Epithelial Cell Division: Keeping Aneuploidy Levels in Check

SummaryAneuploidy is deleterious at the cellular and organismal level and can promote tumorigenesis. Two new studies in Drosophila imaginal discs underscore the cellular and tissue-wide mechanisms that prevent the accumulation of aneuploid cells in symmetrically dividing epithelial tissues upon changes in centrosome number

Correlation Between Ischemic Retinal Accidents and Radial Peripapillary Capillaries in the Optic Nerve Using Optical Coherence Tomographic Angiography: Observations in 6 Patients

Background: Perfusion of the optic nerve has been widely studied using fluorescein angiography (FAG), which is currently regarded as the criterion standard. However, FAG has adverse effects associated with intravenous contrast administration and is limited in its capacity to characterize and stratify the different vascular layers of the optic nerve and retina. The use of new imaging techniques, such as optical coherence tomographic angiography (Angio-OCT), is therefore important. Aim: A qualitative description is made of the vascular layers of the optic nerve and of how vascular events affect radial peripapillary capillaries (RPC). Two patients with central retinal artery occlusion (CRAO), 1 with arteritic anterior ischemic optic neuropathy (AAION), and 3 healthy subjects were studied. Results : The Angio-OCT imaging afforded better visualization of the depth of the RPC and rest of the vascular layers of the retina compared with FAG. Optic nerve surface perfusion was affected in AAION and proved normal in CRAO. Conclusions : Our results indicate that perfusion of the papilla and RPC mainly arises from the papillary plexus that depends on the posterior ciliary artery

Internalization of the anti-carcinogenic IBB1, a major Bowman-Birk isoinhibitor from soybean (Glycine max), in HT29 colon cancer cells

Proceedings of the I Congress PIIISA celebrado en la Estación Experimental del Zaidín (Granada), en mayo de 2013.Protease inhibitors of the Bowman-Birk type, a major protease inhibitor family in legume seeds, which inhibit potently trypsin- and chymotrypsin-like proteases, are currently being investigated as colorectal chemopreventive agents. Although the therapeutic target/s and the action mechanism/s of Bowman-Birk inhibitors (BBI) have not yet been elucidated, the emerging evidence suggests that BBI exert their chemopreventive properties via protease inhibition; in this sense, serine proteases should be considered as primary targets in early stages of carcinogenesis. In this work, we have demonstrated that IBB1, a major protease inhibitor of the Bowman-Birk family in soybean (Glycine max), exerts anti-proliferative effect in human colorectal HT29 cancer cells at concentrations higher than 15 μM, in a dose dependent manner. By using confocal microscopy, we have demonstrated that IBB1 is taken up by HT29 colon cancer cells in a time-dependent manner, being the bulk of the internalized protease inhibitor localized in the cytoplasm where might interact with their potential therapeutic target/s.This work was supported by ERDF-co-financed grants AGL2011-26353 (Spanish Ministry of Economy and Competitiveness) and PE2010-CVI-5767 (Junta de Andalucía).Peer reviewe

Modelo estocástico de traducción basado en N-gramas de tuplas bilingües y combinación log-lineal de características

En esta comunicación se presenta un sistema de traducción estocástica basado en el modelado mediante N-gramas de la probabilidad conjunta de textos bilingües. La unidad básica del modelo es la tupla, par de cadenas de palabras del lenguaje fuente (a traducir) y el lenguaje destino (traducción). La traducción se lleva a cabo mediante la maximización de una combinación lineal de los logaritmos de la probabilidad asignada a la traducción por el modelo de traducción y otras características, siguiendo la aproximación de entropía máxima. Las prestaciones del sistema de traducción son evaluadas con una tarea de traducción del habla: la traducción entre inglés y español (y viceversa) de transcripciones de intervenciones de los miembros del Parlamento Europeo. Los resultados alcanzados se encuentran al nivel del estado del arte.This communication introduces a stochastic machine translation system based on Ngram modelling of the joint probability of bilingual texts. The basic unit of this model is called a tuple and consists of a pair of both source (to be translated) language and target language (translation) word-strings. Translation is driven by a log-linear combination of the N-gram model probability and other features, according to the maximum entropy language modelling approach. The translation performance is evaluated by means of a speech-to-speech translation tasks: translation from Spanish to English (and viceversa) of European Parliament speeches. The system reaches a state-of-art performance.Este trabajo ha sido financiado parcialmente por la CICYT a través del proyecto TIC2002-04447-C02 (ALIADO) y la Unión Europea mediante el proyecto FP6-506738 (TC-STAR)

Faunal evidence of the 1755 Lisbon Tsunami in Gibraltar (S Iberian Peninsula)

This paper analyzes the first systematic faunal record of the 1755 Lisbon tsunami in the Mediterranean. On the basis of sedimentological and paleontological features, the sedimentary record of a core collected in Gibraltar was divided into six sedimentary facies, with a paleoenvironmental evolution from a shallow marine paleoenviroment to an increasingly restricted lagoon. This record includes a bioclastic layer deposited by the 1755 Lisbon tsunami and characterized by an erosive base, presence of basal rip-up clasts and abundant shell debris composed by marine and brackish molluscs. The paleoenvironmental reconstruction derived from the foraminiferal analysis is congruent with that inferred from the sedimentary and the macrofaunal reconstructions, with the introduction of brackish species into the innermost, intertidal areas of a confined lagoon. This paleontological record is the first faunal evidence of the 1755 Lisbon tsunami in the Mediterranean.We thank the Gibraltar National Museum and its Director, Dr. Clive Finlayson, for the efforts made to conserve and acquire the BH borehole core. In addition, we thank the review of Dr. Akihisa Kitamura and Dr. Briony Mamo, whose suggestions greatly improved the manuscript, and the associate-editor of Geobios, Dr. Frédéric Quillévéré, for his kind help and comments during the revision process. This research was supported by two postdoctoral fellows of the Spanish Ministry of Science and Innovation Government (Subprograma JDCMICINN, JCI-2010-06160) and the Huelva University (PP2010 P-01). Furthermore, this work is carried out through DGYCIT project CTM2006-06722/MAR, DGYCIT project CGL2006-01412, FEDER 2014-2020 project UHU-126029, PID2021- 127268NB-I00 project funded by MCIN/ AEI /10.13039/50110 0011033/ and by FEDER, and AYUDA PUENTE 2021 project M2615 of the Rey Juan Carlos University. Other funds have come from the Andalusian Government (groups RNM-238, RNM-293 and RNM-349) and Autonomous University of Madrid (GPG-418 Research Group). It is a contribution to the Research Center in Historical, Cultural and Natural Heritage (CIPHCN) of the University of Huelva

Histone H3K56 Acetylation, CAF1, and Rtt106 Coordinate Nucleosome Assembly and Stability of Advancing Replication Forks

Chromatin assembly mutants accumulate recombinogenic DNA damage and are sensitive to genotoxic agents. Here we have analyzed why impairment of the H3K56 acetylation-dependent CAF1 and Rtt106 chromatin assembly pathways, which have redundant roles in H3/H4 deposition during DNA replication, leads to genetic instability. We show that the absence of H3K56 acetylation or the simultaneous knock out of CAF1 and Rtt106 increases homologous recombination by affecting the integrity of advancing replication forks, while they have a minor effect on stalled replication fork stability in response to the replication inhibitor hydroxyurea. This defect in replication fork integrity is not due to defective checkpoints. In contrast, H3K56 acetylation protects against replicative DNA damaging agents by DNA repair/tolerance mechanisms that do not require CAF1/Rtt106 and are likely subsequent to the process of replication-coupled nucleosome deposition. We propose that the tight connection between DNA synthesis and histone deposition during DNA replication mediated by H3K56ac/CAF1/Rtt106 provides a mechanism for the stabilization of advancing replication forks and the maintenance of genome integrity, while H3K56 acetylation has an additional, CAF1/Rtt106-independent function in the response to replicative DNA damage

The SWR1 Histone Replacement Complex Causes Genetic Instability and Genome-Wide Transcription Misregulation in the Absence of H2A.Z

The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 in yeast) at specific chromatin regions. This dynamic alteration in nucleosome structure provides a molecular mechanism to regulate transcription, gene silencing, chromosome segregation and DNA repair. Here we show that genetic instability, sensitivity to drugs impairing different cellular processes and genome-wide transcriptional misregulation in htz1Δ can be partially or totally suppressed if SWR1 is not formed (swr1Δ), if it forms but cannot bind to chromatin (swc2Δ) or if it binds to chromatin but lacks histone replacement activity (swc5Δ and the ATPase-dead swr1-K727G). These results suggest that in htz1Δ the nucleosome remodelling activity of SWR1 affects chromatin integrity because of an attempt to replace H2A with Htz1 in the absence of the latter. This would impair transcription and, either directly or indirectly, other cellular processes. Specifically, we show that in htz1Δ, the SWR1 complex causes an accumulation of recombinogenic DNA damage by a mechanism dependent on phosphorylation of H2A at Ser129, a modification that occurs in response to DNA damage, suggesting that the SWR1 complex impairs the repair of spontaneous DNA damage in htz1Δ. In addition, SWR1 causes DSBs sensitivity in htz1Δ; consistently, in the absence of Htz1 the SWR1 complex bound near an endonuclease HO-induced DSB at the mating-type (MAT) locus impairs DSB-induced checkpoint activation. Our results support a stepwise mechanism for the replacement of H2A with Htz1 and demonstrate that a tight control of this mechanism is essential to regulate chromatin dynamics but also to prevent the deleterious consequences of an incomplete nucleosome remodelling

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true