103 research outputs found
Genome editing for clinically relevant mutations in genetic diseases and cancer
No full textThe present thesis concerns of two sections. The first one focuses on the application of Cluster Regularly Interspaced Short Palindromic Repeats (CRISPR) system as a tool for precise genome targeting and genome editing; the association between specific endonuclease and RNA guides complementary to the DNA target allows its targeting with single-nucleotide precision. CRISPR/Cas is able to perform Double-Strand Breaks (DSBs) at a target site which are soon repaired by cellular repairing mechanism, non-homologous end joining (NHEJ) or homology-directed repair (HDR).
The first part of my project aims to explore and demonstrate the efficacy of a personalized therapeutic approach based on the CRISPR/Cas9 technology associated with adeno-associated viral vectors (AAVs)s, a mutation-specific gene therapy to restore mutated genes in genetic diseases to their original sequence trough the HDR-mediated correction. I developed an mCherry/EGFP reporter cassette where the reporter gene bears a mutation-specific target. It connects the mCherry and the EGFP (out of frame) coding sequences. Due to a frameshift, the reactivation of the EGFP allows the visualization of cells in which Cas9 had targeted the mutation-specific sequence leading to the production of Indels. I worked to edit mutations involved in specific genetic diseases such as mutations in FOXG1 or in MECP2, which are responsible for Rett syndrome, in the IQSEC2 gene that causes an intellectual disability clinically related to the Rett syndrome and in COL4A3 and COL4A5 causing Alport syndrome.
In the second part of my study, I worked on developing a gene editing system aims to selective targeting to cancer cells while preserving the genetic integrity of normal cells. To this aim, I plan to exploit microhomology-mediated end joining (MMEJ) through Cas12a, an RNA-directed endonuclease that causes double-strand breaks with staggered ends, to insert in-frame the Herpes Simplex Virus –Thymidine Kinase suicide gene to trigger cell death. I designed and developed a construct to target a patient-specific single nucleotide variant within a coding sequence of the TP53 gene, from a patient with Chronic Lymphocytic Leukemia characterized by clonal expansion of clones bearing this TP53 mutation. I am able to detect the proper integration of the suicide gene sequence by analyzing the treated cells by fluorescence-activated cell sorting (FACS). Indeed, a green fluorescent protein (EGFP) sequence is linked to the TK by a 2A peptide system, thus green fluorescent cells are also the one expressing for the TK gene.
The second section of my thesis concerns the COVID-19 pandemic global crisis and the need to understand how best to study and treat COVID-19. A key focus is sharing and analyzing data to learn about the genetic determinants of COVID-19 susceptibility, severity, and outcomes. In particular, my work has been focused on the TLR7 gene that has been involved as an important pattern recognition receptor for the ssRNA of SARS-CoV-2. We demonstrate that rare loss-of-function variants in the TLR7 gene in young men with severe COVID-19 and with no prior history of major chronic diseases were associated with impaired TLR7 signaling and type I and II IFN responses
Weaving Cross-cultural Narratives: Hybrid Forms and Historico-political Discourse of the Anglophone Indian Novel
No full textAs the anglophone Indian novel exists in the in-between space between transnational and local cultures, it has repeatedly staged the encounter between a variety of cultural dimensions while remaining acutely aware of the way they interact with historical and political discourse. This essay examines four novels—Raja Rao’s Kanthapura, Salman Rushdie’s Midnight’s Children, Anita Desai’s In Custody and Amitav Ghosh’s The Hungry Tide—that have conceived their narratives as a site of encounter between cultures in response to articulations of Indian national identity. The essay stresses the authors’ shared concerns but also the different formal solutions and ideological positions they adopt. Rao—a pre-Partition author—deals with otherness within a nationalist paradigm. Rushdie, Desai and Ghosh, on the other hand, tackle otherness in different modes that are dependent on their writing after Partition and in a climate of growing violence and fundamentalis
La regolamentazione giuridica delle fonti di energia rinnovabili tra tutela dell'ambiente e tutela della concorrenza
No full textThis PhD thesis analyses, from a constitutional perspective, the different aspects distinguishing the legislation of renewable energy, which is the link between the economic development needs and those of environmental protection, and which allows the exploitation of natural resources within the limits of their capacity for restoration.
As for the abovementioned legislation, the intention of the author is to highlight the critical issues that identify the sector, but also to ascertain common evolutionary lines.
At the outset, attention is given to the evolution of the legal notion of the environment and the development of constitutional case law on such question, which profoundly affects the regulation of the energy sector.
Afterwards, the constitutional case law on renewable energy sources is analyzed, as it is considered particularly emblematic for the complexity of the division of legislative power between the State and the Regions, outlined by art. 117 of the Constitution, and the evolution of the principle of sustainable development.
Following a brief overview of the regulatory framework set up at the European level for the promotion of energy production from renewable sources, the evolution and analysis of subsidy systems shall be contemplated. In particular, the different support mechanisms shall be explained, which can be divided into quantitative systems and price-based systems, highlighting their respective critical profiles.
Finally, two in-depth analyzes shall be carried out in relation to areas that have experienced a profoundly different evolution, and which present particular problematic features.
The first concerns the photovoltaic sector, with particular reference to the slight linear evolution of "Conto energia" subsidy program.
The second in-depth enquiry consists in an analysis of the hydroelectric sector legislation, and it demonstrates the criticalities stemming from the strong regulatory uncertainty related to the revision of the legislation on public bids for the assignment of hydroelectric water concessions for hydroelectric purposes
Complications and recurrence of patellar instability after medial patellofemoral ligament reconstruction in children and adolescents : a systematic review
No full textBackground: This study aimed to review the data available in the current literature concerning the complications and recurrence of instability following medial patellofemoral ligament (MPFL) reconstruction for patellar instability in young and adolescent patients (those <20 years old).
Methods: A systematic review was performed based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Two independent reviewers searched the PubMed, Scopus, EMBASE, and Cochrane databases. The terms “medial patellofemoral ligament” or “MPFL”
and “reconstruction” and “young” or “adolescents” or “children” were used. The inclusion criteria for the literature review comprised studies that reported the complications and recurrences of instability in patients who had undergone MPFL reconstruction for patellar instability.
Results: In all, 332 patients were included in the review, of which 195 were females (63.5%) and 112 were males (36.5%), and they totaled 352 treated knees. The mean age at the time of the surgery was 14.28 years, and the mean follow-up duration was 30.17 months. A total of 16 (4.5%) complications were reported: one (0.3%) patella fracture, one (0.3%) screw removal due to intolerance, one (0.3%) infection, five (1.4%) wound complications, six (1.7%) subluxations and two (0.6%) instances of post-operative stiffness. A total of 18 (5.1%) recurrences of patellar instability were recorded.
Conclusions: MPFL reconstruction in young patients can be considered an effective and safe treatment leading to clinical improvement in terms of recurrence of dislocation. No major complications related to the technique were reported, but a high level of research evidence is required to better evaluate the clinical results in a long-term follow-up
Other Pneumoconioses [outras Pneumoconioses]
No full textThe most prevalent pneumoconioses are silicosis, asbestosis and coal worker's pneumoconiosis. Other pneumoconioses that have distinct clinical, functional and structural repercussions are caused by inhalation of metal powder in fumes from metals or organic salts. The distinction in terms of the chemical form of the inhaled compound is related to the tissue reaction and to the prognosis. Simple pneumoconiosis, siderosis, berylliosis and phosphate rock-related pneumoconiosis, as well as chronic obstructive pulmonary disease caused by exposure to heavy metals, are succinctly discussed. As an instrument of etiologic investigation of these pneumoconioses, the taking of occupational histories is essential.32SUPPL. 2S54S59Parkes, W.R., Aerosols: Their deposition and clearance (1994) Occupational Lung Disorders. 3rd Ed., pp. 35-49. , Parkes WR, editor. Oxford, UK: Butterworth-HeinemannNemery, B., Lung diseases from metal exposure (1998) Occupational Lung Disease: An International Perspective, pp. 279-306. , Banks DE, Parker JE, editors. London: Chapman & Hall MedicalWright, J.L., Churg, A., Diseases caused by gases and fumes (1998) Pathology of Occupational Lung Diseases. 2nd., pp. 57-75. , Churg A, Green FH, editors. Baltimore: Williams & WilkinsParkes, W.R., Non-fibrogenic ('inert') minerals and pneumoconiosis (1994) Occupational Lung Disorders, pp. 253-284. , Parkes WR, editor. Oxford, UK: Butterworth-HeinemannChurg, A., Colby, T.V., Diseases caused by metals and related compounds (1998) Pathology of Occupational Lung Disease. 2nd Ed., pp. 77-128. , Churg A, Green FHY, editors. Baltimore: Willians & WilkinsAntonini, J.M., Taylor, M.D., Zimmer, A.T., Roberts, J.R., Pulmonary responses to welding fumes: Role of metal constituents (2004) J Toxicol Environ Health A, 67 (3), pp. 233-249Attfield, M.D., Ross, D.S., Radiological abnormalities in electric-arc welders (1978) Br J Ind Med, 35 (2), pp. 117-122Algranti, E., Morrone, L.C., Morrone, N., Furlaneto, J.A., Garcia, R.C., Cardoso, R.S., Siderose pulmonar por óxido de fero em trabalhadores: Uma poeira inerte? (1985) Rev Paul Med, 103 (5), pp. 259-264Yoshii, C., Matsuyama, T., Takazawa, A., Ito, T., Yatera, K., Hayashi, T., Welder's pneumoconiosis: Diagnostic usefulness of high-resolution computed tomography and ferritin determinations in bronchoalveolar lavage fluid (2002) Intern Med, 41 (12), pp. 1111-1117Doherty, M.J., Healy, M., Richardson, S.G., Fisher, N.C., Total body iron overload in welder's siderosis (2004) Occup Environ Med, 61 (1), pp. 82-85De Capitani, E.M., Pneumoconioses não usuais (1999) Pneumologia: Atualização e Reciclagem, 3, pp. 431-445. , Fernandes ALG, Mendes ESPS, Terra Filho M, editores. São Paulo: AtheneuDe Capitani, E.M., Prevalência de pneumoconiose em trabalhadores expostos a rocha fosfática (1989) Rev Saúde Pública, 23 (2), pp. 98-106Gibbs, A.E., Pooley, F.D., Griffiths, D.M., Mitha, R., Craighead, J.E., Ruttner, J.R., Talc pneumoconiosis: A pathologic and mineralogic study (1992) Hum Pathol, 23 (12), pp. 1344-1354Chibante, A.M.S., Padilha, C.P., Bethlem, E.P., Dias, R.M., Oliveira, C.A.B., Magarão, S.L., Pneumoconiose dos moedores de talco: Estudo de sete casos (1990) J Pneumol, 16 (2), pp. 57-61Brancaleone, P., Weynand, B., De Vuyst, P., Stanescu, D., Pieters, T., Lung granulomatosis in a dental technician (1998) Am J Ind Med, 34 (6), pp. 628-631Algranti, E., Chibante, A.M.S., Pneumoconiose em trabalhadores de laboratório odontológico (1993) Rev Assoc Paulista Cir Dent, 47, pp. 969-972De Capitani, E.M., Altemani, A.M.A., Kavakama, J.I., Nunes, G.Y., Paschoal, I.A., Beriliose pulmonar: Revisão da literatura e relato de caso (1995) J Pneumol, 21 (3), pp. 135-142Morrone, N., Campos Neto, J.S., Shibata, N.P., Pratscher, P., Lima Filho, M.T., Importância da cintilografia com gálio (67Ga) em pneumologia (1982) Rev Paul Méd, 100 (3), pp. 30-33Newman, L.S., Kreiss, K., King Jr., T.E., Seay, S., Campbell, P.A., Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of disease definition and natural history (1989) Am Rev Respir Dis, 139 (6), pp. 1479-1486(1989) Am Rev Respir Dis, 140 (6), pp. 1834-1835. , Comment(1990) Am Rev Respir Dis, 142 (3), pp. 739-740Kern, D.G., Crausman, R.S., Durand, K.T., Nayer, A., Kuhn III, C., Flock worker's lung: Chronic interstitial lung disease in the nylon flocking industry (1998) Ann Intern Med, 129 (4), pp. 261-272. , Erratum in: Ann Intern Med 1999;130(3):246(1998) Ann Intern Med, 129 (4), pp. 327-328. , Comment(1999) Ann Intern Med, 130 (7), pp. 615-616(1999) Ann Intern Med, 130 (7), p. 615. , author reply 615-6(1999) Ann Intern Med, 130 (7), p. 615Eschenbacher, W.L., Kreiss, K., Lougheed, M.D., Pransky, G.S., Day, B., Castellan, R.M., Nylon flock-associated interstitial lung disease (1999) Am J Respir Crit Care Med, 159 (6), pp. 2003-2008Kern, D.G., Kuhn III, C., Ely, E.W., Pransky, G.S., Mello, C.J., Fraire, A.E., Flock worker's lung: Broadening the spectrum of clinicopathology, narrowing the spectrum of suspected etiologies (2000) Chest, 117 (1), pp. 251-259(2000) Chest, 117 (1), pp. 10-13. , Commen
Multi-Party Private Set Intersection Protocols for Practical Applications
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Les ‘musulmans’ dans quelques narrations chevaleresques italiennes des XIVe et XVe siècles : entre persistances et changements
No full textInternational audienceThis article analyzes the representation of Muslims in italian and franco-italian chivalric production of the XIVth and XVth centuries. The author highlights that the word Muslim didn't have the same religious connotation as nowadays and then studies three aspects: the representation of the muslim warrior, the representation of Muslim woman and of Muslim ReligionCet article étudie la représentation des "Musulmans" dans la production narrative chevaleresque italienne et franco-italienne. Après avoir rappelé que le mot musulman à cette époque n'avait pas la signification qu'il a actuellement, l'article considère trois aspects:la représentation du guerrier musulman, l'mage de la femme musulmane et la représentation de la religio
Pyrazolotriazolopyrimidine derivatives sensitize melanoma cells to the chemotherapic drugs: taxol and vindesine
No full textIn this study, we have evaluated the "in vitro" modulatory activity of a series
of pyrazolotriazolopyrimidine derivatives (PTP-d) in sensitizing malignant
melanoma cells to the chemotherapic drugs: taxol and vindesine. To that end, we
have described the impact of chemotherapeutic agents on the cell cycle and on the
induction of apoptosis when used alone or in combination with PTP-d. We have
demonstrated that four PTP-d reduced chemotherapic drugs EC(50) doses of the
G(2)/M accumulation with an average of 1.7-fold for taxol and 9.5-fold for
vindesine when challenged on A375 human melanoma cell line. This sensitization
activity was also confirmed by analyzing the apoptosis degree induced by the
chemotherapic drugs. Interestingly, PTP-d had no effects on the response to
cytotoxic agents by skin-derived human keratinocyte cells, NCTC 2544. Therefore,
we have investigated the signaling pathway sustaining the sensitizing effect of
PTP-d, providing functional evidence that active compounds are able to inhibit
multidrug resistance-associated ATP-binding cassette drug transporter. These
results suggested that PTP-d hold great promise for the treatment of multidrug
resistance in cancers, leading to potential new therapies for melanom
Correction: New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells
No full textNo abstract availabl
Correction to: High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot
No full textNo abstract availabl
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