interacts_with DB00495?
Inhibition of P51587 and DB01643 Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined " Complementary Lethality " . A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers . Paradoxically , however , genomic instability can also render tumors vulnerable to therapeutic attack . Thus , targeting DNA repair may induce an intolerable level of DNA damage in tumor cells . P51587 mediates homologous recombination repair , and P51587 polymorphisms increase cancer risk . However , tumors with P51587 mutations respond better to chemotherapy and are associated with improved patient prognosis . P04818 ( TS ) is also involved in DNA maintenance and generates cellular thymidylate . We determined that antisense downregulation of P51587 synergistically potentiated drugs with mechanisms of action related to P51587 function ( cisplatin , melphalan ) , a phenomenon we named " complementary lethality. " TS knockdown induced complementary lethality to TS-targeting drugs ( 5-FUdR and pemetrexed ) but not DNA cross-linking agents . Combined targeting of P51587 and TS induced complementary lethality to both DNA-damaging and TS-targeting agents , thus creating multidrug sensitive tumors . In addition , we demonstrated for the first time that simultaneous downregulation of both targets induced combined complementary lethality to multiple mechanistically different drugs in the same cell population . In this study , we propose and define the concept of " complementary lethality " and show that actively targeting P51587 and TS is of potential therapeutic benefit in multidrug treatment of human tumors . This work has contributed to the development of a P51587 -targeting antisense oligdeoxynucleotide ( ASO ) " BR-1 " which we will test in vivo in combination with our TS-targeting ASO " Q8N1L9 83 " and attempt early clinical trials in the future.Molecular Therapy - Nucleic Acids ( 2013 ) 2 , e78 ; doi:10.1038/mtna.2013.7 published online 12 March 2013 . P34995 antagonist reduces blood-brain barrier leakage after cerebral ischemia . Disruption of the blood-brain barrier ( BBB ) after cerebral ischemia is considered to be the initial step in the development of brain injuries , and an increase in the tyrosine phosphorylation of the tight junctional protein occludin has been shown to cause an increase in BBB permeability . DB00917 ( DB00917 ) appears to be associated with both toxic and protective effects on neuronal survival in vitro . However , it remains to be determined whether the prostanoid EP1 receptor is involved in the disruption of the BBB after cerebral ischemia . So we examined the effect of a prostanoid EP1 receptor antagonist , SC51089 , on BBB leakage and tyrosine phosphorylation of occludin after cerebral ischemia . We demonstrated that SC51089 attenuated the increase in the tyrosine phosphorylation of occludin in isolated brain capillaries , which was coincident with a decrease in BBB leakage . These results suggest that the prostanoid EP1 receptor is involved in the tyrosine phosphorylation of occludin at tight junction , which may lead to disruption of the BBB and be linked to the development of cerebral infarctions . Comparative impacts of knockouts of two antioxidant enzymes on acetaminophen-induced hepatotoxicity in mice . We have previously shown a more potent impact of knockout of Cu,Zn-superoxide dismutase ( P00441 ) than that of Se-dependent glutathione peroxidase-1 ( P07203 ) on murine hepatotoxicity induced by an intraperitoneal ( ip ) injection of a high dose of acetaminophen ( DB00316 , 600 mg/kg ) . The objective of this experiment was to compare the temporal impacts of knockouts of P07203 and P00441 alone or together on mouse susceptibility to an injection of a low dose of DB00316 ( 300 mg/kg ) . The DB00316 -mediated rises in plasma alanine aminotransferase activity and nitrate/nitrite concentrations , hepatic DB00143 depletion , and hepatic protein nitration at 5 and ( or ) 24 h were nearly abolished ( P < 0.05 ) in P00441 -/- or P07203 and P00441 double-knockout ( DKO ) mice , while P07203 -/- mice exerted only moderate or no change compared with the WT . Despite an increased ( P < 0.05 ) DB00316 - DB06151 and decreased DB00316 -glucuronide ( P < 0.05 ) relative to the total DB00316 metabolites in urine collected for 24 h after the DB00316 injection , the P00441 -/- mice displayed no shift in urinary DB00316 -cysteine compared with the WT mice . Knockout of P00441 prevented the DB00316 -induced hepatic GPX inactivation ( P < 0.05 ) , whereas knockout of P07203 aggravated the DB00316 -induced hepatic SOD activity loss ( P < 0.05 ) . However , the DB00316 -mediated activity changes of these enzymes in liver accompanied no protein alterations . In conclusion , knockout of P07203 or P00441 exerted differential impact on mouse susceptibility to this low dose of DB00316 , but neither shifted urinary DB00316 -cysteine formation . Genomic imbalances in key ion channel genes and telomere shortening in sudden cardiac death victims . Sudden cardiac death ( O00767 ) can be caused by a number of reasons . Previous works have identified the genetic causes , such as alterations in the DNA sequence , for many of these diseases . We hypothesize that some patients may show genomic imbalances and changes in the gene copy number leading to genetic instability . To clarify this , we analysed DNA samples from O00767 victims using comparative genomic hybridization ( CGH ) , a molecular cytogenetic technique that permits the genome-wide screening of chromosomal imbalances , and telomere length measurement . DNA derived from peripheral blood and heart tissue of 14 O00767 cases and six apparently healthy control individuals were subjected to CGH analysis . Telomere length measurements were done by the Southern blotting method . Eight out of 14 O00767 cases exhibited changes in DNA/gene copy number . CGH analysis showed variation in the gene copy number of some of the genes associated with potassium ( Q14722 , Q12809 , and P22459 ) and calcium ( Q92736 , P16615 ) ions which are involved in maintaining the ionic balance of the heart . Alterations in TERC and O14746 genes were also detected in O00767 victims . In nine O00767 victims shorter telomeres were detected . This might have resulted from excessive cellular proliferation and/or oxidative stress in these individuals . Copy number changes observed and telomere shortening detected in O00767 cases would possibly explain at least some of the causes of O00767 at early ages in humans . Identification of biomarkers of O00767 is of great importance and thus the present study will facilitate the identification of some of the biomarkers . Comprehensive expression analysis of prostanoid enzymes and receptors in the human endometrium across the menstrual cycle . Prostanoids are well-described primary mediators of inflammatory processes and are essential for the normal physiological function of the female reproductive system . The aim of this study was to determine the temporal expression of the prostanoid biosynthetic enzymes ( P23219 , P35354 , O14684 , Q9H7Z7 , Q15185 , P15121 , P42330 , P16152 , O60760 , P41222 , Q16647 , P24557 and P15428 ) and the prostanoid receptors ( P34995 , PTGER2 , P43115 , P35408 , P43088 , Q13258 , Q9Y5Y4 , P43119 and P21731 ) in the human endometrium throughout the menstrual cycle . The analysis identified P43088 to have a distinct expression profile compared with other components of the prostanoid system , as expression is maximal during the proliferative phase . Immunohistochemical analysis for P34995 suggests a dual function for this receptor depending on its temporal ( proliferative versus secretory ) and spatial ( nuclear versus cell membrane ) expression . The expression profiles of the P49763 (2α) synthases identified P15121 and P16152 as the likely regulators of P49763 (2α) production during the menstrual phase . Immunohistochemical analysis for P15121 , P16152 and P42330 suggest expression to be in the glandular epithelium and vasculature . This study represents the first comprehensive analysis of the components of prostanoid biosynthetic and signalling pathway in the human endometrium . The expression profiles described have the potential to identify specific prostanoid components that may be dysregulated in inflammatory-associated disorders of the endometrium . Host genetic background at P51681 chemokine receptor and vitamin D receptor loci and human immunodeficiency virus ( HIV ) type 1 disease progression among HIV-seropositive injection drug users . The effect of polymorphisms on genes encoding the P51681 chemokine receptor and vitamin D receptor ( P11473 ) in human immunodeficiency virus ( HIV ) type 1 disease progression was analyzed in a cohort of 185 HIV-seropositive injection drug users . Results confirmed a lack of association in patients with HIV disease between P51681 wtDelta32 heterozygosity and a slow progression to AIDS and to a P01730 cell count < 200 cells/microL . In contrast , a more rapid disease progression was associated with the P11473 -BB genotype . A higher proportion of this genotype was found in patients with < 200 P01730 cells/microL ( P=.009 ; odds ratio [ OR ] , 2.4 ; 95 % confidence interval [ CI ] , 1.3-4.7 ) , as well as a faster progression both to AIDS ( 1993 CDC classification [ CDC 1993 ] ) and to a P01730 cell count < 200 cells/microL . When the analysis was restricted to patients with a P11473 -bb genetic background , patients with P51681 wtDelta32 heterozygosity were overrepresented in CDC 1993 nonprogressors ( P=.033 ; OR , 0.28 ; 95 % CI , 0.08-0.92 ) and in those with > 200 P01730 cells/microL ( P=.062 ; OR , 0.26 ; 95 % CI , 0.06-1.08 ) . Also , patients with P51681 wtDelta32 heterozygosity showed a slow progression both to AIDS CDC 1993 and to a P01730 cell count < 200 cells/microL . Effect of increased serotonin levels on [18F]MPPF binding in rat brain : fenfluramine vs the combination of citalopram and ketanserin . [18F]MPPF is a selective serotonin-1A ( P08908 ) receptor antagonist and may be used to measure changes in the functional levels of serotonin ( 5-HT ) . The technique is based on the assumption that the injected radiolabeled ligand competes for the same receptor as the endogenous transmitter . Results from studies using serotonergic ligands are not always consistent . The aim of the present study was to investigate if [18F]MPPF binding is decreased after an increase in 5-HT levels . [18F]MPPF binding was assessed in conscious rats using ex vivo autoradiography . We studied the effect of the 5-HT-releasing agent and reuptake inhibitor fenfluramine ( 10 mg/kg i.p. ) and of a combination of the selective serotonin reuptake inhibitor ( SSRI ) citalopram ( 10 micromol/kg , s.c. ) with the P28335 antagonist ketanserin ( 100 nmol/kg , s.c ) . The effect of both treatments on extracellular 5-HT levels was determined using microdialysis . DB00574 treatment resulted in a 30-fold increase in extracellular 5-HT levels in the ventral hippocampus and induced a significant reduction of [18F]MPPF binding in the frontal cortex , hypothalamus , amygdala , and hippocampus . The microdialysis results showed a 10-fold 5-HT increase in the ventral hippocampus after combined administration of ketanserin and citalopram . The combination , however , did not affect [18F]MPPF binding . Our data show that [18F]MPPF binding in conscious rats is only reduced after substantial and therefore nonphysiological increases in 5-HT levels . These results may imply that the majority of P08908 receptors is in the low-affinity state , in vivo . Q9Y5Y4 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease . Cells expressing the chemoattractant receptor-homologous molecule expressed on Th2 cells ( Q9Y5Y4 ) and the chemokine C receptor (CCR)4 were consistently detected in the circulation of healthy subjects , whereas numbers of cells expressing P51677 were much lower . While all CCR4+ cells were T cells , a small proportion of Q9Y5Y4 + , and about a half of the few P51677 + cells were basophils . Only Q9Y5Y4 + T cells contained Th2 or Tc2 cells , but neither Th0 or Tc0 , nor Th1 or Tc1 cells , although not all of them produced Th2-type cytokines . By contrast , CCR4+ T cells contained both Th2 or Tc2 and Th0 or Tc0 cells and even Th1 or Tc1 cells , whereas the few P51677 + T cells were not clearly classifiable for their cytokine profile . Q9Y5Y4 + T lymphocytes were virtually devoid of chemokine CX receptor (CXCR)3+ and P51681 + cells , but enriched in P51677 + and CCR4+ cells . By contrast , P51677 + or CCR4+ T cells did not show a similar clear-cut dichotomy in the expression of P51681 / P49682 or P51677 / CCR4 . Subjects with atopic dermatitis or HIV infection with low levels of circulating P01730 + T cells revealed a significant increase of Q9Y5Y4 + cells within both the P01730 + and the CD8+ T cell subset . These data support the concept that at present Q9Y5Y4 is the more reliable marker for detection of both human Th2 and Tc2 cells in health and disease . Integration of hormone signaling in the regulation of human DB00146 24-hydroxylase transcription . The current study sought