261 research outputs found

    The genetic interactions of PKHD1 and ATMIN in autosomal recessive polycystic kidney disease (ARPKD)

    Get PDF
    A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.The main gene associated with Autosomal Recessive Polycystic Kidney Disease (ARPKD) is PKHD1 which encodes a ciliary protein associated with planar cell polarity. In mice, mutations in the transcription factor Atmin can present with an ARPKD-like phenotype with kidney disease similar to an early manifestation of ARPKD. Like the mouse gene Pkhd1, mutations in Atmin are associated with altered WNT/PCP expression. Previous work has suggested that Atmin and Pkhd1 do not physically interact, but Atmin may modulate Pkhd1 expression. However, the mechanisms governing this relationship are unknown. ARPKD is a rare disorder typically associated with severe kidney and liver disease in children. The disease has considerable clinical and familial variability, but little is known regarding genotype-phenotype relationships. It has been proposed that genetic modifiers may influence disease severity. Next-generation sequencing (NGS) using ChIP-Seq and RNA-Seq techniques in mouse kidneys and intermedullary collecting duct (mIMCD3) cells identified new transcriptional targets of Atmin, which did not include Pkhd1 but included genes associated with cystic kidneys in animal models (Camk2g and G6pc). NGS in Atmin and Pkhd1 KDs identified a common transcriptional network between the two genes. Gene enrichment analysis suggests this common network is associated with immune system processes. Dysregulated genes associated with double KDs showed greater enrichment of processes associated with the actin cytoskeleton, cell cycle and energy metabolism. Loss of Atmin expression negatively impacts the ciliary localisation of Fibrocystin, suggesting that Atmin may be needed for the proper localisation of Fibrocystin to the cilium. NGS in ARPKD kidneys highlights mutations in ATMIN as a potential regulator of disease severity, associated with reduced ARPKD severity. Expression differences in WNT genes may be present between severe and moderate ARPKD and transcriptomic profiling identified candidate diagnostic markers in ARPKD which included MSC, FGA, WNT4, WNT9B and KIF26B. This work indicates that Atmin and Pkhd1 interact in a similar transcriptional network in mice. Atmin is not a transcription factor of Pkhd1 but may modulate its function by governing its ciliary localisation by a yet unknown mechanism. Additionally, ATMIN mutations may modulate ARPKD disease severity, and the amount of differential expression in WNT/PCP genes may be a marker of disease severity.PKD Charity, Arran Brown Rainbow Foundation, and the University of Wolverhampton

    Molecular Mechanisms and Therapies of Colorectal Cancer

    Get PDF
    Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality, with 1.9 million incidence cases and 0.9 million deaths worldwide. The global number of new CRC cases is predicted to reach 3.2 million in 2040, based on the projection of aging, population growth, and human development.In clinics, despite advances of diagnosis and surgical procedures, 20% of the patients with CRC present with metastasis at the time of diagnosis, caused by residual tumor cells that have spread to distant organs prior to surgery, affecting the patient survival rate. Standard systemic chemotherapy, alternative therapies that target mechanisms involved in cancer progression and metastasis, immunotherapy, and combination therapies are the major CRC-treatment strategies. In the advanced stage of CRC the transforming growth factor-beta (TGF-β) plays an oncogenic role by promoting cancer cell proliferation, cancer cell self-renewal, epithelial-to-mesenchymal transition, invasion, tumor progression, metastatic spread, and immune escape. Furthermore, high levels of TGF-β1 confers poor prognosis and is associated with early recurrence after surgery, resistance to chemo- or immunotherapy, and shorter survival. Based on the body of experimental evidence indicating that TGF-β signaling has the potential to be a good therapeutic target in CRC, several anti-TGF-β drugs have been investigated in cancer clinical trials. Here, we presented a comprehensive collection of manuscripts regarding studies on targeting the TGF-β signaling in CRC to improve patient’s prognosis and personalized treatments

    Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes

    Get PDF
    Fruiting bodies (sporocarps, sporophores or basidiomata) of mushroom-forming fungi (Agaricomycetes) are among the most complex structures produced by fungi. Unlike vegetative hyphae, fruiting bodies grow determinately and follow a genetically encoded developmental program that orchestrates their growth, tissue differentiation and sexual sporulation. In spite of more than a century of research, our understanding of the molecular details of fruiting body morphogenesis is still limited and a general synthesis on the genetics of this complex process is lacking. In this paper, we aim at a comprehensive identification of conserved genes related to fruiting body morphogenesis and distil novel functional hypotheses for functionally poorly characterised ones. As a result of this analysis, we report 921 conserved developmentally expressed gene families, only a few dozens of which have previously been reported to be involved in fruiting body development. Based on literature data, conserved expression patterns and functional annotations, we provide hypotheses on the potential role of these gene families in fruiting body development, yielding the most complete description of molecular processes in fruiting body morphogenesis to date. We discuss genes related to the initiation of fruiting, differentiation, growth, cell surface and cell wall, defence, transcriptional regulation as well as signal transduction. Based on these data we derive a general model of fruiting body development, which includes an early, proliferative phase that is mostly concerned with laying out the mushroom body plan (via cell division and differentiation), and a second phase of growth via cell expansion as well as meiotic events and sporulation. Altogether, our discussions cover 1 480 genes of Coprinopsis cinerea, and their orthologs in Agaricus bisporus, chrysosporium, Pleurotus ostreatus, and Schizophyllum commune, providing functional hypotheses for similar to 10 % of genes in the genomes of these species. Although experimental evidence for the role of these genes will need to be established in the future, our data provide a roadmap for guiding functional analyses of fruiting related genes in the Agaricomycetes. We anticipate that the gene compendium presented here, combined with developments in functional genomics approaches will contribute to uncovering the genetic bases of one of the most spectacular multicellular developmental processes in fungi

    Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes.

    Get PDF
    Fruiting bodies (sporocarps, sporophores or basidiomata) of mushroom-forming fungi ( Agaricomycetes) are among the most complex structures produced by fungi. Unlike vegetative hyphae, fruiting bodies grow determinately and follow a genetically encoded developmental program that orchestrates their growth, tissue differentiation and sexual sporulation. In spite of more than a century of research, our understanding of the molecular details of fruiting body morphogenesis is still limited and a general synthesis on the genetics of this complex process is lacking. In this paper, we aim at a comprehensive identification of conserved genes related to fruiting body morphogenesis and distil novel functional hypotheses for functionally poorly characterised ones. As a result of this analysis, we report 921 conserved developmentally expressed gene families, only a few dozens of which have previously been reported to be involved in fruiting body development. Based on literature data, conserved expression patterns and functional annotations, we provide hypotheses on the potential role of these gene families in fruiting body development, yielding the most complete description of molecular processes in fruiting body morphogenesis to date. We discuss genes related to the initiation of fruiting, differentiation, growth, cell surface and cell wall, defence, transcriptional regulation as well as signal transduction. Based on these data we derive a general model of fruiting body development, which includes an early, proliferative phase that is mostly concerned with laying out the mushroom body plan (via cell division and differentiation), and a second phase of growth via cell expansion as well as meiotic events and sporulation. Altogether, our discussions cover 1 480 genes of Coprinopsis cinerea, and their orthologs in Agaricus bisporus, Cyclocybe aegerita, Armillaria ostoyae, Auriculariopsis ampla, Laccaria bicolor, Lentinula edodes, Lentinus tigrinus, Mycena kentingensis, Phanerochaete chrysosporium, Pleurotus ostreatus, and Schizophyllum commune, providing functional hypotheses for ~10 % of genes in the genomes of these species. Although experimental evidence for the role of these genes will need to be established in the future, our data provide a roadmap for guiding functional analyses of fruiting related genes in the Agaricomycetes. We anticipate that the gene compendium presented here, combined with developments in functional genomics approaches will contribute to uncovering the genetic bases of one of the most spectacular multicellular developmental processes in fungi. Citation: Nagy LG, Vonk PJ, Künzler M, Földi C, Virágh M, Ohm RA, Hennicke F, Bálint B, Csernetics Á, Hegedüs B, Hou Z, Liu XB, Nan S, M. Pareek M, Sahu N, Szathmári B, Varga T, Wu W, Yang X, Merényi Z (2023). Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes. Studies in Mycology 104: 1-85. doi: 10.3114/sim.2022.104.01

    Tradução médica: uma experiência de estágio (curricular) na Escola de Medicina

    Get PDF
    Dissertação de mestrado em Tradução e Comunicação MultilingueNo âmbito de um esforço crescente de internacionalização, a Escola de Medicina da Universidade do Minho criou o Núcleo de Internacionalização (IAO), cujo objetivo principal é apoiar todas as atividades desenvolvidas nas redes internacionais existentes na Escola e estimular novas iniciativas. Além disso, pretende também apoiar a dinamização de um ambiente de aprendizagem global no qual estudantes, docentes e membros de serviços administrativos possam usufruir dos privilégios transformativos de uma educação internacional e em expansão, construindo, assim, um espaço de diálogo e partilha. Com o objetivo de promover a internacionalização da Escola, a EM promove e participa em vários Programas de Mobilidade nacionais e internacionais. O objetivo do presente projeto de estágio é apresentar e descrever o trabalho desenvolvido durante o estágio curricular correspondente ao segundo semestre do 2º ano do Mestrado em Tradução e Comunicação Multilingue da Universidade do Minho. Este estágio durou quatro meses, no Núcleo Internacionalização, da Escola de Medicina, localizado no Campus de Gualtar da UMinho, em Braga. Este relatório consistirá de um breve enquadramento teórico sobre tradução médica, as principais caraterísticas e dificuldades, assim como o papel do tradutor enquanto especialista nesta área e a função das cat tools nesta área da tradução. Serão apresentadas as vantagens e desvantagens da utilização de ferramentas de tradução e a sua utilidade em tradução médica, especialmente durante o meu estágio.As part of a growing internationalization effort, the School of Medicine of the University of Minho created the International Affairs Office (IAO), whose main objective is to support all activities carried out in the international networks existing at the School and to encourage new initiatives. In addition, it also intends to support the promotion of a global learning environment in which students, teachers and members of administrative services can enjoy the transformative privileges of an international and expanding education, thus building a space for dialogue and sharing. With the aim of promoting the internationalization of the School, EMED promotes and participates in several national and international Mobility Programs. The objective of this internship report is to present and describe the work carried out during the curricular internship corresponding to the second semester of the second year of the Master in Translation and Multilingual Communication at the University of Minho. This internship lasted four months, at the International Affairs Office, at the School of Medicine, located at the UMinho’s Gualtar Campus, in Braga. This report will consist of a brief theoretical framework on medical translation, the main characteristics and difficulties, as well as the role of the translator as a specialist in this area and the role of cat tools in this area of translation. The advantages and disadvantages of using translation tools and their usefulness in medical translation will be presented, especially during my internship

    ATHENA Research Book, Volume 2

    Get PDF
    ATHENA European University is an association of nine higher education institutions with the mission of promoting excellence in research and innovation by enabling international cooperation. The acronym ATHENA stands for Association of Advanced Technologies in Higher Education. Partner institutions are from France, Germany, Greece, Italy, Lithuania, Portugal and Slovenia: University of Orléans, University of Siegen, Hellenic Mediterranean University, Niccolò Cusano University, Vilnius Gediminas Technical University, Polytechnic Institute of Porto and University of Maribor. In 2022, two institutions joined the alliance: the Maria Curie-Skłodowska University from Poland and the University of Vigo from Spain. Also in 2022, an institution from Austria joined the alliance as an associate member: Carinthia University of Applied Sciences. This research book presents a selection of the research activities of ATHENA University's partners. It contains an overview of the research activities of individual members, a selection of the most important bibliographic works of members, peer-reviewed student theses, a descriptive list of ATHENA lectures and reports from individual working sections of the ATHENA project. The ATHENA Research Book provides a platform that encourages collaborative and interdisciplinary research projects by advanced and early career researchers

    Microtubule and chromosome dynamics during mitosis in budding yeast

    Get PDF
    As a cell divides, DNA must be replicated and faithfully segregated between the mother and daughter cells. This segregation is facilitated by the mitotic spindle, assembled to pull sister chromatids apart as the cell divides. In budding yeast, spindle pole bodies nucleate microtubules that make up the mitotic spindle, position it at the site of division, and physically link chromosomes to opposing poles via the kinetochores. The chromosomes are held together by cohesin, which is also involved in the architecture of chromatin. In this thesis, I have explored mechanisms controlling microtubule dynamics, kinetochore positioning and chromosome dynamics during mitotic cell division in budding yeast. Bik1 is a microtubule-associated protein shown to play a role in the cytosol to position the spindle before anaphase. In paper I, we have characterized the nuclear function of Bik1 and identified a novel role in clustering kinetochores prior to spindle elongation. Cells lacking nuclear Bik1 have a delayed cell cycle progression, with prolonged metaphase, and fail to cluster kinetochores. We also connect this function to the nuclear kinesin Cin8, which has previously been described to regulate kinetochore microtubule dynamics in metaphase. The spindle pole body anchors microtubule nucleating γ-tubulin complexes using two different receptors, Spc72 in the cytosol and Spc110 in the nucleus. In paper II, we have isolated ‘old’ Spc110, originating from the previous cell cycle, and mapped its phosphorylation sites. These analyses revealed that old Spc110 is phosphorylated at serine 36 and at a novel site, serine 11. Non-phosphorylatable mutant strains revealed that these sites influence microtubule dynamics and cell cycle progression. The Spc110S11A mutant strain frequently had brighter spindle microtubules with asymmetric distribution of α-tubulin. Furthermore, Spc110S11A S36A cells had slightly delayed cell cycle progression and spindle disassembly. The cohesin complex has been shown to shape the chromosomes into loops in budding yeast through a mechanism known as loop extrusion. This phenomenon has primarily been studied using genome-wide sequencing techniques, which report detailed population averages of contact frequencies throughout the genome. How chromosomes of individual cells are affected, and whether this looping affects physical compaction remains poorly understood. In paper III we have generated a microscopy-based system to study chromosome dynamics in single yeast cells by fluorescently tagging specific chromosomal loci. We then used this system to investigate how physical distances between the fluorescently marked loci change after inhibiting loop extruding cohesin. This study revealed that loop extrusion does not significantly affect physical distances but may limit the dynamic movement of chromosomes. In conclusion, these studies reveal novel mechanisms controlling spindle and chromosome dynamics during mitotic cell division: 1) We have uncovered a new role of Bik1 at the spindle. 2) We have mapped phosphorylation sites in old Spc110 and characterized a novel site. 3) We have created a system to study chromosome dynamics in single cells and found that loop extrusion does not significantly compact mitotic yeast chromosomes

    Využití kognitivích testů u Huntingtonovy nemoci v klinické praxi

    Get PDF
    Úvod: Huntingtonova nemoc (HN) je dědičné neurodegenerativní onemocnění projevující se poruchami hybnosti, chování a kognitivním deficitem s fatálními následky. Cíle: Cílem této studie bylo ověřit psychometrické vlastnosti standardní kognitivní baterie používané u HN a stanovit jazykově specifické normativní hodnoty. Soubor a metodika: V první studii byl porovnáván kognitivní výkon u 106 pacientů v různých stádiích HN a u 100 zdravých kontrol párovaných podle věku, pohlaví a vzdělání. Neuropsychologická baterie zahrnovala Test modalit čísel a symbolů (SDMT), Stroopův test, Test cesty, kategoriální a fonemickou verbální fluenci. U pacientů byl navíc komplexně hodnocen motorický a funkční stav. Ve druhé studii byl hodnocen kognitivní výkon 3 267 zdravých osob. Práce byla zaměřena na stratifikaci kognitivního výkonu v souvislosti s věkem, pohlavím, rodným jazykem a vzděláním. Dalším cílem bylo na základě získaných dat vytvořit normativní kalukátor pro hodnocení míry kognitivního deficitu v různých jazycích (angličtina, němčina, španělština, italština, polština, francouzština, nizozemština, dánština). Výsledky: V první studii analýza rozptylu ukázala, že zdravé kontroly dosahovaly významně lepších výsledků než pacienti. Kognitivní výkon koreloval s motorickým a funkčním postižením (p < 0,001) nezávisle na věku...Introduction: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder manifested by motor, behavioural and cognitive deficits with fatal consequences. Aims: This study aims to validate the psychometric properties of a standard cognitive battery used in HD and establish language-specific normative values. Methods: In the first study, cognitive performance was compared in 106 patients at different stages of HD and 100 healthy controls matched for age, sex, and education. The neuropsychological battery included the Symbol Digit Modalities Test, Stroop Word Reading Test, Stroop Colour Naming Test, Stroop Interference Test, Trail Making Test-A and B, Category and Letter Verbal Fluency. In addition, patients were comprehensively assessed for motor and functional status. In the second study, the cognitive performance of 3,267 healthy subjects was assessed. The work focused on the stratification of cognitive performance concerning age, gender, language and level of education. Another aim was to establish the language-specific normative values and implement a web-based normative calculator to assess the degree of cognitive deficit in different languages (English, German, Spanish, Italian, Polish, French, Dutch, Danish). Results: In the first study, analysis of variance showed that healthy...Neurologická klinika 1. LF UK a VFNDepartment of Neurology First Faculty of Medicine Charles University and General University Hospital in Prague1. lékařská fakultaFirst Faculty of Medicin

    A guide to designing photocontrol in proteins: methods, strategies and applications

    Get PDF
    Light is essential for various biochemical processes in all domains of life. In its presence certain proteins inside a cell are excited, which either stimulates or inhibits subsequent cellular processes. The artificial photocontrol of specifically proteins is of growing interest for the investigation of scientific questions on the organismal, cellular and molecular level as well as for the development of medicinal drugs or biocatalytic tools. For the targeted design of photocontrol in proteins, three major methods have been developed over the last decades, which employ either chemical engineering of small-molecule photosensitive effectors (photopharmacology), incorporation of photoactive non-canonical amino acids by genetic code expansion (photoxenoprotein engineering), or fusion with photoreactive biological modules (hybrid protein optogenetics). This review compares the different methods as well as their strategies and current applications for the light-regulation of proteins and provides background information useful for the implementation of each technique
    corecore