bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypically identical hemopoietic stem cells isolated from different regions of bone marrow have different biologic potential
Authors: Grassinger Jochen , Haylock David N. , Williams Brenda , Olsen Gemma H. , Nilsson Susan K. 
Published: July 2010

AbstractHemopoietic stem cells (HSCs) reside within a specified area of the bone marrow (BM) cavity called a “niche” that modulates HSC quiescence, proliferation, differentiation, and migration. Our previous studies have identified the endosteal BM region as the site for the HSC niche and demonstrated that hemopoietic stem and progenitor populations (HSPCs, LSK) isolated from different BM regions exhibit significantly different hemopoietic potential. In this study, we have analyzed subpopulations of LSK cells isolated from different regions of the BM and showed that CD150+CD48−LSK HSCs within the endosteal BM region have superior proliferative capacity and homing efficiency compared with CD150+CD48−LSK HSCs isolated from the central BM. Furthermore, we show, for the first time, that a subset of CD150+CD48+LSK progenitor cells, previously defined as B-lymphoid primed hemopoietic cells, are capable of multilineage reconstitution, however, only when isolated from the endosteal region. In addition, we provide evidence for an unrecognized role of CD48 in HSC homing. Together, our data provide strong evidence that highly purified HSCs show functional differences depending on their origin within the BM and that the most primitive HSCs reside within the endosteal BM region.
Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance
Authors: Campbell Kirsteen J. , Bath Mary L. , Turner Marian L. , Vandenberg Cassandra J. , Bouillet Philippe , Metcalf Donald , Scott Clare L. , Cory Suzanne 
Published: July 2010

AbstractDiverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.
Resistance of Leishmania (Viannia) braziliensis to nitric oxide: correlation with antimony therapy and TNF-α production
Authors: Souza Anselmo S , Giudice Angela , Pereira Júlia MB , Guimarães Luís H , de Jesus Amelia R , de Moura Tatiana R , Wilson Mary E , Carvalho Edgar M , Almeida Roque P 
Published: July 2010

AbstractBackgroundNitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent. A previous study has demonstrated that 20% of theL. (V.) braziliensisisolated from initial cutaneous lesions of patients from the endemic area of Corte de Pedra, Bahia, Brazil, were NO resistant. Additionally, 5 to 11% of the patients did not respond to three or more antimony treatments" (refractory patients). The aim of this study is to investigate if there is an association between the resistance ofL. (V.) braziliensisto NO and nonresponsiveness to antimony therapy and cytokine production.MethodsWe evaluated thein vitrotoxicity of NO against the promastigotes stages ofL. (V.) braziliensisisolated from responsive and refractory patients, and the infectivity of the amastigote forms of these isolates against human macrophages. The supernatants fromLeishmaniainfected macrophage were used to measure TNF-α and IL-10 levels.ResultsUsing NaNO2(pH 5.0) as the NO source,L. (V.) braziliensisisolated from refractory patients were more NO resistant (IC50 = 5.8 ± 4.8) thanL. (V.) braziliensisisolated from responsive patients (IC50 = 2.0 ± 1.4). Four isolates were selected to infect human macrophages: NO-susceptible and NO-resistantL. (V.) braziliensisisolated from responsive and refractory patients. NO-resistantL. (V.) braziliensisisolated from refractory patients infected more macrophages stimulated with LPS and IFN-γ at 120 hours than NO-susceptibleL. (V.) braziliensisisolated from refractory patients. Also, lower levels of TNF-α were detected in supernatants of macrophages infected with NO-resistantL. (V.) braziliensisas compared to macrophages infected with NO-susceptibleL. (V.) braziliensis(p < 0.05 at 2, 24 and 120 hours), while no differences were detected in IL-10 levels.ConclusionThese data suggest that NO resistance could be related to the nonresponsiveness to antimony therapy seen in American Tegumentary Leishmaniasis.
Evidence for alternative quaternary structure in a bacterial Type III secretion system chaperone
Authors: Barta Michael L , Zhang Lingling , Picking Wendy L , Geisbrecht Brian V 
Published: July 2010

