bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice
Authors: Funk Ryan K. , Maxwell Taylor J. , Izumi Masayo , Edwin Deepa , Kreisel Friederike , Ley Timothy J. , Cheverud James M. , Graubert Timothy A. 
Published: June 2008

AbstractTherapy-related acute myelogenous leukemia (t-AML) is an important late adverse effect of alkylator chemotherapy. Susceptibility to t-AML has a genetic component, yet specific genetic variants that influence susceptibility are poorly understood. We analyzed an F2 intercross (n = 282 mice) between mouse strains resistant or susceptible to t-AML induced by the alkylator ethyl-N-nitrosourea (ENU) to identify genes that regulate t-AML susceptibility. Each mouse carried the hCG-PML/RARA transgene, a well-characterized initiator of myeloid leukemia. In the absence of ENU treatment, transgenic F2 mice developed leukemia with higher incidence (79.4% vs 12.5%) and at earlier time points (108 days vs 234 days) than mice in the resistant background. ENU treatment of F2 mice further increased incidence (90.4%) and shortened median survival (171 vs 254 days). We genotyped F2 mice at 384 informative single nucleotide polymorphisms across the genome and performed quantitative trait locus (QTL) analysis. Thirteen QTLs significantly associated with leukemia-free survival, spleen weight, or white blood cell count were identified on 8 chromosomes. These results suggest that susceptibility to ENU-induced leukemia in mice is a complex trait governed by genes at multiple loci. Improved understanding of genetic risk factors should lead to tailored treatment regimens that reduce risk for patients predisposed to t-AML.
Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression
Authors: Schmidlin Heike , Diehl Sean A. , Nagasawa Maho , Scheeren Ferenc A. , Schotte Remko , Uittenbogaart Christel H. , Spits Hergen , Blom Bianca 
Published: June 2008

AbstractThe terminal differentiation of B cells into antibody-secreting plasma cells is tightly regulated by a complex network of transcription factors. Here we evaluated the role of the Ets factor Spi-B during terminal differentiation of human B cells. All mature tonsil and peripheral blood B-cell subsets expressed Spi-B, with the exception of plasma cells. Overexpression of Spi-B in CD19+ B cells inhibited, similar to the known inhibitor BCL-6, the expression of plasma cell–associated surface markers and transcription factors as well as immunoglobulin production, ie, in vitro plasma cell differentiation. The arrest in B-cell differentiation enforced by Spi-B was independent of the transactivation domain, but dependent on the Ets-domain. By chromatin immunoprecipitation and assays using an inducible Spi-B construct BLIMP1 and XBP-1 were identified as direct target genes of Spi-B mediated repression. We propose a novel role for Spi-B in maintenance of germinal center and memory B cells by direct repression of major plasma cell factors and thereby plasma cell differentiation.
Stem cell–specific epigenetic priming and B cell–specific transcriptional activation at the mouse Cd19 locus
Authors: Walter Korden , Bonifer Constanze , Tagoh Hiromi 
Published: June 2008

AbstractLow-level expression of multiple lineage-specific genes is a hallmark of hematopoietic stem cells (HSCs). HSCs predominantly express genes specific for the myeloid or megakaryocytic-erythroid lineages, whereas the transcription of lymphoid specific genes appears to begin after lymphoid specification. It has been demonstrated for a number of genes that epigenetic priming occurs before gene expression and lineage specification; however, little is known about how epigenetic priming of lymphoid genes is regulated. To address the question of how B cell–restricted expression is established, we studied activation of the Cd19 gene during hematopoietic development. We identified a B cell–specific upstream enhancer and showed that the developmental regulation of Cd19 expression involves precisely coordinated alterations in transcription factor binding and chromatin remodeling at Cd19 cis-regulatory elements. In multipotent progenitor cells, Cd19 chromatin is first remodeled at the upstream enhancer, and this remodeling is associated with binding of E2A. This is followed by the binding of EBF and PAX5 during B-cell differentiation. The Cd19 promoter is transcriptionally activated only after PAX5 binding. Our experiments give important mechanistic insights into how widely expressed and B lineage–specific transcription factors cooperate to mediate the developmental regulation of lymphoid genes during hematopoiesis.
Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection
Authors: Welner Robert S. , Pelayo Rosana , Nagai Yoshinori , Garrett Karla P. , Wuest Todd R. , Carr Daniel J. , Borghesi Lisa A. , Farrar Michael A. , Kincade Paul W. 
Published: June 2008

