Population, immigration and growth in a Romer endogenous growth model

Producción CientíficaEndogenous growth theory has not yet consistently incorporated population growth or immigration into its models. As a result, in the present day, there is no universally accepted endogenous growth model explaining the empirical observed relationships between growth, population and immigration. The present paper overcomes this inconvenience by designing a fully specified Romer endogenous growth model, completely micro-founded, that incorporates the existence of population growth and immigration and that allows the stylised facts of growth as well as the relationships between growth, population and immigration to be explained. In addition, the proposed model is susceptible to calibration and simulation, and, when applied to the US economy, provides a good fit to the data.Financial support from Spanish Office of Economy and Competitiveness and European FEDER Funds, Research Projects MTM2014-56022-C2-2-P and MTM2017-85476-C2-1-P, is gratefully acknowledged

The effects of time valuation in cancer optimal therapies: a study of chronic myeloid leukemia

Background The mathematical design of optimal therapies to fight cancer is an important research field in today’s Biomathematics and Biomedicine given its relevance to formulate patient-specific treatments. Until now, however, cancer optimal therapies have considered that malignancy exclusively depends on the drug concentration and the number of cancer cells, ignoring that the faster the cancer grows the worse the cancer is, and that early drug doses are more prejudicial. Here, we analyze how optimal therapies are affected when the time evolution of treated cancer is envisaged as an additional element determining malignancy, analyzing in detail the implications for imatinib-treated Chronic Myeloid Leukemia. Methods Taking as reference a mathematical model describing Chronic Myeloid Leukemia dynamics, we design an optimal therapy problem by modifying the usual malignancy objective function, unaware of any temporal dimension of cancer malignance. In particular, we introduce a time valuation factor capturing the increase of malignancy associated to the quick development of the disease and the persistent negative effects of initial drug doses. After assigning values to the parameters involved, we solve and simulate the model with and without the new time valuation factor, comparing the results for the drug doses and the evolution of the disease. Results Our computational simulations unequivocally show that the consideration of a time valuation factor capturing the higher malignancy associated with early growth of cancer and drug administration allows more efficient therapies to be designed. More specifically, when this time valuation factor is incorporated into the objective function, the optimal drug doses are lower, and do not involve medically relevant increases in the number of cancer cells or in the disease duration. Conclusions In the light of our simulations and as biomedical evidence strongly suggests, the existence of a time valuation factor affecting malignancy in treated cancer cannot be ignored when designing cancer optimal therapies. Indeed, the consideration of a time valuation factor modulating malignancy results in significant gains of efficiency in the optimal therapy with relevant implications from the biomedical perspective, specially when designing patient-specific treatments.This work was supported by projects MTM2014-56022-C2-2-P and MTM2017-85476-C2-1-P of the Spanish Office of Innovation and Competitiveness and European FEDER Funds, and by projects of the Castile and León Autonomous Government: VA041P17 (with European FEDER Funds), VA138G18 and VA148G18

Retinoid-dependent mRNA expression and poly-(A) contents in bovine oocytes meiotically arrested and/or matured in vitro

The presence of retinoic acid (RA) during in vitro maturation (IVM) improves bovine oocyte quality and developmental potential. In this work, we investigated the underlying molecular mechanisms. Cumulus–oocyte complexes were meiotically arrested by roscovitine and/or matured in defined medium containing RA, 1% ethanol (vehicle), or no additives. Cumulus-free oocytes were analyzed for poly-(A) mRNA contents and relative mRNA expression of genes involved in cell cycle regulation (cyclin B1 and H1) and antioxidative defence (Mn-superoxide dismutase and glucose-6-phosphate dehydrogenase). Poly-(A) mRNA increased after meiotic inhibition and decreased with IVM completion, both in meiotically arrested and permissively matured oocytes, i.e., matured without previous meiotic arrest. RA dramatically increased poly-(A) mRNA in meiotically arrested oocytes, but more than half of the poly-(A) mRNA disappeared during maturation. Irrespective of oocyte origin, transcripts were detected for all the genes analyzed. IVM, with or without previous meiotic inhibition, increased expression of cyclin B1 and glucose-6-phosphate dehydrogenase, and decreased cyclin H1 and Mn-superoxide dismutase. Except for a decreasing of Mn-superoxide dismutase in meiotically arrested and matured oocytes, RA did not affect mRNA expression. Ethanol led to an abnormal poly-(A) mRNA profile and expression of all the genes analyzed. RA does not modify expression of cyclin B1 and HI genes in the bovine oocyte, and probably does not generate oxidative stress. In addition, RA enhanced mRNA amount as measured by poly-(A) mRNA contents

