Inhibition of zygotic DNA repair: transcriptome analysis of the offspring in trout (Oncorhynchus mykiss)

Palabras clave extraídas del título[EN] Zygotic repair of the paternal genome is a key event after fertilization. Spermatozoa accumulate DNA strand breaks during spermatogenesis and can suffer additional damage by different factors, including cryopreservation. Fertilization with DNA-damaged spermatozoa (DDS) is considered to promote implantation failures and abortions, but also long-term effects on the progeny that could be related with a defective repair. Base excision repair (BER) pathway is considered the most active in zygotic DNA repair, but healthy oocytes contain enzymes for all repairing pathways. In this study, the effects of the inhibition of the BER pathway in the zygote were analyzed on the progeny obtained after fertilization with differentially DDS. Massive gene expression (GE; 61 657 unique probes) was analyzed after hatching using microarrays. Trout oocytes are easily fertilized with DDS and the high prolificacy allows live progeny to be obtained even with a high rate of abortions. Nevertheless, the zygotic inhibition of Poly (ADP-ribose) polymerase, upstream of BER pathway, resulted in 810 differentially expressed genes (DEGs) after hatching. DEGs are related with DNA repair, apoptosis, telomere maintenance, or growth and development, revealing a scenario of impaired DNA damage signalization and repair. Downregulation of the apoptotic cascade was noticed, suggesting a selection of embryos tolerant to residual DNA damage during embryo development. Our results reveal changes in the progeny from defective repairing zygotes including higher malformations rate, weight gain, longer telomeres, and lower caspase 3/7 activity, whose long-term consequences should be analyzed in depthSIThis work was supported by the Junta de Castilla y León (Spain) (project LE365A11-2) and the Spanish Ministry of Economy and Competitiveness (project AGL2011-27787

Development and clinical validation of real-time artificial intelligence diagnostic companion for fetal ultrasound examination

OBJECTIVE: Prenatal diagnosis of a rare disease on ultrasound relies on a physician's ability to remember an intractable amount of knowledge. We developed a real-time decision support system (DSS) that suggests, at each step of the examination, the next phenotypic feature to assess, optimizing the diagnostic pathway to the smallest number of possible diagnoses. The objective of this study was to evaluate the performance of this real-time DSS using clinical data. METHODS: This validation study was conducted on a database of 549 perinatal phenotypes collected from two referral centers (one in France and one in the UK). Inclusion criteria were: at least one anomaly was visible on fetal ultrasound after 11 weeks' gestation; the anomaly was confirmed postnatally; an associated rare disease was confirmed or ruled out based on postnatal/postmortem investigation, including physical examination, genetic testing and imaging; and, when confirmed, the syndrome was known by the DSS software. The cases were assessed retrospectively by the software, using either the full phenotype as a single input, or a stepwise input of phenotypic features, as prompted by the software, mimicking its use in a real-life clinical setting. Adjudication of discordant cases, in which there was disagreement between the DSS output and the postnatally confirmed (‘ascertained’) diagnosis, was performed by a panel of external experts. The proportion of ascertained diagnoses within the software's top-10 differential diagnoses output was evaluated, as well as the sensitivity and specificity of the software to select correctly as its best guess a syndromic or isolated condition. RESULTS: The dataset covered 110/408 (27%) diagnoses within the software's database, yielding a cumulative prevalence of 83%. For syndromic cases, the ascertained diagnosis was within the top-10 list in 93% and 83% of cases using the full-phenotype and stepwise input, respectively, after adjudication. The full-phenotype and stepwise approaches were associated, respectively, with a specificity of 94% and 96% and a sensitivity of 99% and 84%. The stepwise approach required an average of 13 queries to reach the final set of diagnoses. CONCLUSIONS: The DSS showed high performance when applied to real-world data. This validation study suggests that such software can improve perinatal care, efficiently providing complex and otherwise overlooked knowledge to care-providers involved in ultrasound-based prenatal diagnosis. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

Towards Machine Wald

The past century has seen a steady increase in the need of estimating and predicting complex systems and making (possibly critical) decisions with limited information. Although computers have made possible the numerical evaluation of sophisticated statistical models, these models are still designed \emph{by humans} because there is currently no known recipe or algorithm for dividing the design of a statistical model into a sequence of arithmetic operations. Indeed enabling computers to \emph{think} as \emph{humans} have the ability to do when faced with uncertainty is challenging in several major ways: (1) Finding optimal statistical models remains to be formulated as a well posed problem when information on the system of interest is incomplete and comes in the form of a complex combination of sample data, partial knowledge of constitutive relations and a limited description of the distribution of input random variables. (2) The space of admissible scenarios along with the space of relevant information, assumptions, and/or beliefs, tend to be infinite dimensional, whereas calculus on a computer is necessarily discrete and finite. With this purpose, this paper explores the foundations of a rigorous framework for the scientific computation of optimal statistical estimators/models and reviews their connections with Decision Theory, Machine Learning, Bayesian Inference, Stochastic Optimization, Robust Optimization, Optimal Uncertainty Quantification and Information Based Complexity.Comment: 37 page

Dispositivos gráficos y pictóricos en la guerra del Paraguay

Datada en 1866, la Figura 1 (ver en "Documento completo") nos presenta un numeroso grupo de hombres bajo la gran copa de un árbol. Junto a ellos se observan algunos carros y carpas, en medio de un paisaje desolador. Sin más preámbulos (y como nos indica su título), se trata pues, de la Guardia de Honor de Mitre durante el conflicto bélico denominado “Guerra de la Triple Alianza”. Con la firma de Bate y Compañía, la imagen fue realizada mediante la técnica del daguerrotipo, método fotográfico divulgado en 1839 por el inventor francés Louis Daguerre. Un año después del tratado secreto de la Triple Alianza, la Compañía Bate obtuvo un permiso de las autoridades para que sus fotógrafos pudieran ingresar al campo de batalla. Llevaron la carpa, el trípode y un laboratorio móvil, elementos indispensables para el daguerrotipo debido a las dificultades de tiempo y exposición de los primeros años de la fotografía. No se puede adjudicar a la Figura 1 el carácter de retrato a gran escala, ya que difícilmente podamos distinguir a alguno de los representados pues, como se observa, la intención fotográfica no estaba puesta en individualizar a los sujetos; tampoco podemos hablar de un paisaje, porque el terreno actúa más como un contenedor o indicador espacial, casi sin ningún rastro distintivo (aunque no hay que restar importancia a la imagen conceptual que genera del campo de batalla). Al ser realizada en el marco de un conflicto bélico y servir de carácter testimonial de aquel, podríamos hablar de una fotografía de tipo social o de fotoperiodismo.Facultad de Arte

The Physics of Hadronic Tau Decays

Hadronic tau decays represent a clean laboratory for the precise study of quantum chromodynamics (QCD). Observables (sum rules) based on the spectral functions of hadronic tau decays can be related to QCD quark-level calculations to determine fundamental quantities like the strong coupling constant, parameters of the chiral Lagrangian, |V_us|, the mass of the strange quark, and to simultaneously test the concept of quark-hadron duality. Using the best available measurements and a revisited analysis of the theoretical framework, the value alpha_s(m_tau) = 0.345 +- 0.004[exp] +- 0.009[theo] is obtained. Taken together with the determination of alpha_s(m_Z) from the global electroweak fit, this result leads to the most accurate test of asymptotic freedom: the value of the logarithmic slope of 1/alpha_s(s) is found to agree with QCD at a precision of 4%. In another approach, the tau spectral functions can be used to determine hadronic quantities that, due to the nonperturbative nature of long-distance QCD, cannot be computed from first principles. An example for this is the contribution from hadronic vacuum polarization to loop-dominated processes like the anomalous magnetic moment of the muon. This article reviews the measurements of nonstrange and strange tau spectral functions and their phenomenological applications.Comment: 89 pages, 32 figures; final version accepted for publication by Reviews of Modern Physic

QCD Description of Hadronic Tau Decays

The QCD analysis of hadronic tau decays is reviewed and a summary of the present phenomenological status is presented. The following topics are discussed: the determination of alpha_s(m_tau) = 0.338 +- 0.012 from the inclusive tau hadronic width, the measurement of |V_us| through the Cabibbo-suppressed decays of the tau, and the extraction of chiral-perturbation-theory couplings from the spectral tau data.Comment: 9 pages, 1 figure. Invited talk at the 11th International Workshop on Tau Lepton Physics (Manchester, September 2010

Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain

Acknowledgements: We thank A Elewa, N Dantuma, C Sjögren for many helpful comments on the manuscript, and H Wang and M Kirkham for advice. This work was supported by grants from the European Research Council, Swedish Research Council, Swedish Cancer Society, AFA Insurances to AS. YC´s laboratory is supported by research grants from the Swedish Research Council, the Swedish Cancer Foundation, the Karolinska Institute Foundation, the Karolinska Institute distinguished professor award, the Torsten Soderbergs foundation, the NOVO Nordisk Foundation, the Advanced grant from the NOVO Nordisk foundation, and the Alice Wallenberg foundation This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.Peer reviewedPublisher PD