6,574 research outputs found
Building information modeling (BIM) in project management: A bibliometric and science mapping review
Purpose (limit 100 words) The impact of building information modeling (BIM) on various aspects of project management has attracted much attention in the past decade. However, previous studies have focused on a particular facet of project management (e.g., safety, quality, facility management) and within identified target journals. Despite numerous existing studies, there is limited research on the mainstream research topics, gaps, and future research directions on BIM in project management. This study aims to conduct a bibliometric and science mapping review of published articles on BIM in project management and to identify mainstream research topics, research gaps, and future research directions in this domain. Design/methodology/approach (limit 100 words) A science mapping approach consisting of bibliometric search, scientometric analysis, and qualitative discussion was used to analyze 521 journal articles that were retrieved from the Scopus database and related to BIM in project management. In the scientometric analysis, keyword co-occurrence analysis and document analysis were performed. This was followed by a qualitative discussion that seeks to propose a framework summarizing the interconnection between the mainstream research topics, research gaps, and future research directions. Findings (limit 100 words) Six mainstream research topics were found including (1) BIM-enabled advanced digital technologies, (2) BIM-based reinforcement and enhancement, (3) BIM and project composition, (4) BIM project elements and attributes, (5) BIM-based collaboration and communication, and (6) BIM-based information and data. Moreover, this study discussed six research gaps, namely (1) integration of BIM and other digital technologies, (2) future maturity of BIM applications in project management, (3) application of BIM in project components and processes, (4) role of BIM application in project elements and attributes, (5) impact of collaboration and communication in BIM application, and (6) stability of information and data interaction. Furthermore, future research directions were discussed. Originality/value (limit 100 words) The findings and proposed framework contribute to providing a deeper understanding to researchers, policymakers, and practitioners in the development of related research and practice in the domain of BIM in project management, thus, promoting digital transformation in project management. Overall, it adds to the global knowledge domain in BIM and promotes the need for digital and data integration, BIM maturity, and BIM collaboration
A novel bottleneck residual and self-attention fusion-assisted architecture for land use recognition in remote sensing images
The massive yearly population growth is causing hazards to spread swiftly around the world and have a detrimental impact on both human life and the world economy. By ensuring early prediction accuracy, remote sensing enters the scene to safeguard the globe against weather-related threats and natural disasters. Convolutional neural networks, which are a reflection of deep learning, have been used more recently to reliably identify land use in remote sensing images. This work proposes a novel bottleneck residual and self-attention fusion-assisted architecture for land use recognition from remote sensing images. First, we proposed using the fast neural approach to generate cloud-effect satellite images. In neural style, we proposed a 5-layered residual block CNN to estimate the loss of neural-style images. After that, we proposed two novel architectures, named 3-layered bottleneck CNN architecture and 3-layered bottleneck self-attention CNN architecture, for the classification of land use images. Training has been conducted on both proposed and original neural-style generated datasets for both architectures. Subsequently, features are extracted from the deep layers and merged employing an innovative serial approach based on weighted entropy. By removing redundant and superfluous data, a novel Chimp Optimization technique is applied to the fused features in order to further refine them. In conclusion, selected features are classified using the help of neural network classifiers. The experimental procedure yielded respective accuracy rates of 99.0% and 99.4% when applied to both datasets. When evaluated in comparison to state-of-the-art (SOTA) methods, the outcomes generated by the proposed framework demonstrated enhanced precision and accuracy
Dataflow Programming and Acceleration of Computationally-Intensive Algorithms
The volume of unstructured textual information continues to grow due to recent technological advancements. This resulted in an exponential growth of information generated in various formats, including blogs, posts, social networking, and enterprise documents. Numerous Enterprise Architecture (EA) documents are also created daily, such as reports, contracts, agreements, frameworks, architecture requirements, designs, and operational guides. The processing and computation of this massive amount of unstructured information necessitate substantial computing capabilities and the implementation of new techniques. It is critical to manage this unstructured information through a centralized knowledge management platform. Knowledge management is the process of managing information within an organization. This involves creating, collecting, organizing, and storing information in a way that makes it easily accessible and usable. The research involved the development textual knowledge management system, and two use cases were considered for extracting textual knowledge from documents. The first case study focused on the safety-critical documents of a railway enterprise. Safety is of paramount importance in the railway industry. There are several EA documents including manuals, operational procedures, and technical guidelines that contain critical information. Digitalization of these documents is essential for analysing vast amounts of textual knowledge that exist in these documents to improve the safety and security of railway operations. A case study was conducted between the University of Huddersfield and the Railway Safety Standard Board (RSSB) to analyse EA safety documents using Natural language processing (NLP). A graphical user interface was developed that includes various document processing features such as semantic search, document mapping, text summarization, and visualization of key trends. For the second case study, open-source data was utilized, and textual knowledge was extracted. Several features were also developed, including kernel distribution, analysis offkey trends, and sentiment analysis of words (such as unique, positive, and negative) within the documents. Additionally, a heterogeneous framework was designed using CPU/GPU and FPGAs to analyse the computational performance of document mapping
Developing a framework leveraging building information modelling to validate fire emergency evacuation
In fire emergency management, a delayed execution will cause a significant number of casualties. Conventional fire drills typically only identify a certain percentage of evacuation bottlenecks after the building has been constructed, which is hard to improve. This paper proposes an innovative framework to validate fire emergency evacuation at the early design stage. According to the experience and knowledge of fire emergency evacuation design, the proposed framework also introduces a seamless two-way information channel to embed fire emergency evacuation simulations into a BIM-based design environment. Several critical factors for fire evacuation have been reviewed in relevant domain knowledge, which is used to build virtual characters to test in experimental scenarios. The results are analyzed to validate fire emergency evacuation factors, and the feedback knowledge is stored as a knowledge model for further applications
Software Design Change Artifacts Generation through Software Architectural Change Detection and Categorisation
Software is solely designed, implemented, tested, and inspected by expert people, unlike other engineering projects where they are mostly implemented by workers (non-experts) after designing by engineers. Researchers and practitioners have linked software bugs, security holes, problematic integration of changes, complex-to-understand codebase, unwarranted mental pressure, and so on in software development and maintenance to inconsistent and complex design and a lack of ways to easily understand what is going on and what to plan in a software system. The unavailability of proper information and insights needed by the development teams to make good decisions makes these challenges worse. Therefore, software design documents and other insightful information extraction are essential to reduce the above mentioned anomalies. Moreover, architectural design artifacts extraction is required to create the developer’s profile to be available to the market for many crucial scenarios. To that end, architectural change detection, categorization, and change description generation are crucial because they are the primary artifacts to trace other software artifacts.
However, it is not feasible for humans to analyze all the changes for a single release for detecting change and impact because it is time-consuming, laborious, costly, and inconsistent. In this thesis, we conduct six studies considering the mentioned challenges to automate the architectural change information extraction and document generation that could potentially assist the development and maintenance teams. In particular, (1) we detect architectural changes using lightweight techniques leveraging textual and codebase properties, (2) categorize them considering intelligent perspectives, and (3) generate design change documents by exploiting precise contexts of components’ relations and change purposes which were previously unexplored. Our experiment using 4000+ architectural change samples and 200+ design change documents suggests that our proposed approaches are promising in accuracy and scalability to deploy frequently. Our proposed change detection approach can detect up to 100% of the architectural change instances (and is very scalable). On the other hand, our proposed change classifier’s F1 score is 70%, which is promising given the challenges. Finally, our proposed system can produce descriptive design change artifacts with 75% significance. Since most of our studies are foundational, our approaches and prepared datasets can be used as baselines for advancing research in design change information extraction and documentation
Signaling Mechanisms Behind the Benefits of Sleep
Hintergrund: Schlaf ist ein streng regulierter Zustand körperlicher Ruhe und reduzierten Bewusstseins, der evolutionär im ganzen Tierreich konserviert ist. Schlafmangel ist in der modernen Gesellschaft weit verbreitet und betrifft 10 – 30 % der Erwachsenen. Dies stellt ein ernstes gesundheitliches Problem dar, da Schlafmangel mit vielen Krankheiten assoziiert ist, darunter Depressionen, Krebs und Herz-Kreislauf-Erkrankungen. Umgekehrt beeinflussen auch Krankheiten und das Immunsystem das Schlafverhalten. Trotz der fundamentalen Rolle dieser Wechselbeziehung sind grundlegende molekulare Mechanismen, die Funktionen des Immunsystems und Schlafkontrolle verbinden, bisher kaum verstanden. Da die Schlafregulation in Säugetieren sehr komplex ist, ist es sinnvoll konservierte Mechanismen zuerst in einfacheren Modellorganismen zu untersuchen. Der Rundwurm C. elegans ist ein solcher etablierter, simpler und vielseitiger Modellorganismus für die Schlafforschung. Er schläft sowohl im Rhythmus seiner Larvenentwicklung immer jeweils während des Lethargus kurz vor der Häutung, als auch nach besonderem Stress, wie zum Beispiel Hunger oder Hitze. C. elegans besitzt ein invariantes Nervensystem, in dem eine rapide Depolarisation des einzelnen RIS-Interneurons genügt, um Schlaf zu induzieren. Eine Mutation des AP2 Transkriptionsfaktors APTF-1 verhindert die Expression von FLP-11, dem schlafinduzierenden Neuropeptid von RIS. Dies führt praktisch zu völliger Schlaflosigkeit, die in C. elegans in der Regel nicht tödlich ist, und deshalb ein nützliches Modell für genetisch-chronischen Schlafmangel darstellt. Unser Labor fand heraus, dass eine Gain-of-function-Mutation in der Kollagenase NAS-38 über Signalwege der angeborenen Immunität und RIS-Aktivierung zu vermehrtem Schlaf während des Lethargus führt. Gleichzeitig wird dabei die Expression einer ganzen Familie antimikrobieller Peptide (AMP) hochreguliert. Derselbe Signalweg, einschließlich der AMP, sowie das Schlafverhalten werden auch durch Verletzungen induziert. Interessanterweise sterben nicht-schlafende Würmer nach einer Verletzung häufiger. Insgesamt deutet dies darauf hin, dass AMP als Signalmoleküle fungieren könnten, die Schlaf als Teil einer globalen Schutzreaktion vom peripheren Gewebe zum Nervensystem signalisieren. Für diese Hypothese fehlten bisher jedoch die Beweise. Fragestellungen und Hypothesen: Mein Ziel war es, den molekularen Mechanismus zu entschlüsseln, durch den verschiedene Reize der angeborenen Immunität, das heißt NAS-38 sowie epidermale Verletzungen, Schlaf induzieren. Zwei Fragen habe ich hierbei im Speziellen adressiert: Welche Domänen des NAS 38-Proteins sind an der Schlafregulation beteiligt? Da die Astacin-Domäne als aktive Proteasedomäne von NAS-38 angesehen wird, erwartete ich eine Schlüsselrolle dieser Domäne auch in der Schlafinduktion. Zweitens, welche Rolle spielen AMP bei der Signalisierung von immunitätsinduziertem Schlaf? Da gezeigt wurde, dass AMP während des NAS-38 Schlafes und auch nach Verwundung hochreguliert sind, erwartete ich, dass AMP an der Signalisierung von Schlaf von der Epidermis zum Nervensystem beteiligt sind. In einem zweiten Schritt untersuchte ich die molekularen Mechanismen, die den Vorteilen von Schlaf für das Überleben von Verletzungen zugrunde liegen. Auch hier habe ich speziell zwei Fragestellungen untersucht: Verändert genetischer Schlafentzug die transkriptionelle Reaktion auf epidermale Verletzungen? Da Schlaf für viele fundamentale Prozesse wichtig ist und Schlaflosigkeit die Sterblichkeit nach Verletzungen erhöht, vermutete ich, dass genetischer Schlafentzug die transkriptionelle Reaktion auf Verletzungen beeinträchtigt. Zweitens, ist Schlaf wichtig für die Entwicklung von Robustheit, um im Falle einer Verletzung weniger Schaden zu nehmen? Während der Larvenentwicklung fällt die Cuticula-Synthese mit Schlaf zeitlich zusammen. Daher stellte ich die Hypothese auf, dass Schlafentzug die korrekte Bildung einer Cuticula beeinträchtigt. Methoden: Zur Analyse der Signalmechanismen, durch die sowohl NAS-38 als auch Verletzungen Schlaf induzieren, filmte ich das Schlafverhalten von C. elegans mittels Langzeit-Bildgebung in Agarose-Mikrokammern. So führte ich eine Struktur-Funktions-Analyse mit verschiedenen nas-38 Mutanten durch, in denen jeweils eine andere NAS-38 Domäne deletiert war. Darüber hinaus testete ich verschiedene Suppressoren für immunvermittelten Schlaf, der durch NAS 38 oder Verletzungen induziert war. Die Redundanz des Suppressionseffektes der verschiedenen Mitglieder der AMP-Familie auf immunvermittelten Schlaf testete ich, indem ich den Suppressionsphänotyp einer CRISPR/Cas9-editierten Multi-Knockout-Mutante analysierte, in der insgesamt 19 AMP deletiert waren. Um Effektoren zu identifizieren, die den AMP nachgeschaltet sind, induzierte ich Schlaf durch Überexpression des AMP NLP 29 unter der Kontrolle eines Hitzeschock-Promotors und analysierte die Sschlafsuppression durch verschiedene Knockout-Mutanten. Im zweiten Projekt beschäftigte ich mich mit der Frage, wie genau Schlaf das Überleben nach Verletzungen unterstützt. Ich verglich die Expression von literaturbekannten Reportern für verschiedene Aspekte der Verwundungsreaktion mittels Langzeit-Fluoreszenzmikroskopie im Wildtyp sowie dem Modell für chronisch-genetischen Schlafmangel. Darüber hinaus habe ich die Transkriptome zwischen jeweils adulten verwundeten und unverwundeten Wildtypen und schlaflosen Mutanten verglichen. Um die Struktur der Cuticula des Wildtyps und der schlaflosen Mutante zu vergleichen, analysierte ich außerdem rasterelektronen-mikroskopische Aufnahmen. Ergebnisse: Im ersten Projekt konnte ich zeigen, dass NAS-38 Schlaf durch seine Astacin-Domäne verlängert. Dieser Prozess wird moderiert durch die TSP-1-Domäne. Weiterhin konnte ich zeigen, dass viele AMP redundant wirken um immunvermittelten Schlaf, verursacht durch NAS-38 oder Verletzungen, zu signalisieren. Ich konnte zeigen, dass das AMP NLP-29 über den Neuropeptidrezeptor NPR-12 wirkt. Dieser kann NLP-29-induzierten Schlaf vermitteln, wenn er in einem neuronalen Netzwerk exprimiert wird, welches nachweislich RIS aktiviert. Interessanterweise fand ich außerdem heraus, dass für NLP-29-vermittelten Schlaf der EGFR Signalweg notwendig ist. Im zweiten Projekt entdeckte ich, dass Schlaflosigkeit die transkriptionelle Reaktion auf Verletzungen nicht dramatisch verändert. Allerdings ist das Transkriptionsprofil bereits in der unverletzten schlaflosen Mutante verändert. Dies betraf unter anderem eine Gruppe oszillierender Gene, die Cuticula-assoziierte Proteine codieren, und deren Expression normalerweise ihren Höhepunkt gegen Ende des Lethargus erreicht. Da angenommen wird, dass der Zeitpunkt der Kollagenexpression entscheidend für eine fehlerfreie Cuticula-Bildung ist, analysierte ich die Cuticula der schlaflosen Mutante. Ich konnte zeigen, dass die Cuticula des adulten Tieres tatsächlich einen strukturellen Defekt aufweist. Dieser betrifft speziell Furchen in der Region nahe den Alae und könnte möglicherweise die Strapazierfähigkeit der Cuticula gegenüber bestimmten Belastungen verringern. Daher könnte Schlaf erforderlich sein, Robustheit in Form einer strukturierten Cuticula zu fördern. Schlussfolgerungen: In diesem Dissertationsprojekt vollendete ich die Charakterisierung eines neuentdeckten Mechanismus in C. elegans, durch den Verwundungen Schlaf als Teil der Immunantwort aus der Peripherie zum Nervensystem signalisieren. Ich konnte zeigen, dass AMP gewebeübergreifend Signale von der Epidermis an ein neuronales Netz vermitteln, welches wiederum RIS aktiviert und dadurch Schlaf induziert. Da Komponenten dieses Signalweges konserviert sind, könnten AMP auch in anderen Tieren, einschließlich des Menschen, Schlaf zur Genesung fördern. Darüber hinaus habe ich die Grundlagen für die Analyse molekularer Mechanismen geschaffen, die den essentiellen Funktionen des Schlafes für Heilung und Überleben zugrunde liegen. Obwohl Schlaflosigkeit die transkriptionelle Reaktion auf Verletzungen nicht drastisch zu verändern scheint, deuten meine Ergebnisse auf eine Rolle des Schlafes bei der richtigen Cuticula-Bildung und möglicherweise sogar auf eine vielfältigere Rolle bei der zeitlichen Regulierung der Genexpression hin.:Summary I
Zusammenfassung IV
Contents VII
List of Figures XII
List of Tables XIV
Abbreviations XV
1. Introduction 1
1.1. Sleep is fascinating 1
1.1.1. The origin and basic features of sleep 1
1.1.2. Regulation of sleep in higher animals 3
1.1.2.1. Neuronal control of sleep 3
1.1.2.2. Molecular control of sleep 5
1.1.3. The functions of sleep 6
1.2. The immune system and its relationship to sleep 7
1.3. Wound healing and its relationship to sleep 10
1.4. Caenorhabditis elegans is a well-studied model organism 12
1.4.1. Sleep in C. elegans 15
1.4.2. The C. elegans cuticle 18
1.4.3. Immunity in C. elegans 19
1.4.4. Wound healing response in C. elegans 22
2. Previous results 25
2.1. A strong gain-of-function mutation in the astacin metallo-proteinase NAS 38 increases lethargus duration and movement quiescence in C. elegans 25
2.2. NAS-38 increases sleep mostly through the RIS neuron 25
2.3. NAS-38 is expressed in the epidermis and oscillates with the developmental rhythm 25
2.4. nas-38(ok3407) acts via innate immunity pathways to increase lethargus duration and AMP expression 27
2.5. Overexpression of AMPs induces RIS dependent quiescence 30
2.6. Epidermal wounding induces RIS-dependent sleep, which is beneficial for survival 31
3. Thesis Aims 34
3.1. Aim 1 – Characterizing the molecular mechanism through which NAS-38, innate immunity, and wounding induce sleep 34
3.2. Aim 2 – Analyzing how sleep promotes survival after wounding 35
4. Materials and Methods 36
4.1. C. elegans maintenance 36
4.2. C. elegans crossing and genotyping 41
4.3. Creation of transgenic animals 45
4.3.1. Creating the npr-12 rescue in nmr-1 expressing neurons 45
4.3.2. Microparticle bombardment 45
4.3.3. CRISPR/Cas9 system 46
4.4. Synchronizing worm cultures by hypochlorite treatment 48
4.5. Imaging 49
4.5.1. Imaging setups 49
4.5.2. DIC Imaging of worm development, lethargus, and sleep behavior 50
4.5.2.1. Imaging of heterozygous mutants 50
4.5.3. DIC imaging in the temperature control device 51
4.5.4. Fluorescent imaging experiments 51
4.5.4.1. nas-38p::d1GFP and nlp-29p::GFP during L1 development 51
4.5.4.2. nlp-29p::GFP in L4 larvae 52
4.5.4.3. nlp-29p::GFP after heat shock-induced lin-3 overexpression 52
4.5.4.4. Imaging fluorescent markers in (wounded) young adults 52
4.5.4.5. Functional Ca2+ imaging in young adults 52
4.5.4.6. Fluorescence imaging across the whole developmental time 54
4.5.4.7. Nuclear decompaction assays 55
4.5.4.8. Transcription factor localization with spinning disc confocal microscopy 55
4.5.4.9. Imaging DPY-13::mKate2 in young adults 56
4.6. Image analysis 56
4.6.1. Assessment of developmental time and lethargus detection 56
4.6.2. Sleep detection in DIC mode 56
4.6.3. Analyzing functional Ca2+ images 57
4.6.4. Fluorescent reporter analysis during long-term imaging 57
4.7. RNAi-by-feeding 58
4.8. Transcriptome analysis 59
4.8.1. Analysis of the nas-38(ok3407) transcriptome 59
4.8.2. Analysis of the wounding transcriptome 59
4.9. Epidermal wounding 62
4.9.1. Laser wounding 62
4.9.2. Needle wounding 62
4.9.3. Survival assay 63
4.10. Scanning Electron Microscopy (SEM) 63
4.11. Histamine-inducible hyperpolarization of RIS 64
4.12. Cuticle integrity test with Sodium hypochlorite 64
4.13. NPR-12 receptor modeling 64
4.14. Quantification and statistical analysis 65
5. Results 66
5.1. Aim 1 – Characterizing the pathway through which NAS 38, wounding and innate immunity induce sleep 66
5.1.1. The loss of function mutation nas-38(tm2655) shows the opposite phenotype to the gain of function mutation nas-38(ok3407) 66
5.1.2. nas-38 gain-of-function mutants act through their astacin protease domain and are semi-dominant 66
5.1.3. Transcriptome analysis of nas-38(ok3407) reveals upregulation of genes associated with secretion, innate immunity and cuticle formation 69
5.1.4. nas-38(knu568) increased movement quiescence can be suppressed by mutations of innate immunity pathways 72
5.1.5. Multiple NLPs and CNCs act in parallel to mediate nas-38(ok3407) induced sleep 75
5.1.6. Wounding-induced sleep requires RIS, ALA, EGFR and immune signaling 77
5.1.7. NLP-29 signals via the NPR-12 receptor in neurons upstream of RIS 80
5.1.8. NLP-29 requires neuronal EGFR signaling to induce sleep 81
5.1.9. Simple in silico models suggest that many different NLPs can bind to NPR-12 83
5.1.10. AMPs contribute to the survival after wounding 85
5.2. Aim 2 – Identifying the advantages sleep provides that help to survive harmful conditions 87
5.2.1. Wounding decreases the lifespan in the wild type and the aptf 1(gk794) mutant 87
5.2.2. Histamine-inducible RIS hyperpolarization suppresses wounding sleep 87
5.2.3. Genetic sleep deprivation decreases translocation of DAF-16 into the nucleus immediately after wounding 89
5.2.4. Genetic sleep deprivation hardly changes the transcriptional wounding response 95
5.2.5. Genetic sleep deprivation and wounding increase nuclear PHA 4 101
5.2.6. Oscillating genes and genes associated with the cuticle and the unfolded protein response are upregulated in young adult aptf 1(gk794) mutants 106
5.2.7. Genetic sleep deprivation leads to a malformation of cuticular furrows 109
5.2.8. Genetic sleep deprivation leads to an increased transcription of lethargus specific oscillating genes in young adults 114
5.2.9. Genetic sleep deprivation does not significantly affect development time or body size 120
5.2.10. Expression of fluorescent reporters of oscillating genes is not phase-shifted in the aptf-1(gk794) mutant 122
6. Discussion and Outlook 128
6.1. NAS-38 acts through its astacin domain to increase sleep via innate immunity pathways 128
6.2. NAS-38 during larval lethargus and epidermal wounding in the adult signal sleep via many AMPs as part of a peripheral immune response 130
6.3. Epidermal AMPs activate a neuronal circuit to induce sleep 131
6.4. Genetically sleep deprived worms can mount a proper wounding response in many ways, except for DAF-16/FOXO regulation 132
6.5. Genetic sleep deprivation alters cuticle formation 135
6.6. The role of PHA-4/FOXA in genetically sleep-deprived animals 137
6.7. Conclusion 139
7. References 140
8. Acknowledgements 163
9. Appendix 166
9.1. Standard reagents 166
9.2. Sequence summary of PHX3754 167
9.3. MATLAB script to analyze the intensity of fluorescent reporters over time 171
9.4. Permissions to reprint figures 174
9.5. Experimental author contributions 175
9.6. Predicted interactions between the NPR-12 receptor and peptides of the nlp and cnc families 176
9.7. Overlap of the adult wounding transcriptome with other data sets 179
9.8. Curriculum Vitae – Marina Patricia Sinner 181Background: Sleep is a tightly regulated state of behavioral quiescence and reduced consciousness, which is conserved throughout the animal kingdom. In modern societies 10 – 30 % of the adult population suffer from insufficient sleep, which poses a serious health problem as sleep deprivation is associated with a variety of diseases including depression, cancer, and cardiovascular diseases. Conversely, sickness and the immune system also influence sleep patterns. Despite the important role of this interrelationship between sleep and immunity, basic molecular mechanisms that link both vital functions are only poorly understood yet. As sleep regulation is complex in mammals and is thus difficult to address experimentally, it is reasonable to investigate its basic conserved mechanisms in simpler models first. The nematode C. elegans is such a well-established, simple, and powerful model organism for sleep research. It displays stress-induced sleep, for example upon starvation or heat shock, but also developmentally-timed sleep during lethargus prior to each larval molt. C. elegans possesses an invariant nervous system in which rapid depolarization of the single RIS interneuron is sufficient to induce sleep. Mutation of the AP2 transcription factor APTF 1 deprives RIS of its sleep-inducing neuropeptide FLP-11 and thus virtually abolishes sleep. This is not per se lethal in C. elegans, thereby presenting a powerful model for genetic sleep deprivation. Our lab found that a gain-of-function mutation in the collagenase NAS-38 strongly increases RIS-dependent sleep during lethargus with a concomitant upregulation of a large family of antimicrobial peptides (AMPs) via immunity pathways. Epidermal wounding also triggers AMP expression via immune signaling and induces sleep in the adult worm. Moreover, genetic sleep deprivation increases mortality upon epidermal injury. Together, this suggests AMPs to act as somnogens from peripheral tissues to the nervous system as part of a protective response. This hypothesis, however, was hitherto lacking final evidence and pathway components.
Research questions and hypotheses: I aimed to characterize the molecular mechanism by which separate triggers of innate immunity, i. e. NAS-38 and wounding, induce sleep. I specifically addressed two questions: Firstly, which domains of the NAS-38 protein are involved in sleep regulation? As the astacin domain is predicted to be the active protease domain of NAS-38, I expected a role for it also in sleep induction by NAS-38. Secondly, what is the role of AMPs in signaling immunity-induced sleep? As they have been shown to be upregulated during times of increased sleep in the nas-38 mutant and after wounding, I expected AMPs to be involved in signaling sleep from the epidermis to the nervous system. In a second step, I investigated the molecular mechanisms underlying the benefits of sleep for surviving injury. Again, I addressed two questions: Firstly, does genetic sleep deprivation alter the transcriptional wounding response? As sleep has a role in many fundamental processes and sleeplessness increases mortality upon wounding, I hypothesized that genetic sleep deprivation impairs wounding-induced changes of transcriptional activity. Secondly, does sleep help building robustness before encountering injury? During larval development the synthesis of a new cuticle coincides with sleep. Thus, I hypothesized that genetic sleep deprivation impairs proper cuticle formation. Methods: To dissect the signaling mechanisms by which NAS-38 and wounding induced sleep, I followed sleep behavior of C. elegans by long-term imaging in agarose microchambers. I performed a structure-function analysis with different nas-38 mutants, each carrying a deletion of a different domain. Moreover, I screened for suppressors of sleep induced by NAS 38 or wounding. To test for redundancy of the AMP family, I investigated the suppression-phenotype of a CRISPR/Cas9 edited multi-knockout mutant lacking 19 AMPs. To identify downstream effectors of the AMP NLP 29, I induced sleep by overexpressing NLP 29 from a heat-shock promoter and analyzed the suppression-phenotype of different knockout mutants. For the second project, I addressed the question how sleep aids recovery from injury. I followed fluorescent reporters of previously described wounding response pathways by fluorescent long-term imaging in wild-type and genetically sleep-deprived animals. Moreover, I compared the transcriptomes of adult wild-type and genetically sleep-deprived worms both wounded and unwounded. To investigate the structure of the cuticle, I analyzed scanning electron microscopy images. Results: In the first project, I could show that NAS-38 indeed increases sleep via its astacin domain in a process that is modulated by the TSP-1 domain. Moreover, I could show that many AMPs act redundantly in mediating immunity-induced sleep downstream of NAS-38 and after wounding. I demonstrated that the AMP NLP-29 signals sleep via the neuropeptide receptor NPR 12. This receptor can mediate sleep when it is specifically expressed in command interneurons of a circuit that has been shown to activate RIS. Interestingly, I also found that EGFR signaling is required to mediate NLP-29-induced sleep.
In the second project, I found that sleeplessness does not dramatically alter the transcriptional wounding response. However, I could show that transcription is altered already in the unwounded non-sleeping mutant. This affects, among others, a specific subset of oscillating collagen-coding genes, whose expression usually peaks around the end of lethargus. As the timing of expression of collagens is thought to be highly important for proper cuticle formation, I characterized the cuticle of the aptf-1(gk794) mutant. I could show that young adult aptf 1(gk794) worms indeed have a structural defect affecting cuticular furrows in the region adjacent to the alae, which could potentially decrease specific aspects of resilience of the cuticle. Thus, sleep might be required to build robustness in the form of a properly structured cuticle. Conclusion: In this PhD project, I completed the characterization of a novel mechanism by which wounding signals sleep from the periphery to the nervous system as part of the immune response in C. elegans. I could show that AMPs act as cross-tissue signals from the epidermis to a neuronal RIS-controlling circuit that ultimately leads to sleep induction. As components of this molecular pathway are highly conserved, AMPs might also induce sleep to promote recovery from injury in other organisms, including humans. Moreover, I laid the foundations for dissecting the molecular mechanisms behind the functions of sleep for healing and survival. Even though the disability to sleep did not seem to drastically change the transcriptional response to wounding, my results indicate a role for
A BIM - GIS Integrated Information Model Using Semantic Web and RDF Graph Databases
In recent years, 3D virtual indoor and outdoor urban modelling has become an essential geospatial information framework for civil and engineering applications such as emergency response, evacuation planning, and facility management. Building multi-sourced and multi-scale 3D urban models are in high demand among architects, engineers, and construction professionals to achieve these tasks and provide relevant information to decision support systems. Spatial modelling technologies such as Building Information Modelling (BIM) and Geographical Information Systems (GIS) are frequently used to meet such high demands. However, sharing data and information between these two domains is still challenging. At the same time, the semantic or syntactic strategies for inter-communication between BIM and GIS do not fully provide rich semantic and geometric information exchange of BIM into GIS or vice-versa. This research study proposes a novel approach for integrating BIM and GIS using semantic web technologies and Resources Description Framework (RDF) graph databases. The suggested solution's originality and novelty come from combining the advantages of integrating BIM and GIS models into a semantically unified data model using a semantic framework and ontology engineering approaches. The new model will be named Integrated Geospatial Information Model (IGIM). It is constructed through three stages. The first stage requires BIMRDF and GISRDF graphs generation from BIM and GIS datasets. Then graph integration from BIM and GIS semantic models creates IGIMRDF. Lastly, the information from IGIMRDF unified graph is filtered using a graph query language and graph data analytics tools. The linkage between BIMRDF and GISRDF is completed through SPARQL endpoints defined by queries using elements and entity classes with similar or complementary information from properties, relationships, and geometries from an ontology-matching process during model construction. The resulting model (or sub-model) can be managed in a graph database system and used in the backend as a data-tier serving web services feeding a front-tier domain-oriented application. A case study was designed, developed, and tested using the semantic integrated information model for validating the newly proposed solution, architecture, and performance
Design of new algorithms for gene network reconstruction applied to in silico modeling of biomedical data
Programa de Doctorado en BiotecnologĂa, IngenierĂa y TecnologĂa QuĂmicaLĂnea de InvestigaciĂłn: IngenierĂa, Ciencia de Datos y BioinformáticaClave Programa: DBICĂłdigo LĂnea: 111The root causes of disease are still poorly understood. The success of current therapies is limited because persistent diseases are frequently treated based on their symptoms rather than the underlying cause of the disease. Therefore, biomedical research is experiencing a technology-driven shift to data-driven holistic approaches to better characterize the molecular mechanisms causing disease. Using omics data as an input, emerging disciplines like network biology attempt to model the relationships between biomolecules. To this effect, gene co- expression networks arise as a promising tool for deciphering the relationships between genes in large transcriptomic datasets. However, because of their low specificity and high false positive rate, they demonstrate a limited capacity to retrieve the disrupted mechanisms that lead to disease onset, progression, and maintenance. Within the context of statistical modeling, we dove deeper into the reconstruction of gene co-expression networks with the specific goal of discovering disease-specific features directly from expression data. Using ensemble techniques, which combine the results of various metrics, we were able to more precisely capture biologically significant relationships between genes. We were able to find de novo potential disease-specific features with the help of prior biological knowledge and the development of new network inference techniques.
Through our different approaches, we analyzed large gene sets across multiple samples and used gene expression as a surrogate marker for the inherent biological processes, reconstructing robust gene co-expression networks that are simple to explore. By mining disease-specific gene co-expression networks we come up with a useful framework for identifying new omics-phenotype associations from conditional expression datasets.In this sense, understanding diseases from the perspective of biological network perturbations will improve personalized medicine, impacting rational biomarker discovery, patient stratification and drug design, and ultimately leading to more targeted therapies.Universidad Pablo de Olavide de Sevilla. Departamento de Deporte e Informátic
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