AbstractHematopoietic stem and progenitor cells were previously found to express Toll-like receptors (TLRs), suggesting that bacterial/viral products may influence blood cell formation. We now show that common lymphoid progenitors (CLPs) from mice with active HSV-1 infection are biased to dendritic cell (DC) differentiation, and the phenomenon is largely TLR9 dependent. Similarly, CLPs from mice treated with the TLR9 ligand CpG ODN had little ability to generate CD19+ B lineage cells and had augmented competence to generate DCs. TNFα mediates the depletion of late-stage lymphoid progenitors from bone marrow in many inflammatory conditions, but redirection of lymphopoiesis occurred in TNFα−/− mice treated with CpG ODN. Increased numbers of DCs with a lymphoid past were identified in Ig gene recombination substrate reporter mice treated with CpG ODN. TLR9 is highly expressed on lymphoid progenitors, and culture studies revealed that those receptors, rather than inflammatory cytokines, accounted for the production of several types of functional DCs. Common myeloid progenitors are normally a good source of DCs, but this potential was reduced by TLR9 ligation. Thus, alternate differentiation pathways may be used to produce innate effector cells in health and disease.
Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease?
Authors: Tenenbaum Alexander , Boyko Valentina , Fisman Enrique Z , Goldenberg Ilan , Adler Yehuda , Feinberg Micha S , Motro Michael , Tanne David , Shemesh Joseph , Schwammenthal Ehud , Behar Solomon 
Published: June 2008

AbstractBackgroundEpidemiologic studies have suggested that hypertriglyceridemia and insulin resistance are related to the development of colon cancer. Nuclear peroxisome proliferator-activated receptors (PPAR), which play a central role in lipid and glucose metabolism, had been hypothesized as being involved in colon cancerogenesis. In animal studies the lipid-lowering PPAR ligand bezafibrate suppressed colonic tumors. However, the effect of bezafibrate on colon cancer development in humans is unknown. Therefore, we proposed to investigate a possible preventive effect of bezafibrate on the development of colon cancer in patients with coronary artery disease during a 6-year follow-up.MethodsOur population included 3011 patients without any cancer diagnosis who were enrolled in the randomized, double blind Bezafibrate Infarction Prevention (BIP) Study. The patients received either 400 mg of bezafibrate retard (1506 patients) or placebo (1505 patients) once a day. Cancer incidence data were obtained by matching a subject's identification numbers with the National Cancer Registry. Each matched record was checked for correct identification.ResultsDevelopment of new cancer (all types) was recorded in 177 patients: in 79 (5.25%) patients from the bezafibrate group vs. 98 (6.51%) from the placebo group. Development of colon cancer was recorded in 25 patients: in 8 (0.53%) patients from the bezafibrate group vs. 17 (1.13%) from the placebo group, (Fisher's exact test: one side p = 0.05; two side p = 0.07).A difference in the incidence of cancer was only detectable after a 4 year lag and progressively increased with continued follow-up. On multivariable analysis the colon cancer risk in patients who received bezafibrate tended to be lower with a hazard ratio of 0.47 and 95% confidence interval 0.2–1.1.ConclusionOur data, derived from patients with coronary artery disease, support the hypothesis regarding a possible preventive effect of bezafibrate on the development of colon cancer.
Mild therapeutic hypothermia shortens intensive care unit stay of survivors after out-of-hospital cardiac arrest compared to historical controls
Authors: Storm Christian , Steffen Ingo , Schefold Joerg C , Krueger Anne , Oppert Michael , Jörres Achim , Hasper Dietrich 
Published: June 2008

Abstract
Introduction
Persistent coma is a common finding after cardiac arrest and has profound ethical and economic implications. Evidence suggests that therapeutic hypothermia improves neurological outcome in these patients. In this analysis, we investigate whether therapeutic hypothermia influences the length of intensive care unit (ICU) stay and ventilator time in patients surviving out-of-hospital cardiac arrest.

