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Motor function after hemispheric lesions has been associated with the structural integrity of either the pyramidal tract (PT) or alternate motor fibers (aMF). In this study, we aimed to differentially characterize the roles of PT and aMF in motor compensation by relating diffusion-tensor-imaging-derived parameters of white matter microstructure to measures of proximal and distal motor function in patients after hemispherotomy. Twenty-five patients (13 women; mean age: 21.1 years) after hemispherotomy (at mean age: 12.4 years) underwent Diffusion Tensor Imaging and evaluation of motor function using the Fugl-Meyer Assessment and the index finger tapping test. Regression analyses revealed that fractional anisotropy of the PT explained (p = 0.050) distal motor function including finger tapping rate (p = 0.027), whereas fractional anisotropy of aMF originating in the contralesional cortex and crossing to the ipsilesional hemisphere in the pons explained proximal motor function (p = 0.001). Age at surgery was found to be the only clinical variable to explain motor function (p < 0.001). Our results are indicative of complementary roles of the PT and of aMF in motor compensation of hemispherotomy mediating distal and proximal motor compensation of the upper limb, respectively.
Limbic encephalitis (LE) is an autoimmune syndrome often associated with temporal lobe epilepsy. Recent research suggests that particular structural changes in LE depend on the type of the associated antibody and occur in both mesiotemporal gray matter and white matter regions. However, it remains questionable to what degree conventional diffusion tensor imaging (DTI)-methods reflect alterations in white matter microstructure, since these methods do not account for crossing fibers. To address this methodological shortcoming, we applied fixel-based analysis as a novel technique modeling distinct fiber populations. For our study, 19 patients with LE associated with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE, mean age = 35.9 years, 11 females), 4 patients with LE associated with autoantibodies against leucine-rich glioma-inactivated 1 (LGI1-LE, mean age = 63.3 years, 2 females), 5 patients with LE associated with contactin-associated protein-like 2 (CASPR2, mean age = 57.4, 0 females), 20 age- and gender-matched control patients with hippocampal sclerosis (19 GAD-LE control patients: mean age = 35.1 years, 11 females; 4 LGI1-LE control patients: mean age = 52.6 years, 2 females; 5 CASPR2-LE control patients: mean age = 42.7 years, 0 females; 10 patients are included in more than one group) and 33 age- and gender-matched healthy control subjects (19 GAD-LE healthy controls: mean age = 34.6 years, 11 females; 8 LGI1-LE healthy controls: mean age = 57.0 years, 4 females, 10 CASPR2-LE healthy controls: mean age = 57.2 years, 0 females; 4 subjects are included in more than one group) underwent structural imaging and DTI at 3 T and neuropsychological testing. Patient images were oriented according to lateralization in EEG resulting in an affected and unaffected hemisphere. Fixel-based metrics fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC = FD · FC) were calculated to retrieve information about white matter integrity both on the micro- and the macroscale. As compared to healthy controls, patients with GAD-LE showed significantly (family-wise error-corrected, p < 0.05) lower FDC in the superior longitudinal fascicle bilaterally and in the isthmus of the corpus callosum. In CASPR2-LE, lower FDC in the superior longitudinal fascicle was only present in the affected hemisphere. In LGI1-LE, we did not find any white matter alteration of the superior longitudinal fascicle. In an explorative tract-based correlation analysis within the GAD-LE group, only a correlation between the left/right ratio of FC values of the superior longitudinal fascicle and verbal memory performance (R = 0.64, Holm-Bonferroni corrected p < 0.048) remained significant after correcting for multiple comparisons. Our results underscore the concept of LE as a disease comprising a broad and heterogeneous group of entities and contribute novel aspects to the pathomechanistic understanding of this disease that may strengthen the role of MRI in the diagnosis of LE.
Noneequilibrium models (three-fluid hydrodynamics and UrQMD) use to discuss the uniqueness of often proposed experimental signatures for quark matter formation in relativistic heavy ion collisions. It is demonstrated that these two models - although they do treat the most interesting early phase of the collisions quite differently(thermalizing QGP vs. coherent color fields with virtual particles) - both yields a reasonable agreement with a large variety of the available heavy ion data.
The behavior of hadronic matter at high baryon densities is studied within Ultrarelativistic Quantum Molecular Dynamics (URQMD). Baryonic stopping is observed for Au+Au collisions from SIS up to SPS energies. The excitation function of flow shows strong sensitivities to the underlying equation of state (EOS), allowing for systematic studies of the EOS. Dilepton spectra are calculated with and without shifting the rho pole. Except for S+Au collisions our calculations reproduce the CERES data.