Abstract

Background
Type III secretion systems are a common virulence mechanism in many Gram-negative bacterial pathogens. These systems use a nanomachine resembling a molecular needle and syringe to provide an energized conduit for the translocation of effector proteins from the bacterial cytoplasm to the host cell cytoplasm for the benefit of the pathogen. Prior to translocation specialized chaperones maintain proper effector protein conformation. The class II chaperone, Invasion plasmid gene (Ipg) C, stabilizes two pore forming translocator proteins. IpgC exists as a functional dimer to facilitate the mutually exclusive binding of both translocators.

Results
In this study, we present the 3.3 Å crystal structure of an amino-terminally truncated form (residues 10-155, denoted IpgC10-155) of the class II chaperone IpgC from Shigella flexneri. Our structure demonstrates an alternative quaternary arrangement to that previously described for a carboxy-terminally truncated variant of IpgC (IpgC1-151). Specifically, we observe a rotationally-symmetric "head-to- head" dimerization interface that is far more similar to that previously described for SycD from Yersinia enterocolitica than to IpgC1-151. The IpgC structure presented here displays major differences in the amino terminal region, where extended coil-like structures are seen, as opposed to the short, ordered alpha helices and asymmetric dimerization interface seen within IpgC1-151. Despite these differences, however, both modes of dimerization support chaperone activity, as judged by a copurification assay with a recombinant form of the translocator protein, IpaB.

Conclusions
From primary to quaternary structure, these results presented here suggest that a symmetric dimerization interface is conserved across bacterial class II chaperones. In light of previous data which have described the structure and function of asymmetric dimerization, our results raise the possibility that class II chaperones may transition between asymmetric and symmetric dimers in response to changes in either biochemical modifications (e.g. proteolytic cleavage) or other biological cues. Such transitions may contribute to the broad range of protein-protein interactions and functions attributed to class II chaperones.
Managing hyperemesis gravidarum: a multimodal challenge
Authors: Jueckstock JK , Kaestner R , Mylonas I 
Published: July 2010

Abstract
Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect.
In most cases, the condition is self limiting and subsides by around 20 weeks gestation. More severe forms require medical intervention once other organic causes of nausea and vomiting have been excluded. In addition, a psychosomatic approach is often helpful.
In view of its potential complexity, general practitioners and obstetricians should be well informed about HG and therapy should be multimodal.
Long Lasting Pain Hypersensitivity following Ligation of the Tendon of the Masseter Muscle in Rats: A Model of Myogenic Orofacial Pain
Authors: Guo Wei , Wang Hu , Zou Shiping , Wei Feng , Dubner Ronald , Ren Ke 
Published: July 2010

Background: A major subgroup of patients with temporomandibular joint (TMJ) disorders have masticatory muscle hypersensitivity. To study myofacial temporomandibular pain, a number of preclinical models have been developed to induce myogenic pain of the masseter muscle, one of the four muscles involved in mastication. The currently used models, however, generate pain that decreases over time and only lasts from hours to weeks and hence are not suitable for studying chronicity of the myogenic pain in TMJ disorders. Here we report a model of constant myogenic orofacial pain that lasts for months. Results: The model involves unilateral ligation of the tendon of the anterior superficial part of the rat masseter muscle (TASM). The ligation of the TASM was achieved with two chromic gut (4.0) ligatures via an intraoral approach. Nocifensive behavior of the rat was assessed by probing the skin site above the TASM with a series of von Frey filaments. The response frequencies were determined and an EF50 value, defined as the von Frey filament force that produces a 50% response frequency, was derived and used as a measure of mechanical sensitivity. Following TASM ligation, the EF50 of the injured side was significantly reduced and maintained throughout the 8-week observation period, suggesting the presence of mechanical hyperalgesia/allodynia. In sham-operated rats, the EF50 of the injured side was transiently reduced for about a week, likely due to injury produced by the surgery. Somatotopically relevant Fos protein expression was indentified in the subnucleus caudalis of the spinal trigeminal sensory complex. In the same region, persistent upregulation of NMDA receptor NR1 phosphorylation and protein expression and increased expression of glial markers glial fibrillary acidic protein (astroglia) and CD1 1b (microglia) were found. Morphine (0.4–8 mg/kg, s.c.) and duloxetine (0.4–20 mg/kg, i.p.), a selective serotonin-norepinephrine reuptake inhibitor, produced dose-dependent attenuation of hyperalgesia. Conclusions: Ligation injury of the TASM in rats led to long-lasting and constant mechanical hypersensitivity of myogenic origin. The model will be particularly useful in studying the chronicity of myogenic pain TMJ disorders. The model can also be adapted to other regions of the body for studying pathology of painful tendinopathy seen in sports injury, muscle overuse, and rheumatoid arthritis.
Does the cortisol response to stress mediate the link between expressed emotion and oppositional behavior in Attention-Deficit/Hyperactivity-Disorder (ADHD)?
Authors: Christiansen Hanna , Oades Robert D , Psychogiou Lamprini , Hauffa Berthold P , Sonuga-Barke Edmund J 
Published: July 2010