The landscape of expression and alternative splicing variation across human traits

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.This study was funded by the HumTranscriptom project with reference PID2019-107937GA-I00. R.G.-P. was supported by a Juan de la Cierva fellowship (FJC2020-044119-I) funded by MCIN/AEI/10.13039/501100011033 and ‘‘European Union NextGenerationEU/PRTR.’’ J.M.R. was supported by a predoctoral fellowship from ‘‘la Caixa’’ Foundation (ID 100010434) with code LCF/BQ/DR22/11950022. A.R.-C. was supported by a Formación Personal Investigador (FPI) fellowship (PRE2019-090193) funded by MCIN/AEI. R.C.-G. was supported by an FPI fellowship (PRE2020-092510) funded by MCIN/AEI. M.M. was supported by a Ramon y Cajal fellowship (RYC-2017-22249).Peer ReviewedPostprint (published version

Genetic Study of SARS-CoV-2 Non Structural Protein 12 in COVID-19 Patients Non Responders to Remdesivir

Remdesivir (RDV) was the first antiviral drug approved by the FDA to treat severe coronavirus disease-2019 (COVID-19) patients. RDV inhibits SARS-CoV-2 replication by stalling the non structural protein 12 (nsp12) subunit of the RNA-dependent RNA polymerase (RdRp). No evidence of global widespread RDV-resistance mutations has been reported, however, defining genetic pathways to RDV resistance and determining emergent mutations prior and subsequent antiviral therapy in clinical settings is necessary. This study identified 57/149 (38.3%) patients who did not respond to one course (5-days) (n = 36/111, 32.4%) or prolonged (5 to 20 days) (n = 21/38, 55.3%) RDV therapy by subgenomic RNA detection. Genetic variants in the nsp12 gene were detected in 29/49 (59.2%) non responder patients by Illumina sequencing, including the de novo E83D mutation that emerged in an immunosuppressed patient after receiving 10 + 8 days of RDV, and the L838I detected at baseline and/or after prolonged RDV treatment in 9/49 (18.4%) non responder subjects. Although 3D protein modeling predicted no interference with RDV, the amino acid substitutions detected in the nsp12 involved changes on the electrostatic outer surface and in secondary structures that may alter antiviral response. It is important for health surveillance to study potential mutations associated with drug resistance as well as the benefit of RDV retreatment, especially in immunosuppressed patients and in those with persistent replication. IMPORTANCE This study provides clinical and microbiologic data of an extended population of hospitalized patients for COVID-19 pneumonia who experienced treatment failure, detected by the presence of subgenomic RNA (sgRNA). The genetic variants found in the nsp12 pharmacological target of RDV bring into focus the importance of monitoring emergent mutations, one of the objectives of the World Health Organization (WHO) for health surveillance. These mutations become even more crucial as RDV keeps being prescribed and new molecules are being repurposed for the treatment of COVID-19. The present article offers new perspectives for the clinical management of non responder patients treated and retreated with RDV and emphasizes the need of further research of the benefit of combinatorial therapies and RDV retreatment, especially in immunosuppressed patients with persistent replication after therapy.This work was financed by a Gilead Sciences grant (IN-ES-540-6089) and CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, España (CB21/13/00081). This work was financed by ad hoc patronage funds for research on COVID-19 from donations from citizens and organizations to the Hospital Clínic de Barcelona-Fundació Clínic per a la Recerca Biomèdica.S

Youtube como herramienta dinamizadora en el proceso de enseñanza-aprendizaje dentro del ámbito de la Microbiología

Memoria ID-0092. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2015-2016

Grabación de vídeo-tutoriales con protocolos básicos de Microbiología y difusión de su contenido a través de Youtube

Memoria ID-0122. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2014-2015

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age �60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial