gebhart/patrepeval huggingface dataset:
Insights into the behaviour of systems biology models from dynamic sensitivity and identifiability analysis: a case study of an NF-κB signalling pathway (2006)

Mathematical modelling offers a variety of useful techniques to help in understanding the intrinsic behaviour of complex signal transduction networks. From the system engineering point of view, the dynamics of metabolic and signal transduction models can always be described by nonlinear ordinary differential equations (ODEs) following mass balance principles. Based on the state-space formulation, many methods from the area of automatic control can conveniently be applied to the modelling, analysis and design of cell networks. In the present study, dynamic sensitivity analysis is performed on a model of the IkappaB-NF-kappaB signal pathway system. Univariate analysis of the Euclidean-form overall sensitivities shows that only 8 out of the 64 parameters in the model have major influence on the nuclear NF-kappaB oscillations. The sensitivity matrix is then used to address correlation analysis, identifiability assessment and measurement set selection within the framework of least squares estimation and multivariate analysis. It is shown that certain pairs of parameters are exactly or highly correlated to each other in terms of their effects on the measured variables. The experimental design strategy provides guidance on which proteins should best be considered for measurement such that the unknown parameters can be estimated with the best statistical precision. The whole analysis scheme we describe provides efficient parameter estimation techniques for complex cell networks.
Fluorescent Indicators for Cyclic GMP Based on Cyclic GMP-Dependent Protein Kinase Iα and Green Fluorescent Proteins (2000)

We describe herein fluorescent indicators for cyclic GMP (cGMP) in single living cells. cGMP-dependent protein kinase Ialpha (PKG Ialpha), a receptor for cGMP, was fused with blue- and red-shifted green fluorescent proteins (GFPs) to its N- and C-termini, respectively. Using PKG lalpha delta1-47, in which the dimerization domain was deleted, fluorescence resonance energy transfer between the GFPs was found to increase upon cGMP-induced conformational change in PKG Ialpha delta1-47. We demonstrated that thus-developed fluorescent indicators reversibly responded to cGMP that was produced in nitric oxide-stimulated HEK293 cells. The present genetically encoded fluorescent indicators open a way not only for understanding the dynamics of cGMP signaling in single cells and organisms but also for discovering pharmaceuticals such as isoform-specific inhibitors for phosphodiesterases.
PCR Cloning Protocols (1996)

The advent of PCR, with its power to amplify tiny amounts of DNA, quickly spawned the development of many analytical procedures that are widely used for detection, measurement, and characterization. H
Indirect fluorometric detection of cations in capillary zone electrophoresis (1990)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIndirect fluorometric detection of cations in capillary zone electrophoresisLarry. Gross and Edward S. YeungCite this: Anal. Chem. 1990, 62, 5, 427–431Publication Date (Print):March 1, 1990Publication History Published online1 May 2002Published inissue 1 March 1990https://pubs.acs.org/doi/10.1021/ac00204a002https://doi.org/10.1021/ac00204a002research-articleACS PublicationsRequest reuse permissionsArticle Views179Altmetric-Citations119LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Lethal action of bacteriophage lambda S gene (1982)

The functions of the bacteriophage lambda lysis genes S, R, and Rz were investigated. Different combinations of wild-type and inactive alleles of all three lysis genes were cloned into the plasmid pBH20 and were expressed under the control of a lac operator-promoter. The involvement of the Rz gene in lysis was proposed in our previous work and was confirmed by the Mg2+-dependent lysis defect of clones in which part of the Rz gene is deleted. Membrane vesicles prepared from induced S+ cells were shown to have a severely reduced capacity for active transport of glucose; this defect was detectable at least 20 min before lysis. Cell viability was also shown to decrease very soon after induction, long before physiological death and lysis; this decrease in viability is absolutely dependent on S expression and independent of R and Rz. The nonviable fraction of cells at any time after induction was demonstrated to be equal to the fraction committed to eventual lysis. Induction of an Sts clone showed that the S gene product is stable and capable of inducing lysis long after the cessation of synthesis of S gene product. A model for S action is proposed.
The Src family tyrosine kinases are required for platelet-derived growth factor-mediated signal transduction in NIH 3T3 cells. (1993)

Three members of the Src family of protein tyrosine kinases Src, Fyn, and Yes associate with the activated platelet-derived growth factor (PDGF) receptor in vivo. This interaction requires the Src homology 2 (SH2) domain of the Src family member and causes activation of the intrinsic activity of the Src family kinases. We microinjected cells with DNA encoding catalytically inactive forms of the Src and Fyn proteins and examined their effects on PDGF-mediated signaling in vivo. Kinase-inactive Src and Fyn inhibited PDGF-stimulated entry of cells into S phase, whereas kinase-active forms of the proteins had no inhibitory effects. An intact SH2 domain was required for inhibition. Furthermore, when kinase-inactive Fyn was comicroinjected with a plasmid expressing activated Ras, the cells could enter S phase, indicating that the expression of kinase-inactive Fyn did not damage cell viability. Injection of an antibody specific for Src, Fyn, and Yes also reduced signal transduction through the PDGF receptor but only when injected within 8 hr of PDGF stimulation. Together these results indicate that the ubiquitously expressed Src family members are required for PDGF-induced mitogenic signaling.
Balanced Approximation of Stochastic Systems (1990)

The state of a linear system is an information interface between past inputs and future outputs, and system approximation (even identification) is essentially a problem of approximating a large-dimensional interface by a low-order partial state. Balanced Model Reduction [IEEE Trans. Automat. Control , 26 (1981), pp. 17–31], the Fujishige–Nagai–Sawaragi Model Reduction Algorithm [Internal. J. Control, 22 (1975), pp. 807–819], and the Principal Hankel Components Algorithm for system identification [Proc. 12th Asilomar Conference on Circuits Systems and Computers, Pacific Grove, CA, November 1978] approximate this input-output interface by its principal components. First generalizations of balanced model reduction to the stochastic system approximation problem are presented. Then the ideas of principal components to the problem of approximating the information interface between two random vectors are generalized; this leads to three approximate stochastic realization methods based on singular value decomposition. These methods and their relationship to the different kinds of balanced stochastic model reduction are discussed.
Cutting Edge: TREM-2 Attenuates Macrophage Activation (2006)

The triggering receptor expressed on myeloid cells 2 (TREM-2) delivers intracellular signals through the adaptor DAP12 to regulate myeloid cell function both within and outside the immune system. The role of TREM-2 in immunity has been obscured by the failure to detect expression of the TREM-2 protein in vivo. In this study, we show that TREM-2 is expressed on macrophages infiltrating the tissues from the circulation and that alternative activation with IL-4 can induce TREM-2. TREM-2 expression is abrogated by macrophage maturation with LPS of IFN-gamma. Using TREM-2(-/-) mice, we find that TREM-2 functions to inhibit cytokine production by macrophages in response to the TLR ligands LPS, zymosan, and CpG. Furthermore, we find that TREM-2 completely accounts for the increased cytokine production previously reported by DAP12(-/-) macrophages. Taken together, these data show that TREM-2 is expressed on newly differentiated and alternatively activated macrophages and functions to restrain macrophage activation.
In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses (2005)

B7-DC, one of the recently described B7 family members, has the capacity to inhibit T cell responses via engagement of the immunoreceptor tyrosine-based inhibitory motif-containing inhibitory PD-1 receptor as well as enhance responses via an as yet unidentified costimulatory receptor. B7-DC is highly homologous to a coinhibitory B7 family member, B7-H1, which also binds PD-1. It is currently unclear which B7-DC function-costimulation or inhibition-predominates in vivo. To study in vivo functions of B7-DC, we evaluated immune responses in B7-DC knockout (KO) mice. Although not eliminated, interferon-gamma (IFN-gamma) production by CD4 T cells and IFN-gamma-dependent humoral responses were reduced in B7-DC KO mice relative to wild type mice. Antigen-specific CD8 T cell responses and cytotoxic T lymphocyte (CTL) activity were also diminished in B7-DC KO mice. Hepatic tumors grew more quickly in B7-DC KO mice, associated with a decrease in intrahepatic tumor-specific CD8 T cells. These results highlight the contrasting in vivo roles of B7-DC and B7-H1 and indicate that B7-DC functions as a tuning molecule, selectively augmenting T helper 1 and CTL responses.
Oral Interleukin-10 Alleviates Polyposis via Neutralization of Pathogenic T-Regulatory Cells (2014)

Immune dysregulation drives the pathogenesis of chronic inflammatory, autoimmune, and dysplastic disorders. While often intended to address localized pathology, most immune modulatory therapies are administered systemically and carry inherent risk of multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles ameliorates local and systemic disease to enhance survival. Mechanistic investigations showed that the therapeutic benefit of this treatment derived from neutralization of disease-promoting FoxP3(+)RoRγt(+)IL17(+) pathogenic T-regulatory cells (pgTreg), with a concomitant restoration of FoxP3(+)RoRγt(-)IL17(-) conventional T-regulatory cells (Treg). These findings provide a proof-of-principle for the ability of an oral biologic to restore immune homeostasis at the intestinal surface. Furthermore, they implicate local manipulation of IL10 as a tractable therapeutic strategy to address the inflammatory sequelae associated with mucosal premalignancy.
Evaluation of the Antimicrobial Activities of Plant Oxylipins Supports Their Involvement in Defense against Pathogens (2005)

Plant oxylipins are a large family of metabolites derived from polyunsaturated fatty acids. The characterization of mutants or transgenic plants affected in the biosynthesis or perception of oxylipins has recently emphasized the role of the so-called oxylipin pathway in plant defense against pests and pathogens. In this context, presumed functions of oxylipins include direct antimicrobial effect, stimulation of plant defense gene expression, and regulation of plant cell death. However, the precise contribution of individual oxylipins to plant defense remains essentially unknown. To get a better insight into the biological activities of oxylipins, in vitro growth inhibition assays were used to investigate the direct antimicrobial activities of 43 natural oxylipins against a set of 13 plant pathogenic microorganisms including bacteria, oomycetes, and fungi. This study showed unequivocally that most oxylipins are able to impair growth of some plant microbial pathogens, with only two out of 43 oxylipins being completely inactive against all the tested organisms, and 26 oxylipins showing inhibitory activity toward at least three different microbes. Six oxylipins strongly inhibited mycelial growth and spore germination of eukaryotic microbes, including compounds that had not previously been ascribed an antimicrobial activity, such as 13-keto-9(Z),11(E),15(Z)-octadecatrienoic acid and 12-oxo-10,15(Z)-phytodienoic acid. Interestingly, this first large-scale comparative assessment of the antimicrobial effects of oxylipins reveals that regulators of plant defense responses are also the most active oxylipins against eukaryotic microorganisms, suggesting that such oxylipins might contribute to plant defense through their effects both on the plant and on pathogens, possibly through related mechanisms.
In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain (1996)

The lateral ventricle subependyma in the adult mammalian forebrain contains both neural stem and progenitor cells. This study describes the in situ modulation of these subependymal neural precursor populations after intraventricular administration of exogenous growth factors. In vivo infusion of epidermal growth factor (EGF) into adult mouse forebrain for 6 consecutive days resulted in a dramatic increase in the proliferation and total number of subependymal cells and induced their migration away from the lateral ventricle walls into adjacent parenchyma. Immediately after EGF infusion, immunohistochemical characterization of the EGF-expanded cell population demonstrated that >95% of these cells were EGF receptor- and nestin-positive, whereas only 0.9% and 0.2% labeled for astrocytic and neuronal markers, respectively. Seven weeks after EGF withdrawal, 25% of the cells induced to proliferate after 6d of EGF were still detectable; 28% of these cells had differentiated into new astrocytes and 3% into new neurons in the cortex, striatum, and septum. Newly generated oligodendrocytes were also observed. These in vivo results (1) confirm the existence of EGF-responsive subependymal neural precursor cells in the adult mouse forebrain and (2) suggest that EGF acts directly as a proliferation, survival, and migration factor for subependymal precursor cells to expand these populations and promote the movement of these cells into normal brain parenchyma. Thus, in situ modulation of endogenous forebrain precursor cells represents a novel model for studying neural development in the adult mammalian brain and may provide insights that will achieve adult replacement of neurons and glia lost to disease or trauma.
P-slice based efficient speculative multithreading (2009)

Microprocessor industry has recently shifted towards multi-core to take advantage of the ever increasing number of transistors provided by the new technologies. Unfortunately, the multi-core approach does not allow single threaded applications to benefit from the additional cores to improve their execution time. Speculative multithreading (SpMT) has been proposed in the past to boost performance of irregular applications in multi-core environments. In this work, we study the main bottlenecks of these architectures, such as the memory behavior and the pre-computation slices and propose two novel schemes that allow SpMT to get 25% average speedup over single threaded execution. We propose Selective Replication as a technique to improve the performance of the SpMT memory system. This technique does not introduce additional traffic in the bus and improves the performance of a conventional SpMT memory model by 6% on average and up to 21% for some applications. Also, we propose a scheme called Slice Specialization that reduces the number of instructions in the pre-computation slices by adapting the slice to every single speculative thread spawned. The later proposal outperforms previous schemes with slices by 15% and overall, both techniques combined achieve an improvement of 20% over a conventional SpMT processor.
A three-dimensional analysis of angular momentum in the hammer throw (1989)

Eight hammer throwers were studied using three-dimensional cinematography. The local term of angular momentum of each thrower (HTL) followed a wide conical path, while the remote term (HTR) and the hammer angular momentum (HH) followed much narrower conical paths. HT, the sum of HTL and HTR, followed a conical path similar to that of HTL, although with smaller amplitude. HH was half of a cycle out of phase with HT. It was also larger but followed a narrower conical path. As a result, the conical paths of HH and HT counteracted each other, and HS, the total angular momentum vector of the thrower-hammer system, had little conical motion. The paths of the angular momentum vectors, the trunk tilt, and the height of the hammer plane relative to the system center of mass were interrelated. Some throwers kept the hammer plane high and the trunk tilting back in all the turns; other throwers kept the hammer plane low and the trunk tilting forward in the early turns, but the hammer plane rose in their late turns and the trunk tilted back. Two theories were proposed to explain why the athletes who had forward trunk tilt in the early turns tilted backward in the final part of the throw.
Factors Affecting Bone Graft Incorporation (1996)

Successful graft incorporation requires that an appropriate match be made among the biologic activity of a bone graft, the condition of the perigraft environment, and the mechanical environment. The authors have studied, in a wide variety of animal models, the factors that affect the main components of bone graft incorporation: revascularization, new bone formation, and host-graft union. The principal determinant of the rate, pattern, and amount of revascularization is the presence or absence of a vascular pedicle. The nonvascularized bone graft is entirely dependent on the surrounding tissue for its revascularization, which results in a noticeable delay in vessel ingrowth. The principal determinant of the rate and amount of new bone formation on, in, or about a bone graft is the presence or absence of living, histocompatible, committed bone-forming cells. When living cells are not part of the graft at the time of implantation, the cells that form new bone are derived from host tissues, and new bone formation is delayed. The principal determinants of host-graft union are stability of the construct and contact between host bone and the graft. Factors that slow or inhibit all of these processes are reduction of the biologic activity of the graft by freezing or some other treatment, histocompatibility antigen disparities between donor and recipient, mechanical instability between the graft and the perigraft environment, and local and systemic interference with the biologic activity of the graft and surrounding tissue, for example, by irradiation or the administration of cisplatin. The task of the clinician who does a bone grafting procedure is to choose the right graft or combination of grafts for the biologic and mechanical environment into which the graft will be placed.
FBXO4 loss facilitates carcinogen induced papilloma development in mice (2015)

Cyclin D1 is frequently overexpressed in esophageal squamous cell carcinoma (ESCC) and is considered a key driver of this disease. Mutations in FBXO4, F-box specificity factor that directs SCF-mediated ubiquitylation of cyclin D1, occur in ESCC with concurrent overexpression of cyclin D1 suggesting a potential tumor suppressor role for FBXO4. To evaluate the contribution of FBXO4-dependent regulation cyclin D1 in esophageal squamous cell homeostasis, we exposed FBXO4 knockout mice to N-nitrosomethylbenzylamine (NMBA), an esophageal carcinogen. Our results revealed that loss of FBXO4 function facilitates NMBA induced papillomas in FBXO4 het (+/-) and null (-/-) mice both by numbers and sizes 11 months after single dose NMBA treatment at 2mg/kg by gavage when compared to that in wt (+/+) mice (P < 0.01). No significant difference was noted between heterozygous or nullizygous mice consistent with previous work. To assess cyclin D1/CDK4 dependence, mice were treated with the CDK4/6 specific inhibitor, PD0332991, for 4 weeks. PD0332991 treatment (150mg/kg daily), reduced tumor size and tumor number. Collectively, our data support a role for FBXO4 as a suppressor of esophageal tumorigenesis.
ORGAN PRESERVATION (1995)

Organ preservation is the supply line for organ transplantation. Currently, the liver, pancreas, and kidney can be successfully preserved for up to two days by flushing the organs with the University of Wisconsin (UW) organ preservation solution and storing them at hypothermia (0-5 degree C). The UW solution is effective because it uses a number of cell impermeant agents (lactobionic acid, raffinose, hydroxyethyl starch) that prevent the cells from swelling during cold ischemic storage. Additionally, the UW solution contains glutathione and adenosine, agents that may stimulate recovery of normal metabolism upon reperfusion by augmenting the antioxidant capacity of the organs (glutathione) or by stimulating high-energy phosphate generation (adenosine) upon reperfusion. Although this method of organ preservation is effective, some organs (5-15% of livers and 20-30% of kidneys) do not function well upon transplant. Injury may be preservation related but may also result from donor and recipient factors that render the organs more susceptible to preservation damage. Results with continuous perfusion of kidneys in the clinics show a reduction in preservation/reperfusion damage. This may be a more appropriate preservation method than cold storage. In this chapter we discuss the development and use of the UW solution and present clinical results. Although intraabdominal organs are well preserved at present, intrathoracic organs (lungs and heart) are less well preserved, and better methods for preservation of these organs are needed for increased use of lung and heart transplantation.
Joint-preserving Tumor Resection and Reconstruction Using Image-guided Computer Navigation (2012)

Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.