Breakdown of Fermi-liquid theory in a cuprate superconductor

The behaviour of electrons in solids is remarkably well described by Landau's Fermi-liquid theory, which says that even though electrons in a metal interact they can still be treated as well-defined fermions, called ``quasiparticles''. At low temperature, the ability of quasiparticles to transport heat is strictly given by their ability to transport charge, via a universal relation known as the Wiedemann-Franz law, which no material in nature has been known to violate. High-temperature superconductors have long been thought to fall outside the realm of Fermi-liquid theory, as suggested by several anomalous properties, but this has yet to be shown conclusively. Here we report on the first experimental test of the Wiedemann-Franz law in a cuprate superconductor, (Pr,Ce)$_2$CuO$_4$. Our study reveals a clear departure from the universal law and provides compelling evidence for the breakdown of Fermi-liquid theory in high-temperature superconductors.Comment: 7 pages, 3 figure

PepDist: A New Framework for Protein-Peptide Binding Prediction based on Learning Peptide Distance Functions

BACKGROUND: Many different aspects of cellular signalling, trafficking and targeting mechanisms are mediated by interactions between proteins and peptides. Representative examples are MHC-peptide complexes in the immune system. Developing computational methods for protein-peptide binding prediction is therefore an important task with applications to vaccine and drug design. METHODS: Previous learning approaches address the binding prediction problem using traditional margin based binary classifiers. In this paper we propose PepDist: a novel approach for predicting binding affinity. Our approach is based on learning peptide-peptide distance functions. Moreover, we suggest to learn a single peptide-peptide distance function over an entire family of proteins (e.g. MHC class I). This distance function can be used to compute the affinity of a novel peptide to any of the proteins in the given family. In order to learn these peptide-peptide distance functions, we formalize the problem as a semi-supervised learning problem with partial information in the form of equivalence constraints. Specifically, we propose to use DistBoost [1,2], which is a semi-supervised distance learning algorithm. RESULTS: We compare our method to various state-of-the-art binding prediction algorithms on MHC class I and MHC class II datasets. In almost all cases, our method outperforms all of its competitors. One of the major advantages of our novel approach is that it can also learn an affinity function over proteins for which only small amounts of labeled peptides exist. In these cases, our method's performance gain, when compared to other computational methods, is even more pronounced. We have recently uploaded the PepDist webserver which provides binding prediction of peptides to 35 different MHC class I alleles. The webserver which can be found at is powered by a prediction engine which was trained using the framework presented in this paper. CONCLUSION: The results obtained suggest that learning a single distance function over an entire family of proteins achieves higher prediction accuracy than learning a set of binary classifiers for each of the proteins separately. We also show the importance of obtaining information on experimentally determined non-binders. Learning with real non-binders generalizes better than learning with randomly generated peptides that are assumed to be non-binders. This suggests that information about non-binding peptides should also be published and made publicly available

Prediction of arterial pressure increase after fluid challenge

<p>Abstract</p> <p>Background</p> <p>Mean arterial pressure above 65 mmHg is recommended for critically ill hypotensive patients whereas they do not benefit from supranormal cardiac output values. In this study we investigated if the increase of mean arterial pressure after volume expansion could be predicted by cardiovascular and renal variables. This is a relevant topic because unnecessary positive fluid balance increases mortality, organ dysfunction and Intensive Care Unit length of stay.</p> <p>Methods</p> <p>Thirty-six hypotensive patients (mean arterial pressure < 65 mmH) received a fluid challenge with hydroxyethyl starch. Patients were excluded if they had active bleeding and/or required changes in vasoactive agents infusion rate in the previous 30 minutes. Responders were defined by the increase of mean arterial pressure value to over 65 mmHg or by more than 20% with respect to the value recorded before fluid challenge. Measurements were performed before and at one hour after the end of fluid challenge.</p> <p>Results</p> <p>Twenty-two patients (61%) increased arterial pressure after volume expansion. Baseline heart rate, arterial pressure, central venous pressure, central venous saturation, central venous to arterial PCO₂difference, lactate, urinary output, fractional excretion of sodium and urinary sodium/potassium ratio were similar between responder and non-responder. Only 7 out of 36 patients had valuable dynamic indices and then we excluded them from analysis. When the variables were tested as predictors of responders, they showed values of areas under the ROC curve ranging between 0.502 and 0.604. Logistic regression did not reveal any association between variables and responder definition.</p> <p>Conclusions</p> <p>Fluid challenge did not improve arterial pressure in about one third of hypotensive critically ill patients. Cardiovascular and renal variables did not enable us to predict the individual response to volume administration.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00721604">NCT00721604</a>.</p

'Unite and conquer': enhanced prediction of protein subcellular localization by integrating multiple specialized tools

<p>Abstract</p> <p>Background</p> <p>Knowing the subcellular location of proteins provides clues to their function as well as the interconnectivity of biological processes. Dozens of tools are available for predicting protein location in the eukaryotic cell. Each tool performs well on certain data sets, but their predictions often disagree for a given protein. Since the individual tools each have particular strengths, we set out to integrate them in a way that optimally exploits their potential. The method we present here is applicable to various subcellular locations, but tailored for predicting whether or not a protein is localized in mitochondria. Knowledge of the mitochondrial proteome is relevant to understanding the role of this organelle in global cellular processes.</p> <p>Results</p> <p>In order to develop a method for enhanced prediction of subcellular localization, we integrated the outputs of available localization prediction tools by several strategies, and tested the performance of each strategy with known mitochondrial proteins. The accuracy obtained (up to 92%) surpasses by far the individual tools. The method of integration proved crucial to the performance. For the prediction of mitochondrion-located proteins, integration via a two-layer decision tree clearly outperforms simpler methods, as it allows emphasis of biologically relevant features such as the mitochondrial targeting peptide and transmembrane domains.</p> <p>Conclusion</p> <p>We developed an approach that enhances the prediction accuracy of mitochondrial proteins by uniting the strength of specialized tools. The combination of machine-learning based integration with biological expert knowledge leads to improved performance. This approach also alleviates the conundrum of how to choose between conflicting predictions. Our approach is easy to implement, and applicable to predicting subcellular locations other than mitochondria, as well as other biological features. For a trial of our approach, we provide a webservice for mitochondrial protein prediction (named YimLOC), which can be accessed through the AnaBench suite at http://anabench.bcm.umontreal.ca/anabench/. The source code is provided in the Additional File <supplr sid="S2">2</supplr>.</p> <suppl id="S2"> <title> <p>Additional file 2</p> </title> <text> <p>This file contains scripts for the online server YimLOC. Please note that there scripts only codes for the ready-to-use STACK-mem-DT described in the main text. The scripts do not provide the training process.</p> </text> <file name="1471-2105-8-420-S2.pdf"> <p>Click here for file</p> </file> </suppl

Progesterone reduces erectile dysfunction in sleep-deprived spontaneously hypertensive rats

BACKGROUND: Paradoxical sleep deprivation (PSD) associated with cocaine has been shown to enhance genital reflexes (penile erection-PE and ejaculation-EJ) in Wistar rats. Since hypertension predisposes males to erectile dysfunction, the aim of the present study was to investigate the effects of PSD on genital reflexes in the spontaneously hypertensive rat (SHR) compared to the Wistar strain. We also extended our study to examine how PSD affect steroid hormone concentrations involved in genital events in both experimental models. METHODS: The first experiment investigated the effects of PSD on genital reflexes of Wistar and SHR rats challenged by saline and cocaine (n = 10/group). To further examine the impact of the PSD on concentrations of sexual hormones, we performed a hormonal analysis of testosterone and progesterone in the Wistar and in SHR strains. Since after PSD progesterone concentrations decreased in the SHR compared to the Wistar PSD group we extended our study by investigating whether progesterone (25 mg/kg or 50 mg/kg) or testosterone (0.5 mg/kg or 1.0 mg/kg) administration during PSD would have a facilitator effect on the occurrence of genital reflexes in this hypertensive strain. RESULTS: A 4-day period of PSD induced PE in 50% of the Wistar rats against 10% for the SHR. These genital reflexes was potentiated by cocaine in Wistar rats whereas this scenario did not promote significant enhancement in PE and EJ in hypertensive rats, and the percentage of SHR displaying genital reflexes still figured significantly lower than that of the Wistar strain. As for hormone concentrations, both sleep-deprived Wistar and SHR showed lower testosterone concentrations than their respective controls. Sleep deprivation promoted an increase in concentrations of progesterone in Wistar rats, whereas no significant alterations were found after PSD in the SHR strain, which did not present enhancement in erectile responses. In order to explore the role of progesterone in the occurrence of genital reflexes, SHR were treated daily during the sleep deprivation period with progesterone; after the administration of this hormone and challenge with cocaine, we observed a significant increase in erectile events compared with the vehicle PSD SHR+cocaine group. CONCLUSION: Our data showed that the low frequency of genital reflexes found in SHR sleep deprived rats may be attributed to the lower concentrations of progesterone in these rats, based on the observation that progesterone replacement increased genital reflexes in this strain

