Entwicklung und Verifikation eines Mess- und Bewertungsverfahrens der elektromagnetischen Immission durch ITS-G5

Immer mehr Bereiche des alltäglichen Lebens werden von drahtlos kommunikationsfähigen elektronischen Geräten beeinflusst, so dass die Relevanz für die persönliche Exposition der Nutzer durch hochfrequente elektromagnetische Felder rapide zunimmt. So soll auch der Straßenverkehr stetig weiter automatisiert und per Funk vernetzt werden, indem so genannte intelligente Transportsysteme (ITS) entwickelt werden. Im Rahmen des vernetzten Fahrens sollen Fahrzeuge im Verkehr untereinander, aber auch mit Infrastruktur und weiteren Verkehrsteilnehmern kommunizieren, um Sensor-, Zustands- und Ortsinformationen austauschen zu können. Hierfür wird der Begriff vehicle-to-everything (V2X)- Kommunikation verwendet. Zukünftig wird somit der Straßenverkehr als ein weiterer und erheblicher Teil der Alltagsumgebung von neuen Funktechnologien durchdrungen, die per Konstruktion einen signifikanten zusätzlichen Beitrag zur persönlichen Exposition liefern. Für die technische Umsetzung der V2X-Kommunikation etabliert sich neben der auf Mobilfunk basierenden Funktechnik cellular-V2X (C-V2X) der Kooperation 3rd Generation Partnership Project derzeit in Europa die Kommunikationstechnologie ITS-G5, die auf dem Standard 802.11p [1] des Verbands Institute of Electrical and Electronics Engineers (IEEE) basiert. Für den europäischen Einsatz wird ITS-G5 durch das europäische Institut für Telekommunikationsnormen (ETSI) spezifiziert und genormt. Ein zuverlässiges und praktikables Verfahren zur Bestimmung der elektromagnetischen Immission durch ITSG5- Geräte existiert allerdings bislang nicht. Um die Exposition der Allgemeinbevölkerung in Verkehrsumgebungen durch die neuen ITS-Funksysteme abschätzen zu können, ist die Entwicklung eines Immissionsmessverfahrens für ITS-G5 dringend erforderlich. Vorliegender Beitrag beschreibt die Entwicklung eines ITS-G5-spezifischen Mess- und Bewertungsverfahrens unter Verwendung des frequenzselektiven Messgeräts SRM-3006 von Narda STS [2]. Abgesehen von der physikalischen Zugangsschicht weist der Standard ITS-G5 Ähnlichkeiten mit dem Sidelink des LTE-Derivats C-V2X auf, so dass die hier beschriebenen Schlussfolgerungen sinngemäß für beide Standards Anwendung finden können

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.</p

Hydrazides Are Potent Transition-State Analogues for Glutaminyl Cyclase Implicated in the Pathogenesis of Alzheimer’s Disease

Amyloidogenic plaques are hallmarks of Alzheimer’s disease (AD) and typically consist of high percentages of modified Aβ peptides bearing N-terminally cyclized glutamate residues. The human zinc(II) enzyme glutaminyl cyclase (QC) was shown in vivo to catalyze the cyclization of N-terminal glutamates of Aβ peptides in a pathophysiological side reaction establishing QC as a druggable target for therapeutic treatment of AD. Here, we report crystallographic snapshots of human QC catalysis acting on the neurohormone neurotensin that delineate the stereochemical course of catalysis and suggest that hydrazides could mimic the transition state of peptide cyclization and deamidation. This hypothesis is validated by a sparse-matrix inhibitor screening campaign that identifies hydrazides as the most potent metal-binding group compared to classic Zn binders. The structural basis of hydrazide inhibition is illuminated by X-ray structure analysis of human QC in complex with a hydrazide-bearing peptide inhibitor and reveals a pentacoordinated Zn complex. Our findings inform novel strategies in the design of potent and highly selective QC inhibitors by employing hydrazides as the metal-binding warhead

Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro

Alzheimer&rsquo;s disease (AD) and Parkinson&rsquo;s disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of &alpha;-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of A&beta;(1&ndash;42) and pGlu-A&beta;(3&ndash;42) on the aggregation of &alpha;-synuclein in vitro. The aggregation of human recombinant &alpha;-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of &alpha;-synuclein in the presence of minor concentrations of A&beta;(1&ndash;42) and pGlu-A&beta;(3&ndash;42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of &alpha;-synuclein and A&beta; in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of &alpha;-synuclein and A&beta; and pGlu-A&beta;, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides &alpha;-synuclein and A&beta; species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases

Consensus Statement on Electronic Health Predictive Analytics: A Guiding Framework to Address Challenges

Context: The recent explosion in available electronic health record (EHR) data is motivating a rapid expansion of electronic health care predictive analytic (e-HPA) applications, defined as the use of electronic algorithms that forecast clinical events in real time with the intent to improve patient outcomes and reduce costs. There is an urgent need for a systematic framework to guide the development and application of e-HPA to ensure that the field develops in a scientifically sound, ethical, and efficient manner. Objectives: Building upon earlier frameworks of model development and utilization, we identify the emerging opportunities and challenges of e-HPA, propose a framework that enables us to realize these opportunities, address these challenges, and motivate e-HPA stakeholders to both adopt and continuously refine the framework as the applications of e-HPA emerge. Methods: To achieve these objectives, 17 experts with diverse expertise including methodology, ethics, legal, regulation, and health care delivery systems were assembled to identify emerging opportunities and challenges of e-HPA and to propose a framework to guide the development and application of e-HPA. Findings: The framework proposed by the panel includes three key domains where e-HPA differs qualitatively from earlier generations of models and algorithms (Data Barriers, Transparency, and Ethics) and areas where current frameworks are insufficient to address the emerging opportunities and challenges of e-HPA (Regulation and Certification; and Education and Training). The following list of recommendations summarizes the key points of the framework: Data Barriers: Establish mechanisms within the scientific community to support data sharing for predictive model development and testing.Transparency: Set standards around e-HPA validation based on principles of scientific transparency and reproducibility.Ethics: Develop both individual-centered and society-centered risk-benefit approaches to evaluate e-HPA.Regulation and Certification: Construct a self-regulation and certification framework within e-HPA.Education and Training: Make significant changes to medical, nursing, and paraprofessional curricula by including training for understanding, evaluating, and utilizing predictive models