tbuckley/cabot-search huggingface dataset:
Phylogenetic Simulation of Promoter Evolution: Estimation and Modeling of Binding Site Turnover Events and Assessing Their Impact on Alignment Tools
Authors: Weichun Huang, Joseph R Nevins, Uwe Ohler
Journal: Genome biology (2007)

Abstract Background The phenomenon of functional site turnover has important implications for the study of regulatory region evolution, such as for promoter sequence alignments and transcription factor binding site (TFBS) identification. At present, it remains difficult to estimate TFBS turnover rates on real genomic sequences, as reliable mappings of functional sites across related species are often not available. As an alternative, we introduce a flexible new simulation system, Phylogenetic Simulation of Promoter Evolution (PSPE), designed to study functional site turnovers in regulatory sequences. Results Using PSPE, we study replacement turnover rates of different individual TFBSs and simple modules of two sites under neutral evolutionary functional constraints. We find that TFBS replacement turnover can happen rapidly in promoters, and turnover rates vary significantly among different TFBSs and modules. We assess the influence of different constraints such as insertion/deletion rate and translocation distances. Complementing the simulations, we give simple but effective mathematical models for TFBS turnover rate prediction. As one important application of PSPE, we also present a first systematic evaluation of multiple sequence aligners regarding their capability of detecting TFBSs in promoters with site turnovers. Conclusion PSPE allows researchers for the first time to investigate TFBS replacement turnovers in promoters systematically. The assessment of alignment tools points out the limitations of current approaches to identify TFBSs in non-coding sequences, where turnover events of functional sites may happen frequently, and where we are interested in assessing the similarity on the functional level. PSPE is freely available at the authors' website.
Race and Gender Differences in C-Reactive Protein Levels
Authors: Amit Khera, Darren K. McGuire, Sabina A. Murphy, Harold G. Stanek, Sandeep R. Das, Wanpen Vongpatanasin, Frank H. Wians, Scott M. Grundy, James A. de Lemos
Journal: Journal of the American College of Cardiology (2005)
ANTIBODY AND IMMUNOGLOBULIN PRODUCTION AT THE CELLULAR LEVEL IN BURSECTOMIZED-IRRADIATED CHICKENS
Authors: Gunnar V. Alm, Raymond D. A. Peterson
Journal: The Journal of Experimental Medicine (1969)

The effect of bursectomy combined with sublethal X-irradiation in the newly hatched chicken on the immunoglobulin and antibody producing capacity in later life was investigated. The previous findings of a significant incidence of hypogammaglobulinemia in such animals were confirmed. Spleen cells from severely hypogammaglobulinemic animals synthesized and secreted little or no immunoglobulin. Such spleen lymphoid cells contained fewer immunoglobulin antigenic determinants than spleen cells from irradiated control animals as evidenced by their relative inability to respond by an increased DNA synthesis after in vitro culture with rabbit antiserum to chicken immunoglobulin. Therefore, the deficiency in the immunoglobulin synthesis extends not only to actively secreting cells such as plasma cells, but to the entire lymphoid cell population. As expected, most irradiated-bursectomized chickens, irrespective of plasma immunoglobulin levels failed to produce detectable amount of circulating antibodies to Brucella abortus antigen in the primary immune response. Severely hypogammaglobulinemic animals were completely unable to elaborate any plaque forming cells (PFC) in the primary response to sheep red blood cells (SRBC). The results of this investigation support the contention that in the severely hypogammaglobulinemic bursectomized-irradiated chicken the entire antibody producing and immunoglobulin producing cell line is absent. The possibility remains that precursor or stem cells are present but are not appropriately directed to antibody synthesis by other cell types.
14-3-3ζ Orchestrates Mammary Tumor Onset and Progression via miR-221–Mediated Cell Proliferation
Authors: Sumaiyah K. Rehman, Shau-Hsuan Li, Shannon L. Wyszomierski, Qingfei Wang, Ping Li, Ozgur Sahin, Yi Xiao, Siyuan Zhang, Yan Xiong, Jun Yang, Hai Wang, Hua Guo, Jitao D. Zhang, Daniel Medina, William J. Muller, Dihua Yu
Journal: Cancer Research (2013)

14-3-3ζ is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors, whereas control mice did not. Whey acidic protein promoter-driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared with MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling, leading to increased miR-221 transcription, which inhibited p27 CDKI translation and, consequently, promoted cell proliferation. Importantly, this 14-3-3ζ-miR-221-p27 proliferation axis is also functioning in breast tumors in patients and is associated with high-grade cancers. Taken together, our findings show that overexpression of 14-3-3ζ has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation.
Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients
Authors: Michelle Yap, Françoise Boeffard, Emmanuel Clave, Annaick Pallier, Richard Danger, Magali Giral, Jacques Dantal, Yohann Foucher, Cécile Guillot-Gueguen, Antoine Toubert, Jean-Paul Soulillou, Sophie Brouard, Nicolas Degauque
Journal: Journal of the American Society of Nephrology (2014)

Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vβ repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8(+) T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vβ diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA(+)CCR7(-)CD27(-)CD28(-)) CD8(+) T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8(+) T cells to secrete TNF-α and IFN-γ. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8(+) T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8(+) T cells may improve the early identification of at-risk patients.
Bupropion and the risk of sudden death: a self-controlled case-series analysis using The Health Improvement Network
Authors: R Hubbard
Journal: Thorax (2005)

Bupropion is an effective smoking cessation therapy but its use in the UK has been limited by concerns that it may increase the risk of sudden death.Data for all patients prescribed bupropion within The Health Improvement Network (a computerised general practice database) were extracted and the self-controlled case-series method was used to estimate the relative incidence of death during the first 28 days of treatment. The incidence of seizures, a recognised adverse effect of bupropion, was also investigated during this period.A total of 9329 individuals had been prescribed bupropion (mean age 44 years, 48% male). The total person-time after the first prescription for bupropion was 17,586 years, and during this time 121 people died. Two people died within the first 28 days of treatment, which was less than expected in comparison with the remaining observation period by an incidence ratio of 0.50 (95% confidence interval (CI) 0.12 to 2.05). Twenty eight people were recorded as having a total of 45 seizures (23 before starting bupropion, two in the first 28 days of treatment, and 20 at a later point). The relative incidence of seizures during the first 28 days of treatment was 3.62 (95% CI 0.87 to 15.09), equivalent to one additional seizure per 6219 first time bupropion users.Bupropion use is probably associated with an increased risk of seizures, but no evidence was found to suggest that the drug is associated with an increased risk of sudden death.
Lymphocyte surface modulation and cyclic nucleotides I. Topographic correlation of cyclic adenosine 3':5'-monophosphate and immunoglobulin immunofluorescence during lymphocyte capping.
Authors: H S Earp, P D Utsinger, W J Yount, M Logue, A L Steiner
Journal: The Journal of Experimental Medicine (1977)

The cross-linking of human peripheral lymphocyte surface Ig results in an early association of cyclic adenosine 3':5'-monophosphate (cAMP) and the cell surface Ig patches. Examination of the subsequent stages of cap formation reveals the continued relationship of cAMP and the clustered surface Ig. In addition, the generalized influx of calcium produced by the ionophore A-23187 disrupts human lymphocyte caps. During the process of cap dissolution cAMP is still associated with surface Ig. Therefore, it is hypothesized that the localized concentration of cyclic nucleotide and calcium ion regulates the movement of cell surface constituents by coordinating the function of the cell's contractile and structural elements.
Sickle β‐thalassemia: Identical twins differing in severity implicate nongenetic factors influencing course
Authors: Suresh K. Joishy, Paul F. Griner, Peter T. Rowley
Journal: American Journal of Hematology (1976)

Abstract 25‐yr old female identical twins of Italian‐American origin concordant for sickle β‐thalassemia were studied to explain their clinical differences. One of them has been severely affected from childhood with one aplastic crisis, an earlier onset of vaso‐occlusive crises, and recent cardiac decompensation; the other twin shows no cardiac decompensation. Similar are their degree of anemia, RBC indices, blood volumes, absence of splenic sequestration, depression of pO 2 , elevation of p50 and 2,3‐DPG, hemoglobin composition, and peripheral blood globin‐synthetic rates. Regarding differences, the more severely affected has a shorter 51 Cr RBC life span, a greater menstrual blood loss, and is more overweight, whereas the less severely affected has functional asplenia by 99m Tc scanning and a larger proportion of RBC with decreased cellular deformability. We conclude that in sickle β‐thalassemia: (1) genotype alone does not determine the clinical course; (2) significant differences in clinical course can occur with almost identical hemoglobin composition and globin synthetic rates; (3) cellular deformability changes do not correlate exactly with clinical course; and (4) functional asplenia and leanness may be advantageous.
Macrophages and Tissue Injury: Agents of Defense or Destruction?
Authors: Debra L. Laskin, Vasanthi R. Sunil, Carol R. Gardner, Jeffrey D. Laskin
Journal: The Annual Review of Pharmacology and Toxicology (2011)

The past several years have seen the accumulation of evidence demonstrating that tissue injury induced by diverse toxicants is due not only to their direct effects on target tissues but also indirectly to the actions of resident and infiltrating macrophages. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity, which function to fight infections, limit tissue injury, and promote wound healing. However, following exposure to toxicants, macrophages can become hyperresponsive, resulting in uncontrolled or dysregulated release of mediators that exacerbate acute tissue injury and/or promote the development of chronic diseases such as fibrosis and cancer. Evidence suggests that the diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the precise roles of these different macrophage populations in the pathogenic response to toxicants is key to designing effective treatments for minimizing tissue damage and chronic disease and for facilitating wound repair.
Where Adolescents and Young Adults With Cancer Receive Their Care: Does It Matter?
Authors: Brad H. Pollock
Journal: Journal of Clinical Oncology (2007)

During the last 25 years, improvement in survival for young children with cancer has been striking. Survival has also increased for older adults; however, 5-year survival rates have fallen for older adolescent and young adult (AYA) cancer patients. 1 Reasons for this decline, termed the “AYA Cancer Survival Gap,” remain unknown. Bleyer et al 2 suggested that a lower participation rate on clinical trials in this age group may partially account for poorer survival, but the reasons why remain unclear. The type of practice where cancer care is delivered may also influence clinical trial participation and outcome. Two articles in this issue of the Journal of Clinical Oncology analyzed where older adolescents and young adults received their cancer care. 3,4 Both utilized statewide, population-based cancer registries to describe the referral patterns for older AYAs with cancer. Newly diagnosed AYAs with cancer were categorized by whether or not they received their care at institutions that participate in the Children’s Oncology Group (COG). Albritton et al 3 identified characteristics predictive of receiving care at a pediatric oncology versus medical oncology treatment program. Whether care was delivered at Utah’s only pediatric cancer treatment program, the Primary Children’s Medical Center (PCMC; Salt Lake City), was determined for all incident cancer cases aged 0 to 24 years from the Utah Cancer Registry. Overall, 34% of older adolescents aged 15 to 19 years were seen at PCMC, whereas 97% of children age 0 to 9 years and 82% of children 10 to 14 years were seen at PCMC. The rate at which older adolescents were cared for at a pediatric center varied by diagnosis: 29% for lymphoma, 34% for brain tumors, and 53% for leukemias. Howell et al 4 found that 87% of young patients 0 to 14 years in Georgia were seen at one of the five COG-affiliated institutions in the state. Compared with younger patients, only 36% of 15- to 19-year-olds were seen at COG institutions. In an earlier analysis of Surveillance, Epidemiology, and End Results (SEER) cases from
Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy
Authors: Gordon C. Sharp, William S. Irvin, Robert L. LaRoque, Carmen Velez, Virginia Daly, A. D. Kaiser, Halsted R. Holman
Journal: Journal of Clinical Investigation (1971)

Using a hemagglutination test which can detect antibodies to (a) native and denatured deoxyribonucleic acid (DNA) and (b) an extractable nuclear antigen (ENA), a comparative study of patterns of autoantibody formation has been done in systemic lupus erythematosus (SLE) and related rheumatic diseases. Antibody to native DNA was present in the serum in 96% of patients with active SLE and disappeared during remissions. Antibody to ENA was found in 86% of those patients with SLE nephritis who responded to treatment but in only 8% of those who did not. The highest titers of antibody to ENA were found in patients having a mixed connective tissue disease syndrome with features of SLE, scleroderma, and myositis. The latter syndrome was notable for the absence of renal disease and for a striking responsiveness to corticosteroid therapy. Hemagglutination testing of 277 sera from normal persons and patients with a wide variety of acute diseases other than SLE revealed the presence of antibody to native DNA in only 1.4% and antibody to ENA in only 0.4%. These results yield significant correlations among the pattern of autoimmune reactivity, the clinical form of the rheumatic disease, and responsiveness to treatment. They implicate the qualitative nature of the patient's immune response as a conditioning factor in the type of disease. Together with other correlations they may allow classification of rheumatic diseases into more biologically meaningful groups and lead to more selective methods of therapy.
IgE antibody and resistance to infection. I. Selective suppression of the IgE antibody response in rats diminishes the resistance and the eosinophil response to Trichinella spiralis infection.
Authors: A J Dessein, W L Parker, S L James, J R David
Journal: The Journal of Experimental Medicine (1981)

Selective suppression of the total IgE antibody response has been achieved in rats by injection of rabbit anti-rat epsilon-chain antibodies. This IgE-specific suppression was maintained during the course of a natural infection by the nematode Trichinella spiralis. Depletion of the IgE antibody response resulted in a marked reduction of the number of eosinophils attracted to the T. spiralis larvae encysted in striated muscle. Blood eosinophilia following T. spiralis infection, although reaching normal peak levels, was abbreviated in IgE-suppressed animals. Moreover, IgE-depleted animals were more susceptible to the infection; they harbored two to three times more larvae encysted in their muscles than their control litter mates.
Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report
Authors: Stephen J Wroe, Suvankar Pal, Durrenajaf Siddique, Harpreet Hyare, Rebecca Macfarlane, Susan Joiner, Jacqueline M Linehan, Sebastian Brandner, Jonathan DF Wadsworth, Patricia Hewitt, John Collinge
Journal: The Lancet (2006)
FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23
Authors: Shiguang Liu, Luke Vierthaler, Wen Tang, Jianping Zhou, L. Darryl Quarles
Journal: Journal of the American Society of Nephrology (2008)

Fibroblast growth factor 23 (FGF23) is a phosphaturic factor that suppresses both sodium-dependent phosphate transport and production of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] in the proximal tubule. In vitro studies suggest that FGFR3 is the physiologically relevant receptor for FGF23 in the kidney, but this has not been established in vivo. Here, immunohistochemical analysis of the mouse kidney revealed that the proximal tubule expresses FGF receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4. Compared with wild-type mice, Hyp mice, which have elevated circulating levels of FGF23, exhibited low levels of serum phosphate and 1,25(OH)(2)D, reduced expression of the sodium-dependent phosphate transporter NPT2a in the proximal tubules, and low bone mineral density as a result of osteomalacia. In contrast, neither the serum phosphate nor 1,25(OH)(2)D levels were altered in FGFR3-null mice. For examination of the role of FGFR3 in mediating the effects of FGF23, Hyp mice were crossed with FGFR3-null mice; interestingly, this failed to correct the aforementioned metabolic abnormalities of Hyp mice. Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mice. Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the kidney localization of FGFR1 was investigated. FGFR1 co-localized with Klotho, the co-factor required for FGF23-dependent FGFR activation, in the distal tubule. In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the proximal tubule, and co-localization of FGFR1 and Klotho suggests that the distal tubule may be an effector site of FGF23.
Depression of atrioventricular sensitivity in the dog by successive brief bursts of vagal stimulation.
Authors: P Martin
Journal: Circulation Research (1976)

When identical, successive single vagal stimulations, separated in time (T) by 2-60 seconds, are applied in the dog, the peak change in atrioventricular conduction time for the second stimulus, deltaAV2, is less than that of the first, deltaAV1, that is, the ratio deltaAV2/deltaAV1 less than 1.0 (the mean minimum deltaAV2/deltaAV1=0.52). It was further determined that at any one given T, the actual value of deltaAV2/deltaAV1 also was a function of the first stimulus amplitude. The same dependence of deltaAV2/deltaAV1 on the first stimulus amplitude was found when the amplitude was varied either by (1) changing the number of vagal fibers stimulated for both the first and second response, but at a constant AD (the delay in the cardiac cycle at which the stimulus was given), or (2) by stimulating the same number of fibers but changing AD for both the first and second response. Also the same characteristic of deltaAV2/deltaAV1 plotted vs. T was found either (1) when both the first and second responses were produced by stimulation of the same nerve, or (2) when stimulated of the nerve from one side produced the first response and the alternate side the second response. These data suggest that the reason for this deltaAV2/deltaAV1 time-dependent effect lies in changes in receptor responsiveness or in acetylcholine inactivation, but not in mechanisms purely internal to the nerve terminal associated with synthesis, storage, or release of acetylcholine.
Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry
Authors: Gareth R. Williams, Kaat Fierens, Stephen G. Preston, Daniel Lunn, Oliwia Rysnik, Sofie De Prijck, Mirjam Kool, Hannah C. Buckley, Bart N. Lambrecht, Dermot O’Hare, Jonathan M. Austyn
Journal: The Journal of Experimental Medicine (2014)

There is currently no paradigm in immunology that enables an accurate prediction of how the immune system will respond to any given agent. Here we show that the immunological responses induced by members of a broad class of inorganic crystalline materials are controlled purely by their physicochemical properties in a highly predictable manner. We show that structurally and chemically homogeneous layered double hydroxides (LDHs) can elicit diverse human dendritic cell responses in vitro. Using a systems vaccinology approach, we find that every measured response can be modeled using a subset of just three physical and chemical properties for all compounds tested. This correlation can be reduced to a simple linear equation that enables the immunological responses stimulated by newly synthesized LDHs to be predicted in advance from these three parameters alone. We also show that mouse antigen–specific antibody responses in vivo and human macrophage responses in vitro are controlled by the same properties, suggesting they may control diverse responses at both individual component and global levels of immunity. This study demonstrates that immunity can be determined purely by chemistry and opens the possibility of rational manipulation of immunity for therapeutic purposes.