The behavior of hadronic matter at high baryon densities is studied within Ultrarelativistic Quantum Molecular Dynamics (URQMD). Baryonic stopping is observed for Au+Au collisions from SIS up to SPS energies. The excitation function of flow shows strong sensitivities to the underlying equation of state (EOS), allowing for systematic studies of the EOS. Effects of a density dependent pole of the rho-meson propagator on dilepton spectra are studied for different systems and centralities at CERN energies.
We study the thermodynamic properties of infinite nuclear matter with the Ultrarelativistic Quantum Molecular Dynamics (URQMD), a semiclassical transport model, running in a box with periodic boundary conditions. It appears that the energy density rises faster than T4 at high temperatures of T approx. 200 - 300 MeV. This indicates an increase in the number of degrees of freedom. Moreover, We have calculated direct photon production in Pb+Pb collisions at 160 GeV/u within this model. The direct photon slope from the microscopic calculation equals that from a hydrodynamical calculation without a phase transition in the equation of state of the photon source.
Nonequilibrium models (three-fluid hydrodynamics, UrQMD, and quark molecular dynamics) are used to discuss the uniqueness of often proposed experimental signatures for quark matter formation in relativistic heavy ion collisions from the SPS via RHIC to LHC. It is demonstrated that these models - although they do treat the most interesting early phase of the collisions quite differently (thermalizing QGP vs. coherent color fields with virtual particles) -- all yield a reasonable agreement with a large variety of the available heavy ion data. Hadron/hyperon yields, including J/Psi meson production/suppression, strange matter formation, dileptons, and directed flow (bounce-off and squeeze-out) are investigated. Observations of interesting phenomena in dense matter are reported. However, we emphasize the need for systematic future measurements to search for simultaneous irregularities in the excitation functions of several observables in order to come close to pinning the properties of hot, dense QCD matter from data. The role of future experiments with the STAR and ALICE detectors is pointed out.
The Compressed Baryonic Matter (CBM) experiment is a dedicated heavy ion collision experiment at the FAIR facility. It will be one of the first HEP experiments which works in a triggerless mode: data received in the DAQ from the detectors will not be associated with events by a hardware trigger anymore. All raw data within a giventime period will be collected continuously in containers, so-called time-slices. The task of the reconstruction algorithms is to create events out of this raw data stream. In this contribution, the optimization of the reconstruction software in the RICH detector to the free-streaming data flow is presented. The implementation of ring reconstruction algorithms which use time measurements of the hits as an additional parameter is discussed.
More than 30% of the world's population are anemic with serious economic consequences including reduced work capacity and other obstacles to national welfare and development. Red blood cell transfusion is the mainstay to correct anemia, but it is also 1 of the top 5 overused procedures. Patient blood management (PBM) is a proactive, patient-centered, and multidisciplinary approach to manage anemia, optimize hemostasis, minimize iatrogenic blood loss, and harness tolerance to anemia. Although the World Health Organization has endorsed PBM in 2010, many hospitals still seek guidance with the implementation of PBM in clinical routine. Given the use of proven change management principles, we propose simple, cost-effective measures enabling any hospital to reduce both anemia and red blood cell transfusions in surgical and medical patients. This article provides comprehensive bundles of PBM components encompassing 107 different PBM measures, divided into 6 bundle blocks acting as a working template to develop institutions' individual PBM practices for hospitals beginning a program or trying to improve an already existing program. A stepwise selection of the most feasible measures will facilitate the implementation of PBM. In this manner, PBM represents a new quality and safety standard.
Background: Conditions during blood product storage and transportation should maintain quality. The aim of this in vitro study was to investigate the effect of interruption of agitation, temporary cooling (TC), and pneumatic tube system transportation (PTST) on the aggregation ability (AA) and mitochondrial function (MF) of platelet concentrates (PC).
Study Design and Methods: A PC was divided equally into four subunits and then allocated to four test groups. The control group (I) was stored as recommended (continuous agitation, 22 ± 2°C) for 4 days. The test groups were stored without agitation (II), stored as recommended, albeit 4°C for 60 minutes on day (d)2 (III) and PTST (IV). Aggregometry was measured using Multiplate (RocheAG; ADPtest, ASPItest, TRAPtest, COLtest) and MF using Oxygraph‐2k (Oroboros Instruments). The basal and maximum mitochondrial respiratory rate (MMRR) were determined. AA and MF were measured daily in I and II and AA in III and IV on d2 after TC/PTST. Statistical analysis was performed using tests for matched observations.
Results: Eleven PCs were used. TRAP‐6 induced AA was significantly lower in II when compared to I on d4 (P = 0.015*). In III the ASPItest was significantly lower (P = 0.032*). IV showed no significant differences. The basal and MMRR were significantly reduced over 4 days in I and II (for both rates in both groups: P = <0.0001*). No significant differences occurred on d4 (P = 0.495).
Conclusion: Our results indicate that ex vivo AA and MF of PCs are unaffected, even in no‐ideal storage and transport circumstances with respect to agitation, temperature, and force.
