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Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB binds to an allosteric site to block DNA binding, both in vitro and in cells. Comparisons of The Cancer Genome Atlas (TCGA) tumors and matched controls implied that POLQ upregulation in tumors stems from its role in replication stress responses to increased cell proliferation: this can now be tested in fifteen tumor types by NVB blocking ssDNA-stimulation of ATPase activity, required for Polθ function at replication forks and DNA damage sites. Structural and functional insights provided in this study suggest a path for developing NVB derivatives with improved potency for Polθ inhibition by targeting ssDNA binding with entropically constrained small molecules.

The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

RAD51C is an enigmatic predisposition gene for breast, ovarian, and prostate cancer. Currently, missing structural and related functional understanding limits patient mutation interpretation to homology-directed repair (HDR) function analysis. Here we report the RAD51C-XRCC3 (CX3) X-ray co-crystal structure with bound ATP analog and define separable RAD51C replication stability roles informed by its three-dimensional structure, assembly, and unappreciated polymerization motif. Mapping of cancer patient mutations as a functional guide confirms ATP-binding matching RAD51 recombinase, yet highlights distinct CX3 interfaces. Analyses of CRISPR/Cas9-edited human cells with RAD51C mutations combined with single-molecule, single-cell and biophysics measurements uncover discrete CX3 regions for DNA replication fork protection, restart and reversal, accomplished by separable functions in DNA binding and implied 5' RAD51 filament capping. Collective findings establish CX3 as a cancer-relevant replication stress response complex, show how HDR-proficient variants could contribute to tumor development, and identify regions to aid functional testing and classification of cancer mutations.

Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to the assumption that DNA-PKcs is a vertebrate-specific PIKK. Here, we find that DNA-PKcs is widely distributed in invertebrates, fungi, plants, and protists, and that threonines 2609, 2638, and 2647 of the ABCDE cluster of phosphorylation sites are highly conserved amongst most Eukaryotes. Furthermore, we identify highly conserved amino acid sequence motifs and domains that are characteristic of DNA-PKcs relative to other PIKKs. These include residues in the Forehead domain and a novel motif we have termed YRPD, located in an α helix C-terminal to the ABCDE phosphorylation site loop. Combining sequence with biochemistry plus structural data on human DNA-PKcs unveils conserved sequence and conformational features with functional insights and implications. The defined generally progressive DNA-PKcs sequence diversification uncovers conserved functionality supported by Evolutionary Trace analysis, suggesting that for many organisms both functional sites and evolutionary pressures remain identical due to fundamental cell biology. The mining of cancer genomic data and germline mutations causing human inherited disease reveal that robust DNA-PKcs activity in tumors is detrimental to patient survival, whereas germline mutations compromising function are linked to severe immunodeficiency and neuronal degeneration. We anticipate that these collective results will enable ongoing DNA-PKcs functional analyses with biological and medical implications.

Abstract RAD51C is an enigmatic predisposition gene for breast, ovarian, and prostate cancer. Currently, missing structural and related functional understanding limits patient mutation interpretation to homology-directed repair (HDR) function analysis. Here we report the RAD51C-XRCC3 (CX3) X-ray co-crystal structure with bound ATP analog and define separable RAD51C replication stability roles informed by its three-dimensional structure, assembly, and unappreciated polymerization motif. Mapping of cancer patient mutations as a functional guide confirms ATP-binding matching RAD51 recombinase, yet highlights distinct CX3 interfaces. Analyses of CRISPR/Cas9-edited human cells with RAD51C mutations combined with single-molecule, single-cell and biophysics measurements uncover discrete CX3 regions for DNA replication fork protection, restart and reversal, accomplished by separable functions in DNA binding and implied 5’ RAD51 filament capping. Collective findings establish CX3 as a cancer-relevant replication stress response complex, show how HDR-proficient variants could contribute to tumor development, and identify regions to aid functional testing and classification of cancer mutations.

La Revista de Economía Argentina (REA) ha sido y es una fuente asidua de consulta para la historia económica y política de la primera mitad del siglo XX, aunque poco transitada como objeto de estudio en sí misma. Asimilada a una tribuna casi unipersonal construida alrededor de Alejandro Bunge y su entorno –académico y corporativo– ha quedado además imbricada a dos ideas fuertes, principalmente desde los pioneros análisis introductorios de Juan Llach a la reedición de una selección de artículos aparecidos en sus páginas, publicada por el Instituto de Desarrollo Económico y Social (IDES) en los años 1980.

Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.

Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However, the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed, mutation rates vary greatly within individual genomes, and lesion recognition by purified DGs in the chromatin context is inefficient. Employing super-resolution microscopy and co-immunoprecipitation assays, we find that acetylated NEIL1 (AcNEIL1), but not its non-acetylated form, is predominantly localized in the nucleus in association with epigenetic marks of uncondensed chromatin. Furthermore, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed non-random AcNEIL1 binding near transcription start sites of weakly transcribed genes and along highly transcribed chromatin domains. Bioinformatic analyses revealed a striking correspondence between AcNEIL1 occupancy along the genome and mutation rates, with AcNEIL1-occupied sites exhibiting fewer mutations compared to AcNEIL1-free domains, both in cancer genomes and in population variation. Intriguingly, from the evolutionarily conserved unstructured domain that targets NEIL1 to open chromatin, its damage surveillance of highly oxidation-susceptible sites to preserve essential gene function and to limit instability and cancer likely originated ∼500 million years ago during the buildup of free atmospheric oxygen.

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase-nuclease-RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary "driver" and "passenger" mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

Homologous recombination/end joining (HR/HEJ)-deficient cancers with BRCA mutations utilize alternative DNA double-strand break repair pathways, particularly alternative non-homologous end joining or microhomology-mediated end joining (alt-EJ/MMEJ) during S and G2 cell cycle phases. Depletion of alt-EJ factors, including XRCC1, PARP1 and POLQ, is synthetically lethal with BRCA2 deficiency; yet, XRCC1 roles in HR-deficient cancers and replication stress are enigmatic. Here, we show that after replication stress, XRCC1 forms an active repair complex with POLQ and MRE11 that supports alt-EJ activity in vitro. BRCA2 limits XRCC1 recruitment and repair complex formation to suppress alt-EJ at stalled forks. Without BRCA2 fork protection, XRCC1 enables cells to complete DNA replication at the expense of increased genome instability by promoting MRE11-dependent fork resection and restart. High XRCC1 and MRE11 gene expression negatively impacts Kaplan-Meier survival curves and hazard ratios for HR-deficient breast cancer patients in The Cancer Genome Atlas. The additive effects of depleting both BRCA2 and XRCC1 indicate distinct pathways for replication restart. Our collective data show that XRCC1-mediated processing contributes to replication fork degradation, replication restart and chromosome aberrations in BRCA2-deficient cells, uncovering new roles of XRCC1 and microhomology-mediated repair mechanisms in HR-deficient cancers, with implications for chemotherapeutic strategies targeting POLQ and PARP activities.

Xeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and a pathway coordinator and structure-specific endonuclease in nucleotide excision repair (NER). Different mutations in the XPG gene ERCC5 lead to either of two distinct human diseases: Cancer-prone xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address the enigmatic structural mechanism for these differing disease phenotypes and for XPG's role in multiple DDRs, here we determined the crystal structure of human XPG catalytic domain (XPGcat), revealing XPG-specific features for its activities and regulation. Furthermore, XPG DNA binding elements conserved with FEN1 superfamily members enable insights on DNA interactions. Notably, all but one of the known pathogenic point mutations map to XPGcat, and both XP-G and XP-G/CS mutations destabilize XPG and reduce its cellular protein levels. Mapping the distinct mutation classes provides structure-based predictions for disease phenotypes: Residues mutated in XP-G are positioned to reduce local stability and NER activity, whereas residues mutated in XP-G/CS have implied long-range structural defects that would likely disrupt stability of the whole protein, and thus interfere with its functional interactions. Combined data from crystallography, biochemistry, small angle X-ray scattering, and electron microscopy unveil an XPG homodimer that binds, unstacks, and sculpts duplex DNA at internal unpaired regions (bubbles) into strongly bent structures, and suggest how XPG complexes may bind both NER bubble junctions and replication forks. Collective results support XPG scaffolding and DNA sculpting functions in multiple DDR processes to maintain genome stability.

Esta introducción presenta algunas reflexiones sobre los hallazgos y argumentos desplegados por los autores que participan en este dossier en torno a los rasgos de las políticas nacionales y su actuación en el interior de la Argentina en el transcurso del siglo XX. A partir de los avances aquí reunidos –relativos a casos, temporalidades, espacialidades y políticas diversas- proponemos algunas consideraciones provisorias en torno a una pregunta que consideramos medular para los estudios históricos y sociales del Estado en Argentina: ¿con qué dimensiones, escalas, geografías y puntos de observación abordar el fenómeno estatal y sus efectos en los balances de poder entre el plano nacional y subnacional, para construir una explicación que otorgue densidad y carnadura a la compleja relación entre nación y provincias?

Topoisomerase 1 (Top1) removes transcription-associated helical stress to sup-press G4-formation and its induced recombination at genomic loci containing guanine-run containing sequences. Interestingly, Top1 binds tightly to G4 struc-tures, and its inhibition or depletion can cause elevated instability at these ge-nomic loci. Top1 is targeted by the widely used anti-cancer chemotherapeutic camptothecin (CPT) and its derivatives, which stabilize Top1 covalently attached on a DNA nick and prevent the re-ligation step. Here we investigated how CPT-resistance conferring Top1 mutants, which emerge in cancer patients and cells treated with CPT, affect G4-induced genomic instability in S. cerevisiae. We found that Top1 mutants form stable complexes with G4 DNA and that expres-sion of Top1 cleavage-defective mutants but not a DNA-binding-defective mu-tant lead to significantly elevated instability at a G4-forming genomic locus. Elevated recombination rates were partly suppressed by their proteolytic re-moval by SPRTN homolog Wss1 SUMO-dependent metalloprotease in vivo. Furthermore, interaction between G4-DNA binding protein Nsr1, a homolog to clinically-relevant human nucleolin, and Top1 mutants lead to a synergistic in-crease in G4-associated recombination. These results in the yeast system are strengthened by our cancer genome data analyses showing that functionally detrimental mutations in Top1 correlate with an enrichment of mutations at G4 motifs. Our collective experimental and computational findings point to cooperative binding of Top1 cleavage-defective mutants and Nsr1 as promoting DNA replication blockage and exacerbating genomic instability at G4-motifs, thus complicating patient treatment.

La pandemia de la covid-19 trajo aparejado múltiples cambios en el mundo del trabajo, modificando sus rutinas, sus formas de comunicación, los vínculos laborales, e inclusive las modalidades en que se expresan, manifiestan y canalizan los descontentos en el espacio público. Este artículo analiza las particularidades de las acciones colectivas protagonizadas por uno de los actores del sector salud, el de la enfermería, el cual tuvo mayor exposición en el contexto de la pandemia, potenciando, un conjunto de tensiones y demandas preexistentes. Sin dejar de contextualizar en el plano nacional, se focalizará en la experiencia de la ciudad de Rosario, ya que nos permite dar cuenta de la protesta más allá del foco habitual de la atención noticiosa nacional en el Área Metropolitana de Buenos Aires (AMBA). En primer lugar se revisan un conjunto de opciones y decisiones teórico metodológicas realizadas para dar cuenta de las formas y prácticas de la protesta a partir del relevamiento de prensa. En segundo lugar, se analizarán los itinerarios de la acción contenciosa en el espacio público a través de la protesta del sector de la salud.

PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects.

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

El texto se interroga acerca de la pervivencia y la naturaleza de las múltiples y por momentos antagónicas representaciones sobre el reformismo universitario a lo largo del siglo XX. Los artículos reunidos en el dossier, sugieren que, más allá de sus respectivos anclajes, el concepto de “Reforma Universitaria” adquirió rápidamente un uso político, deviniendo, en palabras del historiador Melvin Richter (2000), una noción “propiamente política” (p. 138). Esto es, un concepto que define su significado en la controversia y cuyo sentido deriva del propio hecho de estar sometido a la discusión desde diferentes posicionamientos y vertientes ideológicas e identitarias. En esta clave, el presente dossier se propone recorrer algunas de esas representaciones, apropiaciones y usos políticos.

El artículo revisita el proceso de invención del peronismo en el espacio santafesino, atendiendo un campo definitorio de dicha identidad política, aquel del mundo del trabajo. Si bien se ha prestado atención a las tradiciones y los actores que le dieron carnadura, como así también a las dinámicas de construcción partidaria, sindical, y el lugar de ciertas agencias estatales en ella, se ha enfocado menos en los modos en que se definen los nuevos horizontes de pertenencia a la comunidad política a través de un lenguaje de derechos en los momentos fundacionales del peronismo en la escala regional. En ese registro el artículo se concentra en las instancias que la acción estatal tendrá para dirimir conflictos: las delegaciones regionales de la Secretaría de Trabajo, y el nuevo fuero del trabajo dentro de la justicia provincial.

The socialist internationalism arises in the late nineteenth century as an innovative phenomenon for the deployment of a sustained response to the rise of militarism and the “new religion” of patriotism. This debate will have an impact on the Argentine socialism, questioned by the border conflict between Argentina and Chile. The 1890s witness a bellicose escalation and mobilization of various sectors of Argentine society and politics, surmounted by the sanction of compulsory military service in 1901. This work thus focuses on two aspects: on one hand, the reception of the debates of the Second International by the rising Argentine socialism; and on the other hand, the forms of antimilitarism intervention that will shape the profile of the Socialist Party in Argentina.

Summary: Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases. : DNA sequences that can adopt alternative structures, such as H-DNA, have been implicated in cancer etiology. Zhao et al. found that such sequences are enriched at translocation breakpoints in human cancer genomes and that repair- and replication-related nucleases cleave H-DNA in both error-free “replication-related” and mutagenic “replication-independent” mechanisms. Keywords: DNA structure, H-DNA, chromosome translocation, mutation hotspot, DNA repair, nuclease, structural simulation

En los últimos decenios la pregnante profundización del fenómeno global, no sólo ha ganado los titulares mediáticos, o las preocupaciones económicas, sino también impulsado nuevas perspectivas –o rememorado algunas pasadas- dentro del espacio académico de las ciencias sociales. Tanto la historia global, transnacional, los estudios sobre transferencia, la histoire croisée, la entangled History, las renovaciones de la historia cultural e intelectual como aquellos sobre la traducción y difusión de conocimientos han abierto puertas interesantes para pensar los fenómenos de circulación de ideas y prácticas. A la par ha erosionado la preeminencia de los límites estrictos del Estado Nación para indagar diversos procesos y objetos, entre ellos al Estado, sus políticas y estructuras. La recuperación de estos prismas globales, ocluidos paradójicamente en momentos en que la formación del mundo moderno en occidente se tornaba cada vez más trasnacional, ha permitido recuperar los parentescos, las inspiraciones y los diálogos de acciones estatales tan vinculadas al Estado Nación como las políticas culturales de invención de la propia nación -señalado ya hace tiempo por Hobsbawm y Ranger- o en la transformación de las capacidades estatales de intervención ante escenarios como las acciones imperiales o coloniales, los procesos de independencia, las crisis económicas, las coyunturas bélicas, la emergencia de diversas consecuencias de la modernización como aquellas delimitadas por la "cuestión social" y las reconsideraciones sobre las relaciones Estado-Sociedad.En este sentido es que este dossier se propone focalizar en esa suerte de “entre espacio”, como lo denomina Daniel Rodgers (2000), en ese campo difuso de lo transnacional, global, que de diversos modos –más amables a veces, más tensos en otros- ha impulsado o restringido en diversas coyunturas la circulación de prácticas, teorías, textos hasta, a veces, la reelaboración de particulares Weltanschauung. Si, por una parte estos registros globales abren todo un nuevo campo de objetos de estudio, por el otro nos invita a interrogarnos por el modo de abordarlos, alejándonos de enfoques ingenuos o unilaterales respecto a las formas en que se dan estos pasajes, prestando por el contrario atención a un conjunto de aspectos que involucran tanto las tareas de recepción, como de reelaboración, el modo en que estas ideas se trasladan, sus soportes materiales tanto en nombres propios como en instituciones, y la cuestión de la agencia en esos procesos de pasaje trasnacional

El nombre de Rafael Bielsa ha quedado impreso en los inicios del derecho administrativo en el escenario académico argentino de principios del siglo XX. Además de su relevancia en el campo jurídico, su trayectoria académica estuvo ligada a la conformación de la primera facultad que dentro de las universidades argentinas formuló una carrera de Ciencia Política, en la década de 1920. Su obra no se detuvo tampoco en los ámbitos del administrativismo, sino que fue acompañada por un buen número de producciones que a partir de diversos objetos de reflexión –los partidos, la universidad, el Estado– dan cuenta de un clima de ideas, discusiones y conceptos que confluyeron en la construcción del campo de los estudios sobre lo político en el país. El presente artículo se detiene en estos aspectos menos abordados de la trayectoria del jurista, reinsertándolo en las dinámicas de constitución de las “ciencias políticas” en Argentina en las primeras décadas del siglo XX.

El artí­culo constituye un primer avance en el estudio de la profesionalización de la enfermerí­a en la provincia de Santa Fe durante la primera mitad del siglo XX, atendiendo a sus ví­nculos con los procesos de consolidación de experticias en los campos de conocimiento sobre la salud, a la par que su conversión en saberes de Estado. Con este objetivo, el trabajo abordará la experiencia de la creación de la Escuela de Nurses y Visitadoras de Higiene de la Universidad Nacional del Litoral, con sede en la Facultad de Medicina de Rosario, primera experiencia nacional a nivel universitario de formación en enfermerí­a. Ordenamos el trabajo a partir de tres ejes: por un lado, los antecedentes locales en torno a la formación en enfermerí­a y las caracterí­sticas del proyecto académico regional que caracterizó las primeras décadas de la Universidad; en segundo término, la particular relación entre proyecto universitario y polí­tica en la entreguerras en Santa Fe. Por último, la circulación transnacional de polí­ticas sanitarias, en el marco de una nueva perspectiva sobre la “cuestión social”, el diálogo de la Fundación Rockefeller con la Universidad y el Estado provincial en este sentido. El trabajo concluye con la institucionalización de un proyecto polí­tico diverso, coincidente con el cierre de la experiencia universitaria cristalizada a inicios de 1940: la Escuela de Enfermeras en Salud Pública dependiente del Ministerio de Salud de la provincia, que iniciada en 1948, presentó notables diferencias tanto en términos formativos como en su administración y los expertos para ello convocados.

The article explores the formation of academic field of labor law in one of the three Argentine universities where the crystallization of specific areas related to its research and technical implementation took place: Universidad Nacional del Litoral. First, the paper reviews the dynamics that influence the beginnings and formation of this legal knowledge. Second, it focuses on the trajectory of one of the pioneers in labour law in Argentina, Mariano Tissembaum, and the Labour Law Institute he founded in 1938. Through its publications, networks and the debates in which is inserted, during the decades of 1930 and 1940, the paper presents some preliminary progress that account not only the dynamics of formation of an academic field but also of a social consensus and the conditions of possibility that converted it in a technical knowledge summoned from the State.

Analyses of chromosomal aberrations in human genetic disorders have revealed that inverted repeat sequences (IRs) often co-localize with endogenous chromosomal instability and breakage hotspots. Approximately 80% of all IRs in the human genome are short (

Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness. Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of genetic alteration found in cancer cells, somatic single base substitutions (SBSs). Cytosine methylation, demethylation and deamination, charge transfer reactions in DNA, DNA replication timing, chromatin status and altered DNA proofreading activities are all now known to contribute to the mechanisms leading to base substitution mutagenesis. We review current hypotheses as to the major processes that give rise to SBSs and evaluate their relative relevance in the light of knowledge acquired from cancer genome sequencing projects and the study of base modifications, DNA repair and lesion bypass. Although gene expression data on APOBEC3B enzymes provide support for a role in cancer mutagenesis through U:G mismatch intermediates, the enzyme preference for single-stranded DNA may limit its activity genome-wide. For SBSs at both CG:CG and YC:GR sites, we outline evidence for a prominent role of damage by charge transfer reactions that follow interactions of the DNA with reactive oxygen species (ROS) and other endogenous or exogenous electron-abstracting molecules.