Bulk viscosity and energy-momentum correlations in high energy hadron collisions

We show how the measurement of appropriately constructed particle-energy/momentum correlations allows access to the bulk viscosity of strongly interacting hadron matter in heavy ion collisions. This measurement can be performed by the LHC and RHIC experiments in events with high-particle multiplicity, following up on existing estimates of the shear viscosity based on elliptic flow.Comment: 7 pages, no figure

Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice

The truncated somatostatin receptor sst5TMD4 stimulates the angiogenic process and is associated to lymphatic metastasis and disease-free survival in breast cancer patients

This work has been funded by the following grants: BIO-0139, CTS-1406, PI-0639-2012, BFU2010-19300, BFU2013-43282-R, PI13/00651 and CIBERobn (to RML and JPC); PI-0541-2013 and “Miguel Servet” program (to MDG); PI13/00132, RETICC RD12/0036/0007, S2010/ BMD-2303 (to GMB). CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain

Cost-effectiveness analysis of stand-alone or combined non-invasive imaging tests for the diagnosis of stable coronary artery disease: results from the EVINCI study

Aim: This study aimed at evaluating the cost-effectiveness of different non-invasive imaging-guided strategies for the diagnosis of obstructive coronary artery disease (CAD) in a European population of patients from the Evaluation of Integrated Cardiac Imaging in Ischemic Heart Disease (EVINCI) study. Methods and results: Cost-effectiveness analysis was performed in 350 patients (209 males, mean age 59 ± 9 years) with symptoms of suspected stable CAD undergoing computed tomography coronary angiography (CTCA) and at least one cardiac imaging stress-test prior to invasive coronary angiography (ICA) and in whom imaging exams were analysed at dedicated core laboratories. Stand-alone stress-tests or combined non-invasive strategies, when the first exam was uncertain, were compared. The diagnostic end-point was obstructive CAD defined as > 50% stenosis at quantitative ICA in the left main or at least one major coronary vessel. Effectiveness was defined as the percentage of correct diagnosis (cd) and costs were calculated using country-specific reimbursements. Incremental cost-effectiveness ratios (ICERs) were obtained using per-patient data and considering “no-imaging” as reference. The overall prevalence of obstructive CAD was 28%. Strategies combining CTCA followed by stress ECHO, SPECT, PET, or stress CMR followed by CTCA, were all cost-effective. ICERs values indicated cost saving from − 969€/cd for CMR-CTCA to − 1490€/cd for CTCA-PET, − 3092€/cd for CTCA-SPECT and − 3776€/cd for CTCA-ECHO. Similarly when considering early revascularization as effectiveness measure. Conclusion: In patients with suspected stable CAD and low prevalence of disease, combined non-invasive strategies with CTCA and stress-imaging are cost-effective as gatekeepers to ICA and to select candidates for early revascularization

A proteomic approach for the identification of novel lysine methyltransferase substrates

<p>Abstract</p> <p>Background</p> <p>Signaling via protein lysine methylation has been proposed to play a central role in the regulation of many physiologic and pathologic programs. In contrast to other post-translational modifications such as phosphorylation, proteome-wide approaches to investigate lysine methylation networks do not exist.</p> <p>Results</p> <p>In the current study, we used the ProtoArray^®platform, containing over 9,500 human proteins, and developed and optimized a system for proteome-wide identification of novel methylation events catalyzed by the protein lysine methyltransferase (PKMT) SETD6. This enzyme had previously been shown to methylate the transcription factor RelA, but it was not known whether SETD6 had other substrates. By using two independent detection approaches, we identified novel candidate substrates for SETD6, and verified that all targets tested <it>in vitro </it>and in cells were genuine substrates.</p> <p>Conclusions</p> <p>We describe a novel proteome-wide methodology for the identification of new PKMT substrates. This technological advance may lead to a better understanding of the enzymatic activity and substrate specificity of the large number (more than 50) PKMTs present in the human proteome, most of which are uncharacterized.</p

In Vivo Generation of Neurotoxic Prion Protein: Role for Hsp70 in Accumulation of Misfolded Isoforms

