4,852 research outputs found

    Exploring multipartite genomes using pangenome analysis

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    Bacteria are small single-celled organisms that are found in nearly every habitat on Earth. While bacterial genomes usually consist of one large circular replicon, about 10% of bacteria have organized their genes onto several large replicons. These multipartite bacteria are often found in symbiotic or pathogenic relationships with other higher organisms and are believed to have greater ability to adapt to new niches and to changing environments. However, much remains unknown about multipartite bacteria. In this study we aimed to gain a better understanding of why some bacteria have organized their genes on several large replicons. To do so, Vibrionacaeae and Pseudoalteromonas, which both consist of two large replicons, were used as model systems. In Paper 1, pangenome analysis and transcriptomic data of Vibrionaceae revealed a highly organized distribution pattern of different gene types on the chromosome, and a strong correlation between gene expression and distance to the origin of replication. In Paper 2, Pseudoalteromonas showed a similar distribution pattern and correlation with gene expression on the chromosome as in Vibrionaceae. In Paper 3, pangenome analysis showed that Vibrio and Pseudoalteromonas have a larger repertoire of genes than genomes with one chromosome. Furthermore, horizontally transferred genes are inserted into specific regions on the replicons. In Paper 4, seven new complete genomes of Vibrio anguillarum genomes were presented. Overall, results from these studies have increased our understanding of how multipartite genomes are organized with respect to their genes, how they are expressed and where newly acquired genes are retained on the replicons

    Full Issue, Volume 2

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    Full issue of volume 2

    Gendered Bodies, Engendered Lives: Bioarchaeological Exploration of the Intersectionality of Gender, Health, and Trauma at Turkey Creek Pueblo, Arizona (AD 1225-1286)

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    This dissertation examines the relationships between sex, gender, and health at Turkey Creek Pueblo (AD 1225-1286), the earliest aggregated Pueblo community in the Point of Pines region of east central Arizona, to better understand their roles in producing differential health outcomes. To gain a view of these interactions, I use osteological, mortuary, and ethnohistoric data to explore how gender, as a social institution, informed divisions of labor and experiences with traumatic injury at Turkey Creek Pueblo, because this site was occupied during a socially dynamic and important period in the pre-contact American Southwest. Using these data, I explore how sex, age, life history, and social status/prestige, as bioarchaeologically recoverable axes of gender identity, intersected to structure experiences of disease, heavy workloads, and traumatic injury between individuals and groups at Turkey Creek Pueblo. Through this research, I identify which bioarchaeologically detectable axes of gender (e.g., sex, age, and social role/status) were significantly promoting or buffering against experiences of disease and physical trauma within this community. I show that, at Turkey Creek Pueblo, osteological sex is not the most significant axis of identity structuring differences in experiences of trauma, health, and social status or social power within this community. This challenges Euro-centric, binary assumptions and portrayals of Indigenous gender roles and inequalities in the past. Gender roles among pre-contact Puebloan communities were complex and not rigidly defined by sex, nor were labor activities, poor health, trauma, and social power/prestige expressly divided along binary dimensions, in contrast to how they have been portrayed by traditional ethnographic and ethnohistoric sources. This research is significant in that it provides another line of evidence that gender and gendered experience are relational social scripts informed by the intersection of multiple axes of individual identity and life history. These analyses shed light on the social consequences of early population aggregation in the Mogollon Highland region and its implications for health, disease, and traumatic injury for aggregating communities

