Identification and Characterization of Epithelial Cell-Derived Dense Bodies Produced upon Cytomegalovirus Infection

Dense bodies (DB) are complex, noninfectious particles produced during CMVinfection containing envelope and tegument proteins that may be ideal candidates as vaccines. Although DB were previously described in fibroblasts, no evidence of DB formation has been shown after propagating CMV in epithelial cells. In the present study, both fibroblast MRC-5 and epithelial ARPE-19 cells were used to study DB production during CMV infection. We demonstrate the formation of epithelial cell-derived DB, mostly located as cytoplasmic inclusions in the perinuclear area of the infected cell. DB were gradient-purified, and the nature of the viral particles was confirmed using CMV-specific immunelabeling. Epithelial cell-derived DB had higher density and more homogeneous size (200-300 nm) compared to fibroblast-derived DB (100-600 nm).In agreement with previous results characterizing DB from CMV-infected fibroblasts, the pp65 tegument protein was predominant in the epithelial cell-derived DB. Our results also suggest that epithelial cells had more CMV capsids in the cytoplasm and had spherical bodies compatible with nucleus condensation (pyknosis) in cells undergoing apoptosis that were not detected in MRC-5 infected cells at the tested time post-infection. Our results demonstrate the formation of DB in CMV-infected ARPE-19 epithelial cells that may be suitable candidate to develop a multiprotein vaccine with antigenic properties similar to that of the virions while not including the viral genome.This study was supported by the Spanish Ministry of Science, Innovation and University, Instituto de Salud Carlos III Grant/Award Numbers: PI17CIII-00014 (MPY110/18); PI20CIII-00009 (MPY303/20); DTS18CIII/00006 (MPY127/19). E.G-R is supported by the Sara Borrell Program (CD18CIII/00007), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades. MJR is supported by the PTA Program (PTA2017-14233-I), Ministerio de Ciencia, Innovación y Universidades.S

Bayesian variable selection and survival modeling: assessing the Most important comorbidities that impact lung and colorectal cancer survival in Spain

ancer survival represents one of the main indicators of interest in cancer epidemiology. However, the survival of cancer patients can be affected by several factors, such as comorbidities, that may interact with the cancer biology. Moreover, it is interesting to understand how different cancer sites and tumour stages are affected by different comorbidities. Identifying the comorbidities that affect cancer survival is thus of interest as it can be used to identify factors driving the survival of cancer patients. This information can also be used to identify vulnerable groups of patients with comorbidities that may lead to worst prognosis of cancer. We address these questions and propose a principled selection and evaluation of the effect of comorbidities on the overall survival of cancer patients. In the first step, we apply a Bayesian variable selection method that can be used to identify the comorbidities that predict overall survival. In the second step, we build a general Bayesian survival model that accounts for time-varying effects. In the third step, we derive several posterior predictive measures to quantify the effect of individual comorbidities on the population overall survival. We present applications to data on lung and colorectal cancers from two Spanish population-based cancer registries. The proposed methodology is implemented with a combination of the R-packages mombf and rstan. We provide the code for reproducibility at https://github.com/migariane/BayesVarImpComorbiCancer

Investigating the inequalities in route to diagnosis amongst patients with diffuse large B-cell or follicular lymphoma in England

Introduction: Diagnostic delay is associated with lower chances of cancer survival. Underlying comorbidities are known to affect the timely diagnosis of cancer. Diffuse large B-cell (DLBCL) and follicular lymphomas (FL) are primarily diagnosed amongst older patients, who are more likely to have comorbidities. Characteristics of clinical commissioning groups (CCG) are also known to impact diagnostic delay. We assess the association between comorbidities and diagnostic delay amongst patients with DLBCL or FL in England during 2005–2013. Methods: Multivariable generalised linear mixed-effect models were used to assess the main association. Empirical Bayes estimates of the random effects were used to explore between-cluster variation. The latent normal joint modelling multiple imputation approach was used to account for partially observed variables. Results: We included 30,078 and 15,551 patients diagnosed with DLBCL or FL, respectively. Amongst patients from the same CCG, having multimorbidity was strongly associated with the emergency route to diagnosis (DLBCL: odds ratio 1.56, CI 1.40–1.73; FL: odds ratio 1.80, CI 1.45–2.23). Amongst DLBCL patients, the diagnostic delay was possibly correlated with CCGs that had higher population densities. Conclusions: Underlying comorbidity is associated with diagnostic delay amongst patients with DLBCL or FL. Results suggest a possible correlation between CCGs with higher population densities and diagnostic delay of aggressive lymphomas

Validation of the Spanish-language Cardiff Anomalous Perception Scale

The Cardiff Anomalous Perceptions Scale (CAPS) is a psychometric measure of hallucinatory experience. It has been widely used in English and used in initial studies in Spanish but a full validation study has not yet been published. We report a validation study of the Spanish-language CAPS, conducted in both Spain and Colombia to cover both European and Latin American Spanish. The Spanish-language version of the CAPS was produced through back translation with slight modifications made for local dialects. In Spain, 329 non-clinical participants completed the CAPS along with 40 patients with psychosis. In Colombia, 190 non-clinical participants completed the CAPS along with 21 patients with psychosis. Participants completed other psychometric scales measuring psychosis-like experience to additionally test convergent and divergent validity. The Spanish-language CAPS was found to have good internal reliability. Test-retest reliability was slightly below the cut-off, although could only be tested in the Spanish non-clinical sample. The scale showed solid construct validity and a principal components analysis broadly replicated previously reported three component factor structures for the CAPS

Feigenbaum graphs: a complex network perspective of chaos

The recently formulated theory of horizontal visibility graphs transforms time series into graphs and allows the possibility of studying dynamical systems through the characterization of their associated networks. This method leads to a natural graph-theoretical description of nonlinear systems with qualities in the spirit of symbolic dynamics. We support our claim via the case study of the period-doubling and band-splitting attractor cascades that characterize unimodal maps. We provide a universal analytical description of this classic scenario in terms of the horizontal visibility graphs associated with the dynamics within the attractors, that we call Feigenbaum graphs, independent of map nonlinearity or other particulars. We derive exact results for their degree distribution and related quantities, recast them in the context of the renormalization group and find that its fixed points coincide with those of network entropy optimization. Furthermore, we show that the network entropy mimics the Lyapunov exponent of the map independently of its sign, hinting at a Pesin-like relation equally valid out of chaos.Comment: Published in PLoS ONE (Sep 2011

Cumplimiento, conocimiento y automedicación como factores asociados a los resultados clínicos negativos de la farmacoterapia

The patient plays a fundamental role in the attainment of good results in pharmacotherapy. Noncompliance,self-medication, or insufficient knowledge of the therapy being employed may provide asource for the causes of these negative clinical outcomes, otherwise known as medicine related problems(MRP). he Dader method was used in the evaluation, identification and classification of MRP. Theassociation of variables was established through the statistical Chi square test. Patient knowledge of themedicine, degree of compliance to therapy and self-medication were studied as causes of the negativeoutcomes encountered. 2556 patients were interviewed throughout the year that the study took place,giving a total of 2261 of valid cases. 33% presented an MRP as the cause of his/her visit to the hospitalemergency ward. Knowledge of the medicine, compliance and self-medication were only studied in thepopulation that presented an MRP and in this work it is demonstrated that these are aspects that areassociated with different dimensions of MRP. It is not possible to establish an association between theexistence or not of negative clinical outcomes in patients with the factors of knowledge of medication,compliance and self-medication. This is due to the fact that these variables are not attributable to thepatient himself, but rather are associated with the characteristics of each medicine.El paciente juega un papel primordial en la consecución de los resultados terapéuticos. El incumplimiento,la automedicación, o la falta de conocimiento del la farmacoterapia pueden ser causas de esosresultados clínicos negativos, denominados en ocasiones problemas relacionados con medicamentos(PRM). El método Dáder se utilizó para la evaluación, identificación y clasificación de PRM. Laasociación de variables se estableció mediante el estadístico chi cuadrado. El conocimiento de la medicación,el cumplimiento y la automedicación fueron estudiados como causa de estos resultados negativosde la medicación. Fueron entrevistados 2556 pacientes durante el año de estudio, resultando 2261 casosválidos. El 33 % presentaron un PRM como causa de visita a urgencias. El conocimiento de la medicación,el cumplimiento y la automedicación fueron estudiados solo en la población que presentó unPRM y se demuestra que son aspectos asociados a las distintas dimensiones de PRM. No es posibleestablecer asociación entre la existencia o no de resultados clínicos negativos en los pacientes con elconocimiento de la medicación, el cumplimiento y la automedicación, debido a que estas variables noson atributos del paciente sino que están asociadas a cada medicamento

Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research

Neural Reuse and the Nature of Evolutionary Constraints

In humans, the reuse of neural structure is particularly pronounced at short, task-relevant timescales. Here, an argument is developed for the claim that facts about neural reuse at task-relevant timescales conflict with at least one characterization of neural reuse at an evolutionary timescale. It is then argued that, in order to resolve the conflict, we must conceptualize evolutionary-scale reuse more abstractly than has been generally recognized. The final section of the paper explores the relationship between neural reuse and human nature. It is argued that neural reuse is not well-described as a process that constrains our present cognitive capacities. Instead, it liberates those capacities from the ancestral tethers that might otherwise have constrained them

Persistent inequalities in 90-day colon cancer mortality: an English cohort study.

BACKGROUND: Variation in colon cancer mortality occurring shortly after diagnosis is widely reported between socio-economic status (SES) groups: we investigated the role of different prognostic factors in explaining variation in 90-day mortality. METHODS: National cancer registry data were linked with national clinical audit data and Hospital Episode Statistics records for 69 769 adults diagnosed with colon cancer in England between January 2010 and March 2013. By gender, logistic regression was used to estimate the effects of SES, age and stage at diagnosis, comorbidity and surgical treatment on probability of death within 90 days from diagnosis. Multiple imputations accounted for missing stage. We predicted conditional probabilities by prognostic factor patterns and estimated the effect of SES (deprivation) from the difference between deprivation-specific average predicted probabilities. RESULTS: Ninety-day probability of death rose with increasing deprivation, even after accounting for the main prognostic factors. When setting the deprivation level to the least deprived group for all patients and keeping all other prognostic factors as observed, the differences between deprivation-specific averaged predicted probabilities of death were greatly reduced but persisted. Additional analysis suggested stage and treatment as potential contributors towards some of these inequalities. CONCLUSIONS: Further examination of delayed diagnosis, access to treatment and post-operative care by deprivation group may provide additional insights into understanding deprivation disparities in mortality