Methods
A prospective observational study with historical controls was conducted at our medical ICU. Fifty-two consecutive patients (median age 62.6 years, 43 males, 34 ventricular fibrillation) submitted to therapeutic hypothermia after out-of-hospital cardiac arrest were included. They were compared with a historical cohort (n = 74, median age 63.8 years, 53 males, 43 ventricular fibrillation) treated in the era prior to hypothermia treatment. All patients received the same standard of care. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. Univariate analyses and multiple regression models were used.

Results
In survivors, therapeutic hypothermia and baseline disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] score) were both found to significantly influence ICU stay and ventilator time (all P < 0.01). ICU stay was shorter in survivors receiving therapeutic hypothermia (median 14 days [interquartile range (IQR) 8 to 26] versus 21 days [IQR 15 to 30] in the control group; P = 0.017). ICU length of stay and time on ventilator were prolonged in patients with CPC 3 or 4 compared with patients with CPC 1 or 2 (P = 0.003 and P = 0.034, respectively). Kaplan-Meier analysis showed improved probability for 1-year survival in the hypothermia group compared with the controls (log-rank test P = 0.013).

Conclusion
Therapeutic hypothermia was found to significantly shorten ICU stay and time of mechanical ventilation in survivors after out-of-hospital cardiac arrest. Moreover, profound improvements in both neurological outcome and 1-year survival were observed.
Identification of transcripts with enriched expression in the developing and adult pancreas
Authors: Hoffman Brad G , Zavaglia Bogard , Witzsche Joy , Ruiz de Algara Teresa , Beach Mike , Hoodless Pamela A , Jones Steven JM , Marra Marco A , Helgason Cheryl D 
Published: June 2008

Abstract
Background
Despite recent advances, the transcriptional hierarchy driving pancreas organogenesis remains largely unknown, in part due to the paucity of comprehensive analyses. To address this deficit we generated ten SAGE libraries from the developing murine pancreas spanning Theiler stages 17-26, making use of available Pdx1 enhanced green fluorescent protein (EGFP) and Neurog3 EGFP reporter strains, as well as tissue from adult islets and ducts.

Results
We used a specificity metric to identify 2,536 tags with pancreas-enriched expression compared to 195 other mouse SAGE libraries. We subsequently grouped co-expressed transcripts with differential expression during pancreas development using K-means clustering. We validated the clusters first using quantitative real time PCR and then by analyzing the Theiler stage 22 pancreas in situ hybridization staining patterns of over 600 of the identified genes using the GenePaint database. These were then categorized into one of the five expression domains within the developing pancreas. Based on these results we identified a cascade of transcriptional regulators expressed in the endocrine pancreas lineage and, from this, we developed a predictive regulatory network describing beta-cell development.

Conclusion
Taken together, this work provides evidence that the SAGE libraries generated here are a valuable resource for continuing to elucidate the molecular mechanisms regulating pancreas development. Furthermore, our studies provide a comprehensive analysis of pancreas development, and insights into the regulatory networks driving this process are revealed.
The intricate interface between immune and metabolic regulation: a role for leptin in the pathogenesis of multiple sclerosis?
Authors: Matarese Giuseppe , Procaccini Claudio , De Rosa Veronica 
Published: June 2008

AbstractOver the last few years, a series of molecules known to play a function in metabolism has also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production (i.e., genetic leptin deficiency, anorexia nervosa, malnutrition) are associated with increased susceptibility to infections. Conversely, immune-mediated disorders such as autoimmune disorders are associated with increased secretion of leptin and production of proinflammatory, pathogenic cytokines. Leptin could represent the “missing link” among immune response, metabolic function, and nutritional status. Indeed, more recently, leptin-deficient mice have been shown to be resistant to a series of experimentally induced autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Finally, leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signaling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3+CD4+ T cells. These data suggest that leptin can be considered as a link among immune tolerance, metabolic state, and autoimmunity and that strategies aimed at interfering with the leptin axis could represent innovative, therapeutic tools for autoimmune disorders.
Differential cell fates induced by all-trans retinoic acid-treated HL-60 human leukemia cells
Authors: Ozeki Munetaka , Shively John E 
Published: June 2008