Helicobacter pylori Type IV Secretion Apparatus Exploits β1 Integrin in a Novel RGD-Independent Manner

Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (T4SS) into host cells is a major risk factor for severe gastric diseases, including gastric cancer. However, the mechanism of translocation and the requirements from the host cell for that event are not well understood. The T4SS consists of inner- and outer membrane-spanning Cag protein complexes and a surface-located pilus. Previously an arginine-glycine-aspartate (RGD)-dependent typical integrin/ligand type interaction of CagL with α5β1 integrin was reported to be essential for CagA translocation. Here we report a specific binding of the T4SS-pilus-associated components CagY and the effector protein CagA to the host cell β1 Integrin receptor. Surface plasmon resonance measurements revealed that CagA binding to α5β1 integrin is rather strong (dissociation constant, KD of 0.15 nM), in comparison to the reported RGD-dependent integrin/fibronectin interaction (KD of 15 nM). For CagA translocation the extracellular part of the β1 integrin subunit is necessary, but not its cytoplasmic domain, nor downstream signalling via integrin-linked kinase. A set of β1 integrin-specific monoclonal antibodies directed against various defined β1 integrin epitopes, such as the PSI, the I-like, the EGF or the β-tail domain, were unable to interfere with CagA translocation. However, a specific antibody (9EG7), which stabilises the open active conformation of β1 integrin heterodimers, efficiently blocked CagA translocation. Our data support a novel model in which the cag-T4SS exploits the β1 integrin receptor by an RGD-independent interaction that involves a conformational switch from the open (extended) to the closed (bent) conformation, to initiate effector protein translocation

Perioperative fluid and volume management: physiological basis, tools and strategies

Fluid and volume therapy is an important cornerstone of treating critically ill patients in the intensive care unit and in the operating room. New findings concerning the vascular barrier, its physiological functions, and its role regarding vascular leakage have lead to a new view of fluid and volume administration. Avoiding hypervolemia, as well as hypovolemia, plays a pivotal role when treating patients both perioperatively and in the intensive care unit. The various studies comparing restrictive vs. liberal fluid and volume management are not directly comparable, do not differ (in most instances) between colloid and crystalloid administration, and mostly do not refer to the vascular barrier's physiologic basis. In addition, very few studies have analyzed the use of advanced hemodynamic monitoring for volume management

Cognitive behavioural therapy versus supportive therapy for persistent positive symptoms in psychotic disorders: The POSITIVE Study, a multicenter, prospective, single-blind, randomised controlled clinical trial

Background: It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention. Methods: The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists. Research relating the psychotherapy process with outcome, neurobiological research addressing basic questions of delusion formation using fMRI and neuropsychological assessment and treatment research investigating adaptations of CBT for adolescents is combined in this network. Problems of transfer into routine clinical care will be identified and addressed by a project focusing on cost efficiency. Discussion: This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care. Furthermore, the study will allow drawing conclusions about the mediators of treatment effects of CBT of psychotic disorders. Trial Registration Current Controlled Trials ISRCTN2924287