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  1. Article ; Online: “Quando a Massa Erra, o Estado Avança”

    Fabio Candotti

    Tomo, Iss

    2022  Volume 40

    Abstract: Em 2017 e 2019 ocorreram dois ‘massacres’ em prisões de Manaus, capital do estado brasileiro do Amazonas. O discurso dominante reduz esses acontecimentos a uma ‘guerra’ entre facções criminosas pelo controle de rotas internacionais de tráfico de drogas. ... ...

    Abstract Em 2017 e 2019 ocorreram dois ‘massacres’ em prisões de Manaus, capital do estado brasileiro do Amazonas. O discurso dominante reduz esses acontecimentos a uma ‘guerra’ entre facções criminosas pelo controle de rotas internacionais de tráfico de drogas. O artigo parte de uma problematização desse discurso (de sua natureza colonial e de seus efeitos de verdade) e esboça uma outra análise que atenta para as correlações entre transformações carcerárias e criminais. O artigo defende a ideia de que uma nova gestão do sofrimento e um novo regime de tortura, experimentados por presos e suas familiares, foram determinantes para a desestabilização e reconfiguração das alianças no crime após os massacres. O texto é fruto de uma experiência de conhecimento imersa na luta anticarcerária, incluindo convivência intensa com familiares de pessoas presas e sobreviventes, comunicações com órgãos de fiscalização e participação em inspeções dentro de unidades prisionais.
    Keywords Social Sciences ; H ; Social sciences (General) ; H1-99
    Language Spanish
    Publishing date 2022-01-01T00:00:00Z
    Publisher Universidade Federal de Sergipe
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Advances of gene therapy for primary immunodeficiencies [version 1; referees

    Fabio Candotti

    F1000Research, Vol

    2 approved]

    2016  Volume 5

    Abstract: In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic ... ...

    Abstract In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. While such progress has widened the choice of therapeutic options in some specific cases of primary immunodeficiency, much remains to be done to extend the geographical availability of such an advanced approach and to increase the number of diseases that can be targeted. At the same time, emerging technologies are stimulating intensive investigations that may lead to the application of precise genetic editing as the next form of gene therapy for these and other human genetic diseases.
    Keywords Genetics of the Immune System ; Hematopoietic Stem Cells ; Immunomodulation ; Immunopharmacology & Hematologic Pharmacology ; Medical Genetics ; Medical Microbiology ; Non-hematopoietic Stem Cells ; Pediatric Hematology ; Pediatric Infectious Diseases ; Pharmacokinetics & Drug Delivery ; Stem Cells & Regeneration ; Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2016-03-01T00:00:00Z
    Publisher F1000 Research Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Critical role of WASp in germinal center tolerance through regulation of B cell apoptosis and diversification

    Marc Descatoire / Remi Fritzen / Samuel Rotman / Genevieve Kuntzelman / Xavier Charles Leber / Stephanie Droz-Georget / Adrian J. Thrasher / Elisabetta Traggiai / Fabio Candotti

    Cell Reports, Vol 38, Iss 10, Pp 110474- (2022)

    2022  

    Abstract: Summary: A main feature of Wiskott-Aldrich syndrome (WAS) is increased susceptibility to autoimmunity. A key contribution of B cells to development of these complications has been demonstrated through studies of samples from affected individuals and ... ...

    Abstract Summary: A main feature of Wiskott-Aldrich syndrome (WAS) is increased susceptibility to autoimmunity. A key contribution of B cells to development of these complications has been demonstrated through studies of samples from affected individuals and mouse models of the disease, but the role of the WAS protein (WASp) in controlling peripheral tolerance has not been specifically explored. Here we show that B cell responses remain T cell dependent in constitutive WASp-deficient mice, whereas selective WASp deletion in germinal center B cells (GCBs) is sufficient to induce broad development of self-reactive antibodies and kidney pathology, pointing to loss of germinal center tolerance as a primary cause leading to autoimmunity. Mechanistically, we show that WASp is upregulated in GCBs and regulates apoptosis and plasma cell differentiation in the germinal center and that the somatic hypermutation-derived diversification is the basis of autoantibody development.
    Keywords Wiskott-Aldrich syndrome ; germinal center B cells ; autoimmunity ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress

    Alberto Rissone / Erin Jimenez / Kevin Bishop / Blake Carrington / Claire Slevin / Stephen M. Wincovitch / Raman Sood / Fabio Candotti / Shawn M. Burgess

    Disease Models & Mechanisms, Vol 12, Iss

    2019  Volume 12

    Abstract: Mutations in the gene AK2 are responsible for reticular dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die, generally from sepsis soon after ... ...

    Abstract Mutations in the gene AK2 are responsible for reticular dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die, generally from sepsis soon after birth. The only available therapeutic option for RD is hematopoietic stem cell transplantation (HSCT). To gain insight into the pathophysiology of RD, we previously created zebrafish models for Ak2 deficiencies. One of the clinical features of RD is hearing loss, but its pathophysiology and causes have not been determined. In adult mammals, sensory hair cells of the inner ear do not regenerate; however, their regeneration has been observed in several non-mammalian vertebrates, including zebrafish. Therefore, we used our RD zebrafish models to determine whether Ak2 deficiency affects sensory organ development and/or hair cell regeneration. Our studies indicated that Ak2 is required for the correct development, survival and regeneration of sensory hair cells. Interestingly, Ak2 deficiency induces the expression of several oxidative stress markers and it triggers an increased level of cell death in the hair cells. Finally, we show that glutathione treatment can partially rescue hair cell development in the sensory organs in our RD models, pointing to the potential use of antioxidants as a therapeutic treatment supplementing HSCT to prevent or ameliorate sensorineural hearing deficits in RD patients.
    Keywords ak2 ; reticular dysgenesis ; scid ; hearing loss ; zebrafish ; hair cells ; lateral line ; antioxidants ; Medicine ; R ; Pathology ; RB1-214
    Subject code 610
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Age-Dependent Defects of Regulatory B Cells in Wiskott-Aldrich Syndrome Gene Knockout Mice.

    Tadafumi Yokoyama / Ayumi Yoshizaki / Karen L Simon / Martha R Kirby / Stacie M Anderson / Fabio Candotti

    PLoS ONE, Vol 10, Iss 10, p e

    2015  Volume 0139729

    Abstract: The Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema, and high incidence of malignancy and autoimmunity. The cellular mechanisms underlying autoimmune complications ...

    Abstract The Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema, and high incidence of malignancy and autoimmunity. The cellular mechanisms underlying autoimmune complications in WAS have been extensively studied; however, they remain incompletely defined. We investigated the characteristics of IL-10-producing CD19+CD1dhighCD5+ B cells (CD1dhighCD5+ Breg) obtained from Was gene knockout (WKO) mice and found that their numbers were significantly lower in these mice compared to wild type (WT) controls. Moreover, we found a significant age-dependent reduction of the percentage of IL-10-expressing cells in WKO CD1dhighCD5+ Breg cells as compared to age-matched WT control mice. CD1dhighCD5+ Breg cells from older WKO mice did not suppress the in vitro production of inflammatory cytokines from activated CD4+ T cells. Interestingly, CD1dhighCD5+ Breg cells from older WKO mice displayed a basal activated phenotype which may prevent normal cellular responses, among which is the expression of IL-10. These defects may contribute to the susceptibility to autoimmunity with age in patients with WAS.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Efficient methods for targeted mutagenesis in zebrafish using zinc-finger nucleases

    Raman Sood / Blake Carrington / Kevin Bishop / MaryPat Jones / Alberto Rissone / Fabio Candotti / Settara C Chandrasekharappa / Paul Liu

    PLoS ONE, Vol 8, Iss 2, p e

    data from targeting of nine genes using CompoZr or CoDA ZFNs.

    2013  Volume 57239

    Abstract: Recently, it has been shown that targeted mutagenesis using zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) can be used to generate knockout zebrafish lines for analysis of their function and/or developing ... ...

    Abstract Recently, it has been shown that targeted mutagenesis using zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) can be used to generate knockout zebrafish lines for analysis of their function and/or developing disease models. A number of different methods have been developed for the design and assembly of gene-specific ZFNs and TALENs, making them easily available to most zebrafish researchers. Regardless of the choice of targeting nuclease, the process of generating mutant fish is similar. It is a time-consuming and multi-step process that can benefit significantly from development of efficient high throughput methods. In this study, we used ZFNs assembled through either the CompoZr (Sigma-Aldrich) or the CoDA (context-dependent assembly) platforms to generate mutant zebrafish for nine genes. We report our improved high throughput methods for 1) evaluation of ZFNs activity by somatic lesion analysis using colony PCR, eliminating the need for plasmid DNA extractions from a large number of clones, and 2) a sensitive founder screening strategy using fluorescent PCR with PIG-tailed primers that eliminates the stutter bands and accurately identifies even single nucleotide insertions and deletions. Using these protocols, we have generated multiple mutant alleles for seven genes, five of which were targeted with CompoZr ZFNs and two with CoDA ZFNs. Our data also revealed that at least five-fold higher mRNA dose was required to achieve mutagenesis with CoDA ZFNs than with CompoZr ZFNs, and their somatic lesion frequency was lower (<5%) when compared to CopmoZr ZFNs (9-98%). This work provides high throughput protocols for efficient generation of zebrafish mutants using ZFNs and TALENs.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector.

    Satoshi Horino / Toru Uchiyama / Takanori So / Hiroyuki Nagashima / Shu-Lan Sun / Miki Sato / Atsuko Asao / Yoichi Haji / Yoji Sasahara / Fabio Candotti / Shigeru Tsuchiya / Shigeo Kure / Kazuo Sugamura / Naoto Ishii

    PLoS ONE, Vol 8, Iss 8, p e

    2013  Volume 71594

    Abstract: X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene ... ...

    Abstract X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the γc gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human γc. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from γc-knockout (γc-KO) mice were infected with the FV vector and transplanted into γc-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Expansion of Hepatic and Hematopoietic Stem Cells Utilizing Mouse Embryonic Liver Explants

    Satdarshan P. S. Monga / Yi Tang / Fabio Candotti / Asif Rashid / Oliver Wildner / Bibhuti Mishra / Shareen Iqbal / Lopa Mishra M.D.

    Cell Transplantation, Vol

    2001  Volume 10

    Abstract: Ex vivo embryonic liver explant culture is a novel and attractive approach to obtain abundant hepatic and hematopoietic stem cells. Gene therapy of autologous hepatic and hematopoietic stem cells represents an alternative therapeutic approach to liver ... ...

    Abstract Ex vivo embryonic liver explant culture is a novel and attractive approach to obtain abundant hepatic and hematopoietic stem cells. Gene therapy of autologous hepatic and hematopoietic stem cells represents an alternative therapeutic approach to liver transplantation for genetic and metabolic disorders. In this study we characterize the growth and differentiation of hepatic stem cells utilizing embryonic liver cultures. Day 9.5 liver buds are microdissected and cultured under specific conditions. Modulation of growth conditions by addition of hepatocyte growth factor, Flt-3 ligand, and stem cell factor leads to enrichment of hepatic progenitor cells in embryonic liver explants. Under these conditions, we also demonstrate the role of a novel marker PRAJA-1 to identify hepatic stem cells and transitional hepatocytes. Utilization of dexamethasone enhanced pseudolobule formation with increased hepatocytic and biliary differentiation. Transforming growth factor-β leads to enrichment of biliary cells in the culture. Gut formation is enhanced in the presence of interleukin-3 and blood formation by increasing the mesodermal tissue in these cultures. We also show increased retroviral-mediated expression of the green fluorescent protein expression in the expanded hepatic and hematopoietic stem cells under different culture conditions. Thus, the embryonic liver explant culture is an attractive source for hepatic progenitors and is a possible step towards generating nontumorigenic immortalized hepatocytes with possible transplantation applications.
    Keywords Medicine ; R
    Subject code 610 ; 571
    Language English
    Publishing date 2001-01-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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