tbuckley/cabot-search huggingface dataset:
Cytotoxic T lymphocyte responses in allogeneic radiation bone marrow chimeras. The chimeric host strictly dictates the self-repertoire of Ia-restricted T cells but not H-2K/D-restricted T cells.
Authors: S M Bradley, A M Kruisbeek, A Singer
Journal: The Journal of Experimental Medicine (1982)

The present report has used fully H-2 allogeneic radiation bone marrow chimeras to assess the role of host restriction elements in determining the self-specificity of Ia- and H-2K/D-restricted T cells that participate in the generation of trinitrophenyl (TNP)-specific cytotoxic T lymphocytes (CTL). It was demonstrated that there exists a stringent requirement for the recognition of host thymic-type Ia determinants, but there exists only a preference for host thymic-type H-2K/D determinants. Indeed, once the stringent requirement for recognition of host Ia determinants was fulfilled, anti-TNP CTL were generated in response to TNP-modified stimulators that expressed either donor-type or host-type H-2K/D determinants. The CTL that were generated in response to TNP-modified donor-type stimulators were shown to be specific for TNP and restricted to the non-thymic H-2K/D determinants of the chimeric donor. Thus, these results demonstrate in a single immune response that the thymic hypothesis accurately predicts the self-specificity expressed by Ia-restricted T cells, but does not fully account for the self-specificity expressed by H-2K/D-restricted T cells. These results are consistent with the concept that H-2K/D-restricted T cells, but not Ia-restricted T cells, can differentiate into functional competence either intrathymically or extra-thymically. The present results are also informative for understanding the cellular interactions that are required for the generation of antigen-specific CTL responses. The Ia-restricted T cells that are required for the generation of H-2K/D-restricted anti-TNP CTL were shown to be helper T (TH) cells since (a) like TH cells functioning in antibody responses, they were specific for Ia determinants expressed by accessory cells, and (b) their function could be replaced by either TNP-primed, irradiated TH cells or by nonspecific soluble helper factors. It was also shown that the T-T cell interaction between Ia-restricted TH cells and H-2K/D-restricted precursor CTL (pCTL) is not Ia restricted. Rather, the results demonstrate that the generation of anti-TNP CTL responses involve two parallel sets of major histocompatibility complex-restricted cell interactions, an Ia-restricted TH-accessory cell interaction required for TH cell activation, and an H-2K/D-restricted pCTL-stimulator cell interaction required for pCTL stimulation. The interaction between activated TH cells and stimulated pCTL is mediated, at least in part, by nonspecific soluble helper factors.
Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
Authors: Gustavo del Real, Sonia Jiménez-Baranda, Rosa Ana Lacalle, Emilia Mira, Pilar Lucas, Concepción Gómez-Moutón, Ana C. Carrera, Carlos Martínez-A., Santos Mañes
Journal: The Journal of Experimental Medicine (2002)

Human immunodeficiency virus (HIV)-1 infection depends on multiple lateral interactions between the viral envelope and host cell receptors. Previous studies have suggested that these interactions are possible because HIV-1 receptors CD4, CXCR4, and CCR5 partition in cholesterol-enriched membrane raft domains. We generated CD4 partitioning mutants by substituting or deleting CD4 transmembrane and cytoplasmic domains and the CD4 ectodomain was unaltered. We report that all CD4 mutants that retain raft partitioning mediate HIV-1 entry and CD4-induced Lck activation independently of their transmembrane and cytoplasmic domains. Conversely, CD4 ectodomain targeting to a nonraft membrane fraction results in a CD4 receptor with severely diminished capacity to mediate Lck activation or HIV-1 entry, although this mutant binds gp120 as well as CD4wt. In addition, the nonraft CD4 mutant inhibits HIV-1 X4 and R5 entry in a CD4+ cell line. These results not only indicate that HIV-1 exploits host membrane raft domains as cell entry sites, but also suggest new strategies for preventing HIV-1 infection.
Anti-Inflammatory and Profibrinolytic Effect of Insulin in Acute ST-Segment–Elevation Myocardial Infarction
Authors: Ajay Chaudhuri, David Janicke, Michael F. Wilson, Devjit Tripathy, Rajesh Garg, Arindam Bandyopadhyay, Janeen Calieri, Debbie Hoffmeyer, Tufail Syed, Husam Ghanim, Ahmad Aljada, Paresh Dandona
Journal: Circulation (2004)

Background— The clinical benefits of insulin previously observed in acute ST-segment–elevation myocardial infarction (STEMI) may be partially explained by an anti-inflammatory effect. We assessed this potential effect of insulin in STEMI patients treated with fibrinolytics. Methods and Results— Thirty-two patients receiving reteplase were randomly assigned infusions of either insulin at 2.5 U/h, dextrose, and potassium (GIK) or normal saline and potassium (C) for 48 hours. Plasma concentrations of high-sensitivity C-reactive protein (CRP), serum amyloid A (SAA), plasminogen activator inhibitor-1 (PAI-1), creatine kinase (CK), and CK-MB were measured at baseline and sequentially for 48 hours. Total p47 phox protein in mononuclear cells was measured in a subgroup of 13 subjects. Baseline CRP and SAA were significantly increased (2- to 4-fold) at 24 and 48 hours in each group ( P &lt;0.01). However, in the insulin group, there was a significant ( P &lt;0.05) attenuation of the absolute rise in concentration of CRP and SAA from baseline. The absolute increase of CRP and SAA was reduced by 40% (CRP) and 50% (SAA) at 24 hours and at 48 hours compared with the control group. The absolute increase in PAI-1 from baseline and the percentage increase in p47 phox over 48 hours were significantly ( P &lt;0.05) lower in the insulin-treated group. CK-MB peaked earlier and tended to be lower in insulin-treated subjects, especially in patients with inferior MI. Conclusions— Insulin has an anti-inflammatory and profibrinolytic effect in patients with acute MI. These effects may contribute to the clinical benefits of insulin in STEMI.
Blocking TGF-β1 Protects the Peritoneal Membrane from Dialysate-Induced Damage
Authors: Jesús Loureiro, Abelardo Aguilera, Rafael Selgas, Pilar Sandoval, Patricia Albar-Vizcaíno, María Luisa Pérez-Lozano, Vicente Ruiz-Carpio, Pedro L. Majano, Santiago Lamas, Fernando Rodríguez-Pascual, Francisco Borras-Cuesta, Javier Dotor, Manuel López-Cabrera
Journal: Journal of the American Society of Nephrology (2011)

During peritoneal dialysis (PD), mesothelial cells undergo mesothelial-to-mesenchymal transition (MMT), a process associated with peritoneal-membrane dysfunction. Because TGF-β1 can induce MMT, we evaluated the efficacy of TGF-β1-blocking peptides in modulating MMT and ameliorating peritoneal damage in a mouse model of PD. Exposure of the peritoneum to PD fluid induced fibrosis, angiogenesis, functional impairment, and the accumulation of fibroblasts. In addition to expressing fibroblast-specific protein-1 (FSP-1), some fibroblasts co-expressed cytokeratin, indicating their mesothelial origin. These intermediate-phenotype (Cyto(+)/FSP-1(+)) fibroblasts had features of myofibroblasts with fibrogenic capacity. PD fluid treatment triggered the appearance of CD31(+)/FSP-1(+) and CD45(+)/FSP-1(+) cells, suggesting that fibroblasts also originate from endothelial cells and from cells recruited from bone marrow. Administration of blocking peptides significantly ameliorated fibrosis and angiogenesis, improved peritoneal function, and reduced the number of FSP-1(+) cells, especially in the Cyto(+)/FSP-1(+) subpopulation. Conversely, overexpression of TGF-β1 in the peritoneum by adenovirus-mediated gene transfer led to a marked accumulation of fibroblasts, most of which derived from the mesothelium. Taken together, these results demonstrate that TGF-β1 drives the peritoneal deterioration induced by dialysis fluid and highlights a role of TGF-β1-mediated MMT in the pathophysiology of peritoneal-membrane dysfunction.
Climate and Dengue Transmission: Evidence and Implications
Authors: Cory W. Morin, Andrew C. Comrie, Kacey Ernst
Journal: Environmental Health Perspectives (2013)

Background: Climate influences dengue ecology by affecting vector dynamics, agent development, and mosquito/human interactions. Although these relationships are known, the impact climate change will have on transmission is unclear. Climate-driven statistical and process-based models are being used to refine our knowledge of these relationships and predict the effects of projected climate change on dengue fever occurrence, but results have been inconsistent.Objective: We sought to identify major climatic influences on dengue virus ecology and to evaluate the ability of climate-based dengue models to describe associations between climate and dengue, simulate outbreaks, and project the impacts of climate change.Methods: We reviewed the evidence for direct and indirect relationships between climate and dengue generated from laboratory studies, field studies, and statistical analyses of associations between vectors, dengue fever incidence, and climate conditions. We assessed the potential contribution of climate-driven, process-based dengue models and provide suggestions to improve their performance.Results and Discussion: Relationships between climate variables and factors that influence dengue transmission are complex. A climate variable may increase dengue transmission potential through one aspect of the system while simultaneously decreasing transmission potential through another. This complexity may at least partly explain inconsistencies in statistical associations between dengue and climate. Process-based models can account for the complex dynamics but often omit important aspects of dengue ecology, notably virus development and host–species interactions.Conclusion: Synthesizing and applying current knowledge of climatic effects on all aspects of dengue virus ecology will help direct future research and enable better projections of climate change effects on dengue incidence.Citation: Morin CW, Comrie AC, Ernst KC. 2013. Climate and dengue transmission: evidence and implications. Environ Health Perspect 121:1264–1272; http://dx.doi.org/10.1289/ehp.1306556
The <scp>TLR</scp>4‐associated phospholipase D1 activation is crucial for Der f 2‐induced <scp>IL</scp>‐13 production
Authors: H.‐J. Choi, S.‐Y. Park, J. H. Cho, J.‐W. Park, J.‐H. Sohn, Y.‐J. Kim, J.‐W. Oh, J.‐S. Han
Journal: Allergy (2015)

House dust mites (HDMs) are the most important source of indoor aeroallergens that contribute to the rising incidence of allergic diseases such as allergic asthma. The major HDM, Der f 2, induces inflammatory cytokine expression. Little is known about the signaling pathway involved.We wanted to define the Der f 2 signaling pathway from its receptor to the transcription factor responsible for IL-13 expression and production.Human bronchial epithelial cells were stimulated with Der f 2. The release and gene expression of IL-13 were measured by means of ELISA and RT-PCR, respectively. In the airway inflammation mouse model, airway responses were assessed using ELISA, histology, BAL fluid, and methacholine responsiveness.Here, we show that Der f 2 binds to TLR4 and induces IL-13 expression and production. In the airway inflammation mouse model, Der f 2-induced IL-13 production significantly decreased with treatment of TAK-242, a novel TLR4 inhibitor. Activation of TLR4 by Der f 2 requires the recruitment and activation of Syk, which leads to phosphorylation of PLCγ and membrane translocation of PKCα. p38 MAPK is then activated by PKCα and stimulates PLD1 activity by phosphorylating the Thr147 residue of PLD1. PLD1 activation enhanced binding of ROCK1 to ATF-2 and leads to increased expression of IL-13.Our data extend the knowledge for a variety of possible roles of PLD1 in allergic disorders including asthma pathogenesis and suggest possible candidacy of PLD1 as a molecular target for novel therapeutic approaches.
Estrogen-Related Receptor α Expression and Function Is Associated with the Transcriptional Coregulator AIB1 in Breast Carcinoma
Authors: Stefanie Heck, Joachim Rom, Verena Thewes, Natalia Becker, Beatrix Blume, Hans Peter Sinn, Ulrich Deuschle, Christof Sohn, Andreas Schneeweiss, Peter Lichter
Journal: Cancer Research (2009)

The significance of the estrogen-related receptor alpha (ERRalpha) as prognostic marker for poor clinical outcome in breast carcinoma has recently been reported. Transcriptional activity of nuclear receptors such as ERRalpha depends on coregulatory proteins. Thus, we compared the expression of different receptors, coregulators, and target genes on RNA and protein level in identical primary breast tumor samples (n = 48). We found a positive correlation between the transcripts of ERRalpha and AIB1 (amplified in breast cancer-1), a coactivator overexpressed in breast cancers and associated with resistance to antihormone treatment. These data were confirmed on protein level, studying an independent patient collection (n = 257). Expression of the estrogen-regulated gene pS2 was associated with ERRalpha only in tumors, where estrogen receptor (ERalpha) expression was low or absent. In ERalpha high expressing tumors, no correlation of ERRalpha and pS2 was observed. AIB1 interacts directly with ERRalpha as shown by fluorescence-resonance energy transfer, mammalian two-hybrid, and coimmunoprecipitation assays with endogenous proteins. It enhances ERRalpha transcriptional activity in ERalpha-negative breast cancer cell lines as shown in functional reporter gene assays. Blocking ERRalpha with an inverse agonist abolished interaction and coactivation by AIB1. Recruitment of both proteins to ERRalpha target gene promoters further supports the significance of their interaction. Our findings identify AIB1 as functionally relevant cofactor for ERRalpha in breast carcinoma. ERRalpha/AIB1 complexes may control estradiol-regulated genes in a hormone-independent manner. Accordingly, ERRalpha might be a rewarding target for treatment of endocrine-resistant tumors.
Fenestrated Glomerular Capillaries Are Unique
Authors: Wilhelm Kriz
Journal: Journal of the American Society of Nephrology (2008)

The article by Ichimura et al. [1][1] in this issue of JASN reports during embryologic development in the rat and under regenerative conditions that glomerular endothelia form PV-1–positive fenestrae bridged by a diaphragm, as fenestrated capillaries elsewhere in the body, including peritubular
Molecular signature of hypersaline adaptation: insights from genome and proteome composition of halophilic prokaryotes
Authors: Sandip Paul, Sumit K Bag, Sabyasachi Das, Eric T Harvill, Chitra Dutta
Journal: Genome biology (2008)

Halophilic prokaryotes are adapted to thrive in extreme conditions of salinity. Identification and analysis of distinct macromolecular characteristics of halophiles provide insight into the factors responsible for their adaptation to high-salt environments. The current report presents an extensive and systematic comparative analysis of genome and proteome composition of halophilic and non-halophilic microorganisms, with a view to identify such macromolecular signatures of haloadaptation.Comparative analysis of the genomes and proteomes of halophiles and non-halophiles reveals some common trends in halophiles that transcend the boundary of phylogenetic relationship and the genomic GC-content of the species. At the protein level, halophilic species are characterized by low hydrophobicity, over-representation of acidic residues, especially Asp, under-representation of Cys, lower propensities for helix formation and higher propensities for coil structure. At the DNA level, the dinucleotide abundance profiles of halophilic genomes bear some common characteristics, which are quite distinct from those of non-halophiles, and hence may be regarded as specific genomic signatures for salt-adaptation. The synonymous codon usage in halophiles also exhibits similar patterns regardless of their long-term evolutionary history.The generality of molecular signatures for environmental adaptation of extreme salt-loving organisms, demonstrated in the present study, advocates the convergent evolution of halophilic species towards specific genome and amino acid composition, irrespective of their varying GC-bias and widely disparate taxonomic positions. The adapted features of halophiles seem to be related to physical principles governing DNA and protein stability, in response to the extreme environmental conditions under which they thrive.
<i>In vivo</i>, Noninvasive, Label-Free Detection and Eradication of Circulating Metastatic Melanoma Cells Using Two-Color Photoacoustic Flow Cytometry with a Diode Laser
Authors: Ekaterina I. Galanzha, Evgeny V. Shashkov, Paul M. Spring, James Y. Suen, Vladimir P. Zharov
Journal: Cancer Research (2009)

Abstract The circulating tumor cell (CTC) count has been shown as a prognostic marker for metastasis development. However, its clinical utility for metastasis prevention remains unclear, because metastases may already be present at the time of initial diagnosis with existing assays. Their sensitivity ex vivo is limited by a small blood sample volume, whereas in vivo examination of larger blood volumes may be clinically restricted by the toxicity of labels used for targeting of CTCs. We introduce a method for in vivo photoacoustic blood cancer testing with a high-pulse-repetition-rate diode laser that, when applied to melanoma, is free of this limitation. It uses the overexpression of melanin clusters as intrinsic, spectrally-specific cancer markers and signal amplifiers, thus providing higher photoacoustic contrast of melanoma cells compared with a blood background. In tumor-bearing mouse models and melanoma-spiked human blood samples, we showed a sensitivity level of 1 CTC/mL with the potential to improve this sensitivity 103-fold in humans in vivo, which is impossible with existing assays. Additional advances of this platform include decreased background signals from blood through changes in its oxygenation, osmolarity, and hematocrit within physiologic norms, assessment of CTCs in deep vessels, in vivo CTC enrichment, and photoacoustic-guided photothermal ablation of CTCs in the bloodstream. These advances make feasible the early diagnosis of melanoma during the initial parallel progression of primary tumor and CTCs, and laser blood purging using noninvasive or hemodialysis-like schematics for the prevention of metastasis. [Cancer Res 2009;69(20):7926–34]
Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke
Authors: Tine Wyseure, Marina Rubio, Frederik Denorme, Sara Martinez de Lizarrondo, Miet Peeters, Ann Gils, Simon F. De Meyer, Denis Vivien, Paul J. Declerck
Journal: Blood (2014)
SHON Is a Novel Estrogen-Regulated Oncogene in Mammary Carcinoma That Predicts Patient Response to Endocrine Therapy
Authors: Yewon Jung, Tarek M.A. Abdel-Fatah, Stephen Y.T. Chan, Christopher C. Nolan, Andrew R. Green, Ian O. Ellis, Lili Li, Baiqu Huang, Jun Lu, Bing Xu, Longxin Chen, Runlin Z. Ma, Min Zhang, Jingru Wang, ZhengSheng Wu, Tao Zhu, Jo K. Perry, Peter E. Lobie, Dong-Xu Liu
Journal: Cancer Research (2013)

Abstract Endocrine therapies are the primary systemic intervention for patients with estrogen receptor–positive (ER+) breast cancer. However, a significant proportion of initially responsive ER+ tumors develop resistance, with relapses occurring in up to 50% of patients. Lack of reliable predictive biomarkers remains an unfilled need for enhanced clinical management of this disease. In this study, we address this need in identifying a novel estrogen-regulated gene called SHON (secreted hominoid-specific oncogene). Enforced expression of SHON in breast cancer cells increased their proliferation, survival, migration, and invasion in vitro. Furthermore, SHON enhanced the oncogenicity of these cells in xenograft models of human breast cancer and was also sufficient to oncogenically transform MCF10A human mammary epithelial cells. Conversely, SHON attenuation mediated by RNA interference- or antibody-based methods reduced the oncogenicity of breast cancer cells. Mechanistic investigations indicated that the oncogenic transforming properties of SHON were mediated by BCL-2 and NF-κB. In primary clinical specimens, SHON was immunohistochemically detected in 62% of breast cancers, in which its expression was positively correlated with ER expression. In this setting, SHON expression predicted a favorable response to endocrine therapy in high-risk patients with ER+ breast cancer. Taken together, our findings identify SHON as a novel human oncogene with predictive utility in ER+ breast cancer, perhaps offering a simple biomarker to predict the therapeutic efficacy of antiestrogen therapy in patients with breast cancer. Cancer Res; 73(23); 6951–62. ©2013 AACR.
What's the Professor Got to Do with It?
Authors: Karen J. Maschke
Journal: The American Journal of Bioethics (2002)

tiple publications, eliminating anomalous or disconarming data or studies: all undermine the integrity of science and public conadence in its products. A discussion of the ethical underpinnings of the scientiac enterprise is a valuable part of bioscience ethics training. Not all three of these areas are best served by didactic methods. I fully concur with other commentators that the best way to instill these values is by having them discussed throughout the curriculum, not just in ethics classes, and by sensitizing mentors to the need to model these attitudes and behaviors to their graduate apprentices. Finally, one last point: Chakrabarty (2002) raises the question of how we make ethical decisions in a multiethnic society. However, the goal of ethics education is not necessarily (or at least not only) to transmit “the answers” to those ethical issues for which consensus exists; even within a homogenous population there can be strong differences in ethical reasoning and conclusions. The purpose of ethical training among scientists is primarily to train them to recognize ethical issues when they arise (which is often more difacult for bench scientists than one might think), to give them tools to analyze and consider those issues, and to engage them in the national and international discussion. The serious engagement of basic scientists with these issues is ultimately more valuable, I believe, than achieving full consensus about them. ■