bluuebunny/crossref_metadata_2025_split huggingface dataset:
After Darwin
Authors: O’Connell Jeff , Ruse Michael 
Published: October 2019

Abstract
In the second half of the nineteenth century, many people lost their faith in the Christian God. Nevertheless, they were eager to show that this move towards a secular world picture did not mean the end of morality and that it could continue as much before. In a Darwinian age this was not possible and the Christian cherishing of the virtue of meekness was replaced by a moral respect for vigor and effort directed both towards self-realization and to the well-being of society. We compare the British moves to those promoted by the German philosopher Friedrich Nietzsche. There are significant similarities but also differences that reflect the British industrialized notion of progress versus the German idealistic notion of progress.
Burden of premature atrial beats in middle-aged endurance athletes with and without lone atrial fibrillation versus sedentary controls
Authors: Cipriani Alberto , Vio Riccardo , Mastella Giulio , Ciarmatori Nicolò , Del Monte Alvise , Trovato Domenico , Iliceto Sabino , Schiavon Maurizio , Bertaglia Emanuele , Corrado Domenico , Zorzi Alessandro 
Published: October 2019

Background The burden of premature atrial beats (PABs) at 24-h electrocardiographic (ECG) monitoring correlates with the risk of atrial fibrillation. It is unknown whether prolonged and intense exercise increases the burden of PABs, thus contributing to the higher prevalence of atrial fibrillation observed in middle-aged athletes. Methods We compared the burden of PABs at 24-h ECG monitoring off therapy in 134 healthy middle-aged (30–60-year-old) competitive athletes who had practised 9 (7-11) h of endurance sports for 8 (4-15) consecutive years, 134 age- and gender-matched healthy sedentary individuals, and 66 middle-aged patients (20 athletes and 46 non-athletes) with ‘lone’ paroxysmal atrial fibrillation. Results More than 50 PABs/24 h or ≥1 run of ≥3 PABs were recorded in 23/134 (17%) healthy athletes and in 29/134 (22%) sedentary controls ( p = 0.61). Healthy athletes with frequent or repetitive PABs were older (median 50 years vs. 43 years, p < 0.01) and had practised sport for a longer time (median 10 years vs. 6 years, p = 0.03). At multivariable analysis only age (odds ratio 1.11, 95% confidence interval 1.04–1.20, p < 0.01) remained an independent predictor of a higher burden of PABs. Also among patients with ‘lone’ paroxysmal atrial fibrillation, there was no difference in the prevalence of >50 PABs/24 h or ≥1 run of ≥3 PABs between athletes (40%) and controls (48%, p = 0.74) . Conclusions Middle-aged endurance athletes, with or without paroxysmal atrial fibrillation, did not show a higher burden of PABs at 24-h ECG monitoring than sedentary controls. Age, but not intensity and duration of sports activity, predicted a higher burden of PABs among healthy athletes.
Involvement and functional impairment of the CD34+CD38−Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8
Authors: Nilsson Lars , Åstrand-Grundström Ingbritt , Anderson Kristina , Arvidsson Ingrid , Hokland Peter , Bryder David , Kjeldsen Lars , Johansson Bertil , Hellström-Lindberg Eva , Hast Robert , Jacobsen Sten Eirik W. 
Published: October 2019

AbstractClonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34+Thy1+hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid HSC is the target for transformation in MDS cases with del(5q), potentially reflecting heterogeneity within MDS. However, since +8 is known to frequently be a late event in the MDS transformation process, it remained a possibility that CD34+CD38−Thy1+ HSC disomic for chromosome 8 might be part of the MDS clone. In the present studies, although a variable fraction of CD34+CD38−Thy1+ cells were disomic for chromosome 8, they did not possess normal HSC activity in long-term cultures and nonobese diabetic–severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34+CD38− cells suggested that this HSC deficiency was intrinsic and not mediated by indirect mechanisms. Furthermore, investigation of 4 MDS cases with combined del(5q) and +8 demonstrated that the +8 aberration was always secondary to del(5q). Whereas del(5q) invariably occurs in CD34+CD38−Thy-1+ HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34+CD38−Thy1+ HSCs are invariably part of the MDS clone also in +8 patients, and little HSC activity can be recovered from the CD34+ CD38−Thy1+ HSC. Finally, in advanced cases of MDS, the MDS reconstituting activity is exclusively derived from the minor CD34+CD38−HSC population, demonstrating that MDS stem cells have a similar phenotype as normal HSCs, potentially complicating the development of autologous transplantation for MDS.
Aurora-B Kinase Translocates to the Midzone in Endomitotic Megakaryocytes.
Authors: Geddis Amy E. , Kaushansky Kenneth 
Published: October 2019

