1,365 research outputs found

    Advanced sequencing technologies applied to human cytomegalovirus

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    The betaherpesvirus human cytomegalovirus (HCMV) is a ubiquitous viral pathogen. It is the most common cause of congenital infection in infants and of opportunistic infections in immunocompromised patients worldwide. The large double-stranded DNA genome of HCMV (236 kb) contains several genes that exhibit a high degree of variation among strains within an otherwise highly conserved sequence. These hypervariable genes encode immune escape, tropism or regulatory factors that may affect virulence. Variation arising from these genes and from an evolutionary history of recombination between strains has been hypothesised to be linked to disease severity. To investigate this, the HCMV genome has been scrutinised in detail over the years using a variety of molecular techniques, most looking only at one or a few of these genes at a time. The advent of high-throughput sequencing (HTS) technology 20 years ago then started to enable more in-depth whole-genome analyses. My study extends this field by using both HTS and the more recently developed long-read nanopore technology to determine HCMV genome sequences directly from clinical samples. Firstly, I used an Illumina HTS pipeline to sequence HCMV strains directly from formalin-fixed, paraffin-embedded (FFPE) tissues. FFPE samples are a valuable repository for the study of relatively rare diseases, such as congenital HCMV (cCMV). However, formalin fixation induces DNA fragmentation and cross-linking, making this a challenging sample type for DNA sequencing. I successfully sequenced five whole HCMV genomes from FFPE tissues. Next, I developed a pipeline utilising the single-molecule, long-read sequencer from Oxford Nanopore Technologies (ONT) to sequence HCMV initially from high-titre cellcultured laboratory strains and then from clinical samples with high HCMV loads. Finally, I utilised a direct RNA sequencing protocol with the ONT sequencer to characterise novel HCMV transcripts produced during infection in cell culture, demonstrating the existence of transcript isoforms with multiple splice sites. Overall, my findings demonstrate how advanced sequencing technologies can be used to characterise the genome and transcriptome of a large DNA virus, and will facilitate future studies on HCMV prognostic factors, novel antiviral targets and vaccine development

    Gesellschaftstheorie im AnthropozÀn

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    Das AnthropozĂ€n ist das Zeitalter, in dem menschliches Handeln zum wichtigsten Einflussfaktor auf die geophysikalischen Prozesse der Erde geworden ist - mit gravierenden Konsequenzen: Klimakrise, Artensterben, Vergiftung von Böden, Wasser und Luft. Was das AnthropozĂ€n fĂŒr die Gesellschaftstheorie bedeutet, ist noch weitgehend unklar. Die BeitrĂ€ge dieses Bandes entwerfen Konzepte, wie Gesellschaft, Wirtschaft, Politik und Natur im Zeitalter des Menschen gesellschaftstheoretisch zu denken sind

    Towards compact bandwidth and efficient privacy-preserving computation

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    In traditional cryptographic applications, cryptographic mechanisms are employed to ensure the security and integrity of communication or storage. In these scenarios, the primary threat is usually an external adversary trying to intercept or tamper with the communication between two parties. On the other hand, in the context of privacy-preserving computation or secure computation, the cryptographic techniques are developed with a different goal in mind: to protect the privacy of the participants involved in a computation from each other. Specifically, privacy-preserving computation allows multiple parties to jointly compute a function without revealing their inputs and it has numerous applications in various fields, including finance, healthcare, and data analysis. It allows for collaboration and data sharing without compromising the privacy of sensitive data, which is becoming increasingly important in today's digital age. While privacy-preserving computation has gained significant attention in recent times due to its strong security and numerous potential applications, its efficiency remains its Achilles' heel. Privacy-preserving protocols require significantly higher computational overhead and bandwidth when compared to baseline (i.e., insecure) protocols. Therefore, finding ways to minimize the overhead, whether it be in terms of computation or communication, asymptotically or concretely, while maintaining security in a reasonable manner remains an exciting problem to work on. This thesis is centred around enhancing efficiency and reducing the costs of communication and computation for commonly used privacy-preserving primitives, including private set intersection, oblivious transfer, and stealth signatures. Our primary focus is on optimizing the performance of these primitives.Im Gegensatz zu traditionellen kryptografischen Aufgaben, bei denen Kryptografie verwendet wird, um die Sicherheit und IntegritĂ€t von Kommunikation oder Speicherung zu gewĂ€hrleisten und der Gegner typischerweise ein Außenstehender ist, der versucht, die Kommunikation zwischen Sender und EmpfĂ€nger abzuhören, ist die Kryptografie, die in der datenschutzbewahrenden Berechnung (oder sicheren Berechnung) verwendet wird, darauf ausgelegt, die PrivatsphĂ€re der Teilnehmer voreinander zu schĂŒtzen. Insbesondere ermöglicht die datenschutzbewahrende Berechnung es mehreren Parteien, gemeinsam eine Funktion zu berechnen, ohne ihre Eingaben zu offenbaren. Sie findet zahlreiche Anwendungen in verschiedenen Bereichen, einschließlich Finanzen, Gesundheitswesen und Datenanalyse. Sie ermöglicht eine Zusammenarbeit und Datenaustausch, ohne die PrivatsphĂ€re sensibler Daten zu kompromittieren, was in der heutigen digitalen Ära immer wichtiger wird. Obwohl datenschutzbewahrende Berechnung aufgrund ihrer starken Sicherheit und zahlreichen potenziellen Anwendungen in jĂŒngster Zeit erhebliche Aufmerksamkeit erregt hat, bleibt ihre Effizienz ihre Achillesferse. Datenschutzbewahrende Protokolle erfordern deutlich höhere Rechenkosten und Kommunikationsbandbreite im Vergleich zu Baseline-Protokollen (d.h. unsicheren Protokollen). Daher bleibt es eine spannende Aufgabe, Möglichkeiten zu finden, um den Overhead zu minimieren (sei es in Bezug auf Rechen- oder Kommunikationsleistung, asymptotisch oder konkret), wĂ€hrend die Sicherheit auf eine angemessene Weise gewĂ€hrleistet bleibt. Diese Arbeit konzentriert sich auf die Verbesserung der Effizienz und Reduzierung der Kosten fĂŒr Kommunikation und Berechnung fĂŒr gĂ€ngige datenschutzbewahrende Primitiven, einschließlich private Schnittmenge, vergesslicher Transfer und Stealth-Signaturen. Unser Hauptaugenmerk liegt auf der Optimierung der Leistung dieser Primitiven

    TreePIR: Sublinear-Time and Polylog-Bandwidth Private Information Retrieval from DDH

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    In Private Information Retrieval (PIR), a client wishes to retrieve the value of an index ii from a public database of NN values without leaking information about the index ii. In their recent seminal work, Corrigan-Gibbs and Kogan (EUROCRYPT 2020) introduced the first two-server PIR protocol with sublinear amortized server time and sublinear, O(Nlog⁥N)O(\sqrt{N}\log N) bandwidth. In a followup work, Shi et al. (CRYPTO 2021) reduced the bandwidth to polylogarithmic by proposing a construction based on privately puncturable pseudorandom functions, a primitive whose only construction known to date is based on heave cryptographic primitives. Partly because of this, their PIR protocol does not achieve concrete efficiency. In this paper we propose TreePIR, a two-server PIR protocol with sublinear amortized server time and polylogarithmic bandwidth whose security can be based on just the DDH assumption. TreePIR can be partitioned in two phases, both sublinear: The first phase is remarkably simple and only requires pseudorandom generators. The second phase is a single-server PIR protocol on \emph{only} N\sqrt{N} indices, for which we can use the protocol by D\ ottling et al. (CRYPTO 2019) based on DDH, or, for practical purposes, the most concretely efficient single-server PIR protocol. Not only does TreePIR achieve better asymptotics than previous approaches while resting on weaker cryptographic assumptions, but it also outperforms existing two-server PIR protocols in practice. The crux of our protocol is a new cryptographic primitive that we call weak privately puncturable pseudorandom functions, which we believe can have further applications

    Supraconductivité dans des isolants de Mott dopés sur le réseau triangulaire anisotrope : un paradigme pour les supraconducteurs organiques

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    Dans ce mémoire, nous présentons des simulations numériques qui modélisent les supraconducteurs organiques en couches et plus particuliÚrement, leur diagramme de phases, leur rigidité superfluide et leur conductivité. Nous démontrons que les valeurs obtenues numériquement sont en accord avec l'expérience. Les relations entre la température critique, l'interaction et la rigidité superfluide sont analysées en lien avec les diagrammes de phases théoriques. Le pseudogap et la transition de Sordi sont de plus étudiés pour plusieurs valeurs de dopage, de frustration et d'interactions. La relation de Homes pour les supraconducteurs non conventionnels est explorée dans le cadre des modélisations physiques de ce présent mémoire. Pour terminer, un logiciel de simulation numérique pour des interactions génériques électroniques et phononiques est développé dans le but de faire l'étude de la transition de Sordi sur des amas de tailles supérieures

    Satellitenbewegung Band IV-A: Zentralkörper bezogene Bewegungen

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    Im ersten Teil des vierten Bandes (IV-A) der Satellitenbewegung werden basierend auf einer allgemeinen Hansen-Bewegung die BezĂŒge einer Satellitenbewegung in unterschiedlichen Relationen zusammengestellt, wie sie zur ErfĂŒllung spezieller Missionsanforderungen benötigt werden. BezĂŒge auf den Basiskörper (insbesondere die Erde) sind die anomalistische, drakonitische, tropische, siderische, Meridianbezogene und topozentrische Bewegung. Spezielle insbesondere fĂŒr die Erdbeobachtung interessante Bewegungsarten sind reproduzierbare, geosynchrone, formstabile ("eingefrorene"), Librations-Bewegungen. Alle der hier behandelten Bewegungsarten können zu Äquivalenzbahnen gekoppelt werde

    Unidirectional Updatable Encryption and Proxy Re-encryption from DDH

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    Updatable Encryption (UE) and Proxy Re-encryption (PRE) allow re-encrypting a ciphertext from one key to another in the symmetric-key and public-key settings, respectively, without decryption. A longstanding open question has been the following: do unidirectional UE and PRE schemes (where ciphertext re-encryption is permitted in only one direction) necessarily require stronger/more structured assumptions as compared to their bidirectional counterparts? Known constructions of UE and PRE seem to exemplify this gap -- while bidirectional schemes can be realized as relatively simple extensions of public-key encryption from standard assumptions such as DDH or LWE, unidirectional schemes typically rely on stronger assumptions such as FHE or indistinguishability obfuscation (iO), or highly structured cryptographic tools such as bilinear maps or lattice trapdoors. In this paper, we bridge this gap by showing the first feasibility results for realizing unidirectional UE and PRE from a new generic primitive that we call Key and Plaintext Homomorphic Encryption (KPHE) -- a public-key encryption scheme that supports additive homomorphisms on its plaintext and key spaces simultaneously. We show that KPHE can be instantiated from DDH. This yields the first constructions of unidirectional UE and PRE from DDH. Our constructions achieve the strongest notions of post-compromise security in the standard model. Our UE schemes also achieve backwards-leak directionality of key updates (a notion we discuss is equivalent, from a security perspective, to that of unidirectionality with no-key updates). Our results establish (somewhat surprisingly) that unidirectional UE and PRE schemes satisfying such strong security notions do not, in fact, require stronger/more structured cryptographic assumptions as compared to bidirectional schemes

    The relationship between hypoxia, hypoxia gene signature and survival in patients with breast cancer

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    Thesis Summary Breast cancer is the most frequently diagnosed cancer in women in the UK. It is a heterogenous disease with subtypes which behave differently. Although several targeted therapies have been approved for patients with oestrogen receptor (ER) positive and Her-2 positive breast cancer, chemotherapy remains the standard systemic option for triple negative breast cancer (TNBC) patients. New prognostic tools for risk stratification and to guide use of the most aggressive treatments and new targeted therapies are desirable. The role of the tumour microenvironment (TME) in tumour progression is increasingly recognised. Features of the TME such as hypoxia have been reported to have a prognostic role in cancer. A better understanding of this feature may lead to identification of new prognostic and predictive tools and of new therapeutic targets for TNBC. The work of this thesis is carried out in three cohorts of patients with primary operable breast cancer and mature follow up. Data was available from clinical records regarding patient age, tumour pathology, treatment details and survival. Several hypoxic markers have been investigated and were reported to be overexpressed in breast cancer tissue. The aim of the current study was to investigate the role of hypoxia inducible factors [HIF1α (1), HIF-1α (2), HIF-2α] and carbonic anhydrases IX (CAIX) in different breast cancer subtypes, to establish biological processes, and key pathways related to cytoplasmic CAIX expression in ER-negative and a node negative subset of ER-negative breast cancer patients, and to identify the mRNA signature associated with CAIX within the tumour and stromal compartments in TNBC. Immunohistochemistry (IHC) was employed on a tissue microarray (TMA) of patients with breast cancer to assess the expression of HIF-1α (1), HIF-1α (2), HIF-2α and CAIX. Clinical outcomes for the marker’s expression were estimated using Kaplan-Meier analysis and compared between groups with the log-rank test. In a cohort of mixed breast cancer subtypes, the expression of cytoplasmic HIF-1α (1), and HIF-2α were only associated with poor overall survival (OS) in luminal A tumours (P = 0.009), and poor recurrence free survival (RFS) in Her-2 disease (P = 0.038), respectively. However, regardless of cellular localisation, high CAIX expression was associated with poor outcome for the full cohort and in breast cancer subtypes. High cytoplasmic CAIX was associated with decrease RFS in the full cohort (P<0.001), and in luminal B tumours (P = 0.025), disease-free survival (DFS) in the full cohort (P<0.001) in luminal B tumours (P = 0.035), and Her-2 disease (P = 0.016). Also, high cytoplasmic CAIX was associated with poor OS in the full cohort (P<0.001) and in Her-2 disease (P = 0.001). Moreover, membranous CAIX was associated with decrease RFS (P= 0.001), and OS (P = 0.003) in the full cohort. In multivariate analysis, cytoplasmic CAIX was an independent prognostic factor for RFS in the entire cohort (HR = 2.24, 95% CI: 1.19–4.22, P = 0.012), DFS in the full cohort (HR = 1.74, 95% CI: 1.08–2.82, P = 0.023) and in luminal B disease (HR = 3.59, 95% CI: 1.23–10.53, P = 0.020), and OS in Her-2 disease (HR = 4.19, 95% CI: 1.37–12.80, P = 0.012). Furthermore, in the cohort of ER-positive breast cancer, high cytoplasmic HIF-1α (1) expression was associated with shorter DFS (P = 0.032), and OS (P = 0.002) in the full cohort. In addition, high nuclear HIF-1α (1) expression was associated with decrease DFS in the full cohort (P = 0.009) and in luminal A disease (P = 0.013), and OS in the full cohort (P = 0.002) and in luminal A tumours (P = 0.003). Moreover, high cytoplasmic CAIX expression was corelated with worse RFS and DFS in the full cohort (P = 0.014, 0.008, respectively) and with RFS, DFS, and OS in luminal B disease (P = 0.018, 0.001, 0.003, respectively). On multivariate Cox regression analysis, nuclear HIF-1α (1) was an independent prognostic marker for DFS in the full cohort (HR = 1.85, 95% CI: 1.10–3.11, P = 0.019), and in luminal A disease (HR = 1.98, 95% CI: 1.02–3.83, P = 0.042), and for OS in the full cohort (HR = 1.85, 95% CI: 1.08–3.19, P = 0.026), and in luminal A disease (HR = 2.08, 95% CI: 1.11–3.89, P = 0.022). Moreover, high cytoplasmic CAIX expression was an independent prognostic marker for RFS and DFS in the full cohort (HR = 2.09, 95% CI: 1.17–3.75, P = 0.013; HR = 1.74, 95% CI: 1.08–2.82, P = 0.023), and in luminal B disease (HR = 2.57, 95% CI: 1.29–5.12, P = 0.007; HR = 2.75, 95% CI: 1.66–4.55, P<0.001), respectively. In TNBC cohort, high cytoplasmic expression of CAIX had lower RFS (P = 0.038). Multivariate analysis showed that cytoplasmic CAIX remained as factor contributing significantly to RFS (HR = 6.59, 95% CI: 1.47–29.58, P = 0.014). Next, Templated Oligo assay with Sequencing readout (TempO-Seq) (bulk RNAseq) was carried out in ER-negative and a node negative subset of ER-negative breast cancer patients to identify gene signatures that associated with CAIX expression to provide further information on biological processes, and key pathways related to cytoplasmic CAIX expression. Whole transcriptome analysis using TempO-Seq identified 10 significant genes within ER-negative cohort (OR8B2, SERHL2, KRT6A, MMP7, SPINK8, TMEM150C, CEACAM6, MUCL1, PITX2, and GALNT6), and 3 genes in node negative group (PCSK1N, SERHL2 and SPNS2). In node negative patients SPNS2 was of particular interest. Further, GeoMx Digital Spatial Profiler (DSP) analyses in TNBC cohort was performed to inform if gene signatures were associated with tumour epithelia or TME. 3 upregulated gene expression signatures, CD68, HIF1A, VSIR, and one down-regulated gene, pan-melanocyte, were identified in tumour compartment. In contrast, 9 downregulated genes, CD86, CD3E, MS4A1, BCL2, CCL5, NKG7, PTPRC, CD27 and FAS were identified in the TME in comparison of high and low CAIX expression groups. Among all 4 selected genes, HIF-1α, BCL2, CD68, and CD3, were further validated by IHC at protein level. Univariate KaplanMeier analysis showed high expression of CD68 and HIF-1α was associated with poor prognosis and high expression of BCL2 and CD3 was associated with good prognosis. By performing multivariate analysis for OS, high levels of CD68 cells in tumour nests and in TME were independent prognostic factor for poorer OS (HR = 2.42, 95% CI: 1.05–5.59, P = 0.038; HR = 3.34, 95% CI: 1.28–8.69, P = 0.014), respectively. In conclusion, this thesis has demonstrated a prognostic role of nuclear HIF-1α (1) and cytoplasmic CAIX in breast cancer. However, their prognostic values were different depending on cellular locations and tumour subtypes. Furthermore, TempO-Seq identified the pathways and genes associated with the CAIX in ER-negative breast cancer. Then, GeoMx DSP technology identified stromal/immune-related genes that were associated with TNBC patients’ survival in comparison of high and low CAIX expression groups that might serve as a potential prognostic biomarker for TNBC. Overall, the results from this thesis provide new evidence to warrant the further investigation of HIF-1α (1) and CAIX in a large contemporaneous cohort of patients with breast cancer and in particular in patients with TNBC

    A holistic review on fatigue properties of additively manufactured metals

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    Additive manufacturing (AM) technology is undergoing rapid development and emerging as an advanced technique that can fabricate complex near-net shaped and light-weight metallic parts with acceptable strength and fatigue performance. A number of studies have indicated that the strength or other mechanical properties of AM metals are comparable or even superior to that of conventionally manufactured metals, but the fatigue performance is still a thorny problem that may hinder the replacement of currently used metallic components by AM counterparts when the cyclic loading and thus fatigue failure dominates. This article reviews the state-of-art published data on the fatigue properties of AM metals, principally including SS--NN data and fatigue crack growth data. The AM techniques utilized to generate samples in this review include powder bed fusion (e.g., EBM, SLM, DMLS) and directed energy deposition (e.g., LENS, WAAM). Further, the fatigue properties of AM metallic materials that involve titanium alloys, aluminum alloys, stainless steel, nickel-based alloys, magnesium alloys, and high entropy alloys, are systematically overviewed. In addition, summary figures or tables for the published data on fatigue properties are presented for the above metals, the AM techniques, and the influencing factors (manufacturing parameters, e.g., built orientation, processing parameter, and post-processing). The effects of build direction, particle, geometry, manufacturing parameters, post-processing, and heat-treatment on fatigue properties, when available, are provided and discussed. The fatigue performance and main factors affecting the fatigue behavior of AM metals are finally compared and critically analyzed, thus potentially providing valuable guidance for improving the fatigue performance of AM metals.Comment: 201 pages, 154 figure

    Savannas at the forest boundary: an understudied biome at risk

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    Savannas receive a fraction of the policy and research attention of forests and are therefore some of the least known biomes in the world. Fundamental to the protection of these unique systems, and the billion people who rely on them globally, is to gain a new understanding of both their evolutionary history, which has structured diversity within them, and to categorise their present-day diversity. This thesis addresses the historical assembly of savannas globally using the widespread and ecologically variable genus Ziziphus as an exemplar, and provides new data on the flora of poorly studied savannas in Asia. Chapter two investigates how functional traits enable Ziziphus to occupy several distinct biomes across the tropics. To do this I collated and examined trait and distributional data. I found that the unusually wide distribution of Ziziphus can be explained by its diversity of habits which enable occupation of different biomes spanning continents. Results showed that liana species are restricted to closed forests and the geoxylic habit is found only in open savannas. For Ziziphus species, habit facilitates range size, with trees having larger ranges than shrubs and lianas. Surprisingly, biome is not correlated with range size. Cultivated species have ranges ~10 times that of non-cultivated tree species and with significantly different and broader environmental niches. A diversity of habits, along with the usage of fruits of many Ziziphus species by people, expands the range and environmental occupation of the genus. Chapter three explores whether geography or ecology structure Ziziphus’ phylogeny to gain a new understanding of the history of the assembly of the savanna biome globally. To do this I created a phylogenetic tree based on chloroplast and nuclear ribosomal internal transcribed spacer (ITS) sequences. I found that at a global scale geography (i.e., the barrier of dispersing amongst continents) structures Ziziphus’ diversification more than ecology (i.e., switches amongst major biomes). Based upon dating the ITS phylogeny, Ziziphus originated in closed biomes in Asia during the Oligocene and subsequently long distance dispersal from Asia to Africa resulted in the novel occupation of two biomes, the tropical savanna biome and the desertic biome. In keeping with the younger age of the savanna biome and the Pliocene radiation of geoxylic species, the youngest species in Ziziphus are found in open biomes, and the most recently evolved habit is geoxylic. Leaf hair is likely to be a key innovation enabling occupancy of drier environments, while occupation of closed biomes is associated with the development of the liana habit. Chapter four investigates the floristic composition and resilience of ground layer vegetation in Southeast Asian savannas via new floristic surveys in 50 sites across four savanna types. I found that the heterogeneity of Southeast Asian savannas means that systematic botanical survey work that incorporates the diversity of savannas is necessary and urgent. Total plant species richness decreased under increasing tree cover, although patterns differed between functional groups. Crucially, research and management should not conflate monocot and dicot herbs due to their divergent functional responses to shade, as non-graminoid monocots are the most affected by increasing tree cover. Further, Southeast Asian savannas support distinct grass assemblages, with implications for assessments of species diversity and for future management of these ecosystems. This thesis expands our understanding of the processes that drive diversification and trait evolution in savannas, and characterises the understory floristic diversity of little-known savanna systems in Southeast Asia. Further work is necessary to assess whether trait and evolutionary patterns seen in Ziziphus across the major tropical and subtropical biomes are replicated in other, unrelated and more species-rich genera, and to characterise the non-graminoid communities of Southeast Asian savannas to determine whether they represent distinct associations compared to the dominant woody flora
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