Miracle-dz/UniFAR-FTUs huggingface dataset:
Calmodulin‐dependent phosphatase, kinases, and transcriptional corepressors involved in T‐cell activation

Summary: The second messenger calcium plays an essential role in mediating the T‐cell receptor (TCR) signaling pathway leading to cytokine production and T‐cell clonal expansion. The immunosuppressive drugs cyclosporine A and FK506 have served both as therapeutic agents and as molecular probes for unraveling the protein phosphatase calcineurin as a rate‐limiting enzyme involved in the transmission of calcium signal from the cytosol into the nucleus to reprogram gene expression. The use of mouse knockout models has helped to verify and further elucidate the functions of different isoforms of calcineurin in both helper T‐cell activation and thymocyte development. In addition to calcineurin, three other classes of calmodulin‐binding proteins have also been shown to play important roles in calcium signaling in T cells. Thus, Cabin1 and class II histone deacetylases have been found to constitute a novel calcium‐signaling module in conjunction with the transcription factor myocyte enhance factor family and the transcriptional coactivator p300 to suppress and activate cytokine gene transcription in a calcium‐dependent manner. The calmodulin‐dependent protein kinases II and IV were also shown to play negative and positive regulatory functions, respectively, in TCR‐mediated cytokine production. The crosstalks among these and other signal transducers in T cells form an extensive nonlinear signaling network that dictates the final outcome of the TCR signaling pathway.
Likelihood maximization for list-mode emission tomographic image reconstruction

The maximum a posteriori (MAP) Bayesian iterative algorithm using priors that are gamma distributed, due to Lange, Bahn and Little, is extended to include parameter choices that fall outside the gamma distribution model. Special cases of the resulting iterative method include the expectation maximization maximum likelihood (EMML) method based on the Poisson model in emission tomography, as well as algorithms obtained by Parra and Barrett and by Huesman et al. that converge to maximum likelihood and maximum conditional likelihood estimates of radionuclide intensities for list-mode emission tomography. The approach taken here is optimization-theoretic and does not rely on the usual expectation maximization (EM) formalism. Block-iterative variants of the algorithms are presented. A self-contained, elementary proof of convergence of the algorithm is included.
Outbreak of parasitic peritonitis in reindeer in Finland

In 2003, there was an outbreak of peritonitis in reindeer in the southern and middle part of the Finnish reindeer herding area caused by the filarioid nematode Setaria species. In the province of Oulu, the proportion of reindeer viscera condemned owing to parasitic lesions increased from 4·9 per cent in 2001 to 40·1 in 2003. In 2004, the focus of the outbreak moved approximately 100 km north. A total of 260 adult and pre-adult Setaria species nematodes were collected for morphological and molecular studies. The parasite was indistinguishable in terms of morphology and molecular biology from Setaria tundra. Samples of parasites were also collected from wild cervids. In elk, only a few cases of pre-adult encapsulated S tundra nematodes were detected on the surface of the liver but there was no peritonitis. Two roe deer had S tundra nematodes in their abdomen but no peritonitis. Of 34 wild forest reindeer, 21 had changes associated with S tundra. At meat inspection of the affected reindeer carcases, the changes observed included ascites, green fibrinous deposits, adhesions, and live and dead S tundra nematodes. There were histological lesions of granulomatous peritonitis with lymphoplasmacytic and eosinophilic infiltration. No specific bacterial growth was found. The parasitic infection had no significant effects on the pH or the organoleptic quality of the meat. There was a significant positive correlation between the worm count and the degree of peritonitis (P<0·001) and a negative correlation between the degree of peritonitis and the thickness of the back fat layer (P=0·015).
Release of ATP by a human retinal pigment epithelial cell line: potential for autocrine stimulation through subretinal space

1 Stimulation of purinergic receptors on retinal pigment epithelial (RPE) cells can increase the rate of fluid transport or decrease phagocytosis. This study aims to: determine whether the purine ATP can be released from RPE cells, begin probing the mechanism of any release and test whether cells degrade ATP extracellularly. 2 ATP release was monitored from cultured human ARPE‐19 cells with the luciferin‐luciferase assay. Biphasic release of ATP was triggered by basic fibroblast growth factor (bFGF), by the pyrimidine uridine triphosphate (UTP) and by hypotonicity. 3 The Cl− channel blocker 5‐nitro‐2‐(3‐phenylpropylamino)‐benzoate (NPPB) inhibited release of ATP, suggesting that release was associated with Cl− channels. 4 Elevating intracellular Ca2+ directly with ionomycin was insufficient to trigger ATP release. 5 UTP induced a biphasic elevation in intracellular Ca2+. NPPB inhibited the second phase, suggesting autostimulation by released ATP. 6 Cells grown on permeable supports showed apical release of ATP, analogous to release into subretinal space in vivo. 7 The presence of ecto‐ATPases on ARPE‐19 cell membranes was suggested by the degradation of ATP added to intact cells. 8 Phagocytosis of fluorescent beads was inhibited by ATP, but the ecto‐5′‐nucleotidase inhibitor α, β‐methylene ADP prevented this, suggesting that inhibition was mediated by extracellular conversion of ATP to adenosine. 9 These results suggest that growth factors, pyrimidines and changes in tonicity could trigger ATP release into subretinal space. The levels of ATP released may be capable of autocrine stimulation of ATP receptors, while conversion to adenosine by ecto‐enzymes could alter phagocytosis.
IL-4 and IL-13 Induce Protection of Porcine Endothelial Cells from Killing by Human Complement and from Apoptosis through Activation of a Phosphatidylinositide 3-Kinase/Akt Pathway1

Vascular endothelial cells (EC) perform critical functions that require a balance of cell survival and cell death. EC death by apoptosis and EC activation and injury by the membrane attack complex of complement are important mechanisms in atherosclerosis and organ graft rejection. Although the effects of various cytokines on EC apoptosis have been studied, little is known about their effects on complement-mediated EC injury. Therefore, we studied the abilities of various cytokines to induce protection of porcine aortic EC against apoptosis and killing by human complement, a model of pig-to-human xenotransplantation. We found that porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-α plus cycloheximide. Maximal protection required 10 ng/ml IL-4 or IL-13, developed progressively from 12 to 72 h of incubation, and lasted 48–72 h after cytokine removal. Protection from complement was not associated with reduced complement activation, C9 binding, or changes in CD59 expression. Inhibition of PI3K prevented development of protection; however, inhibition of p38 MAPK or p42/44 MAPK had no effect. IL-4 and IL-13 induced rapid phosphorylation of Akt. Although protection was inhibited by an Akt inhibitor and a dominant negative Akt mutant transduced into EC, it was induced by transduction of EC with the constitutively active Akt variant, myristylated Akt. We conclude that IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway.
Corneal Confocal Microscopy: An Imaging Endpoint for Axonal Degeneration in Multiple Sclerosis.

Purpose To evaluate whether corneal confocal microscopy (CCM) detects axonal degeneration and whether this is associated with retinal nerve fiber degeneration and clinical disability in patients with multiple sclerosis (MS). Methods Twenty-five patients with MS and 25 healthy control subjects underwent CCM, optical coherence tomography (OCT), and assessment of neurological disability using the expanded disability status scale (EDSS) and MS severity score (MSSS). Results In patients with MS compared with controls, there was a significant reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL). There was no significant difference in CCM parameters between patients with optic neuritis (MS-ON) and without (MS-NON), or between relapsing-remitting (RRMS) and secondary-progressive MS (SPMS). There was significant thinning of the retinal nerve fiber layer (RNFL) in the global, temporal, temporal superior, and temporal inferior quadrants, with no difference between MS-ON and MS-NON. Patients with SPMS compared with RRMS had a significantly lower global, temporal superior, temporal inferior, nasal, and nasal superior RNFL. The EDSS and MSSS correlated significantly with CNBD, nasal, nasal superior, and nasal inferior RNFL and with CNBD and nasal inferior RNFL, respectively. Conclusions CCM and OCT detect significant corneal and retinal nerve degeneration which relates to the severity of neurological deficits in patients with mild MS.
Glycogen-targeting Subunits and Glucokinase Differentially Affect Pathways of Glycogen Metabolism and Their Regulation in Hepatocytes*