Abstract
Megakaryocyte (MK) differentiation is marked by the development of progressive polyploidy, facilitating platelet production by the creation of a large cytoplasmic volume. MKs become polyploid through repeated cycles of endomitosis (EnM), in which mitosis is initiated but subsequently aborted in late anaphase with failure to complete karyokinesis and cytokinesis. However, the mechanisms underlying EnM remain poorly understood. Recent hypotheses explored in the literature have focused on the possible absence or mislocalization of the chromosomal passenger protein Aurora-B kinase, as it has a pivotal role in many aspects of cytokinesis. Along with the other passenger proteins, Aurora-B kinase transits from the centromeres of metaphase chromosomes to the bundled microtubules of the spindle midzone and overlying cortex between separating chromosomes in anaphase. The midzone and its associated proteins, are thought to be critical for determining the position of the cleavage furrow. One of these proteins, the kinesin MKLP-2, is required for the translocation of Aurora-B kinase to the midzone, where it co-localizes with the GTPase MgcRacGAP and stimulates its activity towards RhoA, potentially regulating actin dynamics at the cleavage furrow. We have previously demonstrated that several chromosomal passenger proteins including Aurora-B kinase are normally expressed and localized to centromeres in EnM MKs. In this work, we use deconvolution microscopy in primary murine and human MKs to extend those findings and demonstrate that EnM MKs form midzone structures that are characteristic of late anaphase; in addition, Aurora-B kinase is clearly present on the spindle midzone, as are MKLP-2 and MgcRacGAP. Although we found images suggestive of initial cleavage furrow formation with cortical localization of Aurora-B kinase in late phase cells, we were unable to demonstrate enhanced localization of actin or anillin to the furrow in EnM cells, despite their normal localization in diploid control cells. Therefore, many of the components of the central spindle are intact during MK EnM, but the formation of the cleavage furrow appears to be incomplete. These data add to our understanding of the possible mechanisms underlying EnM and offer an alternative hypothesis to that of failed expression or localization of the chromosomal passenger proteins. Ongoing studies will focus on the assembly and function of the cleavage furrow in this enigmatic process.
Oligoclonal Expansion of Revertant T Cells Leads to Omenn Syndrome in a Patient with RAG1-Deficient Severe Combined Immunodeficiency.
Authors: Wada Taizo , Okamoto Hiroyuki , Toma Tomoko , Kasahara Yoshihito , Koizumi Shoichi , Kato Masahiko , Yachie Akihiro 
Published: October 2019

Abstract
Omenn syndrome (OS) is an autosomal recessive primary immunodeficiency characterized by early-onset generalized erythroderma, lymphadenopathy, hepatosplenomegaly, hypogammaglobulinemia, and elevated serum IgE levels. OS patients carry mutations of the recombination activating genes (RAG1 and RAG2) that are essential for V(D)J recombination. OS mutations maintain a residual recombination activity that allows limited T-cell receptor (TCR) gene rearrangements in the thymus, whereas null mutations cause a complete block of T- and B-cell development and lead to severe combined immune deficiency with absence of mature T and B lymphocytes (T-B- SCID). Revertant mosaicism due to back mutations or second-site mutations has been described in an increasing number of primary immunodeficiencies. The occurrence of reversion is considered rare and revertant cells have been shown to carry a single revertant sequence. Here we describe somatic mosaicism due to multiple events of second-site mutations in a patient affected with Omenn syndrome. We found that the patient is homozygous for a single base C deletion after nucleotide 2113 of the RAG1 gene in DNA obtained from his granulocytes. This novel mutation leads to a frameshift at codon 668 and a premature termination, and likely abrogates RAG function. The patient, however, showed typical features of OS including expansion of activated and oligoclonal T cells in peripheral blood. Molecular analysis using various sorted samples revealed that several different second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations located in the RAG2 interacting domain, were simultaneously demonstrated in DNA from CD3+ T cells. On the contrary, such sequences were not detectable in DNA obtained from granulocytes, CD14+ monocytes and CD56+ NK cells. We also showed that TCRVβ8+ and TCRVβ1+ T cells, which were predominantly expanded within CD4+ and CD8+ T cells respectively, had different second-site mutations. The presence of multiple second-site mutations in a single patient is an unprecedented finding that supports the possibility that genetic reversions may be more common than previously thought. In addition, these observations indicate that T-B- SCID with reverse mutations that impair but do not abolish the V(D)J recombination process is a novel mechanism for the pathogenesis of OS.
Self-Reactivity in a Lymphopenic Mouse: A Model of Acute Graft-versus-Host Disease.
Authors: Knoechel Birgit , Lohr Jens G. , Kahn Estelle , Abbas Abul K. 
Published: October 2019

