69 research outputs found
Systematic Review and Meta-Analysis of the Incidence of Rupture, Repair, and Death of Small and Large Abdominal Aortic Aneurysms under Surveillance
No full textBackground: The ultimate goal of treating patients with abdominal aortic aneurysms (AAAs) is to repair them when the risk of rupture exceeds the risk of repair. Small AAAs demonstrate a low rupture risk, and recently, large AAAs just above the threshold (5.5–6.0 cm) seem to be at low risk of rupture as well. The present review aims to investigate the outcomes of AAAs under surveillance through a comprehensive systematic review and meta-analysis. Methods: PubMed, Embase, and the Cochrane Central Register were searched (22 March 2022; PROSPERO; #CRD42022316094). The Cochrane and PRISMA statements were respected. Blinded systematic screening of the literature, data extraction, and quality assessment were performed by two authors. Conflicts were resolved by a third author. The meta-analysis of prevalence provided estimated proportions, 95% confidence intervals, and measures of heterogeneity (I2). Based on I2, the heterogeneity might be negligible (0–40%), moderate (30–60%), substantial (50–90%), and considerable (75–100%). The primary outcome was the incidence of AAA rupture. Secondary outcomes included the rate of small AAAs reaching the threshold for repair, aortic-related mortality, and all-cause mortality. Results: Fourteen publications (25,040 patients) were included in the analysis. The outcome rates of the small AAA group (<55 mm) were 0.3% (95% CI 0.0–1.0; I2 = 76.4%) of rupture, 0.6% (95% CI 0.0–1.9; I2 = 87.2%) of aortic-related mortality, and 9.6% (95% CI 2.2–21.1; I2 = 99.0%) of all-cause mortality. During surveillance, 21.4% (95% CI 9.0–37.2; I2 = 99.0%) of the initially small AAAs reached the threshold for repair. The outcome rates of the large AAA group (>55 mm) were 25.7% (95% CI 18.0–34.3; I2 = 72.0%) of rupture, 22.1% (95% CI 16.5–28.3; I2 = 25.0%) of aortic-related mortality, and 61.8% (95% CI 47.0–75.6; I2 = 89.1%) of all-cause mortality. The sensitivity analysis demonstrated a higher rupture rate in studies including <662 subjects, patients with a mean age > 72 years, >17% of female patients, and >44% of current smokers. Conclusion: The rarity of rupture and aortic-related mortality in small AAAs supports the current conservative management of small AAAs. Surveillance seems indicated, as one-fifth reached the threshold for repair. Large aneurysms had a high incidence of rupture and aortic-related mortality. However, these data seem biased by the sparse and heterogeneous literature overrepresented by patients unfit for surgery. Specific rupture risk stratified by age, gender, and fit-for-surgery patients with large AAAs needs to be further investigated
The selective addition of water
No full textWater is omnipresent and essential. Yet at the same time it is a rather unreactive molecule. The direct addition of water to C[double bond, length as m-dash]C double bonds is therefore a challenge not answered convincingly. In this perspective we critically evaluate the selectivity and the applicability of the different catalytic approaches for water addition reactions: homogeneous, heterogeneous and bio-catalytic. Here we would like to discuss how to speed up water addition and even make it selective.BiotechnologyApplied Science
Essential Features and Rational Design of CRISPR RNAs That Function With the Cas RAMP Module Complex to Cleave RNAs
No full textSmall RNAs target invaders for silencing in the CRISPR-Cas pathways that protect bacteria and archaea from viruses and plasmids. The CRISPR RNAs (crRNAs) contain sequence elements acquired from invaders that guide CRISPR-associated (Cas) proteins back to the complementary invading DNA or RNA. Here, we have analyzed essential features of the crRNAs associated with the Cas RAMP module (Cmr) effector complex, which cleaves targeted RNAs. We show that Cmr crRNAs contain an 8-nucleotide 5’ sequence tag (also found on crRNAs associated with other CRISPR-Cas pathways) that is critical for crRNA function and can be used to engineer crRNAs that direct cleavage of novel targets. We also present data that indicates that the Cmr complex cleaves an endogenous complementary RNA in Pyrococcus furiosus, providing direct in vivo evidence of RNA targeting by the CRISPR-Cas system. Our findings indicate that the CRISPR RNA-Cmr protein pathway may be exploited to cleave RNAs of interest
Transcriptome Analysis Reveals Strain-Specific and Conserved Stemness Genes in Schmidtea Mediterranea
No full textThe planarian Schmidtea mediterranea is a powerful model organism for studying stem cell biology due to its extraordinary regenerative ability mediated by neoblasts, a population of adult somatic stem cells. Elucidation of the S. mediterranea transcriptome and the dynamics of transcript expression will increase our understanding of the gene regulatory programs that regulate stem cell function and differentiation. Here, we have used RNA-Seq to characterize the S. mediterranea transcriptome in sexual and asexual animals and in purified neoblast and differentiated cell populations. Our analysis identified many uncharacterized genes, transcripts, and alternatively spliced isoforms that are differentially expressed in a strain or cell type-specific manner. Transcriptome profiling of purified neoblasts and differentiated cells identified neoblast-enriched transcripts, many of which likely play important roles in regeneration and stem cell function. Strikingly, many of the neoblast-enriched genes are orthologs of genes whose expression is enriched in human embryonic stem cells, suggesting that a core set of genes that regulate stem cell function are conserved across metazoan species
MsAcT in siliceous monolithic microreactors enables quantitative ester synthesis in water
No full textAcyltransferase from Mycobacterium smegmatis (MsAcT) immobilised in continuous-flow microchannel (30-50 ?m dia.) reactors with hierarchical pore structure (4 cm3/g total pore volume) enabled quantitative, full and rapid transesterification of neopentylglycol with ethyl acetate in a biphasic 50/50 % system in less than one minute. MsAcT was attached either covalently via amino groups or by a specific His-tag-mediated adsorption on Ni or Co sites. Both methods gave similar results for enzyme loading (ca.3 mg/g of carrier, 60-70 % immobilisation yield) and specific activity. The experiments revealed that the rate of monoester formation in the microreactor was exceedingly fast compared to that of diester synthesis and also the native enzyme behaviour in batch reactor. The studies show that the course of transesterification was fully controlled by biocatalytic properties of MsAcT confined in the mesoporous environment. These findings may be of significant interest from both fundamental and practical perspective.BiotechnologyApplied Science
Research in medical education - chances and challenges : international conference, 20th - 22nd May 2009, Heidelberg ; congress abstracts
No full textLoss of DNA mismatch repair imparts a selective advantage in planarian adult stem cells.
No full textLynch syndrome (LS) leads to an increased risk of early-onset colorectal and other types of cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes. Loss of MMR function results in a mutator phenotype that likely underlies its role in tumorigenesis. However, loss of MMR also results in the elimination of a DNA damage-induced checkpoint/apoptosis activation barrier that may allow damaged cells to grow unchecked. A fundamental question is whether loss of MMR provides pre-cancerous stem cells an immediate selective advantage in addition to establishing a mutator phenotype. To test this hypothesis in an in vivo system, we utilized the planarian Schmidtea mediterranea which contains a significant population of identifiable adult stem cells. We identified a planarian homolog of human MSH2, a MMR gene which is mutated in 38% of LS cases. The planarian Smed-msh2 is expressed in stem cells and some progeny. We depleted Smed-msh2 mRNA levels by RNA-interference and found a striking survival advantage in these animals treated with a cytotoxic DNA alkylating agent compared to control animals. We demonstrated that this tolerance to DNA damage is due to the survival of mitotically active, MMR-deficient stem cells. Our results suggest that loss of MMR provides an in vivo survival advantage to the stem cell population in the presence of DNA damage that may have implications for tumorigenesis
Maternal psychosocial stress during pregnancy and placenta weight: evidence from a national cohort study
No full textTo study in a large-scale cohort with prospective data the associations between psychosocial stress during pregnancy and placenta weight at birth. Animal data suggest that the placenta is involved in stress-related fetal programming.; We defined a priori two types of psychosocial stress during pregnancy, life stress (perceived burdens in major areas of life) and emotional symptoms (e.g. anxiety). We estimated the associations of maternal stress during pregnancy with placenta weight at birth, controlled for length of gestation, by predicting gestational age- and sex-specific z-scores of placenta weight through multiple regression analysis, adjusted for potential confounders (N?=?78,017 singleton pregnancies). Life stress (per increase in stress score by 1, range: 0-18) during pregnancy was associated with increased placenta weight at birth (z-score, reported in 10(-3); B, 14.33; CI, 10.12-18.54). In contrast, emotional symptoms during pregnancy were not associated with placenta weight at birth.; Maternal life stress but not emotional symptoms during pregnancy was associated with increased placenta weight at birth; yet, the association-estimate was rather small. Our results may contribute to a better understanding of the role of the placenta in the regulation of intrauterine processes in response to maternal stress
Evolution of alternative and constitutive regions of mammalian 5'UTRs
No full textAbstract Background Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. By contrast, the extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'-untranslated regions (5'UTRs) of mammalian genes are not well characterized. Results We evaluated the abundance, conservation and evolution of putative regulatory control elements, namely, upstream start codons (uAUGs) and open reading frames (uORFs), in the 5'UTRs of human and mouse genes impacted by alternative events. For genes with alternative 5'UTRs, the fraction of alternative sequences (those present in a subset of the transcripts) is much greater than that in the corresponding coding sequence, conceivably, because 5'UTRs are not bound by constraints on protein structure that limit AS in coding regions. Alternative regions of mammalian 5'UTRs evolve faster and are subject to a weaker purifying selection than constitutive portions. This relatively weak selection results in over-abundance of uAUGs and uORFs in the alternative regions of 5'UTRs compared to constitutive regions. Nevertheless, even in alternative regions, uORFs evolve under a stronger selection than the rest of the sequences, indicating that some of the uORFs are conserved regulatory elements; some of the non-conserved uORFs could be involved in species-specific regulation. Conclusion The findings on the evolution and selection in alternative and constitutive regions presented here are consistent with the hypothesis that alternative events, namely, AS and ATI, in 5'UTRs of mammalian genes are likely to contribute to the regulation of translation.</p
Analysis of continuum mechanical, anisotropic material parameters by direct mechanical simulation
No full textIn Kapitel 1, Einleitung der folgenden Abhandlung, werden zunächst die Motivation für die durchgeführten Untersuchungen, der Stand der Technik auf dem Gebiet der kontinuumsmechanischen Materialdatenermittlung von mikrostrukturiertem bzw. im hier bearbeiteten, speziellen Fall von spongiösem Knochenmaterial sowie die Ziele der Arbeit dargelegt.
Im folgenden Kapitel 2, Grundlagen, werden die mathematischen und technischen Prinzipien erläutert, die als Basis für die im Rahmen der Arbeit erfolgten Entwicklungen dienten. Hierzu zählen Grundlagen der Elastizitätstheorie, der Methode der Finiten Elemente (FEM), der multivariaten Statistik sowie die Erläuterung der Prinzipien der Computertomographie (CT).
In Kapitel 3, Direkter mechanischer Ansatz zur Berechnung von elastischen Eigenschaften mikrostrukturierter Volumina, wird die Theorie der direkten mechanischen Simulation zur Bestimmung effektiver Materialparameter mikrostrukturierter Volumina auf Kontinuumsebene dargelegt. Da die von Hill entwickelte [1], klassische bzw. im folgenden als analytische Methode bezeichnete Vorgehensweise aus Sicht des Verfassers die Schwäche aufweist, dass die mit ihrer Hilfe berechneten Materialdaten von der Wahl der Randbedingungen abhängen, wird im gleichen Kapitel eine Erweiterung der Methode vorgeschlagen, die zur Berechnung der effektiven numerischen Steifigkeit mikrostrukturierter Volumina führt. Die effektive numerische Steifigkeit wird mit Hilfe der FEM abgeleitet, wodurch die entstehenden effektiven Steifigkeitseigenschaften direkt zum Einsatz mit dieser Methode geeignet sind.
In Kapitel 4, Gewebeproben und Datensätze, werden die Parameter der mit Hilfe von Mikrofokus Computertomographien (μ-CT) und klinischer Computertomographie (k-CT) erhobenen Volumendatensätze angegeben. Als Basisdatensatz für die Entwicklung und erste Analyse der Implementierung sowie der, dieser Arbeit zu Grunde liegenden, Konzepte wird der μ-CT-Volumendatensatz eines menschlichen Femurkopfes verwendet. Der Femurkopf wurde im Rahmen der Implantation einer Totalhüftendoprothese in der Klinik für Unfallchirurgie und Orthopädie des Universitätsklinikum Freiburg entnommen. Der Volumendatensatz wurde nach der Entnahme durch das Institut für Bauweisen und Strukturtechnologie des Deutschen Zentrums für Luft- und Raumfahrt (DLR) Stuttgart erstellt. In diesem Kapitel werden desweiteren ausgezeichnete Bereiche des μ-CT-Datensatzes beschrieben, die im Verlauf der Arbeit zu Analysen herangezogen werden.
In Kapitel 5, Implementierung, wird eine Prozesskette beschrieben, welche es ermöglicht, aus μ-CT-Datensätzen ganzer Knochenbereiche mit Hilfe direkter, mechanischer Simulation das Feld der linear elastischen Materialeigenschaften sowie das Feld der numerischen effektiven Steifigkeitsmatrizen auf Kontinuumsebene zu berechnen. Ein durch μ-CT gewonnener Datensatz kann in virtuelle Proben beliebiger Größe und Form zerlegt werden. Durch das Vorgehen ist es somit möglich, die Auflösung kontinuumsmechanischer Materialdaten entsprechend der Auflösung des verwendeten kontinuumsmechanischen Berechnungsgitters anzupassen. Als zentrales Glied der Prozesskette wird das Finite Elemente Programmsystem FMPS [2] verwendet. Die vorgelagerten Programme wie Gebietszerlegung und Geometrieextraktion sowie die nachfolgenden Berechnungen der effektiven Materialparameter wurden durch eigene Implementierungen realisiert. Im Hinblick auf die reibungslose Ausführung der Prozesskette auf den Ressourcen des High Performance Computing Center Stuttgart (HLRS) wurde ein für alle Teile der Kette gemeinsames Datenformat entwickelt, welches auch in FMPS integriert wurde. Das Datenformat zeichnet sich im wesentlichen durch die einfache Benutzbarkeit im Zusammenhang mit paralleler Ein- und Ausgabe (E/A), durch einen von den eigentlichen Daten unabhängigen Index sowie seine allgemeine Benutzbarkeit aus. In diesem Kapitel wird des weiteren die Kopplung zwischen FMPS, einem monolithischen Fortran 77 Softwarepaket mit tiefer Aufrufstruktur und der C++ Löserbibliothek PETSc [3] erläutert. Diese Entwicklung war notwendig, um auch Auflösungen der effektiven Materialparameter mit Gitterzellen größer als 2,4mm effektiv berechnen zu können.
In Kapitel 6, Ergebnisse, werden die Analysen der auf unterschiedlichen Auflösungsstufen berechneten Datenfelder der effektiven Steifigkeit und deren Zusammenhang mit strukturbeschreibenden Parametern auf kontinuumsmechanischer Ebene diskutiert. Die erzeugten Felder der effektiven Steifigkeit werden mit Hilfe multivariater Methoden analysiert, und es wird gezeigt, dass eine wesentliche Reduktion deren 21-dimensionalen Parameterraumes möglich ist. Abschließend werden erste Vergleiche zwischen kontinuumsmechanischen Berechnungsergebnissen, die mit Hilfe der berechneten effektiven Steifigkeitsmatrizen erzeugt wurden, und Ergebnissen aus mikromechanischen Simulationen größerer Knochenbereiche, dargestellt und erläutert. Es wird gezeigt, dass es Zusammenhänge zwischen den Ergebnissen dieser beiden Skalen gibt und dass diese Zusammenhänge in Abhängigkeit der Porengröße der Spongiosa nichtlineares Verhalten annehmen.In chapter 1, Einleitung of the following essay the motivation, the state of the art in the field of continuum mechanical material data determination for micro structured materials as well as the targets of the presented work are stated.
The next chapter presents the basics of the mathematical and technical principles forming the foundation of the developments and derivations done in this thesis. This includes the basics of elasticity theory, the basics of the Finite Element Method (FEM), multivariate statistics as well as the basics of computed tomography (CT).
In chapter 3, Direkter mechanischer Ansatz zur Berechnung von elastischen Eigenschaften mikrostrukturierter Volumina, the theory of the direct mechanics approach to determine effective material parameters of micro-structured volumes on the continuum mechanical scale is introduced. Since the classical method developed by Hill [1] has, in the opinion of the author, the drawback, that the material data calculated with this method depend upon the chosen boundary conditions, a method is presented in the same chapter, that leads to what we call the effective numerical stiffness. The effective numerical stiffness is derived based on the principles of FEM which makes the resulting effective parameters directly applicable to this method.
In chapter 4, Gewebeproben und Datensätze, the parameters of the volume data sets recorded by micro-focus computed tomography (μ-CT) and clinical computed tomography (k-CT) are written down. The basis for all development and analyses done in this thesis is the μ-CT volume dataset of a human femoral head. The femoral head was extracted in the Klinik für Unfallchirurgie und Orthopädie of the University of Freiburg Medical Centre during a total hip replacement surgery. The volume dataset was recorded at the Institut für Bauweisen und Strukturtechnologie of the Deutsches Zentrum für Luft- und Raumfahrt (DLR) in Stuttgart. In this chapter the special regions of the femoral head, used for analyses in the results section, are described.
In the following chapter 5, Implementierung a simulation process chain is described, which enables the calculation of the effective material parameters as well as the field of the effective numerical stiffness matrices with arbitrary resolution for complete bone structures on the basis of μ-CT volume datasets. A μ-CT data set can be decomposed in virtual specimens of arbitrary size and shape. By this approach it becomes possible to fit the resolution of the continuum mechanical material field to the one of the used simulation mesh. A central link of the process chain is the FEM software package FMPS [2]. The preceding chain links domain decomposition, geometry extraction as well as the trailing calculation of the effective material parameters are realized by custom implementations. With the focus of the implementations done in this thesis laying on the efficient execution of the process chain on the resources of the High Performance Computing Center Stuttgart (HLRS) a data format was developed which is common for all links of the process chain and that was also integrated into FMPS. The data format is essentially characterized by its easy application in connection with parallel input and output operations, its index which is independent from the data and its common usability. In this chapter it is also shown, how the coupling of FMPS, a monolithic Fortran 77 code package with deep calling stack to the C++ solver library PETSc [3] was done. This coupling was necessary to efficiently carry out the calculations of the effective material parameters on resolutions bigger than 2.4mm edge length.
In the final chapter 6, Ergebnisse, the analyses carried out with the data fields of the effective stiffness, calculated on various resolutions along with their connection to the descriptive parameters on the continuum mechanical scale, are discussed. The calculated fields are analysed by means of multivariate statistical methods and it is shown, that an essential reduction of their 21-dimensional parameter space is possible. After that some first comparisons between simulation results, calculated on the continuum mechanical scale by means of the derived effective material parameters and micro-mechanical simulation results of larger regions of cancellous bone, are presented and discussed
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