Prion diseases are incurable neurodegenerative disorders in which the normal cellular prion protein (PrPC) converts into a misfolded isoform (PrPSc) with unique biochemical and structural properties that correlate with disease. In humans, prion disorders, such as Creutzfeldt-Jakob disease, present typically with a sporadic origin, where unknown mechanisms lead to the spontaneous misfolding and deposition of wild type PrP. To shed light on how wild-type PrP undergoes conformational changes and which are the cellular components involved in this process, we analyzed the dynamics of wild-type PrP from hamster in transgenic flies. In young flies, PrP demonstrates properties of the benign PrPC; in older flies, PrP misfolds, acquires biochemical and structural properties of PrPSc, and induces spongiform degeneration of brain neurons. Aged flies accumulate insoluble PrP that resists high concentrations of denaturing agents and contains PrPSc-specific conformational epitopes. In contrast to PrPSc from mammals, PrP is proteinase-sensitive in flies. Thus, wild-type PrP rapidly converts in vivo into a neurotoxic, protease-sensitive isoform distinct from prototypical PrPSc. Next, we investigated the role of molecular chaperones in PrP misfolding in vivo. Remarkably, Hsp70 prevents the accumulation of PrPSc-like conformers and protects against PrP-dependent neurodegeneration. This protective activity involves the direct interaction between Hsp70 and PrP, which may occur in active membrane microdomains such as lipid rafts, where we detected Hsp70. These results highlight the ability of wild-type PrP to spontaneously convert in vivo into a protease-sensitive isoform that is neurotoxic, supporting the idea that protease-resistant PrPSc is not required for pathology. Moreover, we identify a new role for Hsp70 in the accumulation of misfolded PrP. Overall, we provide new insight into the mechanisms of spontaneous accumulation of neurotoxic PrP and uncover the potential therapeutic role of Hsp70 in treating these devastating disorders

Bilateral Sensory Abnormalities in Patients with Unilateral Neuropathic Pain; A Quantitative Sensory Testing (QST) Study

In patients who experience unilateral chronic pain, abnormal sensory perception at the non-painful side has been reported. Contralateral sensory changes in these patients have been given little attention, possibly because they are regarded as clinically irrelevant. Still, bilateral sensory changes in these patients could become clinically relevant if they challenge the correct identification of their sensory dysfunction in terms of hyperalgesia and allodynia. Therefore, we have used the standardized quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS) to investigate somatosensory function at the painful side and the corresponding non-painful side in unilateral neuropathic pain patients using gender- and age-matched healthy volunteers as a reference cohort. Sensory abnormalities were observed across all QST parameters at the painful side, but also, to a lesser extent, at the contralateral, non-painful side. Similar relative distributions regarding sensory loss/gain for non-nociceptive and nociceptive stimuli were found for both sides. Once a sensory abnormality for a QST parameter at the affected side was observed, the prevalence of an abnormality for the same parameter at the non-affected side was as high as 57% (for Pressure Pain Threshold). Our results show that bilateral sensory dysfunction in patients with unilateral neuropathic pain is more rule than exception. Therefore, this phenomenon should be taken into account for appropriate diagnostic evaluation in clinical practice. This is particularly true for mechanical stimuli where the 95% Confidence Interval for the prevalence of sensory abnormalities at the non-painful side ranges between 33% and 50%

Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors

[Abstract] The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order kth (Wk). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the Wk(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated Wk(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation)

Coupling dynamics of a geared multibody system supported by Elastohydrodynamic lubricated cylindrical joints

A comprehensive computational methodology to study the coupling dynamics of a geared multibody system supported by ElastoHydroDynamic (EHD) lubricated cylindrical joints is proposed throughout this work. The geared multibody system is described by using the Absolute-Coordinate-Based (ACB) method that combines the Natural Coordinate Formulation (NCF) describing rigid bodies and the Absolute Nodal Coordinate Formulation (ANCF) characterizing the flexible bodies. Based on the finite-short bearing approach, the EHD lubrication condition for the cylindrical joints supporting the geared system is considered here. The lubrication forces developed at the cylindrical joints are obtained by solving the Reynolds’ equation via the finite difference method. For the evaluation of the normal contact forces of gear pair along the Line Of Action (LOA), the time-varying mesh stiffness, mesh damping and Static Transmission Error (STE) are utilized. The time-varying mesh stiffness is calculated by using the Chaari’s methodology. The forces of sliding friction along the Off-Line-Of-Action (OLOA) are computed by using the Coulomb friction models with a time-varying coefficient of friction under the EHD lubrication condition of gear teeth. Finally, two numerical examples of application are presented to demonstrate and validate the proposed methodology.National Natural Science Foundations of China under Grant 11290151, 11221202 and 11002022, Beijing Higher Education Young Elite Teacher Project under Grant YETP1201