Background: The aim of this study was to compare outcome of patients with previous cardiac surgery undergoing transapical aortic valve implantation (Redo-TAVI) to those undergoing classic aortic valve replacement (Redo-AVR) by using propensity analysis.
Methods: From January 2005 through May 2012, 52 high-risk patients underwent Redo-TAVI using a pericardial xenograft fixed within a stainless steel, balloon-expandable stent (Edwards SAPIEN™). During the same period of time 167 patients underwent classic Redo-AVR. Logistic regression analysis was used to identify covariates among 11 baseline patient variables including the type of initial surgery. Using the significant regression coefficients, each patient’s propensity score was calculated, allowing selectively matched subgroups of 40 patients each. Initial surgery included coronary artery bypass grafting in 30 patients, aortic valve replacement in 7 patients and mitral valve reconstruction in 3 patients in each group. Follow-up was 4 ± 2 years and was 100% complete.
Results: Postoperative chest tube drainage (163 ± 214 vs. 562 ± 332 ml/24 h, p = 0.02) and incidence of early permanent neurologic deficit (0 vs. 13%, p = 0.04) was lower in patients with Redo-TAVI and there was a trend towards improved 30-day survival (p = 0.06). Also we detected a decreased ventilation time (p = 0.04) and lower transfusion rate of allogenic blood products (p ≤ 0.05) in the Redo-TAVI group. At late follow up differences regarding incidence of major adverse events, including death and permanent neurologic deficits (25% vs. 43%, p = 0.01) statistically supported early postoperative findings.
Conclusion: The encouraging results regarding early and long-term outcomes following TAVI in patients with previous cardiac surgery show, that this evolving approach may be particularly beneficial in this patient cohort.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
Our ability to select relevant information from the environment is limited by the resolution of attention – i.e., the minimum size of the region that can be selected. Neural mechanisms that underlie this limit and its development are not yet understood. Functional magnetic resonance imaging (fMRI) was performed during an object tracking task in 7- and 11-year-old children, and in young adults. Object tracking activated canonical fronto-parietal attention systems and motion-sensitive area MT in children as young as 7 years. Object tracking performance improved with age, together with stronger recruitment of parietal attention areas and a shift from low-level to higher-level visual areas. Increasing the required resolution of spatial attention – which was implemented by varying the distance between target and distractors in the object tracking task – led to activation increases in fronto-insular cortex, medial frontal cortex including anterior cingulate cortex (ACC) and supplementary motor area, superior colliculi, and thalamus. This core circuitry for attentional precision was recruited by all age groups, but ACC showed an age-related activation reduction. Our results suggest that age-related improvements in selective visual attention and in the resolution of attention are characterized by an increased use of more functionally specialized brain regions during the course of development.
The microscopic phasespace approach URQMD is used to investigate the stopping power and particle production in heavy systems at SPS and RHIC energies. We find no gap in the baryon rapidity distribution even at RHIC. For CERN energies URQMD shows a pile up of baryons and a supression of multi-nucleon clusters at midrapidity.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
mRNA-Abbau ist ein essentieller Prozess der Genexpression, der den Zellen ermöglicht, die Qualität und die Quantität der mRNA zu kontrollieren. Besonders unter Stressbedingungen könnte der mRNA-Abbau eine bedeutende Rolle neben der Speicherung von mRNAs sowie der Regulation der Proteinhomöostase zum Schutz vor schädigenden Einflüssen spielen. Studien mit Hefen und Säugerzellen zeigten, dass dem 5'-3'mRNA-Abbau ein wichtige Rolle sowohl unter normalen Bedingungen als auch unter Stressbedingungen zukommt und dieser in zytoplasmatischen Processing bodies (P-bodies) stattfindet. Im Rahmen dieser Arbeit sollten Erkenntnisse über den 5'-3'mRNA-Abbau erhalten werden. Im Vordergrund stand die Frage nach der Existenz von P-bodies in Arabidopsis thaliana und die Identifikation und Charakterisierung deren Komponenten. Weiterhin sollten Erkenntnisse über die Rolle der P-bodies unter Stressbedingungen gewonnen werden. Dabei sollten besonders Informationen über die Beziehungen zwischen den P-bodies und RNA Stressgranula (mRNA Speicherkompartimente) und Hitzestressgranula (Regulation der Proteinhomöostase) erhalten werden. Das komplette