Abstract

Background
Expressed Emotions (EE) are associated with oppositional behavior (OPB) in children with Attention Deficit/Hyperactivity Disorder (ADHD). EE has been linked to altered stress responses in some disorders, but ADHD has not been studied. We test the hypothesis that OPB in ADHD is mediated by altered stress-related cortisol reactivity to EE.

Methods
Two groups of children (with/without ADHD) and their respective parents were randomly assigned to two different conditions with/without negative emotion and participated in an emotion provocation task. Parents' EE, their ratings of their children's OPB and their children's salivary cortisol levels were measured.

Results
Low parental warmth was associated with OPB in ADHD. High levels of parental EE elicited a larger cortisol response. Stress-related cortisol reactivity mediated the EE-OPB link for all children. This highlights the general importance of parent-child interactions on externalizing behavior problems.

Conclusion
High EE is a salient stressor for ADHD children that leads to increased levels of cortisol and OPB. The development of OPB might be mediated by the stress-response to high EE.
Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors
Authors: Caenepeel Sean , Renshaw-Gegg Lisa , Baher Angelo , Bush Tammy L , Baron Will , Juan Todd , Manoukian Raffi , Tasker Andrew S , Polverino Anthony , Hughes Paul E 
Published: July 2010

Abstract

Background
Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).

Methods
This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.

Results
Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Δ552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays.

Conclusions
In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.
Maintenance of cytomegalovirus-specific CD4pos T-cell response in rheumatoid arthritis patients receiving anti-tumor necrosis factor treatments
Authors: Davignon Jean-Luc , Boyer Jean-Frédéric , Jamard Bénédicte , Nigon Delphine , Constantin Arnaud , Cantagrel Alain 
Published: July 2010

Abstract
Introduction
Anti-tumor necrosis factor (TNF)-α biotherapies have considerably changed the treatment of rheumatoid arthritis (RA). However, serious infections are a major concern in patients with rheumatic diseases treated with anti-TNF-α. Little is known about viral, especially latent, infections in anti-TNF-α treatments. Infections by cytomegalovirus (CMV), a β-herpes virus, are frequent and induce a strong CD4pos T-cell immunity, which participates in the control of infection. We thus have chosen to analyze the CD4pos T-cell response to CMV antigens as a model of antiviral response in RA patients treated with anti-TNF-α. CD28 expression was evaluated.

Methods
We have measured the CD4pos response to CMV antigens in RA patients, before and after initiation of treatment with an anti-TNF-α agent. The intracellular production of interferon (IFN)-γ in total and CD28neg CD4pos T cells in response to CMV antigens (Ags) was evaluated with flow cytometry. The proliferation of total CD4pos T cells in the presence of CMV antigens was measured with 3H-thymidine incorporation.

Results
Anti-TNF-α treatments impaired neither the anti-CD4pos anti-CMV IFN-γ response nor the proliferative response in patients. The percentage of CD28neg CD4pos cells remained constant.

Conclusions
Our data suggest that the CD4pos T-cell response against CMV is not altered by anti-TNF-α treatments and that infection remains controlled in treated RA patients latently infected with CMV. Our observation brings new insight into the current knowledge of the risks of infection in patients treated with anti-TNF-α biotherapies.
Quantifying the mechanisms of domain gain in animal proteins
Authors: Buljan Marija , Frankish Adam , Bateman Alex 
Published: July 2010

Abstract
Background
Protein domains are protein regions that are shared among different proteins and are frequently functionally and structurally independent from the rest of the protein. Novel domain combinations have a major role in evolutionary innovation. However, the relative contributions of the different molecular mechanisms that underlie domain gains in animals are still unknown. By using animal gene phylogenies we were able to identify a set of high confidence domain gain events and by looking at their coding DNA investigate the causative mechanisms.

Results
Here we show that the major mechanism for gains of new domains in metazoan proteins is likely to be gene fusion through joining of exons from adjacent genes, possibly mediated by non-allelic homologous recombination. Retroposition and insertion of exons into ancestral introns through intronic recombination are, in contrast to previous expectations, only minor contributors to domain gains and have accounted for less than 1% and 10% of high confidence domain gain events, respectively. Additionally, exonization of previously non-coding regions appears to be an important mechanism for addition of disordered segments to proteins. We observe that gene duplication has preceded domain gain in at least 80% of the gain events.

Conclusions
The interplay of gene duplication and domain gain demonstrates an important mechanism for fast neofunctionalization of genes.
A Randomized, Controlled Trial of Vitamin D Supplementation upon Musculoskeletal Health in Postmenarchal Females
Authors: Ward K. A. , Das G. , Roberts S. A. , Berry J. L. , Adams J. E. , Rawer R. , Mughal M. Z. 
Published: July 2010

Context: There has been a resurgence of vitamin D deficiency rickets throughout the developed world, with infants and adolescents being primarily affected. Adolescence is a crucial period for muscle and bone mineral accumulation.
Objective: The aim was to determine the effect of vitamin D supplementation on the adolescent musculoskeletal system.
Design and Setting: We conducted a community-based, double-blind, randomized controlled trial in a secondary school.
Participants: Postmenarchal 12- to 14-yr-old females participated in the trial. Ninety-nine were screened, 73 were included in randomized controlled trial, and 69 completed the trial. There were no adverse events.
Intervention: Four doses of 150,000 IU vitamin D2 (ergocalciferol) were given over 1 yr.
Main Outcome Measures: Dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and jumping mechanography were used.
Results: At follow-up, 25-hydroxyvitamin D [25(OH)D] status was 56.0 ± 8.9 nmol/liter in the intervention group and 15.8 ± 6.6 nmol/liter in controls. There were no effects of supplementation on bone; however, for muscle function, efficiency of movement improved in the vitamin D-treated group. There was an interaction between baseline 25(OH)D concentration and response to vitamin D supplementation for muscle jump velocity.
Conclusions: Despite improvements in 25(OH)D status, treatment with vitamin D2 was not shown to increase mineral accretion, bone geometry or strength, muscle force, or power. There were greater increases in jump velocity in girls with the lowest baseline 25(OH)D concentrations. Lack of effect of intervention after the period of peak mineral and muscle mass accretion suggests that earlier action is required.
Haplotype Analysis Discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease
Authors: Baker Peter R. , Baschal Erin E. , Fain Pam R. , Triolo Taylor M. , Nanduri Priyaanka , Siebert Janet C. , Armstrong Taylor K. , Babu Sunanda R. , Rewers Marian J. , Gottlieb Peter A. , Barker Jennifer M. , Eisenbarth George S. 
Published: July 2010

Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease.
Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD).
Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34.
Main Outcome Measures: AD and genotype were measured.
Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A.
Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype.