Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich's ataxia

Frataxin (FXN) deficiency causes Friedreich's ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the beta-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence

La reforma de la formación inicial del profesorado de ciencias de secundaria: propuesta de un diseño del currículo basado en competencias

El principal objetivo de este trabajo es proponer un mecanismo de selección de competencias específicas para la formación inicial del profesorado de ciencias experimentales, contando para ello con distintas fuentes relevantes para dicha formación. Con tal fin hemos hecho uso de un procedimiento consistente en ir incorporando de forma crítica las competencias procedentes de las siguientes fuentes curriculares: los modelos de formación inicial del profesorado vigentes en la literatura educativa, el currículo actual de ciencias en la educación secundaria obligatoria en España, el Programa internacional de evaluación PISA, la opinión del profesorado en activo mediante una encuesta cuyos resultados más relevantes son mostrados, las concepciones epistemológicas del profesorado, la profesionalización docente y las demandas que genera y, finalmente, la dimensión social de la ciencia.The primary objective of this paper is to propose a mechanism for selecting specific competences for preservice science teacher training, referring to relevant sources for such training. To this end we have used an trans-disciplinary procedure consistent with incorporating critical competences from the following curricular sources: Models of current preservice teacher training in educational literature, the current curriculum of Science in Compulsory Secondary Education in Spain, the Program for International Student Assessment (PISA), the views of in-service secondary school teachers (through a survey whose most relevant results are given), teachers' epistemological conceptions, the professionalization of teaching and the demands it generates and, finally the social dimension of science

Frataxin Deficit Leads to Reduced Dynamics of Growth Cones in Dorsal Root Ganglia Neurons of Friedreich’s Ataxia YG8sR Model: A Multilinear Algebra Approach

Data Availability Statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.Supplementary Material: The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnmol.2022.912780/full#supplementary-material Supplementary Video 1 | Phase-contrast imaging of living growth cone two months old isolated from the first Y47R mouse. Supplementary Video 2 | Phase-contrast imaging of living growth cone two months old isolated from the second Y47R mouse. Supplementary Video 3 | Phase-contrast imaging of living growth cone two months old isolated from the third Y47R mouse. Supplementary Video 4 | Phase-contrast imaging of living growth cone two months old isolated from the first YG8sR mouse. Supplementary Video 5 | Phase-contrast imaging of living growth cone two months old isolated from the second YG8sR mouse. Supplementary Video 6 | Phase-contrast imaging of living growth cone two months old isolated from the third YG8sR mouse.© 2022 Muñoz-Lasso, Mollá, Sáenz-Gamboa, Insuasty, de la Iglesia-Vaya, Pook, Pallardó, Palau and Gonzalez-Cabo. Computational techniques for analyzing biological images offer a great potential to enhance our knowledge of the biological processes underlying disorders of the nervous system. Friedreich’s Ataxia (FRDA) is a rare progressive neurodegenerative inherited disorder caused by the low expression of frataxin, which is a small mitochondrial protein. In FRDA cells, the lack of frataxin promotes primarily mitochondrial dysfunction, an alteration of calcium (Ca2+) homeostasis and the destabilization of the actin cytoskeleton in the neurites and growth cones of sensory neurons. In this paper, a computational multilinear algebra approach was used to analyze the dynamics of the growth cone and its function in control and FRDA neurons. Computational approach, which includes principal component analysis and a multilinear algebra method, is used to quantify the dynamics of the growth cone (GC) morphology of sensory neurons from the dorsal root ganglia (DRG) of the YG8sR humanized murine model for FRDA. It was confirmed that the dynamics and patterns of turning were aberrant in the FRDA growth cones. In addition, our data suggest that other cellular processes dependent on functional GCs such as axonal regeneration might also be affected. Semiautomated computational approaches are presented to quantify differences in GC behaviors in neurodegenerative disease. In summary, the deficiency of frataxin has an adverse effect on the formation and, most importantly, the growth cones’ function in adult DRG neurons. As a result, frataxin deficient DRG neurons might lose the intrinsic capability to grow and regenerate axons properly due to the dysfunctional GCs they build.Ministerio de Economía y Competitividad de España (SAF2015-66625-R); Agencia Estatal de Investigación (PID2020-115190RB-I00) within the framework of the National R + D + I Plan and co-funded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación and FEDER funds; Generalitat Valenciana (ACOMP/2014/058 and PROMETEO/2018/135); CIBERER is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases. EMBO Short Fellowship (ASTF 562-2015)

The science of storytelling: different levels of narrative integration in teaching innovation applied to Human Physiology

[EN] The incorporation of narrative features into teaching materials of different formats, such as graphic and audiovisual ones, has proven to be an efficient way of encouraging student motivation. Besides, it strengthens the teaching of abstract concepts like those frequent in experimental sciences, such as Physiology, a basic subject in life sciences studies. From the Department of Physiology of the University of Valencia we present the creation of a teaching innovation group focused on the development of Narrative Physiology, FISIONARR, with the aim of promoting the narrative nature of teaching Physiology through two strategic lines. The first one focuses on graphic narrative and its integration as a teaching tool at different levels; the second deals with the generation of audiovisual narrative. In this sense, specific audiovisual material has been prepared for a series of videos entitled " Invisible Physiology", and as a conductive element of the digital educational escape room "Alimental, querida Watson".[ES] La incorporación de elementos narrativos en material docente de distintos formatos gráficos y audiovisuales es una manera eficiente de incentivar la motivación del estudiantado y de reforzar la docencia de conceptos abstractos como los relacionados con ciencias experimentales como la Fisiología, materia básica en estudios de ciencias de la salud. Desde el Departamento de Fisiología de la Universitat de València presentamos la creación de un grupo de innovación docente centrado en el uso de la Fisiología Narrativa, FISIONARR, con el objetivo de potenciar el carácter narrativo de la docencia en Fisiología a través de dos líneas estratégicas. La primera de ellas se centra en la narrativa gráfica y en su integración como herramienta docente a distintos niveles. La segunda trata sobre la generación de narrativa audiovisual y concretamente de ha elaborado material para una serie de videos titulados “La Fisiología Invisible” y como elemento conductor de la escape room educacional digital “Alimental, querida Watson”.Olaso Gonzalez, G.; Calvo Saiz, C.; González Cabo, P.; García Giménez, JL.; Gómez-Cabrera, MC.; Arribas Rodríguez, S.; Gal Iglesias, B.... (2023). La ciencia de contar historias: distintos niveles de integración narrativa en innovación docente aplicada a la Fisiología Humana. Editorial Universitat Politècnica de València. 1050-1060. https://doi.org/10.4995/INRED2023.2023.166551050106

EBioMedicine

BACKGROUND: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. METHODS: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. FINDINGS: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. INTERPRETATION: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. FUNDING: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union

Differential Expression of PGC-1α and Metabolic Sensors Suggest Age-Dependent Induction of Mitochondrial Biogenesis in Friedreich Ataxia Fibroblasts

11 pages, 6 figures. PMID:21687738[PubMed] PMCID: PMC3110204BACKGROUND: Friedreich's ataxia (FRDA) is a mitochondrial rare disease, which molecular origin is associated with defect in the expression of frataxin. The pathological consequences are degeneration of nervous system structures and cardiomyopathy with necrosis and fibrosis, among others. PRINCIPAL FINDINGS: Using FRDA fibroblasts we have characterized the oxidative stress status and mitochondrial biogenesis. We observed deficiency of MnSOD, increased ROS levels and low levels of ATP. Expression of PGC-1α and mtTFA was increased and the active form of the upstream signals p38 MAPK and AMPK in fibroblasts from two patients. Interestingly, the expression of energetic factors correlated with the natural history of disease of the patients, the age when skin biopsy was performed and the size of the GAA expanded alleles. Furthermore, idebenone inhibit mitochondriogenic responses in FRDA cells. CONCLUSIONS: The induction of mitochondrial biogenesis in FRDA may be a consequence of the mitochondrial impairment associated with disease evolution. The increase of ROS and the involvement of the oxidative phosphorylation may be an early event in the cell pathophysiology of frataxin deficiency, whereas increase of mitochondriogenic response might be a later phenomenon associated to the individual age and natural history of the disease, being more evident as the patient age increases and disease evolves. This is a possible explanation of heart disease in FRDA.This work was supported by grants SAF2008-01338, SAF2006-01047 and SAF2009-07063 from the Ministerio de Ciencia e Innovación and financial support from the CIBERER (Biomedical Network Research Center for Rare Diseases). A.G. thanks the Conselleria de Educación of the Generalitat Valenciana for the financial support by grants GVPRE/2008/154. A.B.-A. is the recipient of a JAE-CSIC predoctoral fellowship. The CIBERER is an initiative of the Instituto de Salud Carlos III and INGENIO 2010.Peer reviewe

Staging Parkinson's Disease Combining Motor and Nonmotor Symptoms Correlates with Disability and Quality of Life.

Introduction: In a degenerative disorder such as Parkinson's disease (PD), it is important to establish clinical stages that allow to know the course of the disease. Our aim was to analyze whether a scale combining Hoehn and Yahr's motor stage (H&Y) and the nonmotor symptoms burden (NMSB) (assessed by the nonmotor symptoms scale (NMSS)) provides information about the disability and the patient's quality of life (QoL) with regard to a defined clinical stage. Materials and methods: Cross-sectional study in which 603 PD patients from the COPPADIS cohort were classified according to H&Y (1, stage I; 2, stage II; 3, stage III; 4, stage IV/V) and NMSB (A: NMSS = 0-20; B: NMSS = 21-40; C: NMSS = 41-70; D: NMSS ≥ 71) in 16 stages (HY.NMSB, from 1A to 4D). QoL was assessed with the PDQ-39SI, PQ-10, and EUROHIS-QOL8 and disability with the Schwab&England ADL (Activities of Daily Living) scale. Results: A worse QoL and greater disability were observed at a higher stage of H&Y and NMSB (p < 0.0001). Combining both (HY.NMSB), patients in stages 1C and 1D and 2C and 2D had significantly worse QoL and/or less autonomy for ADL than those in stages 2A and 2B and 3A and 3B, respectively (p < 0.005; e.g., PDQ-39SI in 1D [n = 15] vs 2A [n = 101]: 28.6 ± 17.1 vs 7.9 ± 5.8; p < 0.0001). Conclusion: The HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the HΨ Patients with a lower H&Y stage may be more affected if they have a greater NMS burden

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.Methods: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method.Results: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.Conclusions: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study

Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%–50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality