 fragments by engineering mutant and truncated versions of Slit2 representing the N-, C-, and full/uncleavable (Slit2-U) fragments. Only Slit2-N and Slit2-U bind the Robo proteins. We found that in collagen gel, olfactory bulb (OB) but not dorsal root ganglia (DRG) axons are repelled by Slit2-N and Slit2-U. Moreover, only Slit2-N membranes or purified protein-induced OB growth cones collapse. Finally, we found that only recombinant Slit2-N could induce branching of DRG axons and that this effect was antagonized by Slit2-U. Therefore, different axons have distinct responses to Slit2 fragments, and these proteins have different growth-promoting capacities.
Alkaline Phosphatase↗
Attenuation of morphine dependence and withdrawal in rats by venlafaxine, a serotonin and noradrenaline reuptake inhibitor.
The effects of venlafaxine, a novel serotonin and adrenaline reuptake inhibitor, on the morphine withdrawal and activation of morphine conditioned place preference (CPP), were investigated in rats. Our results showed that the most morphine withdrawal signs, including jumping, writhing, shakes, exploring, lacrimation, piloerection, irritability, and diarrhea, were attenuated by pretreatment with 10 or 20 mg/kg venlafaxine. To investigate the effects of venlafaxine on relapse to opiate dependence, the morphine CPP was used and a dopamine D2 antagonist sulpiride was selected as a control drug. The morphine CPP disappeared following a 28-day drug-free period and appeared again after given a single injection of 1 mg/kg morphine. Acute treatment with sulpiride (25 or 50 mg/kg, i.p.) 30 min prior to 1 mg/kg morphine injection significantly blocked the reacquisition of CPP, while venlafaxine (10 or 20 mg/kg, i.p.) did not show significant effect. However, chronic treatment with venlafaxine (5 or 10 mg/kg, i.p. twice, daily, for seven consecutive days) significantly attenuated the reacquisition of morphine CPP, whereas chronic treatment with sulpiride (10 or 20 mg/kg, i.p.) have no significant effect. Our results demonstrated for the first time that venlafaxine strongly attenuates morphine withdrawal and morphine-induced reaquisition of
Adrenergic Uptake Inhibitors↗
Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release.
Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcer-associated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.
Angiogenesis Inhibitors↗
Different role of cholecystokinin (CCK)-A and CCK-B receptors in relapse to morphine dependence in rats.
The possible effect of different cholecystokinin (CCK) receptor antagonists (MK-329 and L-365260) on the maintenance and reactivation of morphine conditioned place preference (CPP) were investigated in rats, respectively. The results show that the maintenance of morphine CPP could be induced by injection of morphine (10 mg/kg, s.c.) once for 3 days and this effects were significantly attenuated by pretreatment with 1 but not by 0.1 mg/kg L-365260. Furthermore, following a 28-day extinction, the morphine CPP disappeared and then reactivated again by a single injection of morphine (10 mg/kg). Pretreatment with L-365260 (1 and 0.1 mg/kg) significantly blocked this reactivation of morphine CPP. In contrast, pretreatment of MK-329 (1 and 0.1 mg/kg) failed to do so. The present study demonstrated that CCK-B receptor but not CCK-A receptor is involved in the maintenance and reactivation of morphine CPP. These findings suggest that CCK-B receptor antagonists might be of some value in the treatment and prevention of relapse to drug dependence long after detoxification.
Animals↗