Vakanuvis International Journal of Historical Researches, Sep 29, 2021
That the Community of Union and Progressive included the Ottoman officers, who had gotten to know... more That the Community of Union and Progressive included the Ottoman officers, who had gotten to know the committee organization by following the gangs in the Balkans, was taken the opposition to a different dimension for Sultan Abdulhamid. These officers, who called the rules of Abdulmamid II "despotism", thought that opposition did not work, and it should revolt the state with military units in order to be able to have the constitutional administration redeclared. In 1908, thus, some officers went up the mountain. The Sultan had assigned Şemsi Pasha, who was his most trusted soldier against this rebellion, to take the situation under control and provide security. However, the assassination of Şemsi Pasha by a Unionist officer in Manastır destroyed one of the sultan's greatest pillars. As a result of the fact that the control in Rumelia could not be fully achieved, together with the events that followed, constitutionalism was declared again on July 24, 1908. The subject of this study is the role and fate of Şemsi Pasha in the 1908 Revolution and the evaluation of the effects of this outcome on the revolution process.
Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give ris... more Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells ...
Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and ratelimiting... more Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and ratelimiting step in the biosynthesis of melanin. Mutations in Tyr might result in non-functional Tyr protein and, consequently, loss of pigment production. This is a rare genetic condition, known as albinism, described for most animal species, and one of the most obvious and simple phenotypes to investigate in model organisms. Mutations in the orthologous human TYR gene are associated with oculocutaneous albinism type 1 (OCA1). Over the last thirty years, the mouse Tyr locus has been studied as a paradigm for how genes and expression domains are organized and regulated in mammalian genomes. This review summarizes the major findings and experimental strategies used, from the production of conventional transgenic mice to the latest CRISPR-Cas9 genomeedited animals. The main conclusion inferred from all of these studies, which extends beyond the analysis of the mouse Tyr locus, is the relevance of analyzing non-coding regulatory DNA elements in their natural chromosomal environment, and not only as randomly inserted transgenes. Further, the identification of evolutionary conserved regulatory sequences might highlight new vulnerable sites in the human TYR gene, whose mutations could also be associated with albinism.
Mammalian genome : official journal of the International Mammalian Genome Society, Jan 6, 2017
Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly... more Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly short but intense history of genome-editing approaches illustrates how a disruptive technology can universally colonize a field when this new methodology, conceived to alter mammalian genomes at specific locations, is found to efficiently and robustly deliver results. This review summarizes the early development of genome editing using nucleases, from the pioneering experiments using yeast meganucleases, to the latest prokaryotic nucleases used for precise genome manipulation. Gene-editing nucleases belong to one of three known categories: zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) tools. All operate on the same principle; they are all capable of inducing a double-strand break (DSB) at a defined genomic sequence that is subsequently correc...
Gene editing is a relatively recent concept in the molecular biology field. Traditional genetic m... more Gene editing is a relatively recent concept in the molecular biology field. Traditional genetic modifications in animals relied on a classical toolbox that, aside from some technical improvements and additions, remained unchanged for many years. Classical methods involved direct delivery of DNA sequences into embryos or the use of embryonic stem cells for those few species (mice and rats) where it was possible to establish them. For livestock, the advent of somatic cell nuclear transfer platforms provided alternative, but technically challenging, approaches for the genetic alteration of loci at will. However, the entire landscape changed with the appearance of different classes of genome editors, from initial zinc finger nucleases, to transcription activator-like effector nucleases and, most recently, with the development of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas). Gene editing is currently achieved by CRISPR-Cas-mediat...
In recent years, fractal measures have been increasingly used to characterize the complexity of g... more In recent years, fractal measures have been increasingly used to characterize the complexity of grey and white matter structures of the human brain in both healthy and conditions due to neuroinflammatory, neuroimmune or neurodegenerative processes. In many cases, these measures can complement more standard approaches such us grey matter volume loss or voxel-based morphometry since they reflect not only the extent of the degeneration but also provide information on the spatial pattern by which volume degradation occurred. T1-segmented sections provide probabilistic information about the extent of gray matter, and the characterization of their fractal properties requires the consideration of two important methodological issues, concerning the setting of an appropriate segmentation threshold as well as identifying the spatial resolution that most accurately characterizes the complexity of the resulting binary volumes. Since both issues jointly affect fractal measures, the aim of this s...
La autofagia es un proceso de degradación intracelular, en el que porciones de citosol y orgánulo... more La autofagia es un proceso de degradación intracelular, en el que porciones de citosol y orgánulos son secuestrados en el autofagosoma para fusionarse con el lisosoma, formando así el autolisosoma. Los compuestos del autofagosoma son degradados, y recicladas las moléculas resultantes. Se han identificado 3 tipos: macroautofagia (en la cual nos centraremos), microautofagia y autofagia mediada por chaperonas. Entre sus funciones cabe destacar: supresión de tumores, prevención del gasto de ATP y de RE, inducción del ciclo celular y mantenimiento de la integridad genómica, de orgánulos y proteínas celulares entre otras. Existen varios genes relacionados con la autofagia (Atg) esenciales para este proceso. Se induce autofagia en situaciones de estrés como limitación de nutrientes, calor y estrés oxidativo. Así mismo está implicada en enfermedades neurodegenerativas, cardiacas, cáncer... El proceso autofágico se da en cinco etapas comprendidas desde la formación del fagóforo hasta la fusi...
High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter ... more High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the grey matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising, 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9-0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations
Vakanuvis International Journal of Historical Researches, Sep 29, 2021
That the Community of Union and Progressive included the Ottoman officers, who had gotten to know... more That the Community of Union and Progressive included the Ottoman officers, who had gotten to know the committee organization by following the gangs in the Balkans, was taken the opposition to a different dimension for Sultan Abdulhamid. These officers, who called the rules of Abdulmamid II "despotism", thought that opposition did not work, and it should revolt the state with military units in order to be able to have the constitutional administration redeclared. In 1908, thus, some officers went up the mountain. The Sultan had assigned Şemsi Pasha, who was his most trusted soldier against this rebellion, to take the situation under control and provide security. However, the assassination of Şemsi Pasha by a Unionist officer in Manastır destroyed one of the sultan's greatest pillars. As a result of the fact that the control in Rumelia could not be fully achieved, together with the events that followed, constitutionalism was declared again on July 24, 1908. The subject of this study is the role and fate of Şemsi Pasha in the 1908 Revolution and the evaluation of the effects of this outcome on the revolution process.
Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give ris... more Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells ...
Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and ratelimiting... more Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and ratelimiting step in the biosynthesis of melanin. Mutations in Tyr might result in non-functional Tyr protein and, consequently, loss of pigment production. This is a rare genetic condition, known as albinism, described for most animal species, and one of the most obvious and simple phenotypes to investigate in model organisms. Mutations in the orthologous human TYR gene are associated with oculocutaneous albinism type 1 (OCA1). Over the last thirty years, the mouse Tyr locus has been studied as a paradigm for how genes and expression domains are organized and regulated in mammalian genomes. This review summarizes the major findings and experimental strategies used, from the production of conventional transgenic mice to the latest CRISPR-Cas9 genomeedited animals. The main conclusion inferred from all of these studies, which extends beyond the analysis of the mouse Tyr locus, is the relevance of analyzing non-coding regulatory DNA elements in their natural chromosomal environment, and not only as randomly inserted transgenes. Further, the identification of evolutionary conserved regulatory sequences might highlight new vulnerable sites in the human TYR gene, whose mutations could also be associated with albinism.
Mammalian genome : official journal of the International Mammalian Genome Society, Jan 6, 2017
Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly... more Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly short but intense history of genome-editing approaches illustrates how a disruptive technology can universally colonize a field when this new methodology, conceived to alter mammalian genomes at specific locations, is found to efficiently and robustly deliver results. This review summarizes the early development of genome editing using nucleases, from the pioneering experiments using yeast meganucleases, to the latest prokaryotic nucleases used for precise genome manipulation. Gene-editing nucleases belong to one of three known categories: zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) tools. All operate on the same principle; they are all capable of inducing a double-strand break (DSB) at a defined genomic sequence that is subsequently correc...
Gene editing is a relatively recent concept in the molecular biology field. Traditional genetic m... more Gene editing is a relatively recent concept in the molecular biology field. Traditional genetic modifications in animals relied on a classical toolbox that, aside from some technical improvements and additions, remained unchanged for many years. Classical methods involved direct delivery of DNA sequences into embryos or the use of embryonic stem cells for those few species (mice and rats) where it was possible to establish them. For livestock, the advent of somatic cell nuclear transfer platforms provided alternative, but technically challenging, approaches for the genetic alteration of loci at will. However, the entire landscape changed with the appearance of different classes of genome editors, from initial zinc finger nucleases, to transcription activator-like effector nucleases and, most recently, with the development of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas). Gene editing is currently achieved by CRISPR-Cas-mediat...
In recent years, fractal measures have been increasingly used to characterize the complexity of g... more In recent years, fractal measures have been increasingly used to characterize the complexity of grey and white matter structures of the human brain in both healthy and conditions due to neuroinflammatory, neuroimmune or neurodegenerative processes. In many cases, these measures can complement more standard approaches such us grey matter volume loss or voxel-based morphometry since they reflect not only the extent of the degeneration but also provide information on the spatial pattern by which volume degradation occurred. T1-segmented sections provide probabilistic information about the extent of gray matter, and the characterization of their fractal properties requires the consideration of two important methodological issues, concerning the setting of an appropriate segmentation threshold as well as identifying the spatial resolution that most accurately characterizes the complexity of the resulting binary volumes. Since both issues jointly affect fractal measures, the aim of this s...
La autofagia es un proceso de degradación intracelular, en el que porciones de citosol y orgánulo... more La autofagia es un proceso de degradación intracelular, en el que porciones de citosol y orgánulos son secuestrados en el autofagosoma para fusionarse con el lisosoma, formando así el autolisosoma. Los compuestos del autofagosoma son degradados, y recicladas las moléculas resultantes. Se han identificado 3 tipos: macroautofagia (en la cual nos centraremos), microautofagia y autofagia mediada por chaperonas. Entre sus funciones cabe destacar: supresión de tumores, prevención del gasto de ATP y de RE, inducción del ciclo celular y mantenimiento de la integridad genómica, de orgánulos y proteínas celulares entre otras. Existen varios genes relacionados con la autofagia (Atg) esenciales para este proceso. Se induce autofagia en situaciones de estrés como limitación de nutrientes, calor y estrés oxidativo. Así mismo está implicada en enfermedades neurodegenerativas, cardiacas, cáncer... El proceso autofágico se da en cinco etapas comprendidas desde la formación del fagóforo hasta la fusi...
High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter ... more High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the grey matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising, 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9-0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations
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Papers by Santiago Josa