Abstract
Transfer of naive antigen-specific T cells into self-antigen expressing transgenic mice leads to the development of hyporesponsiveness and deletion of the self-reactive T cells. This form of functional tolerance is characterized by decreased recall responses both in vivo and in vitro. Although the development of tolerance has been studied extensively, few studies have analyzed the factors that determine the breakdown of tolerance and how host cell populations influence the process. Using transgenic mice that express a secreted form of ovalbumin (sOVA Tg) in the serum either on a wildtype (WT) or a T-cell deficient (TCRa−/−), or B- and T-cell deficient (Rag−/−) background, we investigate tolerance development of OVA-specific DO11.10 CD4+ T cells that have been transferred into these mice. We report kinetics, phenotypes and cytokine production of the antigen-specific T cells after transfer. We further describe the histological, immunohistochemical and clinical picture and the effects of cytokine blockade by administration of antibodies.
Naïve OVA-specific T cells that encounter OVA as a self-antigen in lymphocyte-sufficient recipients undergo some expansion, followed by a contraction phase, and become functionally hyporesponsive to the antigen. In contrast, adoptive transfer of DO11 cells into Rag-deficient sOVA Tg animals results in rapid development of wasting and death, phenotypically and histologically resembling cytokine release syndrome or acute GvHD. Histologic examination reveals inflammatory infiltrates predominantly in the skin and gut. Under these circumstances the transferred DO11 cells undergo massive expansion and produce abundant amounts of IL-2 and IFN-g. In contrast, transfer into TCRa-deficient sOVA Tg animals, in which B cells are present, leads to similar T cell expansion but substantially reduced IFN-g production and no death.
Our data suggest that T cell tolerance in vivo is critically dependent on an intact, lymphocyte-sufficient host. In the absence of endogenous lymphocytes, T cells specific for a systemic self-antigen are activated and cause lethal immune reactions.
Cancer Immunotherapy: Cytotoxic Activity of γδ T-Cells Expanded Ex Vivo by the Third Generation Bisphosphonate Zoledronate.
Authors: Sato Kiyoshi , Kimura Shinya , Yuasa Takeshi , Wada Hiromi , Maekawa Taira 
Published: October 2019

Abstract
Bisphosphonates (BPs), widely used to treat bone diseases, have recently been attracted much interest for their antitumor activity and have been reported to exert direct antitumor effects on several cancer cell lines via the inactivation of Ras proteins. BPs inhibit farnesyl pyrophosphate (FPP) synthetase in the mevalonate pathway and deplete cellular pools of PPs such as farnesyl PP and geranylgeranyl PP which are indispensable for the activation of Ras proteins. In addition to their direct antitumor activity, BPs expand γδ T-cells which are potent effector cells and also induce the accumulation of isopentenyl PP as a tumor antigen in target cancer cells. The purpose of this study was to clarify the cytotoxic activity of γδ T-cells expanded ex vivo by the potent third generation BP zoledronate (ZOL). Peripheral blood mononuclear cells of five healthy donors were incubated with different concentrations of ZOL and interleukin-2. After 14 days incubation, 1 μM ZOL increased the absolute number of γδ T-cells 500–800 fold. Expanded γδ T-cells were of the Vγ9Vδ2 subset and cytokine levels of IL-2, -4, -5, -10, TNF-α and IFN-γ were not elevated at resting i.e. before contact to target cancer cells. In vitro cytotoxic activities of γδ T-cells against the luciferase-labeled small cell lung cancer (SCLC) cell line SBC-5 were examined by a newly developed cytotoxic assay using an in vivo imaging system (Xenogen, Alameda, CA) and video microscopy, Leica AS MDW (Leica Microsystems Inc., Bannockburn, IL). γδ T-cells killed SBC-5 cells pre-treated with 5 μM ZOL for 12 h after 1.5–3.0 h contact with the target cells whereas untreated SBC-5 were rarely killed. SBC-5 cells pretreated with 5 μM ZOL showed a marked increase in their sensitivity to lysis by γδ T-cells, percentages of specific lysis were 42% and 55% at effector/target (E/T) ratios of 5:1 and 10:1, respectively, while those of untreated SBC-5 cells were 8% and 13% at E/T ratios of 5:1 and 10:1, respectively. In vivo efficacy of γδ T-cells was investigated in mice xenografted subcutaneously with SBC-5 cells. Pretreatment with 80 μg/kg ZOL enhanced significantly antitumor activity of γδ T-cells also in vivo. These findings showed that ZOL stimulated the proliferation of γδ T-cells significantly and that the cytotoxic activity of γδ T-cells required pre-treatment of target cells with ZOL, indicating the potential use of autologous ex vivo expanded γδ T-cells for cancer immunotherapy.
Birth Order, Atopy, and Risk of Non-Hodgkin Lymphoma.
Authors: Grulich Andrew E. , Vajdic Claire , Kaldor John M. , Hughes Anne-Maree , Kricker Anne , Fritschi Lin , Turner Jennifer J. , Milliken Sam , Benke Geza , Armstrong Bruce K. 
Published: October 2019

