bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEKK3 Is Essential for Lymphopenia-Induced T Cell Proliferation and Survival
Authors: Wang Xiaofang , Chang Xing , Facchinetti Valeria , Zhuang Yuan , Su Bing 
Published: March 2009

Abstract
T cell homeostasis is crucial for maintaining an efficient and balanced T cell immunity. The interaction between TCR and self peptide (sp) MHC ligands is known to be the key driving force in this process, and it is believed to be functionally and mechanistically different from that initiated by the antigenic TCR stimulation. Yet, very little is known about the downstream signaling events triggered by this TCR-spMHC interaction and how they differ from those triggered by antigenic TCR stimulation. In this study, we show that T cell conditional ablation of MEKK3, a Ser/Thr kinase in the MAPK cascade, causes a significant reduction in peripheral T cell numbers in the conditional knockout mice, but does not perturb thymic T cell development and maturation. Using an adoptive mixed transfer method, we show that MEKK3-deficient T cells are severely impaired in lymphopenia-induced cell proliferation and survival. Interestingly, the Ag-induced T cell proliferation proceeds normally in the absence of MEKK3. Finally, we found that the activity of ERK1/2, but not p38 MAPK, was attenuated during the lymphopenia-driven response in MEKK3-deficient T cells. Together, these data suggest that MEKK3 may play a crucial selective role for spMHC-mediated T cell homeostasis.
Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8+ T Cells
Authors: Kijima Mika , Iwata Akiko , Maekawa Yoichi , Uehara Hisanori , Izumi Keisuke , Kitamura Akiko , Yagita Hideo , Chiba Shigeru , Shiota Hiroshi , Yasutomo Koji 
Published: March 2009

Abstract
Distinct Notch ligands possess a characteristic ability in terms of functional T cell differentiation. However, the precise role or the therapeutic potential of each Notch ligand in autoimmune diseases is largely unknown. In this study, we examined whether Jagged1 modulates a collagen-induced rheumatoid arthritis (CIA) model by altering T cell responses. The injection of a soluble Jagged1-encoding plasmid, sJag1-P, before or even after initial type II collagen (CII) immunization suppressed the disease severity of CIA. However, this treatment did not suppress CII-specific CD4+ T cell proliferation and CII-specific Ab production. Depletion of either CD4+ or CD8+ T cells ameliorated CIA severity and sJag1-P further improved CIA in CD4+ but not CD8+ T cell-depleted mice. Injection of OVA and Jagged1-encoding plasmids inhibited proliferation of OVA-specific granzyme B-producing CD8+ T cells, although Jagged1 could not directly inhibit CD8+ T cell proliferation in vitro. The blockade of Jagged1 by an anti-Jagged1 Ab exacerbated CIA, whereas this effect was not observed in the absence of CD8+ T cells. These data indicate that Jagged1 is able to deliver an indirect negative signal into CD8+ T cells in vivo, which suggests its therapeutic potential in the treatment of CD8+ T cell-mediated diseases, including rheumatoid arthritis.
Villitis of Unknown Etiology Is Associated with a Distinct Pattern of Chemokine Up-Regulation in the Feto-Maternal and Placental Compartments: Implications for Conjoint Maternal Allograft Rejection and Maternal Anti-Fetal Graft-versus-Host Disease
Authors: Kim Mi Jeong , Romero Roberto , Kim Chong Jai , Tarca Adi L. , Chhauy Sovantha , LaJeunesse Christopher , Lee Deug-Chan , Draghici Sorin , Gotsch Francesca , Kusanovic Juan Pedro , Hassan Sonia S. , Kim Jung-Sun 
Published: March 2009

Abstract
The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p &lt; 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p &lt; 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p &lt; 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p &lt; 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
Loss of Mandibular Lymph Node Integrity Is Associated with an Increase in Sensitivity to HSV-1 Infection in CD118-Deficient Mice
Authors: Conrady Christopher D. , Thapa Manoj , Wuest Todd , Carr Daniel J. J. 
Published: March 2009