Overexpression of the glucose-phosphorylating enzyme glucokinase (GK) or members of the family of glycogen-targeting subunits of protein phosphatase-1 increases hepatic glucose disposal and glycogen synthesis. This study was undertaken to evaluate the functional properties of a novel, truncated glycogen-targeting subunit derived from the skeletal muscle isoform GM/RGl and to compare pathways of glycogen metabolism and their regulation in cells with overexpressed targeting subunits and GK. When overexpressed in hepatocytes, truncated GM/RGl (GMΔC) was approximately twice as potent as full-length GM/RGl in stimulation of glycogen synthesis, but clearly less potent than GK or two other native glycogen-targeting subunits, GL and PTG. We also found that cells with overexpressed GMΔC are unique in that glycogen was efficiently degraded in response to lowering of media glucose concentrations, stimulation with forskolin, or a combination of both maneuvers, whereas cells with overexpressed GL, PTG, or GK exhibited impairment in one or both of these glycogenolytic signaling pathways. 2H NMR analysis of purified glycogen revealed that hepatocytes with overexpressed GK synthesized a larger portion of their glycogen from triose phosphates and a smaller portion from tricarboxylic acid cycle intermediates than cells with overexpressed glycogen-targeting subunits. Additional evidence for activation of distinct pathways of glycogen synthesis by GK and targeting subunits is provided by the additive effect of co-overexpression of the two types of proteins upon glycogen synthesis and a much larger stimulation of glucose utilization, glucose transport, and lactate production elicited by GK. We conclude that overexpression of the novel targeting subunit GMΔC confers unique regulation of glycogen metabolism. Furthermore, targeting subunits and GK stimulate glycogen synthesis by distinct pathways.
tcaA Inactivation Increases Glycopeptide Resistance in Staphylococcus aureus

ABSTRACT The experimental deletion of the tcaRAB region has been shown to increase teicoplanin resistance in Staphylococcus aureus. By sequential genetic complementation of a tcaRAB mutant, we identified tcaA as the key gene within tcaRAB that is responsible for changes in glycopeptide resistance levels. Northern blot analysis of the tcaRAB region showed that the tcaA gene is expressed only weakly over the growth cycle and is strongly inducible by teicoplanin. Among some clinical isolates tested, glycopeptide-intermediate-resistant (GISA) strains Michigan and SA137/93G were found to have truncated tcaA genes. While the former carries a nucleotide insertion that creates a premature stop codon, the latter was found to harbor an IS256 insertion. Complementation of these two GISA strains with a functional tcaA allele reduced their levels of teicoplanin and vancomycin resistance five- to eightfold and twofold, respectively. The data presented here indicate that inactivation of tcaA contributes to and plays a relevant role in glycopeptide resistance in S. aureus clinical isolates.
Union is strength

Purpose The purpose of this paper is to fill a gap in the management systems (MSs) field by addressing whether the implementation of an integrated management system (IMS) and the integration level of its elements bring benefits and/or challenges to companies and whether these are related to corporate financial performance (CFP). Design/methodology/approach Drawing on a Spanish sample of 76 organizations with at least an environmental and a quality MS, the authors perform a partial least squares (PLS) analysis. Findings The results showed evidence of a positive relationship of the integration benefits with respect to the integration level of MS documentation and the integration level of MS procedures that overweights the negative significant effect of difficulties of integration in relation to the integration level of MS documentation and the integration level of MS procedures. The authors also found new evidence on this topic, related to a positive significant relationship between the integration level of MS procedures and CFP that overweights the negative significant effect of integration level of MS documentation on CFP. Research limitations/implications This study used cross-sectional data from interviewees who are Catalan managers. Furthermore, the mail survey was answered in 2010 at the beginning of the economic crisis from which results should be taken with caution given that the situation might have changed due to the continuation of the Spanish economic crisis. Practical implications The findings could allow companies’ managers to understand the extent to which the integration of quality management practices and environmental management practices influences some of the most relevant firms’ financial performance dimensions. Originality/value As far as the authors know, there are not empirical studies that address the relationship of IMS with a measure of performance such as CFP.
Defining a binding pocket for sulfonylureas in ATP‐sensitive potassium channels