Abstract
People with congenital or acquired immune deficiency have rates of non-Hodgkin lymphoma (NHL) that are raised 50 fold or more above population rates, but it is unknown whether risk of NHL is associated with other forms of immune dysregulation. We performed a population based case-control study of risk factors for NHL in adults aged 20–74 years in New South Wales and the Australian Capital Territory, Australia. We investigated the association of NHL risk with atopy, which is associated with a Th2 dominant immune response. In addition, we investigated the association of NHL with birth order and childhood crowding, which are known to predict atopy. Cases with NHL were selected from a cancer register (n=704), and controls (n=694) were randomly selected from state electoral rolls and frequency-matched to cases by age, sex and area. Cases with clinically apparent immune deficiency were excluded. Birth order, childhood crowding and history of atopic conditions (hayfever, asthma, eczema, and specific allergies) were assessed by questionnaire and by interview. Logistic regression models of NHL risk included the three matching variables as covariates. Being an only child or first born child of a larger family was strongly inversely associated with risk of NHL. Compared to a fourth or later born child, the odds ratios (OR) for development of NHL were 0.52 (95% CI 0.32–0.84) for an only child, 0.55 (95% CI 0.40–0.75) for a first-born child, and 0.70 (95% CI 0.51–0.96) and 0.81 (95 % CI 0.57–1.14) respectively for second and third born children (p trend < 0.0001). Indicators of crowding in later childhood, such as ever sharing a bed or bedroom, and number of years of sharing, were not associated with NHL risk. Diagnosis of atopic conditions was also inversely associated with NHL risk. Self-reported histories of hayfever, asthma, eczema and food allergies were each associated with reduced NHL risk; this reduction was significant for hayfever (OR 0.65, 95% CI 0.52–0.82) and food allergies (OR 0.29, 95% CI 0.20–0.42), but not significant for asthma (OR 0.88, 95% CI 0.67–1.17) and eczema (OR 0.79, 95% CI 0.57–1.10). In summary, being an only or other first born child and reporting a history of atopic conditions were associated with reduced NHL risk. Taken together, these data suggest a hypothesis that late exposure to infections in early life and atopic conditions, both of which are associated with a predominant Th2 response, are associated with a reduced risk of NHL.
UV-Induced B-Cell Lymphomas in p53 Heterozygous Mice.
Authors: Miyahara Yasuko , Kazimi Nasser , Multani Asha S. , Pathak Sen , Chang Sandy , Angkasekwinai Yee , Qin Xiao-Feng , Ullrich Stephen E. 
Published: October 2019