to define the molecular mechanisms involved in the cross talk between 1,25-dihydroxyvitamin D(3) [ 1,25(OH)(2)D(3) ] and activators of PKC in the regulation of 25(OH)D(3) 24-hydroxlyase [ 24(OH)ase ] . Transfection of the h24(OH)ase promoter construct [ -5,500/-22 luciferase ; vitamin D response elements at -294/-274 and -174/-151 ; AP-1 site at -1,167/-1,160 ] in vitamin D receptor ( P11473 ) -transfected COS-7 cells resulted in strong activation by 1,25(OH)(2)D(3) . In these cells , cotreatment with the PKC activator TPA and 1,25(OH)(2)D(3) yielded a 27-fold increase in luciferase activity , which was 2- to 3-fold greater than activation obtained with 1,25(OH)(2)D(3) alone ( P < 0.05 ) . Similar results were observed using LLCPK-1 kidney cells , suggesting that the previously observed enhancement of 1,25(OH)(2)D(3)-induced renal 24(OH)ase mRNA and activity by PKC activation occurs at the level of transcription . The functional cooperation between PKC activation and P11473 was not found to be mediated by the AP-1 site in the h24(OH)ase promoter or by enhanced binding of GRIP or Q15648 to P11473 and was also not due to PKC-mediated phosphorylation of P11473 on DB00133 (51) . Our study demonstrates that , in LLCPK-1 kidney cells , the PKC enhancement of 1,25(OH)(2)D(3)-stimulated transcription may be due , in part , to an increase in P11473 concentration . In addition , inhibitors of the MAPK pathway were found to decrease the TPA enhancement ( P < 0.05 ) . Because activation of MAPK has been reported to result in the phosphorylation of Q15788 and in functional cooperation between Q15788 and CREB binding protein , we propose that the potentiation of P11473 -mediated transcription may also be mediated through changes in the phosphorylation of specific P11473 coregulators . Hippocampal telomerase is involved in the modulation of depressive behaviors . Telomere and telomerase alterations have been reported in mood disorders . However , the role of telomerase in depression remains unclear . Here we show that chronic mild stress ( CMS ) led to a significant decrease in telomerase reverse transcriptase ( O14746 ) level and telomerase activity in the hippocampus . Treatment with antidepressant fluoxetine reversed the CMS-induced O14746 and telomerase activity changes . Inhibiting telomerase by systemic administration ( 100 mg · kg(-1) · d(-1) , i.p. , for 14 d ) , intrahippocampal microinjection ( 0.7 μmol , 2 μl ) , or infusion ( using an osmotic minipump , 0.134 μg/μl , 0.25 μl/h ) of 3'-azido-deoxythymidine ( DB00495 ) resulted in depression-like behaviors and impaired hippocampal neurogenesis in mice . In contrast , overexpressing telomerase by intrahippocampal infusion of recombinant adenovirus vector expressing mouse O14746 ( Ad-mTERT-GFP ) led to neurogenesis upregulation , produced antidepressant-like behaviors , and prevented the CMS-induced behavioral modifications . Disrupting neurogenesis in the dentate gyrus by X-irradiation ( 15 Gy ) of a restricted region of mouse brain containing the hippocampus abolished the antidepressant-like effect of Ad-mTERT-GFP . Additionally , DB00495 had no effect on DNA polymerase activity and did not cause cell damage in vitro and in vivo . Microinjection of DB00495 into the subventricular zone of lateral ventricle ( 0.7 μmol , 2 μl ) inhibited local neurogenesis but had no behavioral effect . These results suggest that hippocampal telomerase is involved in the modulation of depression-related behaviors , possibly by regulating adult neurogenesis . DB00996 prevents oxaliplatin-induced central sensitization in the dorsal horn neurons in rats . OBJECTIVES : The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin-induced neuropathic pain in rats . MATERIALS AND METHODS : DB00526 ( 5 mg/kg ) or saline was administered to adult male Sprague-Dawley rats . DB00996 ( 60 mg/kg , IP ) or vehicle was injected daily . Mechanical allodynia was assessed using a series of von Frey filaments . The expression of glutamate receptor subunits ( Q13224 and GluR1 ) and brain-derived neurotrophic factor ( P23560 ) was measured in the dorsal horn . The glutamatergic strength was recorded in the spinal cord slices . RESULTS : Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats , which was attenuated by gabapentin . Significant increase in the expression of P23560 was found in the dorsal horn in rats receiving