Reconstruction of a first-order phase transition from computer simulations of individual phases and subphases

We present a new method for investigating first-order phase transitions using Monte Carlo simulations. It relies on the multiple-histogram method and uses solely histograms of individual phases. In addition, we extend the method to include histograms of subphases. The free energy difference between phases, necessary for attributing the correct statistical weights to the histograms, is determined by a detour in control parameter space via auxiliary systems with short relaxation times. We apply this method to a recently introduced model for structure formation in polypeptides for which other methods fail.Comment: 13 pages in preprint mode, REVTeX, 2 Figures available from the authors ([email protected], [email protected]

Untersuchungen zur in vivo Funktion der Aspartylprotease BACE1

Die Alzheimersche Erkrankung ist die häufigste altersbedingte Form der Demenz. Bisher gibt es keine wirksame Therapie, die den Ausbruch und die Progression der Krankheit verhindern kann. Einen vielversprechenden Ansatz für die Therapie stellt zur Zeit die Inhibition der β-Sekretase BACE1 dar. Die Aspartat-Protease BACE1 (β-site APP cleaving enzyme) ist an der Generierung des neurotoxischen Amyloid β-Peptids beteiligt und trägt somit maßgeblich zur molekularen Pathogenese der Alzheimer-Kankheit bei. Neben dem β-Amyloid-Vorläufer-Protein βAPP konnten zahlreiche weitere Substrate von BACE1 identifiziert werden. Diese Substrate sind unter anderem an immunologischen Prozessen (PSGL-1, St6GalI, IL1-RII) und an der Erregbarkeit von Neuronen (Untereinheiten der spannungsabhängigen Natriumkanäle β2/β4) beteiligt. Über die genaue physiologische Funktion von BACE1 ist bisher jedoch wenig bekannt. Die phänotypischen und biochemischen Untersuchungen eines BACE1-defizienten Mausmodells sollten näheren Einblick für die Bedeutung von BACE1 in vivo geben. Ein wichtiger Ansatz waren dabei Studien zur Funktion und Regulation des Immunsystems. Es zeigte sich, dass der Verlust von BACE1 in Mäusen zu einer Reduktion der B-Zellen in der Milz, sowie zu niedrigeren Immunglobulinkonzentrationen im Serum führt. Weiterhin konnte gezeigt werden, dass BACE1-defiziente Mäuse anfälliger auf eine Infektion mit dem pathogenen Mikroorganismus Listeria monocytogenes reagierten als Wildtyp-Tiere. Eine mögliche Erklärung für diese immunologischen Defekte der BACE1-defizienten Mäuse könnte eine gestörte proteolytische Prozessierung von immunologisch relevanten Substraten darstellen. Deshalb stand die Identifizierung noch unbekannter Substrate von BACE1 im Vordergrund. Untersucht wurden der B-Zell aktivierende Faktor BAFF (B cell-activating factor belonging to the TNF family), TRANCE (tumor necrosis factor-related activation-induced cytokine) und ICAM-1 (Intercellular adhesion molecule-1). Es konnte gezeigt werden, dass BACE1 TRANCE nach Überexpression im Zellkulturmodell proteolytisch spaltet. Allerdings konnte eine auf das Mausmodell übertragene Relevanz in vivo bisher nicht gezeigt werden. Für BAFF und ICAM-1 konnte eine proteolytische Prozessierung durch BACE1 nicht eindeutig belegt werden. Die gezielte Proteolyse der Ektodomäne von βAPP erfolgt entweder durch BACE1, das den N-Terminus von Aβ generiert, oder durch eine α-Sekretase, welche innerhalb der Aβ Sequenz schneidet und somit die Erzeugung von Aβ verhindert. Da die beiden Sekretasen um βAPP als Substrat konkurrieren, führt die Inhibition der einen Protease zu einer vermehrten Prozessierung durch die andere Protease. In einem weiteren Teil dieser Arbeit wurde deshalb untersucht, ob BACE1 die Expression und Aktivität der α-Sekretasen ADAM10 und ADAM17 beeinflusst. Erste Daten deuten an, dass BACE1 die Reifung und Aktivität der α-Sekretase ADAM17 beeinflussen könnte. In BACE1-defizienten Zellen und Geweben wurde eine Akkumulation der proteolytisch inaktiven Pro-Form sowie eine geringere proteolytische Aktivität von ADAM17 beobachtet. Die Überexpression von BACE1 resultierte dagegen in einer erhöhten ADAM17-Aktivität. Eine völlig neue, proteolyse-unabhängige Funktion von BACE1 konnte bei elektro-physiologischen Analysen des spannungsabhängigen Natriumkanals Nav1.2α beobachtet werden. BACE1 beeinflusst die Aktivierung von Nav1.2α über die Proteolyse seiner modulatorischen Untereinheiten β2 und β4, bewirkt aber auch unabhängig von den β-Untereinheiten eine erhöhte Aktivierbarkeit des Kanals. Die in dieser Arbeit erzielten Ergebnisse deuten darauf hin, dass BACE1 im Gegensatz zu bisherigen Annahmen, an vielen weiteren und komplexeren zellulären und systemischen Prozessen beteiligt ist. Intensivere Studien des Immunsystems von BACE1-defizienten Mäusen, insbesondere der B-Zellreifung und der Listerienabwehr, sowie die Erforschung der zugrunde liegenden Mechanismen bezüglich der Reifung von ADAM17 und der Modulation der Natriumkanäle durch BACE1 könnten diese Hypothese bestätigen.Alzheimer disease is the most common form of dementia in elderly people. Until now no potent therapy against the onset and progression of the disease is available. As a promising basic approach for such therapy, the inhibition of the β-secretase BACE1 (βAPP cleaving enzyme 1) is discussed. The aspartyl protease BACE1 initiates the generation of the neurotoxic amyloid β peptide (Aβ) and is therefore one of the key players in the molecular pathogenesis of Alzheimer disease. In addition to the amyloid precursor protein (βAPP) several other substrates for BACE1 could be identified. Those substrates are involved in immunity (PSGL-1, St6GalI, IL1-RII) and in neuronal excitability (VGSC β2/β4) among other functions. However the exact physiological function of BACE1 remains elusive. To gain further insight into the in vivo function of BACE1, BACE1 deficient mice were analyzed with regard to the role of this protease in the immune system. Loss of BACE1 in vivo led to a decreased number of spleenic B-cells as well as reduced levels of serum immunoglobulin. Furthermore, the fact that BACE1 deficient mice are more susceptible to infection with Listeria monocytogenes when compared with wildtype mice could be conveyed. A possible explanation for the observed immunological defects may be the impaired proteolysis of immunological relevant BACE1 substrates. Therefore, the identification of novel substrates for BACE1 was another emphasis of this work. The transmembrane proteins BAFF (B cell-activating factor belonging to the TNF family), TRANCE (tumor necrosis factor-related activation-induced cytokine) and ICAM-1 (Intercellular adhesion molecule-1) were analyzed. TRANCE was shown to be processed by BACE1 after over-expression in cultured cells, however, no in vivo relevance could be proven. BAFF and ICAM-1 could not be identified as physiological substrates for BACE1. The targeted proteolysis of the βAPP ectodomain occurs either by BACE1, which generates the N-terminus of Aβ or by an α-secretase that cleaves inside the Aβ sequence of βAPP and therefore prevents the generation of Aβ. Since both enzymes compete for their substrate, the inhibition of one of the secretases leads to increased processing of βAPP by the other secretase. Thus, another approach of this work was to investigate whether BACE1 affects the expression and activity of the α-secretases ADAM10 and ADAM17. Preliminary results indicate that BACE1 impairs the maturation and activity of ADAM17. In BACE1 deficient cells and tissues the accumulation of pro-ADAM17 and reduced ADAM17 proteolytic activity was observed. In contrast, the over-expression of BACE1 led to increased ADAM17 activity. A completely new non-proteolytic function of BACE1 could be observed when the electrophysiological properties of the voltage gated sodium channel, Nav1.2α were analyzed. BACE1 produced complex effects on the sodium channel gating that could be only partially explained by the cleavage of the auxiliary β-subunits of the channel, which are substrates for BACE1. Co-expression of Nav1.2α with BACE1 led to increased excitability independent from the β-subunits and BACE1 proteolytic activity. Results from this work indicate that BACE1 is involved in much more complex cellular and systemic processes than previously assumed. Intensive studies of the immune system in BACE1 deficient mice, especially of B-cell development and host defense against Listeria monocytogenes, the investigation of the mechanisms of impaired ADAM17 maturation and the modulatory effects of BACE1 on channel gating could support this hypothesis

Comparison of new-generation drug-eluting stents versus drug-coated balloon for in-stent restenosis: a meta-analysis of randomised controlled trials

OBJECTIVE: The study sought to compare angiographic and clinical outcomes of new-generation drug-eluting stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR). DESIGN: Meta-analysis using data from randomised trial found by searches on PubMed, the Cochrane Library, ClinicalTrials.gov and websites of major cardiovascular congresses. SETTING: Only randomised trials comparing DES with DCB were included. PARTICIPANTS: Patients with ISR in the included trials. INTERVENTIONS: New-generation DES versus DCB. OUTCOMES: The angiographic and clinical outcomes including cardiac death, all-cause death, myocardial infarction, target lesion revascularisation (TLR), target vessel revascularisation (TVR), major adverse cardiac events (MACE) and stent thrombosis were investigated. RESULTS: Five trials including 913 patients were eligible and included. Pooled analysis in angiographic results identified that new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI -0.42 to -0.20, P<0.001) and lower per cent diameter stenosis (risk ratio (RR): 0.28, 95% CI 0.02 to 0.55, P=0.04). DES significantly reduced the risk of TLR (RR: 1.96, 95% CI 1.17 to 3.28, P=0.01) compared with DCB; however, there was no statistical differences for MACE (RR: 1.21, 95% CI 0.67 to 2.17, P=0.53), myocardial infarction (RR: 1.16, 95% CI 0.55 to 2.48, P=0.69) and cardiac death (RR: 1.80, 95% CI 0.60 to 5.39, P=0.29). CONCLUSIONS: Interventions with new-generation DES appear to be associated with significant reduction in per cent diameter stenosis and TLR at short-term follow-up, but had similar MACE, myocardial infarction and cardiac death for patients with coronary ISR compared with DCB. Appropriately powered studies with longer term follow-up are warranted to confirm these findings

Bestimmung der W-Masse aus dem Leptonenergiespektrum mit dem Detektor ALEPH

Aus den Daten, die mit dem ALEPH-Detektor am LEP-Ring 1997 und 1998 bei Schwerpunktenergien von 183 GeV und 189 GeV aufgenommen wurden, wurde die W-Masse aus dem Energiespektrum des geladenen Leptons in semileptonischen WW-Zerfaellen bestimmt. Dabei wurde ein kinematischer Fit und eine Monte-Carlo-Umgewichtungstechnik angewandt

In vivo comparison of arterial lumen dimensions assessed by co-registered three-dimensional (3D) quantitative coronary angiography, intravascular ultrasound and optical coherence tomography

This study sought to compare lumen dimensions as assessed by 3D quantitative coronary angiography (QCA) and by intravascular ultrasound (IVUS) or optical coherence tomography (OCT), and to assess the association of the discrepancy with vessel curvature. Coronary lumen dimensions often show discrepancies when assessed by X-ray angiography and by IVUS or OCT. One source of error concerns a possible mismatch in the selection of corresponding regions for the comparison. Therefore, we developed a novel, real-time co-registration approach to guarantee the point-to-point correspondence between the X-ray, IVUS and OCT images. A total of 74 patients with indication for cardiac catheterization were retrospectively included. Lumen morphometry was performed by 3D QCA and IVUS or OCT. For quantitative analysis, a novel, dedicated approach for co-registration and lumen detection was employed allowing for assessment of lumen size at multiple positions along the vessel. Vessel curvature was automatically calculated from the 3D arterial vessel centerline. Comparison of 3D QCA and IVUS was performed in 519 distinct positions in 40 vessels. Correlations were r = 0.761, r = 0.790, and r = 0.799 for short diameter (SD), long diameter (LD), and area, respectively. Lumen sizes were larger by IVUS (P < 0.001): SD, 2.51 ± 0.58 mm versus 2.34 ± 0.56 mm; LD, 3.02 ± 0.62 mm versus 2.63 ± 0.58 mm; Area, 6.29 ± 2.77 mm2versus 5.08 ± 2.34 mm2. Comparison of 3D QCA and OCT was performed in 541 distinct positions in 40 vessels. Correlations were r = 0.880, r = 0.881, and r = 0.897 for SD, LD, and area, respectively. Lumen sizes were larger by OCT (P < 0.001): SD, 2.70 ± 0.65 mm versus 2.57 ± 0.61 mm; LD, 3.11 ± 0.72 mm versus 2.80 ± 0.62 mm; Area 7.01 ± 3.28 mm2versus 5.93 ± 2.66 mm2. The vessel-based discrepancy between 3D QCA and IVUS or OCT long diameters increased with increasing vessel curvature. In conclusion, our comparison of co-registered 3D QCA and invasive imaging data suggests a bias towards larger lume

His bundle pacing guided by automated intrinsic morphology matching is feasible in patients with narrow QRS complexes

Pace mapping and visual comparison of the local pacing response with the intrinsic QRS morphology form the mainstay of His bundle pacing (HBP). We evaluated the performance of a surface lead morphology match algorithm for automated classification of the pacing response in patients with narrow intrinsic QRS undergoing electroanatomic mapping (EAM)-guided HBP. HBP was attempted in 43 patients. In 28 cases with narrow QRS, the EnSite AutoMap Module was used for automated assessment of the QRS morphology resulting from pace mapping in the His cloud area with either a diagnostic catheter or the His lead. An intrinsic morphology match score (IMS) was calculated for 1.546 QRS complexes and assessed regarding its accuracy and performance in classifying the individual pacing response as either selective HBP (S-HBP), nonselective HBP (NS-HBP) or right ventricular stimulation. Automated morphology comparison of 354 intrinsic beats with the individual reference determined a test accuracy of 99% (95% CI 98.96–99.04) and a precision of 97.99–99.5%. For His-lead stimulation, an IMS ≥ 89% identified S-HBP with a sensitivity, specificity and positive predictive value of 1.00 (0.99, 1.00) and a negative predictive value of 0.99 (0.98, 1.00). An IMS between 78 and &lt; 89% indicated NS-HBP with a sensitivity and specificity of 1.00 (0.99, 1.00) and 0.99 (0.98, 1.00), respectively. IMS represents a new automated measure for standardized individual morphology classification in patients with normal QRS undergoing EAM-guided HBP. Clinical trial registration: NCT04416958

Case study of spatial and temporal variability of snow cover, grain size, albedo and radiative forcing in the Sierra Nevada and Rocky Mountain snowpack derived from imaging spectroscopy

Quantifying the spatial distribution and temporal change in mountain snow cover, microphysical and optical properties is important to improve our understanding of the local energy balance and the related snowmelt and hydrological processes. In this paper, we analyze changes of snow cover, optical-equivalent snow grain size (radius), snow albedo and radiative forcing by light-absorbing impurities in snow and ice (LAISI) with respect to terrain elevation and aspect at multiple dates during the snowmelt period. These snow properties are derived from the NASA/JPL Airborne Visible/Infrared Imaging Spectrometer (AVIRIS) data from 2009 in California's Sierra Nevada and from 2011 in Colorado's Rocky Mountains, USA. Our results show a linearly decreasing snow cover during the ablation period in May and June in the Rocky Mountains and a snowfall-driven change in snow cover in the Sierra Nevada between February and May. At the same time, the snow grain size is increasing primarily at higher elevations and north-facing slopes from 200 microns to 800 microns on average. We find that intense snowmelt renders the mean grain size almost invariant with respect to elevation and aspect. Our results confirm the inverse relationship between snow albedo and grain size, as well as between snow albedo and radiative forcing by LAISI. At both study sites, the mean snow albedo value decreases from approximately 0.7 to 0.5 during the ablation period. The mean snow grain size increased from approximately 150 to 650 microns. The mean radiative forcing increases from 20 W m−2 up to 200 W m−2 during the ablation period. The variability of snow albedo and grain size decreases in general with the progression of the ablation period. The spatial variability of the snow albedo and grain size decreases through the melt season while the spatial variability of radiative forcing remains constant.</p

Retrieval of subpixel snow covered area, grain size, and albedo from MODIS

We describe and validate a model that retrieves fractional snow-covered area and the grain size and albedo of that snow from surface reflectance data (product MOD09GA) acquired by NASA\u27s Moderate Resolution Imaging Spectroradiometer (MODIS). The model analyzes the MODIS visible, near infrared, and shortwave infrared bands with multiple endmember spectral mixtures from a library of snow, vegetation, rock, and soil. We derive snow spectral endmembers of varying grain size from a radiative transfer model specific to a scene\u27s illumination geometry; spectra for vegetation, rock, and soil were collected in the field and laboratory. We validate the model with fractional snow cover estimates from Landsat Thematic Mapper data, at 30 m resolution, for the Sierra Nevada, Rocky Mountains, high plains of Colorado, and Himalaya. Grain size measurements are validated with field measurements during the Cold Land Processes Experiment, and albedo retrievals are validated with in situ measurements in the San Juan Mountains of Colorado. The pixel-weighted average RMS error for snow-covered area across 31 scenes is 5%, ranging from 1% to 13%. The mean absolute error for grain size was 51 μm and the mean absolute error for albedo was 4.2%. Fractional snow cover errors are relatively insensitive to solar zenith angle. Because MODSCAG is a physically based algorithm that accounts for the spatial and temporal variation in surface reflectances of snow and other surfaces, it is capable of global snow cover mapping in its more computationally efficient, operational mode