    Comparative genomics of recent adaptation in Candida pathogens

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    [eng] Fungal infections pose a serious health threat, affecting >1,000 million people and causing ~1.5 million deaths each year. The problem is growing due to insufficient diagnostic and therapeutic options, increased number of susceptible patients, expansion of pathogens partly linked to climate change and the rise of antifungal drug resistance. Among other fungal pathogens, Candida species are a major cause of severe hospital-acquired infections, with high mortality in immunocompromised patients. Various Candida pathogens constitute a public health issue, which require further efforts to develop new drugs, optimize currently available treatments and improve diagnostics. Given the high dynamism of Candida genomes, a promising strategy to improve current therapies and diagnostics is to understand the evolutionary mechanisms of adaptation to antifungal drugs and to the human host. Previous work using in vitro evolution, population genomics, selection inferences and Genome Wide Association Studies (GWAS) have partially clarified such recent adaptation, but various open questions remain. In the three research articles that conform this PhD thesis we addressed some of these gaps from the perspective of comparative genomics. First, we addressed methodological issues regarding the analysis of Candida genomes. Studying recent adaptation in these pathogens requires adequate bioinformatic tools for variant calling, filtering and functional annotation. Among other reasons, current methods are suboptimal due to limited accuracy to identify structural variants from short read sequencing data. In addition, there is a need for easy-to-use, reproducible variant calling pipelines. To address these gaps we developed the “personalized Structural Variation detection” pipeline (perSVade), a framework to call, filter and annotate several variant types, including structural variants, directly from reads. PerSVade enables accurate identification of structural variants in any species of interest, such as Candida pathogens. In addition, our tool automatically predicts the structural variant calling accuracy on simulated genomes, which informs about the reliability of the calling process. Furthermore, perSVade can be used to analyze single nucleotide polymorphisms and copy number-variants, so that it facilitates multi-variant, reproducible genomic studies. This tool will likely boost variant analyses in Candida pathogens and beyond. Second, we addressed open questions about recent adaptation in Candida, using perSVade for variant identification. On the one hand, we investigated the evolutionary mechanisms of drug resistance in Candida glabrata. For this, we used a large-scale in vitro evolution experiment to study adaptation to two commonly-used antifungals: fluconazole and anidulafungin. Our results show rapid adaptation to one or both drugs, with moderate fitness costs and through few mutations in a narrow set of genes. In addition, we characterize a novel role of ERG3 mutations in cross-resistance towards fluconazole in anidulafungin-adapted strains. These findings illuminate the mutational paths leading to drug resistance and cross-resistance in Candida pathogens. On the other hand, we reanalyzed ~2,000 public genomes and phenotypes to understand the signs of recent selection and drug resistance in six major Candida species: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. We found hundreds of genes under recent selection, suggesting that clinical adaptation is diverse and complex. These involve species-specific but also convergently affected processes, such as cell adhesion, which could underlie conserved adaptive mechanisms. In addition, using GWAS we predicted known drivers of antifungal resistance alongside potentially novel players. Furthermore, our analyses reveal an important role of generally-overlooked structural variants, and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Taken together, our findings provide novel insights on how Candida pathogens adapt to human-related environments and suggest candidate genes that deserve future attention. In summary, the results of this thesis improve our knowledge about the mechanisms of recent adaptation in Candida pathogens, which may enable improved therapeutic and diagnostic applications.[cat] Les infeccions fúngiques representen una greu amenaça per a la salut, afectant a més de 1.000 milions de persones i causant aproximadament 1,5 milions de morts cada any. El problema està augmentant a causa d’unes opcions terapèutiques i diagnòstiques insuficients, l'increment del nombre de pacients susceptibles, l'expansió dels patògens parcialment vinculada al canvi climàtic i l'augment de la resistència als fàrmacs antifúngics. D’entre diversos fongs patògens, els llevats del gènere Candida són una causa important d'infeccions nosocomials, amb una alta mortalitat en pacients immunodeprimits. Diverses espècies de Candida constitueixen un problema de salut pública, cosa que requereix més esforços per a desenvolupar nous medicaments, optimitzar els tractaments disponibles i millorar els diagnòstics. Tenint en compte el dinamisme genòmic d’aquests patògens, una estratègia prometedora per millorar les teràpies i diagnòstics actuals és comprendre els mecanismes evolutius d'adaptació als fàrmacs antifúngics i a l’hoste humà. Treballs anteriors utilitzant l'evolució in vitro, la genòmica de poblacions, les inferències de selecció i els estudis d'associació de genoma complet (GWAS, per les sigles en anglès) han aclarit parcialment aquesta adaptació recent, però encara hi ha diverses preguntes obertes. En els tres articles que conformen aquesta tesi doctoral, hem abordat algunes d'aquestes preguntes des de la perspectiva de la genòmica comparativa. En primer lloc, hem abordat qüestions metodològiques relatives a l'anàlisi dels genomes de les espècies Candida. L'estudi de l'adaptació recent en aquests patògens requereix eines bioinformàtiques adequades per a la detecció, filtratge i anotació funcional de variants genètiques. Entre altres raons, els mètodes actuals són subòptims a causa de la limitada precisió per identificar variants estructurals a partir de dades de seqüenciació amb lectures curtes. A més, hi ha una necessitat d’eines computacionals per a la detecció de variants que siguin senzilles d'utilitzar i reproduibles. Per abordar aquestes mancances, hem desenvolupat el mètode bioinformàtic "personalized Structural Variation detection" (perSVade), una eina que permet la detecció, filtratge i anotació de diversos tipus de variants, incloent-hi les variants estructurals, directament des de les lectures. PerSVade permet la identificació precisa de les variants estructurals en qualsevol espècie d'interès, com ara els patògens Candida. A més, la nostra eina prediu automàticament la precisió de la detecció d’aquestes variants en genomes simulats, la qual cosa informa sobre la fiabilitat del procés. Finalment, perSVade es pot utilitzar per analitzar altres tipus de variants, com els polimorfismes de nucleòtid únic o els canvis en el nombre de còpies, facilitant així estudis genòmics integrals i reproduibles. Aquesta eina probablement impulsarà les anàlisis genòmiques en els patògens Candida i també en altres espècies. En segon lloc, hem abordat algunes de les preguntes obertes sobre l'adaptació recent en els llevats Candida, utilitzant perSVade per a la identificació de variants. D'una banda, hem investigat els mecanismes evolutius de resistència als fàrmacs antifúngics en Candida glabrata. Per a això, hem utilitzat un experiment d'evolució in vitro a gran escala per estudiar l'adaptació a dos antifúngics comuns: el fluconazol i l’anidulafungina. Els nostres resultats mostren una adaptació ràpida a un o ambdós fàrmacs, amb un cost per al creixement moderat i a través de poques mutacions en un nombre reduït de gens. A més, hem caracteritzat un paper nou de les mutacions en ERG3 en la resistència creuada al fluconazol en soques adaptades a anidulafungina. Aquests descobriments aclareixen els processos mutacionals que condueixen a la resistència als fàrmacs i a la resistència creuada en els patògens Candida. D'altra banda, hem re-analitzat aproximadament 2.000 genomes i fenotips disponibles en repositoris públics per a comprendre els senyals genòmics de selecció recent i de resistència a fàrmacs antifúngics, en sis espècies rellevants de Candida: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis i C. orthopsilosis. Hem trobat centenars de gens sota selecció recent, suggerint que l'adaptació clínica és diversa i complexa. Aquests gens estan relacionats amb funcions específiques de cada espècie, però també trobem processos alterats de manera similar en diferents patògens, com per exemple l’adhesió cel·lular, cosa que indica fenòmens d’adaptació conservats. A part, utilitzant GWAS hem predit mecanismes esperats de resistència a antifúngics i també possibles nous factors. A més, les nostres anàlisis revelen un paper important de les variants estructurals, generalment poc estudiades, i suggereixen una implicació inesperada de la recombinació (para)sexual en la propagació de la resistència. En conjunt, els nostres descobriments proporcionen noves perspectives sobre com els patògens Candida s'adapten als entorns humans, i suggereixen gens candidats que mereixen investigacions futures. En resum, els resultats d’aquesta tesi milloren el nostre coneixement sobre els mecanismes d'adaptació recent en els patògens Candida, cosa que pot permetre el disseny de noves teràpies i diagnòstics

    Life in Health 2021: Research and Practice

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    This proceedings contain a selection of papers from the international interdisciplinary conference Life in Health 2021, which took place from 9 to 10 September 2021 in the Czech Republic at the Faculty of Education, Masaryk University. The papers focus on general as well as specific approaches to public health protection and promotion. The findings presented are based on research data and are applicable in health education and general education of children and the whole population

    The Efficacy of Analgesic Subdissociative Dose Ketamine in Trauma Casualties Treated by U.S. Military Special Operations Medical Professionals in a Prehospital Environment

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    Research Focus. This study’s main objective was to determine the efficacy of sub-dissociative ketamine to reduce the pain of trauma casualties treated by U.S. military medical professionals in a prehospital environment evidenced by the 0–10 numeric rating scale (NRS) for pain. Research Methods. This quantitative study was accomplished using a pragmatic approach integrating social cognitive theory complemented by mixing methods using qualitative phenomenological influence through narrative inquiry. This exploratory retrospective, cross-sectional study, utilizing a quasi-experimental pretest-posttest design, used deidentified sample data (N = 47) for secondary analysis from U.S. Special Operations medical providers and were included in a casualty data collection tool. Quantitative study inclusion criteria were adult casualties treated by U.S. military medical professionals with ketamine in a prehospital environment, had documented injury data, and had both pre- and post-ketamine pain scores. Descriptive statistics, followed by inferential statistical analyses using Shapiro-Wilkes, Wilcoxon Signed Rank, Spearman rho, and Kruskal Wallis tests were used. Additionally, phenomenology guided the analysis of two (n = 2) case studies. In vivo coding was used to develop themes and subthemes. Case studies collected from U.S. military medical professionals provided qualitative insight that reinforced the quantitative data and provided clinical validity to the study. Research Results/Findings. The study showed safe, efficacious use of analgesic sub-disociative ketamine use in prehospital trauma casualties relative to the 0–10 NRS for pain. The median reported pre-ketamine pain scale for casualties was 9.0 (IQR 2). The median post-ketamine pain scale was 0.0 (IQR 3). The mean total dosage of ketamine administered was 98.19 mg (SE = 9.545). There were 6 (12.8%) casualties who experienced side effects from ketamine that were neither permanent nor life-threatening. The case studies provided the human aspect of the study, reinforced the quantitative data, and provided clinical validity. Post-ketamine pain scores were better than pre-ketamine pain scores. Higher dosages of ketamine provided greater pain relief. No life threatening nor adverse drug reactions were found in this study. Conclusions From Research. This study demonstrated a safe, efficacious analgesic ketamine use in prehospital trauma casualties used by U.S. military special operations medical professionals relative to the 0–10 NRS for pain. The results of this study may inform medical practitioners and policymakers regarding the efficacy of analgesic ketamine in a prehospital environment, aid in making informed treatment decisions regarding trauma casualties, and provide facts for updating and improving clinical practice guidelines and policies focused on the U.S. military. Advancing the understanding to promote better prehospital pain management guidelines, procedures, and practices is essential. Education efforts will make medical professionals aware of the importance of analgesic ketamine for trauma casualties in a prehospital environment. @font-face {font-family: Cambria Math ; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-536859905 -1073732485 9 0 511 0;}@font-face {font-family: Calibri HeadingsHeadings ; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-alt:Calibri; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:auto; mso-font-signature:0 0 0 0 0 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent: ; margin:0in; mso-pagination:widow-orphan; font-size:11.0pt; font-family: Calibri ,sans-serif; mso-fareast-font-family:Arial; mso-bidi-font-family: Calibri HeadingsHeadings ; color:black; mso-themecolor:text1;}.MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:11.0pt; mso-ansi-font-size:11.0pt; mso-bidi-font-size:11.0pt; font-family: Calibri ,sans-serif; mso-ascii-font-family:Calibri; mso-fareast-font-family:Arial; mso-hansi-font-family:Calibri; mso-bidi-font-family: Calibri HeadingsHeadings ; color:black; mso-themecolor:text1; mso-font-kerning:0pt; mso-ligatures:none;}div.WordSection1 {page:WordSection1;

    Artificial Intelligence and International Conflict in Cyberspace

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    This edited volume explores how artificial intelligence (AI) is transforming international conflict in cyberspace. Over the past three decades, cyberspace developed into a crucial frontier and issue of international conflict. However, scholarly work on the relationship between AI and conflict in cyberspace has been produced along somewhat rigid disciplinary boundaries and an even more rigid sociotechnical divide – wherein technical and social scholarship are seldomly brought into a conversation. This is the first volume to address these themes through a comprehensive and cross-disciplinary approach. With the intent of exploring the question ‘what is at stake with the use of automation in international conflict in cyberspace through AI?’, the chapters in the volume focus on three broad themes, namely: (1) technical and operational, (2) strategic and geopolitical and (3) normative and legal. These also constitute the three parts in which the chapters of this volume are organised, although these thematic sections should not be considered as an analytical or a disciplinary demarcation

    Digital agriculture: research, development and innovation in production chains.

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    Digital transformation in the field towards sustainable and smart agriculture. Digital agriculture: definitions and technologies. Agroenvironmental modeling and the digital transformation of agriculture. Geotechnologies in digital agriculture. Scientific computing in agriculture. Computer vision applied to agriculture. Technologies developed in precision agriculture. Information engineering: contributions to digital agriculture. DIPN: a dictionary of the internal proteins nanoenvironments and their potential for transformation into agricultural assets. Applications of bioinformatics in agriculture. Genomics applied to climate change: biotechnology for digital agriculture. Innovation ecosystem in agriculture: Embrapa?s evolution and contributions. The law related to the digitization of agriculture. Innovating communication in the age of digital agriculture. Driving forces for Brazilian agriculture in the next decade: implications for digital agriculture. Challenges, trends and opportunities in digital agriculture in Brazil

    Exploring the gut microbiota of breast cancer patients

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    Host-associated microbial communities play a key role in health and disease, and more recently there has been a growing appreciation for how particular microbes and microbial ‘signatures’ are associated with different cancers. However, breast cancer remains an understudied cancer type, and there is a pressing need to define, if and how, the gut microbiota maybe be linked to disease progression and treatment outcomes. To investigate the gut microbiota and breast cancer, two clinical cohorts were profiled (using a range of sequencing and bioinformatics approaches) and additional mechanistic in vitro and in vivo studies were also undertaken. First, a local Norfolk cohort was established – BEAM, with the aim of longitudinally profiling newly diagnosed breast cancer patients (1 control and 35 breast cancer patients, as of 30 June 2023), however study recruitment was severely impacted due to the SARS-Cov-2 pandemic. My initial analysis indicated no significant shifts in microbiome profiles in the limited number of patients profiled, however I was able to establish a large culture collection through untargeted culturing. I obtained 298 strains from 50 different species which were whole genome sequenced and phylogenetically characterised. This work also led to the discovery and detailed description of one novel genus and one novel species - Allocoprobacillus halotolerans gen. nov., sp. nov and Coprobacter tertius sp. nov. Concurrent to BEAM, the oral and gut microbiota samples from a phase 2a clinical trial (KELLY) that had been completed were processed, sequenced, and analysed which led to the creation of the CALADRIO study. The KELLY trial had one arm where all patients received treatment, a chemotherapeutic and immunotherapeutic. Overall, treatment did not cause significant gut or oral microbiota perturbations, which is usually indicative of drug-related microbiota toxicity. Differential analysis indicated that clinical benefit was driven, in part, by gut-associated Bacteroides fragilis. Further in vitro studies indicated a product present in the cell-free supernatant of B. fragilis led to greater cellular stress in breast cancer cells, but it did not result in complete cell death. Bifidobacterium, generally considered a beneficial gut-associated bacterium, was consistently in the top ten most abundant genera of the gut microbiota in the BEAM and CALADRIO study. Thus, to define if Bifidobacterium was mechanistically associated with breast cancer outcomes, a Bifidobacterium longum subsp. longum isolate was selected and used as a live oral supplementation in a murine breast cancer model that was also treated with chemotherapy (cyclophosphamide). Oral supplementation resulted in larger primary tumours than cyclophosphamide alone suggesting that oral supplementation interfered with treatment efficacy. Genomic screening of the isolate showed that it possessed aldehyde dehydrogenase which is known to inactivate cyclophosphamide. These data allowed me to explore how the gut microbiota of breast cancer patients may link to treatment outcomes and indicated both positive (e.g., B. fragilis) and negative (e.g., B. longum subsp. longum) impacts. Translating it into the clinic, such findings could provide avenues for improving efficacy of anti-cancer therapeutics. To test these further in vivo studies could be conducted to determine how candidate bacterial strains could influence the immune system in the context of breast cancer and building on those findings in vitro studies would investigate the intricacies of the gut-immune axis. Overall, my thesis outputs highlight the complex interactions between the microbiota and their host, and suggest new avenues for biomarker and therapy development, particularly in breast cancer
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