oxaliplatin , which was prevented by gabapentin . Further studies also observed a significant increase in the expression of GluR1 and Q13224 , as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin . The upregulation of glutamatergic transmission was significantly reversed by gabapentin . CONCLUSION : These results illustrated an increased expression of P23560 and enhanced glutamatergic transmission in rats with oxaliplatin-induced neuropathic pain , which was markedly attenuated by gabapentin . P03372 -alpha 36 mediates mitogenic antiestrogen signaling in ER-negative breast cancer cells . It is prevailingly thought that the antiestrogens tamoxifen and ICI 182 , 780 are competitive antagonists of the estrogen-binding site of the estrogen receptor-alpha ( ER-α ) . However , a plethora of evidence demonstrated both antiestrogens exhibit agonist activities in different systems such as activation of the membrane-initiated signaling pathways . The mechanisms by which antiestrogens mediate estrogen-like activities have not been fully established . Previously , a variant of ER-α , EP-α36 , has been cloned and showed to mediate membrane-initiated estrogen and antiestrogen signaling in cells only expressing ER-α36 . Here , we investigated the molecular mechanisms underlying the antiestrogen signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of endogenous ER-α36 . We found that the effects of both 4-hydoxytamoxifen ( DB04468 ) and ICI 182 , 780 ( ICI ) exhibited a non-monotonic , or biphasic dose response curve ; antiestrogens at low concentrations , elicited a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations , antiestrogens inhibited cell growth . Antiestrogens at l nM induced the phosphorylation of the Src-Y416 residue , an event to activate Src , while at 5 µM induced Src-Y527 phosphorylation that inactivates Src . Antiestrogens at 1 nM also induced phosphorylation of the MAPK/ P29323 and activated the P12004 D1 promoter activity through the Src/ P00533 / P42229 pathways but not at 5 µM . Knock-down of ER-α36 abrogated the biphasic antiestrogen signaling in these cells . Our results thus indicated that ER-α36 mediates biphasic antiestrogen signaling in the ER-negative breast cancer cells and Src functions as a switch of antiestrogen signaling dependent on concentrations of antiestrogens through the P00533 / P42229 pathway . Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV-1 , we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV-1 , immortalized oral keratinocytes ( OKF6/ O14746 -2 ; O14746 -2 cells ) were characterized for the fate of HIV-specific RNA and DNA . At 6 h post inoculation with X4 or R5-tropic HIV-1 , HIV-1gag RNA was detected maximally within O14746 -2 cells . Reverse transcriptase activity in O14746 -2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Deltaenv-EGFP . DB00495 inhibited EGFP expression in a dose-dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV-1 DNA was detected in O14746 -2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non-productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 -2 cells trans infected co-cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell-to-cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non-replicative integration , while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h . Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether-a-go-go-related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38.9 +/- 1.2 microM and Hill Slope factor of 0.4 +/- 0.1 . DB01211 produced a similar concentration-dependent block with an IC50 of 45.7 +/- 1.1 microM and Hill Slope factor of 1.0 +/- 0.1 . Erythromycin ( 25-250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations . Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity . Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage . DNA double-strand breaks ( DSB ) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites . DSB may lead to chromosome aberrations , apoptosis and hematopoietic progenitor cell suppression . We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity . We analyzed one or more single nucleotide polymorphisms ( SNPs ) in each of seven candidate genes ( Q14191 , P04637 , NBS1 , P38398 , P51587 , O43542 and Q13426 ) in a study of 250 workers exposed to benzene and 140 controls in China . Four SNPs in Q14191 ( Ex4 -16 G > A , Ex6 +9 C > T , Ex20 -88 G > T and Ex26 -12 T > G ) , one SNP in P04637 ( Ex4 +119 C > G ) and one SNP in P51587 ( Ex11 +1487 A > G ) were associated with a statistically significant decrease in total white blood cell ( WBC ) counts among exposed workers . The SNPs in Q14191 and P04637 remained significant after accounting for multiple comparisons . One or more SNPs in Q14191 had broad effects on WBC subtypes , with significantly decreased granulocyte , total lymphocyte , P01730 (+)-T cell , CD8(+)-T cell and monocyte counts . Haplotypes of Q14191 were associated with decreased WBC counts among benzene-exposed subjects . Likewise , subjects with P04637 Ex4 +119 C > G variant had reduced granulocyte , P01730 (+)-T cell and B cell counts . The effect of P51587 Ex11 +1487 A > G polymorphism was limited to granulocytes . These results suggest that genetic polymorphisms in Q14191 , P04637 and P51587 that maintain genomic stability impact benzene-induced hematotoxicity . Differential involvement of Galpha16 in CC chemokine-induced stimulation of phospholipase Cbeta , P29323 , and chemotaxis . Chemokines are known to regulate the chemotaxis of leukocytes and play an important role in immunological processes . Chemokine receptors are widely distributed in hematopoietic cells and are often co-localized with the hematopoietic-specific G(16) and its close relative , G(14) . Yet , many chemokine receptors utilize pertussis toxin-sensitive G(i) proteins for signaling . Given that both G(16) and G(14) are capable of linking G(i)-coupled receptors to the stimulation of phospholipase Cbeta , we examined the capacity of six CC chemokine receptors ( P32246 , CCR2a , CCR2b , P51677 , P51681 and P32248 ) to interact with G(14) and G(16) in a heterologous expression system . Among the CC chemokine receptors tested , P32246 , CCR2b , and P51677 were capable of mediating chemokine-induced stimulation of phospholipase Cbeta via either G(14) or G(16) . The G(14)/G(16)-mediated responses exhibited CC chemokine dose-dependency and were resistant to pertussis toxin ( PTX ) treatment . In contrast , CCR2a , P51681 and P32248 were unable to interact with G(14) and G(16) . Under identical experimental conditions , all six CC chemokine receptors were fully capable of inhibiting adenylyl cyclase via G(i) as well as stimulating phospholipase Cbeta via 16z44 , a G(16/z) chimera that possesses increased promiscuity toward G(i)-coupled receptors . Moreover , P32246 -mediated P27361 /2 phosphorylation was largely PTX-insensitive in THP-1 monocytic cells that endogenously express Galpha(16) . In addition , P32246 agonist was less efficacious in mediating chemotaxis of THP-1 cells following the knockdown of Galpha(16) by overexpressing siRNA , indicating the participation of Galpha(16) in P32246 -induced cell migration . These results show that different CC chemokine receptors can discriminate against G(14) and G(16) for signal transduction . T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of P35858 . Amyotrophic Lateral Sclerosis ( P35858 ) is an adult-onset , progressive , motor neuron degenerative disease , in which the role of inflammation is not well established . Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 ( P00441 ) (G93A) transgenic mouse model of P35858 . P01730 + and CD8+ T cells infiltrated P00441 (G93A) spinal cords during disease progression . Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia , including dendritic cell receptor acquisition , and expression of genes linked to neuroprotection , cholesterol metabolism and tissue remodeling . Microglia dramatically up-regulated DB01277 and down-regulated P05231 expression . When mutant P00441 mice were bred onto a TCRbeta deficient background , disease progression was significantly accelerated at the symptomatic stage . In addition , microglia reactivity and DB01277 levels were reduced in spinal cords of P00441 (G93A) ( TCRbeta-/- ) mice . These results indicate that T cells play an endogenous neuroprotective role in P35858 by modulating a beneficial inflammatory response to neuronal injury . P48061 inhibits expression of the DB01221 receptor 's Q13224 subunit through a histone deacetylase-dependent pathway contributing to neuronal survival . Homeostatic chemokines , such as P48061 , can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission , but the mechanisms involved are still undefined . Our previous studies have shown