Abstract
Type I IFNs are potent antiviral cytokines that contribute to the development of the adaptive immune response. To determine the role of type I IFNs in this process in an infectious disease model, mice deficient in the type I IFN receptor (CD118−/−) were ocularly infected with HSV-1 and surveyed at times post infection in the nervous system and lymph node for virus and the host immune response. Virus titers were elevated in the trigeminal ganglia and brain stem with virus disseminating rapidly to the draining lymph node of CD118−/− mice. T cell and plasmacytoid dendritic cell infiltration into the brain stem was reduced in CD118−/− mice following infection, which correlated with a reduction in CXCL10 but not CXCL9 expression. In contrast, CXCL1 and CCL2 levels were up-regulated in the brainstem of CD118−/− mice associated with an increase in F4/80+ macrophages. By day 5 post infection, there was a significant loss in T, NK, and plasmacytoid dendritic cell numbers in the draining lymph nodes associated with an increase in apoptotic/necrotic T cells and an appreciable lack of HSV-specific CD8+ T cells. The adoptive transfer of HSV-specific TCR transgenic CD8+ T cells into CD118−/− mice at the time of infection modestly reduced viral titers in the nervous system suggesting in addition to the generation of HSV-specific CD8+ T cells, other type I IFN-activated pathways are instrumental in controlling acute infection.
Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes
Authors: Saccone Nancy L. , Saccone Scott F. , Hinrichs Anthony L. , Stitzel Jerry A. , Duan Weimin , Pergadia Michele L. , Agrawal Arpana , Breslau Naomi , Grucza Richard A. , Hatsukami Dorothy , Johnson Eric O. , Madden Pamela A.F. , Swan Gary E. , Wang Jen C. , Goate Alison M. , Rice John P. , Bierut Laura J. 
Published: March 2009

AbstractTobacco smoking continues to be a leading cause of preventable death. Recent research has underscored the important role of specific cholinergic nicotinic receptor subunit (CHRN) genes in risk for nicotine dependence and smoking. To detect and characterize the influence of genetic variation on vulnerability to nicotine dependence, we analyzed 226 SNPs covering the complete family of 16 CHRN genes, which encode the nicotinic acetylcholine receptor (nAChR) subunits, in a sample of 1,050 nicotine‐dependent cases and 879 non‐dependent controls of European descent. This expanded SNP coverage has extended and refined the findings of our previous large‐scale genome‐wide association and candidate gene study. After correcting for the multiple tests across this gene family, we found significant association for two distinct loci in the CHRNA5–CHRNA3–CHRNB4 gene cluster, one locus in the CHRNB3–CHRNA6 gene cluster, and a fourth, novel locus in the CHRND–CHRNG gene cluster. The two distinct loci in CHRNA5–CHRNA3–CHRNB4 are represented by the non‐synonymous SNP rs16969968 in CHRNA5 and by rs578776 in CHRNA3, respectively, and joint analyses show that the associations at these two SNPs are statistically independent. Nominally significant single‐SNP association was detected in CHRNA4 and CHRNB1. In summary, this is the most comprehensive study of the CHRN genes for involvement with nicotine dependence to date. Our analysis reveals significant evidence for at least four distinct loci in the nicotinic receptor subunit genes that each influence the transition from smoking to nicotine dependence and may inform the development of improved smoking cessation treatments and prevention initiatives. © 2009 Wiley‐Liss, Inc.
Suggestive linkage at 9p22 in bipolar disorder weighted by alcohol abuse
Authors: Saunders Erika F.H. , Zhang Peng , Copeland J. Nathan , Mclnnis Melvin G. , Zöllner Sebastian 
Published: March 2009

AbstractBipolar disorder (BP) is a highly heritable disorder, however attempts to map genetic risk factors are challenging. One possible reason for these difficulties is the genetic heterogeneity of BP. Hence, focusing on clinically homogeneous families to create a genetically more homogeneous sample may increase the power of finding a specific variant. Alcohol abuse (AA) and alcohol dependence (AD) are familial in BP families, and these families may carry a specific risk variant for BP. We tested this hypothesis by performing a genome‐wide linkage scan in 638 pedigrees (1,835 individuals) from the National Institute of Mental Health Genetics Initiative for BP, weighting the evidence for linkage according to the family's frequency of AA or AD. Using AA weighting, we identified a linkage region on 9p22.2 with an NPL score of 3.23. The region had previously been identified in a meta‐analysis of linkage in bipolar disorder. We used permutation analysis to assess if weighting by AA increased the linkage signal more than expected by chance and observed a significant P‐value (P = 0.048). Therefore, the genetic risk factor for BP on 9p22.2 has an increased effect in families with high levels of AA. In summary, we present an example of using covariates such as AA and AD to define subtypes of BP, demonstrate how using such subtypes can improve the power of a linkage scan, and demonstrate statistical approaches to validate the suggested interaction. © 2009 Wiley‐Liss, Inc.
Association of the α4 integrin subunit gene (ITGA4) with autism
Authors: Correia Catarina , Coutinho Ana M. , Almeida Joana , Lontro Raquel , Lobo Cristina , Miguel Teresa S. , Martins Madalena , Gallagher Louise , Conroy Judith , Gill Michael , Oliveira Guiomar , Vicente Astrid M. 
Published: March 2009

AbstractIn the present work, we provide further evidence for the involvement of the integrin alpha‐4 precursor gene (ITGA4) in the etiology of autism, by replicating previous findings of a genetic association with autism in various independent populations. The ITGA4 gene maps to the autism linkage region on 2q31‐33 and is therefore a plausible positional candidate. We tested eight single nucleotide polymorphisms (SNPs) in the ITGA4 gene region for association with autism in a sample of 164 nuclear families. Evidence for association was found for the rs155100 marker (P = 0.019) and for a number of specific marker haplotypes containing this SNP (0.00053 < P < 0.022). α4 integrins are known to play a key role in neuroinflammatory processes, which are hypothesized to contribute to autism. In this study, an association was found between the ITGA4 rs1449263 marker and levels of a serum autoantibody directed to brain tissue, which was previously shown to be significantly more frequent in autistic patients than in age‐matched controls in our population. This result suggests that the ITGA4 gene could be involved in a neuroimmune process thought to occur in autistic patients and, together with previous findings, offers a new perspective on the role of integrins in the etiology of autism to which little attention has been paid so far. © 2009 Wiley‐Liss, Inc.
Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking
Authors: Sonnen Joshua A. , Larson Eric B. , Gray Shelly L. , Wilson Angela , Kohama Steven G. , Crane Paul K. , Breitner John C. S. , Montine Thomas J. 
Published: March 2009

AbstractEvidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study. Ann Neurol 2009;65:226–229
Medullary pain facilitating neurons mediate allodynia in headache‐related pain
Authors: Edelmayer Rebecca M. , Vanderah Todd W. , Majuta Lisa , Zhang En‐Tan , Fioravanti Beatriz , De Felice Milena , Chichorro Juliana G. , Ossipov Michael H. , King Tamara , Lai Josephine , Kori Shashi H. , Nelsen Andrew C. , Cannon Keri E. , Heinricher Mary M. , Porreca Frank 
Published: March 2009

AbstractObjectiveTo develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia.MethodsInflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind‐paws were characterized.ResultsIM elicited robust facial and hind‐paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene–related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin‐1 antagonist. Having established facial and hind‐paw allodynia as a useful animal surrogate of headache‐associated allodynia, we next showed that blocking pain‐facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain‐facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM‐induced allodynia. Electrophysiological studies confirmed activation of pain‐facilitating RVM “on” cells and transient suppression of RVM “off” cells after IM.InterpretationFacial and hind‐paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders. Ann Neurol 2009;65:184–193
Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy
Authors: Banno Haruhiko , Katsuno Masahisa , Suzuki Keisuke , Takeuchi Yu , Kawashima Motoshi , Suga Noriaki , Takamori Motoko , Ito Mizuki , Nakamura Tomohiko , Matsuo Koji , Yamada Shinichi , Oki Yumiko , Adachi Hiroaki , Minamiyama Makoto , Waza Masahiro , Atsuta Naoki , Watanabe Hirohisa , Fujimoto Yasushi , Nakashima Tsutomu , Tanaka Fumiaki , Doyu Manabu , Sobue Gen 
Published: March 2009

AbstractObjectiveSpinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA.MethodsFifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo‐controlled trial for 48 weeks, followed by an open‐label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open‐label trial were also followed up for the 96‐week period (UMIN000000474).ResultsLeuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem.InterpretationThese observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large‐scale clinical trials of androgen deprivation for SBMA. Ann Neurol 2009;65:140–150
Lacunar stroke is associated with diffuse blood–brain barrier dysfunction
Authors: Wardlaw Joanna M. , Doubal Fergus , Armitage Paul , Chappell Francesca , Carpenter Trevor , Muñoz Maniega Susana , Farrall Andrew , Sudlow Cathie , Dennis Martin , Dhillon Baljean 
Published: March 2009

AbstractObjectiveLacunar stroke is common (25% of ischemic strokes) and mostly because of an intrinsic cerebral microvascular disease of unknown cause. Although considered primarily to be an ischemic process, the vessel and tissue damage could also be explained by dysfunctional endothelium or blood–brain barrier (BBB) leak, not just ischemia. We tested for subtle generalized BBB leakiness in patients with lacunar stroke and control patients with cortical ischemic stroke.MethodsWe recruited patients with lacunar and mild cortical stroke. We assessed BBB leak in gray matter, white matter, and cerebrospinal fluid, at least 1 month after stroke, using magnetic resonance imaging before and after intravenous gadolinium. We measured tissue enhancement for 30 minutes after intravenous gadolinium by two image analysis approaches (regions of interest and tissue segmentation). We compared the enhancement (leak) between lacunar and cortical patients, and associations with key variables, using general linear modeling.ResultsWe recruited 51 lacunar and 46 cortical stroke patients. Signal enhancement after gadolinium was higher in lacunar than cortical stroke patients in white matter (p < 0.001) and cerebrospinal fluid (p < 0.003) by both analysis methods, independent of other variables. Signal enhancement after gadolinium was also associated with increasing age and enlarged perivascular spaces, but these did not explain the lacunar‐cortical difference.InterpretationPatients with lacunar stroke have subtle, diffuse BBB dysfunction in white matter. Further studies are required to determine the relative contributions of BBB dysfunction and/or ischemia to the microvascular and brain abnormalities in lacunar stroke. Ann Neurol 2009;65:194–202
Reperfusion normalizes motor activation patterns in large‐vessel disease
Authors: Chmayssani Mohamad , Lazar Ronald M. , Hirsch Joy , Marshall Randolph S. 
Published: March 2009

AbstractObjectiveHemodynamic impairment in one hemisphere has been shown to trigger ipsilateral motor activation in the opposite hemisphere on functional imaging. We hypothesized that reversing the hypoperfusion would normalize the motor activation pattern.MethodsWe studied four patients with high‐grade stenosis and impaired vasomotor reactivity (VMR) but no stroke. Functional magnetic resonance imaging motor activation pattern before and after VMR normalization was compared with seven healthy control subjects scanned at an interval of 3 months using voxel‐wise statistical parametric maps and region of interest analysis. Subjects performed a repetitive hand closure task in synchrony with 1Hz metronome tone. We used repeated‐measures analysis of variance to compute the interaction between group (patients/control subjects) and time by obtaining the average blood oxygen level dependent signal of three motor regions of interest in each hemisphere.ResultsTwo patients normalized their VMR after spontaneous resolution of dissection, and two after revascularization procedures. Both voxel‐wise statistical maps and region of interest analysis showed that VMR normalization was associated in each case with a reduction in the atypical activation in the hemisphere opposite to the previously hypoperfused hemisphere (p < 0.001).InterpretationIn the presence of a physiological stressor such as hypoperfusion, the brain is capable of dynamic functional reorganization to the opposite hemisphere that is reversible when normal blood flow is restored. These findings are important to our understanding of the clinical consequences of hemodynamic failure and the role of the ipsilateral hemisphere in maintaining normal neurological function. Ann Neurol 2009;65:203–208
Decreased cerebrospinal fluid Aβ42 correlates with brain atrophy in cognitively normal elderly
Authors: Fagan Anne M. , Head Denise , Shah Aarti R. , Marcus Daniel , Mintun Mark , Morris John C. , Holtzman David M. 
Published: March 2009

AbstractObjectiveFor therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the “preclinical” (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD.MethodsWe investigated the relation between structural neuroimaging measures (whole‐brain volume) and levels of CSF amyloid‐β (Aβ)40, Aβ42, tau, and phosphorylated tau181 (ptau181), and plasma Aβ40 and Aβ42 in well‐characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age‐matched, cognitively normal control subjects (n = 69).ResultsLevels of CSF tau and ptau181, but not Aβ42, correlated inversely with whole‐brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Aβ42, but not tau or ptau181, were positively correlated with whole‐brain volume in nondemented control subjects.InterpretationReduction in CSF Aβ42, likely reflecting Aβ aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Aβ aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau181) are later events that correlate with further structural damage and occur with clinical onset and progression. Ann Neurol 2009;65:176–183