sequenzierte Genom von Arabidopsis thaliana eignete sich zur Identifikation von mRNA-Abbauproteine kodierender Gene. Unter Verwendung von Aminosäuresequenzen bereits bekannter mRNA-Abbauproteine aus Hefe und Säugerzellen konnten Homologe für die Decappingproteine Dcp1 und Dcp2 sowie für die Proteine LSm1,2,5,8 als Untereinheiten des LSm1-7 Komplexes, welcher an der Regulation der Decappingreaktion beteiligt ist, identifiziert werden. Über Hefe-Zwei-Hybrid Analysen konnten anschließend Protein-Protein-Interaktionen zwischen den untersuchten Proteinen identifiziert werden. Weiterhin konnte unter Einsatz der BIFC-Analyse gezeigt werden, dass die Interaktionen zwischen den untersuchten Proteinen hauptsächlich in zytoplasmatischen Strukturen stattfanden. Aufbauend auf diesen Befunden wurde ein Antikörper gegen Dcp1 als Marker für die zytoplasmatischen Strukturen erstellt. Dieser ermöglichte erstmals die Detektion der endogenen Strukturen in Arabidopsis thaliana. Die weitere Charakterisierung über Immunofluoreszenzanalysen zeigten, dass diese P-bodies sind. Wie die P-bodies anderer Organismen sind sie hochdynamisch und benötigen untranslatierte mRNA für die Assemblierung. Die Größe und Anzahl der P-bodies hängt dabei vom Verhältniss des Zuflusses von mRNA und der mRNA-Abbaurate ab. Weiterhin konnte beobachtet werden, das die P-bodies besonders groß unter Stressbedingungen sind und deuten eine wichtige Funktion des mRNA-Abbaus unter Stress an. Dies führte zu der Frage nach der Beziehung der P-bodies zu RNA Stressgranula, die der Speicherung von mRNA unter Stressbedingungen dienen, sowie zu Hitzestressgranula, die an der Aufrechterhaltung der Proteinhomöostase beteiligt sind. Durch Kolokalisationsanalysen mit Markern der RNA Stressgranula, der Hitzestressgranula und der P-bodies konnte erstmals gezeigt werden, dass es sich um voneinander unabhängige Mikrokompartimente handelt, und dass unter Stressbedingungen die zellulären Prozesse mRNA-Abbau, mRNA-Speicherung und Aufrechterhaltung der Proteinhomöostase auf einzelne Mikrkompartimente beschränkt sind. Allerdings konnte zwischen P-bodies und RNA Stressgranula häufig eine räumliche Nähe beobachtet werden. Dies deutet auf einen Austausch von Komponenten zwischen diesen Strukturen hin. Zusammen zeigen die erhaltenen Ergebnisse, dass die identifizierten Proteine Komponenten des 5'-3'mRNA-Abbaus darstellen, und dass der 5'-3'mRNA-Abbau in Pflanzen auch in P-bodies stattfindet. Die Identifizierung und Charakterisierung der pflanzlichen P-bodies bildet eine Grundlage für zukünftige Untersuchungen. Vor allem die massive Bildung von P-bodies unter Stressbedingungen und die Interaktion der P-bodies mit RNA Stressgranula zeigen neue Aspekte der pflanzlichen Hitzestressantwort auf.
Background: The branched chain alcohol isobutanol exhibits superior physicochemical properties as an alternative biofuel. The yeast Saccharomyces cerevisiae naturally produces low amounts of isobutanol as a by-product during fermentations, resulting from the catabolism of valine. As S. cerevisiae is widely used in industrial applications and can easily be modified by genetic engineering, this microorganism is a promising host for the fermentative production of higher amounts of isobutanol.
Results: Isobutanol production could be improved by re-locating the valine biosynthesis enzymes Ilv2, Ilv5 and Ilv3 from the mitochondrial matrix into the cytosol. To prevent the import of the three enzymes into yeast mitochondria, N-terminally shortened Ilv2, Ilv5 and Ilv3 versions were constructed lacking their mitochondrial targeting sequences. SDS-PAGE and immunofluorescence analyses confirmed expression and re-localization of the truncated enzymes. Growth tests or enzyme assays confirmed enzymatic activities. Isobutanol production was only increased in the absence of valine and the simultaneous blockage of the mitochondrial valine synthesis pathway. Isobutanol production could be even more enhanced after adapting the codon usage of the truncated valine biosynthesis genes to the codon usage of highly expressed glycolytic genes. Finally, a suitable ketoisovalerate decarboxylase, Aro10, and alcohol dehydrogenase, Adh2, were selected and overexpressed. The highest isobutanol titer was 0.63 g/L at a yield of nearly 15 mg per g glucose.
Conclusion: A cytosolic isobutanol production pathway was successfully established in yeast by re-localization and optimization of mitochondrial valine synthesis enzymes together with overexpression of Aro10 decarboxylase and Adh2 alcohol dehydrogenase. Driving forces were generated by blocking competition with the mitochondrial valine pathway and by omitting valine from the fermentation medium. Additional deletion of pyruvate decarboxylase genes and engineering of co-factor imbalances should lead to even higher isobutanol production.