Abstract
The association between ultraviolet (UV) irradiation and skin cancer induction is well known. Recently, UV exposure was associated with the induction of internal lymphoid malignancies in UV-irradiated p53 heterozygous mice. Here we characterize the non-skin cancer that develops in the lymphoid organs of UV-irradiated mice and found that UV exposure promotes the induction of a B-cell lymphoma. p53 heterozygous mice were exposed to UVB irradiation (10KJ/m2; three times a week) supplied by a bank of FS40 sunlamps. After thirty weeks, we collected spleen cells from 5 irradiated mice, prepared single suspensions, pooled the cells and injected 2X106 cells/flank (subcutaneous injection) into Rag2−/−mice. The subcutaneous tumors that developed in the Rag2−/−mice were successfully transplanted into other Rag2−/−mice and adapted to grow in vitro. Flow cytometric analysis indicated that enlarged cells were positive for CD19, B220, IgM, CD24, CD40, B7-1, B7-2, but negative for CD43, BP-1, CD127, CD3, CD4, CD8, CD49b, NK1.1, Thy1.2, Gr-1. This phenotype is compatible with a mature B cell but also express CD5, CD11b, CD117. Immunohistchemical analysis confirmed that the tumor cells were of B-cell origin and southern blot analysis demonstrated rearrangement of Immunoglobulin heavy chain. Chromosomal analysis revealed a translocations, t (14;19). Subcutaneous injection of the tumor cells into Rag2−/− mice resulted in an aggressive tumor that infiltrated into the lymph nodes, the spleen and the bone marrow. After establishing the cell line from this B-cell lymphoma, we transfected GFP by using lentiviral vector to mark and injected into Rag2−/− mice. First, the cells bearing GFP infiltrated into the lymph nodes, and then into the spleen and the bone marrow. We also found that this cell line produced IL-10, which can promote lymphoma growth and can cause systemic immunosuppression (Masood et al., 1995Blood85:3423–30; Rivas et al., 1994J Leukoc Biol.59:769–75). The B-cell lymphoma, which grew progressively in immune compromised Rag2−/−mice, was rejected when injected into wild type mice and syngeneic UV-irradiated C57Bl/6 mice. This data indicates that UV induced B-cell lymphoma in p53 heterozygous mice does not express UV common antigen found on UV-induced skin cancer because UV irradiated mice are unable to reject UV induced tumor cells bearing this antigen as previously reported (Kripke et al., 1974J.Natl Cancer Inst.53:1333–6). Since sunlight exposure has been associated with the development of non-Hodgkin’s lymphomas in humans, tumor development in UV-irradiated p53 heterozygous mice may provide a useful animal model for lymphoma development in humans.
Endoglin Is Required for Hemangioblast Development.
Authors: Perlingeiro Rita R. 
Published: October 2019

Abstract
A critical role for endoglin (CD105) in early development has been demonstrated in mice deficient for this gene. Embryos homozygous for the endoglin mutation (eng−/−) fail to progress beyond 10.5 days postcoitum due primarily to vascular and cardiac abnormalities (Bordeau et al, 1999). Analysis of 9.5 dpc eng−/− embryos revealed abnormal vasculature and anemia of the yolk sac, suggesting that endoglin may be required for both blood and endothelial lineages. The hemangioblast, the bipotent precursor for hematopoietic and endothelial cells, can be assessed through the blast colony assay (BL-CFC) using a model system based on the in vitro differentiation of embryonic stem (ES) cells into embryoid bodies (EBs). To evaluate a role for endoglin in this early precursor, we differentiated eng−/−, eng+/−, and eng+/+ (wild-type) ES cells into EBs. At day 3 of EB differentiation, cells were disrupted and plated for blast colony formation in methylcellulose media containing vascular endothelial growth factor (VEGF), stem cell factor (SCF), and thrombopoietin (TPO). We found no difference in blast colony formation between heterozygous and wild-type ES cells. However, a significant reduction in the number of BL-CFCs was observed in eng−/− cells when compared to eng+/− or eng+/+ BL-CFCs (p < 0.001). Single eng−/−, eng+/−, and eng+/+ BL-CFCs gave rise to secondary hematopoietic colonies as well as endothelial cells, confirming their nature as hemangioblasts. These results suggest that although endoglin is required for hemangioblast development, its absence does not affect the bipotentiality of formed BL-CFCs. Since anemia was a feature of 9.5 dpc eng−/− yolk sac embryos, we also examined early erythropoiesis using the ES/EB system. For this purpose, eng−/−, eng+/−, and eng+/+ ES cells were differentiated into EBs for 4 days, at which time cells were disrupted and plated for primitive erythroid colonies (EryP) in methylcellulose media containing IL-3, IL-6, SCF, and Epo. We observed a reduction in the number of EryP colonies in eng−/− (p < 0.01) and eng+/− (p < 0.05) EBs when compared to controls (eng+/+). These results corroborate the anemia observed in vivo in the eng−/− embryos. We used RT-PCR and flow cytometry analysis to detect endoglin expression during a time course of EB differentiation. Endoglin is expressed in ES cells and disappears with differentiation. Expression re-appears at day 3 of differentiation, concomitantly with specification of the hemangioblast. Expression thereafter increases, correlating with mature endothelial cells at later time points. We did not find major differences in gene expression for Brachyury, Flk-1, Tie-2, embryonic and adult globins in a time course of EB differentiation for eng−/−, eng+/−, and eng+/+ ES cells. These data point out a role for endoglin, an ancillary receptor for several members of the transforming growth factor (TGF)-beta superfamily, in hemangioblast development.