Sulfonylurea receptors SUR1 and SUR2 are the regulatory subunits of KATP channels. Their differential affinity for hypoglycemic sulfonylureas provides a basis for the selectivity of these compounds for different KATP channel isoforms. Sulfonylureas have a 100‐to 1000‐fold greater affinity for SUR1 vs. SUR2. Structure‐activity studies suggested a bipartite binding pocket. Chimeric SUR1~SUR2 receptors have shown TMD2, the third bundle of transmembrane helices, to be part of an “A” site that confers SUR1 selectivity for sulfonylureas. The purpose of this study is to determine the position of the “B” site. Previous photoaffinity labeling studies have placed the B site on the amino‐terminal third of SUR and colabeled the associated KIR. In our study, deletion of TMD0, the first bundle of transmembrane helices, did not compromise labeling. Further deletions into the cytoplasmic linker, L0, eliminated binding and labeling. Alanine substitutions in L0 identified a limited number of conserved residues, Y230 and W232, important for affinity labeling. A fragment of KIR6.2, missing M2 and the entire carboxyl terminal, assembles with SUR1 and is affinity labeled, while deletion of 10 or more amino‐terminal residues compromises labeling. These studies indicate that the B site involves L0 and the KIR amino terminus, elements that are critical for control of channel gating. Vila‐Carriles, W. H. , Zhao, G. , Bryan, J. Defining a binding pocket for sulfonylureas in ATP‐sensitive potassium channels. FASEB J. 21, 18–25 (2007)
Documents of Life 2: An Invitation to A Critical Humanism Second Edition

Documents of Life was originally published in 1983 and became a classic text, providing both a persuasive argument for a particular approach and a manifesto for social research. As a critique of anti-humanist methodology in the social sciences, it championed the use of life stories and other personal documents in research which are now widely used today. This book is a substantially revised and expanded version which takes on recent developments. Providing numerous illustrations from a range of life documents, the book traces the history of the method, examines ways of 'doing life story' research, and discusses the many political and ethical issues raised by such research. The whole book has been substantially re-written and updated, and there are four wholly new chapters. These look at the wider emergence of an auto/biographical society; writing and narrative; memory and truth; and humanism. Whilst the original book argued for more life stories in social research, this book senses a major celebration and proliferation of the method over the past twenty years. At the same time. in the wake of postmodernism, feminist and queer writings, the writing of a life can never again be a simple exercise in 'telling it like it is'. Plummer's new book confronts these new concerns head on, whilst restating his strong commitment to the methodologies of humanism. Passionate and unashamedly partisan, this is no ordinary 'methods text'. Even more than its predecessor, it sees the research process as social, moral, and political at every stage. Like the earlier book, Documents of Life 2 is written in an easy and engaging style which should make it equally accessible to first year undergraduates and much more advanced graduate scholars across a range of social science disciplines.
Inhibition of Lytic Reactivation of Kaposi'S Sarcoma-Associated Herpesvirus by Alloferon

Background Alloferon, an immunomodulatory peptide, has antiviral capability against herpesvirus. In this research, we aimed to investigate the effect of alloferon on the regulation of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), and its mechanisms. We also assessed the antiviral activity of alloferon on natural killer (NK) cells as an early antiviral immune responder. Methods We first examined the change in cell proliferation and the expression of the viral genes in a KSHV- infected cell line, body-cavity-based B lymphoma (BCBL)-1, under the lytic cycle by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment. To elucidate the antiviral mechanism of alloferon, we tested calcium influx and the activation of the extracellular signal-regulated kinase (ERK) pathway. Furthermore, we evaluated the cytotoxicity of NK cells against BCBL-1 by alloferon. Results Alloferon effectively recovered the suppressed proliferation of BCBL-1 by TPA, which was achieved by the down-regulation of lytic-cycle-related viral genes, RTA, K8 and vIRF2. To clarify the signal transduction pathways related to the regulation of the viral genes by alloferon, we confirmed that the calcium influx into BCBL-1 was apparently inhibited by alloferon, which preceded the suppression of the phosphorylation of ERK and the activation of AP-1 by TPA. Moreover, when NK cells were exposed to alloferon, their cytolytic activity was improved, and this was mediated by the enhancement of perforin/granzyme secretion. Conclusions The results of this study suggest that alloferon can be used as an effective antiviral agent for the regulation of the KSHV life cycle by the down-regulation of AP-1 activity and for the the enhancement of antiviral immunity by up-regulation of NK cell cytotoxicity.
Crisis, cambio en la UE y estrategias sindicales: el impacto de la condicionalidad en el repertorio estratégico de los sindicatos españoles durante la crisis de la eurozona

During the eurozone crisis, the PSOE’s and PP’s governments implemented a series of reforms of the Welfare State and the labour market in exchange for financial help from the EU; what is known as conditionality. The trade unions, CC. OO. and UGT, responded to these reforms as the representatives of the sectors most affected by them. There are two narratives to explain trade unions’ strategies during the crisis. On the one hand, it is argued that trade unions used traditional political action to influence political decision making processes. On the other hand, trade unions have developed new actions either of a transnational character or related to typical social movements’ activities. The article explains why the crisis led to this new combination of trade union repertories calling on different sectors and levels of action. The main argument is that the EU conditionality led to the emergence of a new political regime that we have dubbed “neoliberal intergovernmentalism” due to the institutional and ideological changes that it brought about. In turn, this new regime impacted upon the political opportunity structure, triggering a strategic reorientation of trade unions.
Towards the artificial evolution of target features in complex chemical systems

The synthesis of abiotic life-like behaviour in complex chemical systems is one of the great scientific challenges in today’s research environment. Very often in this type of design, the parameter space is so large and the system so complex that analytical, rational design techniques are extremely difficult to manage, and more often than not, unavailable altogether. Machine learning methods have found many applications in the realm of design and manufacture and the research described in this thesis describes the application of these tools towards the development of pre-specified chemical functionality in complex systems. A detailed description of the ‘Evolutionary Engine’ built with this sort of design in mind is given, including preliminary investigations into coupling this engine to a ‘real life’ chemical reactor array. Studies are performed on a range of complex systems, including benchmark problems based on cellular automata, and, for the first time in this domain, on real world problems in self-organised scanning probe microscopy. Given a target behaviour of the system in question, usually represented by a series of patterns in a 2D image, it is shown that parameters can be ‘reverse engineered’ through a sophisticated combination of machine learning techniques and image analysis methods, such that the target behaviour/pattern can be faithfully reproduced. Finally, techniques for the approximation of a complex system and its associated fitness function are explored, giving rise to a dramatic decrease in computation time with little compromise to the quality of results.
Dynamic trajectory generation via numerical multi-objective optimisation

An algorithm for dynamic trajectory generation employing numerical multi-objective optimisation is presented. The crucial innovations are the description of the trajectory through velocity and curvature on the one hand and the restriction of the otherwise infinite function space to a set of basis functions on the other hand. A number of boundary conditions and inequality constraints ensuring the feasibility of the planned trajectory for real vehicles are adhered to. This algorithm is embedded in a rudimentary map-building scheme and an efficient path-planning concept working with incomplete environment information. The performance of the system is demonstrated by application to randomly generated environments.