AbstractHL-60 human leukemia cells, differentiated into a neutrophil lineage by all-trans retinoic acid (ATRA) treatment, express three members of the carcinoembryonic antigen (CEA) gene family, CEA-related cell adhesion molecule 1 (CEACAM1; CD66a), CEACAM3 (CD66d), and CEACAM6 (CD66c). CD66d is a neutrophil lineage-specific marker, and CD66a and CD66c are found on epithelial and other cells. HL-60 cells continuously treated with ATRA underwent apoptosis, and cells transiently treated for 1 day underwent cell-cycle arrest, entered into senescence, and exhibited reduced apoptosis with CD66-positive cells accounting for the majority of live cells. CD66 antigens were also induced in NB4 leukemic cells upon continuous treatment with ATRA. NB4 cells underwent apoptosis with a higher frequency in transient versus continuous-treated cells (38% vs. 19% at Day 5), in contrast to HL-60 cells that underwent cell-cycle arrest and senescence when transiently treated with ATRA. CD66 antigens were not induced in transient, ATRA-treated NB4 cells compared with HL-60 cells. Cell-cycle arrest in HL-60 cells involved reduction in expression levels of p21, cyclins D and E, while Rb1 exhibited reduction in protein levels without changes in mRNA levels over the time course of ATRA treatment. Analysis of several proapoptotic proteins implicated the activation of calpain and cleavage of Bax in the intrinsic apoptotic pathway, similar to published studies about the apoptosis of neutrophils. CD1d expression was also induced by ATRA in HL-60 cells and ligation with anti-CD1d antibody-induced apoptosis. In contrast, CD1d-positive primary monocytes were protected from spontaneous apoptosis by CD1d ligation. These studies demonstrate distinct cell fates for ATRA-treated HL-60 cells that provide new insights into ATRA-induced cell differentiation.
Induction of IL-33 expression and activity in central nervous system glia
Authors: Hudson Chad A , Christophi George P , Gruber Ross C , Wilmore Joel R , Lawrence David A , Massa Paul T 
Published: June 2008

AbstractIL-33 is a novel member of the IL-1 cytokine family and a potent inducer of type 2 immunity, as mast cells and Th2 CD4+ T cells respond to IL-33 with the induction of type 2 cytokines such as IL-13. IL-33 mRNA levels are extremely high in the CNS, and CNS glia possess both subunits of the IL-33R, yet whether IL-33 is produced by and affects CNS glia has not been studied. Here, we demonstrate that pathogen-associated molecular patterns (PAMPs) significantly increase IL-33 mRNA and protein expression in CNS glia. Interestingly, IL-33 was localized to the nucleus of astrocytes. Further, CNS glial and astrocyte-enriched cultures treated with a PAMP followed by an ATP pulse had significantly higher levels of supernatant IL-1β and IL-33 than cultures receiving any single treatment (PAMP or ATP). Supernatants from PAMP + ATP-treated glia induced the secretion of IL-6, IL-13, and MCP-1 from the MC/9 mast cell line in a manner similar to exogenous recombinant IL-33. Further, IL-33 levels and activity were increased in the brains of mice infected with the neurotropic virus Theiler’s murine encephalomyelitis virus. IL-33 also had direct effects on CNS glia, as IL-33 induced various innate immune effectors in CNS glia, and this induction was greatly amplified by IL-33-stimulated mast cells. In conclusion, these results implicate IL-33-producing astrocytes as a potentially critical regulator of innate immune responses in the CNS.
Effects of exogenous thyroid hormones on visual pigment composition in coho salmon (Oncorhynchus kisutch)
Authors: Temple Shelby E. , Ramsden Samuel D. , Haimberger Theodore J. , Veldhoen Kathy M. , Veldhoen Nik J. , Carter Nicolette L. , Roth Wolff-Michael , Hawryshyn Craig W. 
Published: June 2008

SUMMARY
The role of exogenous thyroid hormone on visual pigment content of rod and cone photoreceptors was investigated in coho salmon (Oncorhynchus kisutch). Coho vary the ratio of vitamin A1- and A2-based visual pigments in their eyes. This variability potentially alters spectral sensitivity and thermal stability of the visual pigments. We tested whether the direction of shift in the vitamin A1/A2 ratio, resulting from application of exogenous thyroid hormone, varied in fish of different ages and held under different environmental conditions. Changes in the vitamin A1/A2visual pigment ratio were estimated by measuring the change in maximum absorbance (λmax) of rods using microspectrophotometry(MSP). Exogenous thyroid hormone resulted in a long-wavelength shift in rod,middle-wavelength-sensitive (MWS) and long-wavelength-sensitive (LWS) cone photoreceptors. Rod and LWS cone λmax values increased,consistent with an increase in vitamin A2. MWS coneλ max values increased more than predicted for a change in the vitamin A1/A2 ratio. To account for this shift, we tested for the expression of multiple RH2 opsin subtypes. We isolated and sequenced a novel RH2 opsin subtype, which had 48 amino acid differences from the previously sequenced coho RH2 opsin. A substitution of glutamate for glutamine at position 122 could partially account for the greater than predicted shift in MWS cone λmax values. Our findings fit the hypothesis that a variable vitamin A1/A2 ratio provides seasonality in spectral tuning and/or improved thermal stability of visual pigments in the face of seasonal environmental changes, and that multiple RH2 opsin subtypes can provide flexibility in spectral tuning associated with migration–metamorphic events.
Detection of patches of coloured discs by bees
Authors: Wertlen Anna M. , Niggebrügge Claudia , Vorobyev Misha , Hempel de Ibarra Natalie 
Published: June 2008

SUMMARYTo find out how grouping of flowers into patches improves their detectability by hymenopteran pollinators, we trained honeybees and bumblebees to detect groups of three spatially separated disks and compared results with the detection limit for single disks. When the discs presented contrast to the long-wavelength-sensitive (L) receptor, grouping of disks improved the detectability. The disks were optically resolvable for the honeybee eye. The improvement of detectability was stronger for bumblebees than for honeybees. When disks did not present contrast to the L-receptor, the grouping did not improve the detectability, i.e. the detection limit was set by the size of a single disk. We conclude that in bees the neural mechanisms that improve detectability of grouped elements require input from the L-receptor. Our results indicate that grouping of flowers into sparse patches can improve their detectability by bees, even when individual flowers can be optically resolved by the eyes of bees, as long as flowers can be detected by the long-wavelength-sensitive receptor.
The responses of Atlantic cod (Gadus morhua L.) to ultrasound-emitting predators: stress, behavioural changes or debilitation?
Authors: Schack Henriette B. , Malte Hans , Madsen Peter T. 
Published: June 2008

SUMMARY
A previous study has reported that Atlantic cod can be conditioned to detect ultrasonic sound pulses of high intensity. This capability has been proposed as a mean for detection and avoidance of echolocating toothed whales that emit intense ultrasonic clicks. In this study, we use acoustic playbacks to test the hypotheses that unconditioned cod can detect and respond to intense ultrasound from toothed whales and from echosounders. Intense ultrasound exposure of 210 dB re. 1μPa (pp) did not cause a short-term stress response in the form of bradycardia in unconditioned cod. Free-swimming cod exposed to ultrasonic clicks and echosounder pulses with received levels of more than 204 dB re. 1 μPa (pp) did not elicit flight responses as seen in ultrasound detecting Alosinae. Furthermore, we tested the debilitating effects of high intensity ultrasound on swimming cod with no detected changes in swimming ability when exposed to more than 213 dB re. 1 μPa (pp). It is concluded that intense ultrasound exposure induces neither an antipredator nor a stress response in Atlantic cod, and that echosounder pulses and biosonar clicks therefore most probably play no ecophysiological role in wild cod populations.