that P48061 protects cortical neurons from excitotoxicity by promoting the function of the gene-repressor protein Rb , which is involved in the recruitment of chromatin modifiers ( such as histone deacetylases ( HDACs ) ) to gene promoters . In neurons , Rb controls activity-dependent genes essential to neuronal plasticity and survival , such as the N-methyl-D-aspartic acid ( DB01221 ) receptor 's subunit Q13224 , the expression of which in the tetrameric ion channel largely affects calcium signaling by glutamate . In this study , we report that P48061 differentially modulates intracellular responses after stimulation of synaptic and extrasynaptic DB01221 receptors , by a specific regulation of the Q13224 gene that involves HDACs . Our results show that P48061 selectively inhibits Q13224 expression in vitro and in vivo altering DB01221 -induced calcium responses associated with neuronal death , while promoting prosurvival pathways that depend on stimulation of synaptic receptors . Along with previous studies , these findings underline the role of P48061 / P61073 in the regulation of crucial components of glutamatergic transmission . These novel effects of P48061 may be involved in the physiological function of the chemokine in both developing and mature brains . Role of nucleotide sequences in the V3 region in efficient replication of P51681 -utilizing human immunodeficiency virus type 1 in macrophages . Macrophages express both P61073 and P51681 coreceptors , but restrict X4 HIV-1 replication unless the Env-V3 region , a major determinant of cell tropism , is exchanged with that of R5 HIV-1 . As the V3 exchange concomitantly alters the nucleotide sequences , we introduced silent mutations in the V3 or P06681 region of macrophage-tropic R5 JRFL without changing the amino acids . Immunoblot analysis confirmed that viral proteins including Env-gp120 were similarly incorporated in wild-type ( wt ) and mutant virions . The silent mutants infected P51681 -positive MAGIC5 cells but not P51681 -negative MAGI cells , as productively as wt viruses , indicating that the silent mutations did not alter coreceptor utilization . In contrast , two of three silent V3-mutant viruses failed to replicate efficiently in primary macrophages , whereas other V3- or P06681 -mutants and wt JRFL infected macrophages productively . Furthermore , synthesis of the full-length viral DNA of the aberrant V3-mutant was largely reduced in macrophages . These results suggest that V3 nucleotide sequences may be one of the postentry factors restricting HIV-1 replication in macrophages . Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors . Q16739 ( Q16739 ) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies , including type 2 diabetes . The clinical drug N-butyldeoxynojirimycin ( DB00419 ) is thought to inhibit through mimicry of its substrate , ceramide . In this work we demonstrate that , in contrast to what is proposed in this model , the P06681 -hydroxyl of the deoxynojirimycin core is important for Q16739 inhibition . Here we show that P13671 -OH appears of less important , which may set guidelines for the development of Q16739 inhibitors that have less affinity ( in comparison with DB00419 ) for other glycoprocessing enzymes , in particular those hydrolases that act on glucosylceramide . Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women . Heterosexual transmission of human immunodeficiency virus ( HIV-1 ) is the predominant mode of infection world-wide . To better understand sexual transmission of HIV-1 in women we have analysed virus co-receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells . Intraepithelial cervical T lymphocytes were obtained with a cytobrush , immunolabelled and analysed by flow cytometry . Activation markers ( Q07108 , CD25 and HLA-DR ) were found to be more highly expressed on cervical than on blood T lymphocytes . These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV-1 infection . P61073 was expressed at marginally higher levels than P51681 on T cells from the cervical epithelium and peripheral blood . Thus , the preferential transmission of macrophage tropic strains of HIV-1 following sexual contact can not be explained solely on the expression of chemokine co-receptors by T lymphocyte subsets . Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 -immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .