Different Outcomes of Experimental Hepatitis E Virus Infection in Diverse Mouse Strains, Wistar Rats, and Rabbits

Hepatitis E virus (HEV) is the causative agent of acute hepatitis E in humans in developing countries, but autochthonous cases of zoonotic genotype 3 (HEV-3) infection also occur in industrialized countries. In contrast to swine, rats, and rabbits, natural HEV infections in mice have not yet been demonstrated. The pig represents a well-established large animal model for HEV-3 infection, but a suitable small animal model mimicking natural HEV-3 infection is currently missing. Therefore, we experimentally inoculated C57BL/6 mice (wild-type, IFNAR−/−, CD4−/−, CD8−/−) and BALB/c nude (nu/nu) mice, Wistar rats, and European rabbits with a wild boar-derived HEV-3 strain and monitored virus replication and shedding, as well as humoral immune responses. HEV RNA and anti-HEV antibodies were detected in one and two out of eight of the rats and all rabbits inoculated, respectively, but not in any of the mouse strains tested. Remarkably, immunosuppressive dexamethasone treatment of rats did not enhance their susceptibility to HEV infection. In rabbits, immunization with recombinant HEV-3 and ratHEV capsid proteins induced protection against HEV-3 challenge. In conclusion, the rabbit model for HEV-3 infection may serve as a suitable alternative to the non-human primate and swine models, and as an appropriate basis for vaccine evaluation studies

Chapter 2 – Health Apps and the Market

"Der Markt für Apps mit Gesundheitsbezug ist unübersichtlich. Einerseits ist er durch die stetig steigenden technischen Möglichkeiten der verschiedensten im Bereich mHealth nutzbaren Geräte, von Smartphones über Tablets bis hin zu Wearables und weiteren ""smarten"" Gerätschaften, die in der Lage sind Apps auszuführen, ständigen Veränderungen unterworfen. Andererseits herrscht auf Seiten der Anbieter eine Goldgräberstimmung und so drängen viele Anbieter auf den Markt, deren Ursprünge nicht unbedingt im Gesundheitssektor liegen. Kommerzielle Anbieter finden sich hier ebenso wie private Entwicklerinnen und Entwickler, die aus eigenem Antrieb, eine App entwickeln und anbieten. Die nur geringen Barrieren, denen sich Entwickler beim Vertrieb über die App Stores der großen Mobilplattformen ausgesetzt sehen, tun ihr übriges und so finden sich inzwischen weit über 100.000 Gesundheits-Apps mit unterschiedlichsten Inhalten und Ansprüchen allein in den offensichtlich gesundheitsbezogenen Kategorien ""Medizin"" sowie ""Gesundheit und Fitness"" der Stores der beiden größten Mobilplattformen. Dennoch sind von den vielen Anbietern dieser Apps nur wenige kommerziell erfolgreich und können tragfähige und gewinnträchtige Geschäftsmodelle über die in den Stores zur Verfügung stehenden Mechanismen (kostenpflichtige Apps, In-App-Käufe, Abonnements) realisieren. Auf Nutzerseite ist das Bild ebenso inhomogen. In der Bevölkerung sind Smartphones und andere mobile Geräte inzwischen quer durch alle Schichten weit verbreitet; nach aktuellen Zahlen nutzen bereits 63 % der deutschen Bevölkerung ein Smartphone (Weicksel und Pentsi 2015) und es ergibt sich somit auch ein breites Spektrum an (potenziellen) Anwenderinnen und Anwendern von Gesundheits-Apps. Es reicht von Jung bis Alt, von im Gesundheitswesen tätigen Personen mit professionellen Ansprüchen über Gesundheitsinteressierte, bis hin zu akut oder chronisch Erkrankten. All diese Anwenderkreise bringen verschiedene Voraussetzungen mit (von vorhandenen Kenntnissen und Fähigkeiten bis hin zu möglichen körperlichen Einschränkungen) und setzen die Apps in verschiedenen Settings zu ebenso vielfältigen Zwecken ein. Hierzu können sie aus einer unüberschaubaren Anzahl möglicher Angebote wählen. Die Identifikation von zur jeweiligen Interessenlage passenden Gesundheits-Apps fällt aber aufgrund verschiedener Faktoren schwer. Während das Angebot in Teilbereichen, wie zum Beispiel gesundheitsbezogenen Nachschlagewerken, Patiententagebüchern oder Fitness- und Wellness-Apps riesig ist, sind Apps für andere Anforderungsprofile teils unterrepräsentiert. Im Rahmen der vorliegenden Analyse traf dies beispielsweise für allgemein barrierefrei nutzbare oder inhaltlich speziell auf die Bedürfnisse von Anwenderinnen und Anwendern mit körperlichen oder sonstigen Einschränkungen angepasste Apps zu. Erschwerend kommt hinzu, dass Interessenten oft bereits bei der Suche nach Applikationen abgeschreckt werden. Gründe dafür sind beispielsweise mangelhafte oder (inhaltlich oder sprachlich) unverständliche Store-Beschreibungen ohne klare Angaben zu den gebotenen Funktionalitäten und Inhalten. Auch fehlen oft Angaben zu möglichen Limitationen, dem Datenschutz oder gar den Herstellern selbst. Insgesamt eröffnen sich durch Gesundheits-Apps für alle Stakeholder vielfältige Chancen, von der Verbesserung der gesundheitlichen Versorgung bis hin zu wirtschaftlichen Potenzialen (Kostensenkungen, Gewinnsteigerungen), die jedoch häufig noch nicht adäquat realisiert werden. Zur Verbesserung der Situation sind Fragen in den unterschiedlichsten Bereichen zu klären, die sowohl rechtliche, regulatorische als auch wirtschaftliche Bereiche berühren, aber auch die Anwendungssicherheit oder Evidenz bezüglich der Wirksamkeit entsprechender Lösungen betreffen. Diese Fragen sollen in den folgenden Kapiteln aus unterschiedlichen Blickwinkeln aufgegriffen und näher beleuchtet werden. "" The market situation for health related apps is chaotic. On the one hand, the rapid growth of technical innovations for mobile devices that can be employed in mHealth related contexts, such as smartphones, tablet PCs and wearables as well as other ""smart"" devices that are able to run apps, opens up exciting new possibilities. On the other hand, on the manufacturers' side, there is a gold-rush atmosphere and many different types of developers are pushing into the market. There are commercially oriented manufacturers as well as private developers that are motivated to publish an app out of personal interest. The low barriers that developers encounter when distributing their products through the app stores of the big mobile platforms also encourage the growth of the market. Currently, the number of health related apps within the categories ""medicine"" as well as ""fitness and health"" available in the stores of the two biggest platforms surpasses 100,000 apps by far. Still, there are only few publishers of health related apps that are able to realize commercial success and to implement sustainable business models based on the sales mechanisms provided within the app stores (e.g. paid apps, in-app purchases, subscriptions). On the users' side, the picture is just as diverse. Throughout the population, smartphones and other mobile devices are a common possession and thus, currently 63 % of the German population already own a smartphone (Weicksel und Pentsi 2015) and are therefore potential users of health related apps as well. There are young as well as old users, those who work within healthcare as well as those who only want to satisfy their curiosity with respect to health related questions or use health related apps to aid them with an acute or chronic condition. All these users have different levels of knowledge or potentially present with various handicaps, and use the apps in varying settings as well as for varying purposes. To match their needs, users can choose from a vast number of offers. However, identifying a matching app is a complicated process that depends on various factors. For example, while there are a number of functional areas that are well represented, such as reference apps, patient diaries, or fitness and wellness related apps, there are other areas that are underrepresented. Within our analysis, this was especially evident for apps that respect accessibility or specifically target handicapped users. Another factor aggravating the situation is that often, users are irritated by (either content or language-wise) incomprehensible store descriptions that also lack adequate information about the app's functionalities and contents or its limitations. Often, information about data privacy as well the manufacturer himself is also missing or incomplete. All this may potentially discourage users from an app installing an app. Still, health apps open up many exciting changes for all stakeholders, and these include possible improvements of health services as well as economic aspects (reduction of costs, increase in profits), but they can not always be successfully realized. To improve this situation, questions touching upon various areas must be answered, and these include legal and regulatory areas and economic aspects, but also application security and safety as well as the need for evidence with respect to the effectiveness of mHealth solutions. In the following chapters, these questions will be taken up and be considered from various angles.

Chapter 1 – Introduction and Definitions

Das vorliegende Kapitel legt mit seinen Begriffsbestimmungen die Basis für alle im weiteren Verlauf der Arbeit untersuchten Aspekte des Bereichs Mobile Health ("mHealth"). Nach einer einführenden Abgrenzung der Bereiche Gesundheit, Medizin und Wellness, die vielfach Synonym verwendet werden, sich aber dennoch inhaltlich wesentlich unterscheiden, sowie einer kurzen Beschreibung der Bereiche Gesundheitsförderung, Prävention und Versorgung, wird zunächst auf eher technische wie organisatorische und weitere im Bereich mHealth relevanten Aspekte kurz eingegangen. Hier geht es zunächst um eine grundlegende Beschreibung und Unterscheidung der eng miteinander verwandten Bereiche Telemedizin, eHealth und mHealth. Auch auf die im Kontext von mHealth nutzbaren Geräte sowie die darauf laufenden Applikationen ("Apps") wird mit besonderem Fokus auf gesundheitsbezogene Anwendungsfelder und Funktionen eingegangen. Abschließend erfolgt ein kurzer Überblick über die unterschiedlichen im mHealth-Bereich relevanten Stakeholder: hier sind einerseits Hersteller von Apps, aber auch Kostenträger und Regulatoren sowie nicht zuletzt Nutzerinnen und Nutzer gesundheitsbezogener Apps und mHealth-Lösungen zu nennen. Die vorgestellten Begriffe und Definitionen werden im Verlauf der Arbeit wiederholt aufgegriffen.With its definitions and descriptions of concepts used in the context of mobile health ("mHealth"), the current chapter lays the foundation for all aspects of mHealth described in the following parts. After providing introductory definitions for health, medicine, and wellness – terms that are often used synonymously, but denote different concepts – short descriptions for the areas of health promotion, prevention and care are given. Subsequently, technical as well as organizational and other relevant aspects and concepts are introduced. This starts off with a few basic remarks about the closely related areas of telemedicine, eHealth and mHealth and how they differ. Mobile devices that can be used in health contexts as well as the applications (apps) running on them are also touched upon, with a special focus on their health related uses, and functions that can be employed in this context. The chapter closes with an overview of the relevant stakeholders that play a role in connection with mHealth and especially health apps. This includes manufacturers of apps as well as those who are involved in financial or regulatory aspects of mHealth, but also users of apps and mHealth related solutions. The provided definitions and terms are used throughout the following chapters

Gene regulatory networks elucidating huanglongbing disease mechanisms.

Next-generation sequencing was exploited to gain deeper insight into the response to infection by Candidatus liberibacter asiaticus (CaLas), especially the immune disregulation and metabolic dysfunction caused by source-sink disruption. Previous fruit transcriptome data were compared with additional RNA-Seq data in three tissues: immature fruit, and young and mature leaves. Four categories of orchard trees were studied: symptomatic, asymptomatic, apparently healthy, and healthy. Principal component analysis found distinct expression patterns between immature and mature fruits and leaf samples for all four categories of trees. A predicted protein - protein interaction network identified HLB-regulated genes for sugar transporters playing key roles in the overall plant responses. Gene set and pathway enrichment analyses highlight the role of sucrose and starch metabolism in disease symptom development in all tissues. HLB-regulated genes (glucose-phosphate-transporter, invertase, starch-related genes) would likely determine the source-sink relationship disruption. In infected leaves, transcriptomic changes were observed for light reactions genes (downregulation), sucrose metabolism (upregulation), and starch biosynthesis (upregulation). In parallel, symptomatic fruits over-expressed genes involved in photosynthesis, sucrose and raffinose metabolism, and downregulated starch biosynthesis. We visualized gene networks between tissues inducing a source-sink shift. CaLas alters the hormone crosstalk, resulting in weak and ineffective tissue-specific plant immune responses necessary for bacterial clearance. Accordingly, expression of WRKYs (including WRKY70) was higher in fruits than in leaves. Systemic acquired responses were inadequately activated in young leaves, generally considered the sites where most new infections occur

Chapter 14 – Orientation for Professional Users of Health Apps

Versorger werden sich in Zukunft aus verschiedenen Gründen verstärkt mit Gesundheits-Apps auseinandersetzen müssen. Für die Nutzung und Bewertung von Apps werden offizielle Orientierungshilfen benötigt. Apps, die ursprünglich nicht mit Fokus auf die Gesundheit entwickelt wurden, erlangen mit dem Einsatz durch klinisches Fachpersonal eine Erweiterung für den Gesundheitsbereich. Da diese nicht primär für eine Anwendung im medizinischen Umfeld gedacht waren, unterlagen sie bei der Entwicklung auch nicht den einschlägigen Regularien und Anforderungen. Insbesondere hier muss daher von Seiten der professionellen Anwender überprüft werden, ob sie den Anforderungen genügen und für einen professionellen Einsatz geeignet sind. Erste Vorschläge konkreter Empfehlungen für Versorger selber und für die Weitergabe an Patientinnen und Patienten sind aufgestellt worden, sollten aber durch ein separates Verfahren weiter konsolidiert und veröffentlicht werden.For various reasons, health care personnel will increasingly be confronted with health apps. There is a strong need for official guidelines on how to use and rate these apps. If used by healthcare professionals, even apps that were not developed with a health related focus in mind may extend into this area. Since from their inception, these apps were never meant to be used in medical or health related setting, their development usually does not take the appropriate regulations and requirements into account. Therefore, professional users need to convince themselves that the apps conform to the necessary requirements and are suited for professional use. In this context, first concrete proposals are given within this chapter and these include recommendations for healthcare professionals themselves, but also aspects that should be covered when providing patients with information about apps. However, these proposals should be consolidated and published in an additional process

Simulation of the furnace of the boiler P-49 in the package of applied programs fire 3D

The combustion of solid low-grade fuel in LTV-boiler furnaces is a pressing research questions currently. The aim of this work is the creation of a computational grid model LTV-furnace to calculate the package of applied programs FIRE 3D. The study created a model LTV-furnace. The model tested on brown coal from the Nazarovo Deposit. The resulting distribution of temperatures and velocities has proved the performance of the model

Tracing Penicillin Movement in Citrus Plants Using Fluorescence-Labeled Penicillin

Huánglóngbìng (HLB), citrus greening, is one of the most destructive diseases of citrusplants worldwide. In North America, HLB is caused by the phloem-limited bacteriumCandidatusLiberibacter asiaticus and is transmitted by the Asian citrus psyllid,Diaphorina citri. No cure exists atpresent, and the use of antibiotics for the control of HLB has gained interest due to the significantlosses to the citrus industry. Because of unsatisfactory results when using foliar applications ofantibiotics, concerns were raised regarding the uptake and translocation of these materials within trees.We, therefore, investigated a method that allows us to study the movement of antibiotic materialsin citrus plants. Herein, we utilized a fluorescence-labeled penicillin, BOCILLIN™FL-Penicillin(FL-penicillin), to study the uptake and translocation of penicillin in citrus plants. FL-penicillin wasapplied by puncture to the stem of young citrus seedlings and was traced by using fluorescencemicroscopy. After application, we detected FL-penicillin in the leaves and in the stem xylem andphloem tissues above and below the application site in both intact and partially bark-girdled citrusseedlings, indicating that it is easily taken up and transported through the plant vascular system.In addition, we detected FL-penicillin in the gut ofD. citri, which were allowed to feed on thetreated plants, suggesting translocation of this molecule into the vascular tissue. We propose thatthe use of fluorescent-labeled molecules could be an effective tool for understanding the uptake andtranslocation of antibiotics and other macromolecules in plants and insects.Funding:This research was funded by the National Institute of Food and Agriculture, grant number2019-70016-29096.Acknowledgments:We thank our lab members for helpful discussion and technical assistance. This work wasgenerously funded by the USDA NIFA-SCRI award number 2019-70016-29096

Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes

<p>Abstract</p> <p>Background</p> <p>Cytokines such as TNF-alpha and IL-1beta are known for their contribution to inflammatory processes in liver. In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization.</p> <p>Results</p> <p>The present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately up-regulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1beta proposed an "IL-1beta-like effect" of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase activity of the up-regulated Zc3h12a have to be considered.</p> <p>Conclusions</p> <p>Our microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signaling pathway. Gene expression profile suggests IL-17 alone and in concert with TNF-alpha a role in sustaining liver inflammatory processes. IL-17 might exceed this function by RNA stabilization.</p

Ahmet Ferdi

Suat Derviş'in Yeni Şark'ta tefrika edilen Ahmet Ferdi adlı romanıTelif hakları nedeniyle romanın tam metni verilememiştir