Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency.

Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function.

Traveling Bax and forth from mitochondria to control apoptosis.

Antiapoptotic Bcl-2 proteins on mitochondria inhibit prodeath proteins, such as Bax, which are found primarily in the cytosol. In this issue, Edlich et al., (2011) show that Bax and Bcl-xL interact on the mitochondrial surface and then retrotranslocate to the cytosol, effectively preventing Bax-induced permeabilization of mitochondria.

TFG binds LC3C to regulate ULK1 localization and autophagosome formation.

The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy.

Integration-segregation dynamics in functional networks of individuals diagnosed with schizophrenia.

Schizophrenia has been associated with dysfunction in information integration/segregation dynamics. One of the neural networks whose role has been most investigated in schizophrenia is the default mode network (DMN). In this study, we have explored the possible alteration of integration and segregation dynamics in individuals diagnosed with schizophrenia with respect to healthy controls, based on the study of the topological properties of the graphs derived from the functional connectivity between the nodes of the DMN in the resting state. Our results indicate that the patients show a diminution of the modularity of the DMN and a higher global efficiency, in sparse graphs. Our data emphasise the interest in studying temporal changes in network measures and are compatible with the hypothesis of randomization of functional networks in schizophrenia.

Niche dynamics along two centuries of multiple crayfish invasions.

The realised ecological niches of species may change in response to dynamic abiotic and biotic environments, particularly under fast global change. To fully understand the dynamics of niche features and their drivers, it is essential to have a long-term view of species distributions and the factors that may have influenced them. Here, we analysed the distribution and niche dynamics of the Italian crayfish (Austropotamobius fulcisianus) in the Iberian Peninsula over the past 200 years. The Italian crayfish was introduced to Spain in the 16th century, and spread due to multiple stocking events until the 1970s, when two North American crayfish (red swamp crayfish Procambarus clarkii, and signal crayfish Pacifastacus leniusculus) were introduced. Both North American species are carriers of a pathogen (Aphanomyces astaci, the causal agent of crayfish plague) lethal to the Italian crayfish. We hypothesised that the realised niche of the Italian crayfish, both in breadth and in position, has changed over time following changes in its range. The distribution of the Italian crayfish expanded from the mid-19th century until the mid-20th century, in association with an enlargement of its realised niched, mostly towards less abrupt and more coastal-influenced areas. After the introduction of the North American crayfishes, the collapse of the Italian crayfish involved a niche shift towards rough terrains in mountain areas. North American crayfish have eventually occupied most of the Italian crayfish's niche space, with the few no-coexistence areas being relegated to the most abrupt and high-elevation territories. Our historical approach allowed us to document and understand the highly dynamic distribution and niche of the Italian crayfish in the presence of invader counterparts, and to explore the environmental conditions under which their coexistence is minimised.

Examining Neural Connectivity in Schizophrenia Using Task-Based EEG: A Graph Theory Approach.

Schizophrenia (SZ) is a complex disorder characterized by a range of symptoms and behaviors that have significant consequences for individuals, families, and society in general. Electroencephalography (EEG) is a valuable tool for understanding the neural dynamics and functional abnormalities associated with schizophrenia. Research studies utilizing EEG have identified specific patterns of brain activity in individuals diagnosed with schizophrenia that may reflect disturbances in neural synchronization and information processing in cortical circuits. Considering the temporal dynamics of functional connectivity provides a more comprehensive understanding of brain networks' organization and how they change during different cognitive states. This temporal perspective would enhance our understanding of the underlying mechanisms of schizophrenia. In the present study, we will use measures based on graph theory to obtain dynamic and static indicators in order to evaluate differences in the functional connectivity of individuals diagnosed with SZ and healthy controls using an ecologically valid task. At the static level, patients showed alterations in their ability to segregate information, particularly in the default mode network (DMN). As for dynamic measures, patients showed reduced values in most metrics (segregation, integration, centrality, and resilience), reflecting a reduced number of dynamic states of brain networks. Our results show the utility of combining static and dynamic indicators of functional connectivity from EEG sensors.

Transmisión del SARS-CoV-2 en escolares durante el primer trimestre del curso 2021/2022 en la provincia de Albacete: incidencia e impacto de las nuevas variantes.

OBJECTIVE: The objective of this study was to know the evolution of the COVID-19 pandemic in the school setting, and the effect of the new variants on it. DESIGN: It is an observational longitudinal descriptive study during the first term of the academic year 21/22. SITE: Community health services. PARTICIPANTS: Preschool, elementary, secondary, and high school students. INTERVENTIONS: none. MAIN MEASUREMENTS: We calculated cumulative incidence stratified by grade, source of infection and follow-up period, percentage of vaccinated cases and correlation between cumulative incidence in schooled children per week and cumulative incidence in the general population. RESULTS: 1526 cases were reported, and the cumulative incidence was 3,17% and 0,48% in within-school acquired cases. 20,9% were vaccinated. During follow-up, there was an important change in incidence from weeks 49/21 on, at the time Omicron began to appear in Spain, with an increase in secondary cases, mostly high school students. We found a high correlation between general population and schooled children's cumulative incidence (R2 = 0,59). CONCLUSIONS: SARS-CoV-2 transmission in school settings has been affected by new circulating variants. Two propagation scenarios were identified, and they were like the community propagation pattern. This supports the hypothesis that school settings reflect the transmission in the community. Reinforcement of preventive measures and surveillance would have a positive effect on school settings.

The displacement of frataxin from the mitochondrial cristae correlates with abnormal respiratory supercomplexes formation and bioenergetic defects in cells of Friedreich ataxia patients.

Friedreich ataxia (FRDA) is a neurodegenerative disease resulting from a severe decrease of frataxin (FXN). Most patients carry a GAA repeat expansion in both alleles of the FXN gene, whereas a small fraction of them are compound heterozygous for the expansion and a point mutation in the other allele. FXN is involved in the mitochondrial biogenesis of the FeS-clusters. Distinctive feature of FRDA patient cells is an impaired cellular respiration, likely due to a deficit of key redox cofactors working as electrons shuttles through the respiratory chain. However, a definite relationship between FXN levels, FeS-clusters assembly dysregulation and bioenergetics failure has not been established. In this work, we performed a comparative analysis of the mitochondrial phenotype of cell lines from FRDA patients, either homozygous for the expansion or compound heterozygotes for the G130V mutation. We found that, in healthy cells, FXN and two key proteins of the FeS-cluster assembly machinery are enriched in mitochondrial cristae, the dynamic subcompartment housing the respiratory chain. On the contrary, FXN widely redistributes to the matrix in FRDA cells with defects in respiratory supercomplexes assembly and altered respiratory function. We propose that this could be relevant for the early mitochondrial defects afflicting FRDA cells and that perturbation of mitochondrial morphodynamics could in turn be critical in terms of disease mechanisms.

Validez y fiabilidad del inventario polidiagnóstico para trastornos psicóticos OPCRIT 4.0 adaptado al español.

OBJETIVO: Adaptar y validar al español el Inventario de Criterios Operativos Diagnósticos (OPCRIT 4.0) para tras-tornos psicóticos. Se trata de una herramienta que permite diagnosticar a un paciente mediante las principales clasifica-ciones diagnósticas. Material y métodos. Se realizó la traducción y retrotraducción del inventario original en inglés al español y se comprobó la validez de criterio, la validez concurrente y la fiabilidad interevaluador del mismo, a partir de una muestra de 106 historias clínicas de usuarios adultos de un centro de salud mental comunitario. RESULTADOS: Los datos obtenidos demostraron la validez y fiabilidad de la adaptación del OPCRIT 4.0 en la evaluación de la muestra de historias clínicas. CONCLUSIONES: La adaptación y validación al español del instrumento OPCRIT 4.0 permite disponer de un sistema rápido, fiable y útil para obtener el diagnóstico del trastorno psicótico en un paciente a través de diferentes sistemas de clasificación.

Molecular Research on Mitochondrial Dysfunction.

This Special Issue collects current knowledge on the molecular mechanisms underlying mitochondrial dysfunction and its related diseases, as well as therapies and perspectives pertaining to their treatment [...].

[Pharmacological treatment of the heart failure according to the ventricular ejection fraction in primary care]. / Tratamiento farmacológico de la insuficiencia cardíaca según la fracción de eyección ventricular en atención primaria.

Despite better diagnoses and treatments, heart failure (HF) is an important cause of death in Spain. The objective of this study is to describe the characteristics and treatment of a population with chronic HF classified according to the left ventricular ejection fraction (LVEF). Population-based observational cohort study in Primary Health Care. Catalonia, Spain, during 2014-2018. Adults with HF classified by the LVEF. Analysis of electronic health data registered in SIDIAP (Information System for Research in Primary Care). Demographics, LVEF, comorbidities, and use of drugs for HF. 10,130 patients were included; 18.9% with LVEF<40 (HFrEF), 15.9% with LVEF 40-49 (HFmEF) and 65.2% with LVEF≥50 (HFpEF), this last group with a higher proportion of women (57.5%) and higher mean age (80.2 years-old). People with HFmEF were similar to those with HFrEF in age, gender, comorbidities and treatment. The most frequent comorbidities were hypertension (78.3%), dyslipidaemia (54%) and atrial fibrillation (41.5%). The most frequent pharmacological treatments were ß blockers with differences according to the LVEF [HFrEF 1515 (79.2%), HFmEF 1142 (70.8%) and HFpEF 3371 (51%)], followed by loop diuretics (65.7%). HF is a prevalent disease. Having information on LVEF could guide its pharmacological management. The HF population has persistent cardiovascular risk factors and habits. Treatment and population characteristics of patients with HFmEF are similar to those with HFrEF.

Pharmacological treatment after acute coronary syndrome: Baseline clinical characteristics and gender differences in a population-based cohort study.

OBJECTIVE: To describe baseline socio-demographic and clinical characteristics and drugs prescribed for secondary prevention after a first episode of ACS and to assess differences between men and women. SETTING: PHC in Catalonia. DATA SOURCE: SIDIAP (Information System for Research in Primary Care). PARTICIPANTS: Patients who suffered an ACS during 2009-2016 and followed-up in PHC centres of the Catalan Health Institute in Catalonia. INTERVENTIONS: Not applicable. MAIN MEASURES: Socio-demographic and clinical characteristics at baseline: sex, age, socioeconomic index, toxic habits, comorbidities, study drugs (prescribed for cardiovascular secondary prevention: antiplatelets, betablockers, statins, drugs acting on the renin-angiotensin system) and comedications. RESULTS: 8071 patients included, 71.3% of them were men and 80.2% had an acute myocardial infarction. Their mean age was 65.3 and women were older than men. The most frequent comorbidities were hypertension, dyslipidaemia and diabetes and they were more common in women. Antiplatelets (91.3%) and statins (85.7%) were the study drugs most prescribed. The uses of all comedications were significantly higher in women, except for nitrates. The combination of four study groups was initially prescribed in 47.7% of patients and combination of beta-blockers, statins and antiplatelets was prescribed in 18.4%. More men than women received all recommended pharmacological groups. CONCLUSION: Women were older, had more comorbidities and received more comedications. Most patients were treated with a combination of four or three study drugs for secondary prevention. Men initiated more drug treatments for secondary prevention and dual antiplatelet therapy than women. EUPAS REGISTER: EUPAS19017.

Risk of ischaemic stroke associated with antiepileptic drugs: a population-based case-control study in Catalonia.

BACKGROUND: Cerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED). METHODS: Population-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009-2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED. RESULTS: 2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2-41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1-1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3-5.2)] and valproic acid [ORadj1.4, CI95 % 1.1-1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7-6.9)]. CONCLUSIONS: Drugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam.

Impact of adherence to drugs for secondary prevention on mortality and cardiovascular morbidity: A population-based cohort study. IMPACT study.

PURPOSE: Adherence to pharmacological therapy for secondary prevention after an acute coronary syndrome (ACS) reduces the risk of new cardiovascular events. However, several studies showed poor adherence. Our study aim was to assess the risk of a composite endpoint of major cardiovascular events (MACE) and all-cause mortality according to the adherence to these drugs in patients after an ACS in a primary health care cohort. METHODS: Population-based observational cohort study of patients with a first episode of ACS during 2009-2016. DATA SOURCE: Information System for Research in Primary Care (SIDIAP) database. Drug adherence was evaluated through proportion of days covered (PDC). RESULTS: We included 7152 patients and 5692 (79.6%) were adherent (PDC ≥ 75%) to the study drugs during the first year after the event. Adherents to any combination showed a significant reduction of the composite endpoint risk (HR 0.80 [0.73-0.88]), and a significant lower probability of the composite endpoint than nonadherents for all drugs, except beta-blockers. Adherents to 2 (HR 1.2; 95% CI 1.0-1.3) and 1 drug (HR 1.5; 95% CI 1.2-1.8) had higher composite endpoint risk compared to adherents to 4-3 drugs. CONCLUSION: Adherence to any combination of recommended drugs reduced the composite endpoint risk, regardless the number of drugs prescribed. Adherence to a combination of 4-3 drugs was significantly associated with a reduced mortality risk compared with adherents to 2 or 1, but it was not significant for MACE.

Assessing ADHD symptoms in clinical public practice: Is a reliable final diagnosis possible?

INTRODUCTION: Attention deficit and hyperactivity disorder (ADHD) rates vary between 1% and 20% depending on the type of diagnosis guide used, the test used in the assessment, psychosocial factors, and professional in charge of the assessment. GOAL: to describe and compare current clinical ADHD assessment processes in public health system in two cohorts and analyze variables related to final diagnosis. DESIGN: Descriptive, multicenter, longitudinal (retrospective-prospective). LOCATION: primary care (PC) centers in Oviedo, Asturias (Spain). PARTICIPANTS: a Spanish clinical ADHD symptomatic sample (n=134) from two cohorts (2004 and 2009). VARIABLES: clinical professional in charge of ADHD assessment (PC, mental health professional [MH], neuropediatrician [NP]), type of test used in the assessment, confirmation/disconfirmation of ADHD diagnosis, and final diagnosis. RESULTS: the use of symptoms checklists and the assessments in charge of primary care (PC) and neuropediatrician (NP) professionals show an upward trend from 2004 to 2009. ADHD final diagnosis shows low inter-professional (NP-MH) reliability (kappa=0.39). Final diagnoses for the same symptoms are different depending on the professional (NP or MH). DISCUSSIONS: the professional in charge of the assessment appears to be a relevant variable for the final diagnosis. ADHD diagnosis criteria seem not to be clear. This data suggests that ADHD diagnosis must be used with caution to ensure good quality clinical standards when assessing and treating ADHD symptoms. Assessments supported by symptoms checklists and performed by NP or PC could be contributing factors to an ADHD over-diagnosis tendency.

[Bibliometric analysis of female authorship in original articles in the journal ATENCIÓN PRIMARIA]. / Análisis bibliométrico de la autoría femenina en artículos originales en la revista ATENCIÓN PRIMARIA.

OBJECTIVES: To determine the percentage of female authors in original articles published during 2periods, in the journal of Atención Primaria (Primary Care), and to examine the differences between the categories of authorship (first, last author, and co-author) between both periods. DESIGN: Cross-sectional study. SETTING: Feminine scientific production published during the periods 2007-2008 and 2017-2018. PARTICIPANTS: The study was focused on original articles. MAIN MEASUREMENTS: The following variables were collected in an ad hoc form: gender based on the name of the author, total number of women and men appearing as authors, and order of authorship. Absolute and relative authorship frequencies were calculated, and the χ2 test was used to examine the evolution of the percentages by type of authorship and gender. RESULTS: A total of 108 articles were analysed in 2007-2008, and 100 in 2017-2018. No statistically significant differences were observed between the mean numbers of women authors within and between periods. In 2007-2008 a total of 548 female authors were identified and 540 in 2017-2018, the percentage of female authors was 48.7% and 54.4%, respectively. Only an increase in the percentage of first authors was observed between periods. CONCLUSIONS: Practically one out of every 2authors of original articles published in the journal Atención Primaria was female. There was also a significant increase in the percentage of female first authors between the 2periods. Nevertheless, and despite the greater number of health workers, the number of latest female authors remain unchanged, which points to the persistence of female under-representation.

Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.

Transcription factor Stat3 directs self-renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial-encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors.

Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis.

Mitochondrial dynamics and functionality are linked to the autophagic degradative pathway under several stress conditions. However, the interplay between mitochondria and autophagy upon cell death signalling remains unclear. The T-cell receptor pathway signals the so-called activation-induced cell death (AICD) essential for immune tolerance regulation. Here, we show that this apoptotic pathway requires the inhibition of macroautophagy. Protein kinase-A activation downstream of T-cell receptor signalling inhibits macroautophagy upon AICD induction. This leads to the accumulation of damaged mitochondria, which are fragmented, display remodelled cristae and release cytochrome c, thereby driving apoptosis. Autophagy-forced reactivation that clears the Parkin-decorated mitochondria is as effective in inhibiting apoptosis as genetic interference with cristae remodelling and cytochrome c release. Thus, upon AICD induction regulation of macroautophagy, rather than selective mitophagy, ensures apoptotic progression.

[Effectiveness, safety and costs of stroke prevention in non-valvular auricular fibrillation. Study of cohorts matched by Propensity score]. / Efectividad, seguridad y costes de la prevención tromboembólica en fibrilación auricular. Estudio de cohortes apareado por Propensity score.

OBJECTIVE: To analyze the use, effectiveness, safety and costs of stroke prevention in non-valvular atrial fibrillation (AF) in patients initiating treatment with dabigatran or vitamin K antagonists (VKA). SETTING: Primary Care (PC) at the Catalan Health Institute (ICS) in Catalonia, during 2011-2013. PARTICIPANTS: Patients attended in ICS PC centres with a registered diagnosis of AF who initiate dabigatran or VKA. INTERVENTIONS: Not applicable MAIN MEASUREMENTS: Number of prescriptions and reimbursements of dabigatran and VKA, incidence of stroke and haemorrhages, incidence of mortatlity, number of sickness leave, and costs associated to all the previous variables. RESULTS: 14,930 patients were included; 94.6% initiated VKA and 5.4%, dabigatran. Dabigatran patients were younger and with less comorbidity. There were no statistically significant differences between VKA and dabigatran in the risk of stroke, haemorrhages or death. The costs associated to AF management were higher for PC visits in the VKA group, and higher for laboratory and pharmacy in the dabigatran group, although overall costs were not statistically different. CONCLUSIONS: Most patients initiated VKA. We found no differences between VKA and dabigatran in the risk of stroke, haemorrhages or mortality.

The use and adherence of oral anticoagulants in Primary Health Care in Catalunya, Spain: A real-world data cohort study.

OBJECTIVE: We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. SETTING: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. PARTICIPANTS: All NVAF adult patients initiating OAC for stroke prevention in August 2013-December 2015. METHODS: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013-December 2014. DATA SOURCE: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. RESULTS: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n=258 (61.7%)] than among the naive [n=11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n=360 (80.1%)] of good adherence at implementation (MPR>80%) while patients starting dabigatran were less adherent [n=203 (47.8%)]. CONCLUSIONS: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest.