The Internet has made tremendous progress since its inception. The kingpin has been the transmission control protocol (TCP), which supports a large fraction of communication. With the Internet's wide-spread access, users now have increased expectations. The demands have evolved to an extent which TCP was never designed to support. Since network stacks do not provide the necessary functionality for modern applications, developers are forced to implement them over and over again --- as part of the application or supporting libraries. Consequently, application developers not only bear the burden of developing application features but are also responsible for building networking libraries to support sophisticated scenarios. This leads to considerable duplication of effort. The challenge for TCP in supporting modern use cases is mostly due to limiting assumptions, simplistic communication abstractions, and (once expedient) implementation shortcuts. To further add to the complexity, the limited TCP options space is insufficient to support extensibility and thus, contemporary communication patterns. Some argue that radical changes are required to extend the networks functionality; some researchers believe that a clean slate approach is the only path forward. Others suggest that evolution of the network stack is necessary to ensure wider adoption --- by avoiding a flag day. In either case, we see that the proposed solutions have not been adopted by the community at large. This is perhaps because the cost of transition from the incumbent to the new technology outweighs the value offered. In some cases, the limited scope of the proposed solutions limit their value. In other cases, the lack of backward compatibility or significant porting effort precludes incremental adoption altogether. In this dissertation, we focus on the development of a communication model that explicitly acknowledges the context of the conversation and describes (much of) modern communications. We highlight how the communication stack should be able to discover, interact with and use available resources to compose richer communication constructs. The model is able to do so by using session, flow and endpoint abstractions to describe communications between two or more endpoints. These abstractions provide means to the application developers for setting up and manipulating constructs, while the ability to recognize change in the operating context and reconfigure the constructs allows applications to adapt to the changing requirements. The model considers two or more participants to be involved in the conversation and thus enables most modern communication patterns, which is in contrast with the well-established two-participant model. Our contributions also include an implementation of a framework that realizes such communication methods and enables future innovation. We substantiate our claims by demonstrating case studies where we use the proposed abstractions to highlight the gains. We also show how the proposed model may be implemented in a backwards compatible manner, such that it does not break legacy applications, network stacks, or middleboxes in the network infrastructure. We also present use cases to substantiate our claims about backwards compatibility. This establishes that incremental evolution is possible. We highlight the benefits of context awareness in setting up complex communication constructs by presenting use cases and their evaluation. Finally, we show how the communication model may open the door for new and richer communication patterns. / PHD

Since the dawn of the genomics era, the genetics of numerous human disorders has been understood which has led to improvements in targeted therapeutics. However, the focus of most research has been primarily on protein coding genes, which account for only 2% of the entire genome, leaving much of the remaining genome relatively unstudied. In particular, repetitive sequences, called microsatellites (MST), which are tandem repeats of 1 to 6 bases, are known to be mutational hotspots and have been linked to diseases, such as Huntington disease and Fragile X syndrome. This work represents a significant effort towards closing this knowledge gap. Specifically, we developed a next generation sequencing based enrichment method along with the supporting computational pipeline for detecting novel MST sequences in the human genome. Using this global MST enrichment protocol, we have identified 790 novel sequences. Analysis of these novel sequences has identified previously unknown functional elements, demonstrating its potential for aiding in the completion of the euchromatic DNA. We also developed a disease risk diagnostic using a novel target specific enrichment method that produces high resolution MST sequencing data that has the potential to validate, for the first time, the link between MST genotype variation and cancer. Combined with publicly available exome datasets of non-small cell lung cancer and 1000 genomes project, the target specific MST enrichment method uncovered a signature set of 21 MST loci that can differentiate between lung cancer and non-cancer control samples with a sensitivity ratio of 0.93. Finally, to understand the molecular causes of MST instability, we analyzed genomic variants and gene expression data for an autosomal recessive disorder, Fanconi anemia (FA). This first of its kind study quantified the heterogeneity of FA cells and demonstrated the possibility of utilizing the DNA crosslink repair dysfunctional FA cells as a suitable system to further study the causes of MST instability. / Ph. D.

Background: Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. Methods: We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan–Meier estimator, log-rank test, and Cox regression. Results: Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR . These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05). Conclusions: Our gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application.

In this thesis, an output-only experimental modal testing and analysis technique known as the Natural Excitation Technique (NExT) is examined for use with large residential structures and interior cavities. The technique which assumes a random, stationary input causing the response data is reviewed and extended for the first time to include the assumption of an impulse input. This technique is examined with respect to the experimental modal analysis of single and two room residential structures. Each structure is first tested using conventional modal testing methods. Then, NExT is applied using each structure's response to a simulated sonic boom, an impulsive input. The results of these analyses along with the results obtained from a finite element model are compared. Then, the interior cavities enclosed by the residential structures are examined using NExT. Therefore, this thesis also demonstrates the successful use of NExT on acoustic systems for the first time. Three configurations of the interconnected cavities enclosed by the two room structure are considered to study physical phenomena. Both interior pressure response to random, stationary inputs and the sonic boom response are used with NExT to determine modal properties. The results of these analyses are compared to a theoretical analysis. Advantages to using NExT with both the response to a random, stationary input and an impulsive input are demonstrated for structural and acoustic systems. / Master of Science

No / Transposable elements (TEs), such as endogenous retroviruses (ERVs), are common in the genomes of vertebrates. ERVs result from retroviral infections of germ-line cells, and once integrated into host DNA they become part of the host's heritable genetic material. ERVs have been ascribed positive effects on host physiology such as the generation of novel, adaptive genetic variation and resistance to infection, as well as negative effects as agents of tumorigenesis and disease. The avian leukosis virus subgroup E family (ALVE) of endogenous viruses of chickens has been used as a model system for studying the effects of ERVs on host physiology, and approximately 30 distinct ALVE proviruses have been described in the Gallus gallus genome. In this report we describe the development of a software tool, which we call Vermillion, and the use of this tool in combination with targeted next-generation sequencing (NGS) to increase the number of known proviruses belonging to the ALVE family of ERVs in the chicken genome by 4-fold, including expanding the number of known ALVE elements on chromosome 1 (Gga1) from the current 9 to a total of 40. Although we focused on the discovery of ALVE elements in chickens, with appropriate selection of target sequences Vermillion can be used to develop profiles of other families of ERVs and TEs in chickens as well as in species other than the chicken. / Financial support was provided by the EW GROUP, as well as grants from the Canada Foundation for Innovation, Canada Research Chairs Program, and the Natural Sciences and Engineering Council of Canada to RGB, and Canada Institutes of Health Research funding to MGIL and CJM.

Denna rapport beskriver ett kandidatarbete utfört av åtta studenter vid Linköpings universitet på uppdrag av Personalkollen AB. Projektet, med titeln ``Framtidens teknikstack för webbapplikationer'', genomfördes av arbetsgruppen Stack Underflow. Studien jämför två egenskapade webbapplikationer med olika renderingstekniker genom prestandatester såsom blockeringstid och hastighetsindex. Det klientrenderade systemet utvecklades med hjälp av biblioteket React, medan det serverrenderade systemet utvecklades i ramverket Next.js. För att utföra jämförelsen användes Google Lighthouse, ett verktyg för att systematiskt testa webbsidor. Prestandatesterna visade att det serverrenderade systemet överträffade det klientrenderade systemet vid större sidstorlekar, främst vad gäller blockeringstid. Resultaten syftar till att ge insikter till kunden om olika teknikstackars fördelar och nackdelar. Rapporten dokumenterar även de gemensamma och individuella erfarenheter som erhölls under projektets gång, specifikt vad gäller utvecklingen av de två systemen som jämförs.

Lymphoma is a common hematopoietic malignancy in canines. Current diagnostic techniques to diagnose lymphoma are often invasive and expensive. Additionally, tumor heterogeneity complicates the accurate classification and diagnosis of specific subtypes, hindering the development of targeted therapy and prognostic assessments. We propose a minimally invasive liquid biopsy technique involving blood collection to detect cell-free DNA from tumors using Next-generation sequencing. We hypothesize that identical tumor aberrations can be found in matching plasma and tumor DNA. Five dogs diagnosed with B-cell lymphoma through flow cytometry or PAAR were enrolled in the study. Samples collected included: (1) blood for plasma (cfDNA), (2) tumor tissue fine-needle aspirates (tumor DNA), and (3) buccal swabs (genomic DNA, germline control). Whole Genome Sequencing was performed using Illumina NovaSeq 6000, and the sequenced output was analyzed with bioinformatics tools to detect somatic variants in plasma and tumor samples. Our results revealed many shared somatic variants between matched cfDNA and tumor DNA samples, with 1.7-49% of tumor variants also found in corresponding plasma samples. Shared variants constituted only 0.5-9% of all plasma somatic variants. Specific B-cell lymphoma mutations were identified in cfDNA, including MYC, POT1, and TRAF3, alongside other cancer-related genes. Tumor samples showed mutations in genes associated with canine and human B-cell lymphoma. This study suggests that tumor-specific genomic mutations can be detected in plasma, supporting the potential of liquid biopsy as a less invasive diagnostic tool. However, cfDNA may not capture the full genetic heterogeneity of tumors due to low tumor-derived DNA content in limited plasma volumes. / Master of Science / Lymphoma is a type of blood cancer affecting white blood cells. Canine lymphoma is a common neoplasia, with an incidence rate of 20 to 100 cases per 100,000 dogs, making it a significant research focus. Current diagnostic methods are invasive and costly. Additionally, the wide variety of tumor types in lymphoma makes it challenging to determine the exact subtypes, which is crucial for selecting the best treatment approach. To overcome these challenges, we proposed a less invasive method known as "liquid biopsy". This technique involves taking a blood sample of a dog to find cell-free DNA from tumor cells using Next-Generation Sequencing technologies. We aimed to see if blood DNA could provide the same information as tumor DNA. In our study, we worked with five dogs diagnosed with B-cell lymphoma through traditional methods. We collected blood, tissue from needle biopsies, and buccal swabs from each dog. We then performed DNA extraction and sequencing on these samples. Our findings showed that 1.7-50% of the mutations in tumor DNA were also detected in matched blood DNA, though these represented only a small fraction of all changes found in blood samples. Additionally, the blood samples also revealed mutations related to canine B-cell lymphoma in genes like MYC, POT1, and TRAF3. In conclusion, our study supports the use of liquid biopsy as a feasible and less invasive method to diagnose lymphoma in dogs. However, they might not show all genetic variations of the tumor due to limited tumor DNA content.

This study attempts to be an exhaustive analysis of the dynamics of developing sustained church planting movements in Asian nations, based on lessons learned in the 2004-2005 NEXT conferences in East Asia. Principles are being discovered and methodologies developed in East Asia on how to build sustained church planting movements around the world. To understand these, consolidate learning, and apply that learning in a variety of crosscultural ministry contexts, a series of conferences were hosted by my wife and myself. Eight week-long ”NEXT conferences” were held, consisting of sixty experienced strategy coordinators plus eleven regional supervisors, to wrestle with these issues. This paper is based on the findings of these conferences; specifically, that there are divine principles and particular methodologies which enable missionaries to cooperate with the Holy Spirit in developing sustained church planting movements that saturate ethno-linguistic people groups and cities of Asia, and ultimately, the rest of the world. / Christian Spirituality, Church History and Missiology) / M.Th. (Missiology)

Es wurden zwei Feldstudien durchgeführt, um zu ermitteln, ob der Verlauf von Eimeria spp.-Infektionen bei Zicklein bei natürlicher Exposition durch die Beimischung von Zusätzen mit ätherischen Ölen (EIMERICOX®= EO1, NEXT Enhance® 200 = EO2) in den Milchaustauscher (MAT) oder das Einbringen eines kommerziellen Pulvers (Stalosan® F = STA) in die Einstreu beeinflusst werden kann. Als Kriterien zur Bewertung der Wirksamkeit dienten die Ausscheidung von Eimeria-Oozysten, die Kotkonsistenz und die klinische Symptomatik sowie die Gewichtsentwicklung. Des Weiteren wurde das Spektrum der caprinen Eimeria-Spezies in der untersuchten Population erfasst. In Studie 1 wurden in einem niederländischen Aufzuchtbetrieb 45 Zicklein verschiedener Herkunft zu je 15 Studientieren auf die Gruppen A1 (Kontrolle), B1 (EO1) und C1 (STA) aufgeteilt. In Studie 2 wurden in einem deutschen Milchziegenbetrieb 45 Zicklein aus betriebseigener Nachzucht in analoger Weise auf die Gruppen A2 (Kontrolle), B2 (EO1) und C2 (EO2) randomisiert. Die Zusätze auf Basis ätherischer Öle wurden während des Studienzeitraums kontinuierlich dem MAT beigemischt (EO1: 4 g/kg MAT; EO2: 125 g/t MAT) und über die MAT-Tränke ad libitum angeboten. Das Einstreupulver wurde zweimal wöchentlich in die Einstreu eingebracht. Insgesamt wurden in Studie 1 (53 Studientage) 484 Kotproben und in Studie 2 (56 Studientage) 847 Kotproben gesammelt, hinsichtlich ihrer Konsistenz bewertet und parasitologisch sowie teilweise differentialdiagnostisch untersucht. Die koproskopischen Untersuchungen umfassten die quantitative Bestimmung der ausgeschiedenen Oozysten pro Gramm Kot (OpG) und die Speziesdifferenzierung. Ferner wurden die Zicklein in Studie 1 am Studientag (ST) 0 und ST 35 und in Studie 2 am ST 0, ST 14, ST 35 und ST 56 gewogen und es erfolgte eine tägliche Kontrolle des Allgemeinbefindens. In beiden Studien wurden natürliche Infektionen der Zicklein mit Eimeria spp. beobachtet. In Studie 1 konnte bei 20 (44,4 %) und in Studie 2 bei 37 (82,2 %) der 45 Studientiere eine Oozystenausscheidung nachgewiesen werden. Die Befallsraten in den Kontrollgruppen (A1 und A2) lagen bei 73,3%in Studie 1 und 93,3%in Studie 2, was einen hohen bis sehr hohen Infektionsdruck anzeigt. Klinisch manifeste Eimeriosen mit Diarrhoe konnten während beider Studien nicht beobachtet werden. In Studie 2 wurde zwar bei 8,1 bis 8,5% der Kotproben in den drei Gruppen Durchfall festgestellt, dieser stand aber in keinem Zusammenhang mit einer Oozystenausscheidung von Eimeria spp. im Allgemeinen oder der pathogenen Spezies E. ninakohlyakimovae im Besonderen. Die Infektionen verliefen also ausnahmslos subklinisch, dennoch ist angesichts der hohen Befallsraten und der Präsenz pathogener Arten das Risiko eines Ausbruchs klinischer Kokzidiosen gegeben. Insgesamt handelte es sich im Falle von Oozystenausscheidung mehrheitlich um Polyinfektionen (Studie 1: 90,0 %; Studie 2: 94,4 %). In beiden Beständen wurde die Präsenz folgender neun Eimeria (E.) spp. nachgewiesen: E. alijevi, E. ninakohlyakimovae, E. hirci, E. arloingi, E. jolchijevi, E. christenseni, E. caprina, E. caprovina. Die höchste Prävalenz in den positiven Proben zeigten (in beiden Studien) E. arlongi (Studie 1: 52,5 %; Studie 2: 78,1 %) und E. ninakohlyakimovae (Studie 1: 55,9 %; Studie 2: 47,8 %). Am seltensten traten E. caprovina (5,1 %) und E. apsheronica (3,4 %) in Studie 1 sowie E. caprina (3,9 %) und E. caprovina (1,7 %) in Studie 2 auf. Die Intensität der Oozystenausscheidung bewegte sich bei 78,0% der positiven Proben in Studie 1 und 88,9% der positiven Proben in Studie 2 im niedrigen bis moderaten Bereich von 50 bis 10 000 OpG. Eine Oozystenausscheidung von mehr als 100 000 OpG (sehr hoher Bereich) trat in Studie 2 bei 1,1% der positiven Proben auf. Die Maxima in Einzelkotproben lagen in Studie 1 bei 67 000 OpG und in Studie 2 bei 157 000 OpG. Anlässlich der Prüfung möglicher Auswirkungen von STA fiel auf, dass gegen Ende des Studienzeitraums in der Gruppe C1 weniger (Re-) Infektionen im Vergleich zur Kontrolle auftraten. Auch die OpG-Werte erwiesen sich bei Auswertung der kumulierten Daten für den gesamten Studienzeitraum und den Zeitraum ab ST 47 sowie am ST 51 in Gruppe C1 als signifikant geringer als in Gruppe A1. Hinsichtlich der Untersuchung von Effekten durch den Einsatz von EO1 und EO2 wurden bei der Analyse von Befallsextensität und Ausscheidungsintensität in Studie 1 in Gruppe B1 niedrigere Befallsraten festgestellt und bei der Auswertung der über den Studienzeitraum kumulierten Daten und gegen Ende der Studie am ST 47, ST 49, ST 51 und ST 52 signifikant weniger positive Kotproben und geringere OpG- Werte als in Gruppe A1 ermittelt. Bei den Befallsraten und der kumulierten Anzahl positiver Proben konnten solche Effekte in Studie 2 nicht reproduziert werden. Gleichwohl zeigte sich am ST 35 und ST 37 in Gruppe B2 eine signifikant niedrigere Eimeria-Prävalenz als in Gruppe A2 und die Intensität der Oozystenausscheidung war in Gruppe B2 am ST 37 und in Gruppe C2 für den Zeitraum ab ST 26 sowie am ST 35, ST 37 und ST 42 signifikant geringer als in Gruppe A2. Bei den mittleren Zunahmen der Körpergewichte fielen stets leichte Gruppenunterschiede zu Gunsten der behandelten Gruppen auf (Gruppe A1: 4,33 kg, Gruppe B1: 5,58 kg, Gruppe C1: 4,55 kg und Gruppe A2: 9,70 kg, Gruppe B2: 10,39 kg, Gruppe C2: 10,74 kg) sie waren jedoch nicht statistisch signifikant. Der subjektive Eindruck einer besseren körperlichen Kondition und Gesamtentwicklung der EO1-behandelten Zicklein wurde dagegen in beiden Studien für einige Parameter und Studientage als signifikant bestätigt. Am Ende der Studien fielen zwölf der 14 Studientiere in Gruppe B1 (Studie 1) und zehn der 14 Studientiere in Gruppe B2 (Studie 2) durch einen exzellenten Entwicklungszustand auf, während dies in den Kontrollgruppen auf drei von zwölf Zicklein in Gruppe A1 (Studie 1) und fünf von 15 Zicklein in Gruppe A2 (Studie 2) zutraf. Der Einsatz von Stalosan® F in Studie 1 schien sich günstig auf den Verlauf der Kokzidiose auszuwirken. Der Eindruck einer kokzidioziden Wirkung sollte jedoch mittels weiterer Studien überprüft werden. Durch die Anwendung der Zusätze auf Basis ätherischer Öle, EIMERICOX® und NEXT Enhance® 200, konnte die Oozystenausscheidung unter subklinischen Bedingungen zwar begrenzt beeinflusst werden, bei einer massiven Exposition ist allerdings kaum davon auszugehen, dass eine Behandlung mit diesen untersuchten ätherischen Ölen eine ausreichend protektive Wirkung hätte, um Eimeriosen effektiv kontrollieren zu können. Bei einer geringen bis moderaten Expositionssituation könnten die geprüften alternativen Maßnahmen ergänzend zu weiteren prophylaktischen Maßnahmen (insbesondere im Haltungs- und Hygienemanagement) dem Aufbau eines kritischen Infektionsdrucks entgegen wirken und somit ein opportunes Anwendungsgebiet finden.

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