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Abstract The presence of somatic mutations, including copy number variants (CNVs), in the brain is well recognized. Comprehensive study requires single-cell whole genome amplification, with several methods available, prior to sequencing. Here we compare PicoPLEX with two recent adaptations of multiple displacement amplification (MDA): primary template-directed amplification (PTA) and droplet MDA, across 93 human brain cortical nuclei. We demonstrate different properties for each, with PTA providing the broadest amplification, PicoPLEX the most even, and distinct chimeric profiles. Furthermore, we perform CNV calling on two brains with multiple system atrophy and one control brain using different reference genomes. We find that 20.6% of brain cells have at least one Mb-scale CNV, with some supported by bulk sequencing or single-cells from other brain regions. Our study highlights the importance of selecting whole genome amplification method and reference genome for CNV calling, while supporting the existence of somatic CNVs in healthy and diseased human brain.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and fourth leading cause for renal replacement therapy worldwide. Disease progression is tightly linked to genotype, however, factors like genetic modifiers and environmental factors are responsible for a high phenotypic variability within- as well as between families. Individual’s risk of progression to kidney failure is assessed using prediction- or risk-assessment tools such as the predicting renal outcomes in ADPKD score (PROPKD score) and the Mayo Imaging Classification (MIC). The PROPKD score encompasses genetic and phenotypic parameters, while the MIC relies on renal imaging, height, and age of patients. Both methods categorize patients into low-risk, intermediate-risk, and high-risk for progression to kidney failure. In this retrospective, cross-sectional study, we calculated the risk of progression to kidney failure in our population and analyzed the agreement between the methods in three separate models with alternating stratification of MIC risk categories. We found a mismatch for risk assessment between the respective risk categories, indicating that the PROPKD score and MIC should not be used interchangeably. Preferably, the MIC should be used as a base for risk assessment and may be enhanced by genotypic and phenotypic information.

The present research studied the relationship between the credentials of teachers and the academic performance of students who, in the 2014–2015 period, joined the bachelor’s degree program in Economics at the Universidad Católica Andrés Bello, Caracas, Venezuela. The hypothesis of a direct relationship between teaching quality and student performance was evaluated using a panel data methodology, in which the students were considered as “individuals,” and the semesters of the degree course were the time period under study. For the fixed and random effects estimations without instrumental variables, the following were found to be significant: the teacher’s marital status, place of study, pedagogical training, student evaluation, and the teacher’s professional commitments outside the academic sphere. The results do not allow us to accept the null hypothesis since academic teaching credentials do not promote significant increases in academic performance.

The scattering of light by polymeric nanoparticles is a crucial phenomenon in various applications, ranging from nanomedicine to nanophononics. This study introduces a theoretical framework for differentiating between absorption and scattering spectra in light interactions with these nanoparticles. Characteristic spectral data of nanoparticles synthesized via the reprecipitation method and suspended in an aqueous medium analyzed under electromagnetic radiation. These nanoparticles exhibit two primary optical phenomena: absorption and scattering. To fully understand their optical response, it is essential to separate these phenomena. This study established a relationship between wavelength variation, nanoparticle size, and radiation loss due to scattering in an aqueous medium. Additionally, we calculated extinction efficiency and extinction factors as functions of wavelength, taking into account variations in nanoparticle radii and refractive indices.

Abstract Objective This study aimed to describe the social representations constructed by the educational community about educational psychology and the educational psychologist in the school context. Method We used a qualitative methodology with a hermeneutical approach, with a total of 34 participants (principals, teachers, psychologists, students, and parents) from eight private schools in the city of Ibagué, Colombia. Data were collected through focus groups and semistructured interviews. Results Thematic network analysis was used to analyze the data, resulting in three global themes that illustrate the main social representations. The results indicate that differentiation from clinical psychology and school counseling are points of reference for identifying educational psychology as an applied discipline and understanding the role of the educational psychologist in schools. Conclusion It is argued that representations and practices related to traditional roles are being transformed towards institutional and contextual practices.

Abstract Background Reduction of the particle size of corn increases energy digestibility and concentrations of digestible and metabolizable energy. Pelleting may also reduce particle size of grain, but it is not known if there are interactions between particle size reduction and pelleting. The objective of this experiment was to test the hypothesis that particle size reduction and pelleting, separately or in combination, increase N balance, apparent total tract digestibility (ATTD) of fiber and fat, and net energy (NE) in corn-soybean meal diets fed to group-housed pigs. Methods Six corn-soybean meal-based diets were used in a 3 × 2 factorial design with 3 particle sizes of corn (i.e., 700, 500, or 300 μm) and 2 diet forms (i.e., meal or pelleted). Pigs were allowed ad libitum access to feed and water. Twenty-four castrated male pigs (initial weight: 29.52 kg; standard diviation: 1.40) were allotted to the 6 diets using a 6 × 6 Latin square design with 6 calorimeter chambers (i.e., 4 pigs/chamber) and 6 periods. Oxygen consumption and CO2 and CH4 productions were measured during fed and fasting states and fecal and urine samples were collected. Results Regardless of particle size of corn, the ATTD of gross energy (GE), N, and acid-hydrolyzed ether extract (AEE), and the concentration of NE were greater (P < 0.05) in pelleted diets than in meal diets. Regardless of diet form, the ATTD of GE, N, and AEE, and the concentration of NE were increased (linear; P < 0.05) by reducing the particle size of corn, but the increase was greater in meal diets than in pelleted diets (interaction; P < 0.05). Conclusions Both pelleting and reduction of corn particle size increased nutrient digestibility and NE, but increases were greater in meal diets than in pelleted diets.

Abstract Background Comprehensive data on patients at high risk of sudden cardiac death (SCD) in emerging countries are lacking. The aim was to deepen our understanding of the SCD phenotype and identify risk factors for death among patients at high risk of SCD in emerging countries. Methods Patients who met the class I indication for implantable cardioverter-defibrillator (ICD) implantation according to guideline recommendations in 17 countries and regions underrepresented in previous trials were enrolled. Countries were stratified by the WHO regional classification. Patients were or were not implanted with an ICD at their discretion. The outcomes were all-cause mortality and SCD. Results We enrolled 4222 patients, and 3889 patients were included in the analysis. The mean follow-up period was 21.6 ± 10.2 months. There were 433 (11.1%) instances of all-cause mortality and 117 (3.0%) cases of SCD. All-cause mortality was highest in primary prevention (PP) patients from Southeast Asia and secondary prevention (SP) patients from the Middle East and Africa. The SCD rates among PP and SP patients were both highest in South Asia. Multivariate Cox regression modelling demonstrated that in addition to the independent predictors identified in previous studies, both geographic region and ICD use were associated with all-cause mortality in patients with high SCD risk. Primary prophylactic ICD implantation was associated with a 36% (HR = 0.64, 95% CI 0.531–0.802, p

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.

Summary: Perturbation of the apoptosis and necroptosis pathways critically influences embryogenesis. Receptor-associated protein kinase-1 (RIPK1) interacts with Fas-associated via death domain (FADD)-caspase-8-cellular Flice-like inhibitory protein long (cFLIPL) to regulate both extrinsic apoptosis and necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality. This lethality is not prevented by further removal of the kinase activity of Ripk1 (Ripk1R588E K45A [REKA]). Both Ripk1RE and Ripk1REKA animals survive to adulthood upon ablation of Ripk3. While embryonic lethality of Ripk1RE mice is prevented by ablation of the necroptosis effector mixed lineage kinase-like (MLKL), animals succumb to inflammation after birth. In contrast, Mlkl ablation does not prevent the death of Ripk1REKA embryos, but animals reach adulthood when both MLKL and caspase-8 are removed. Ablation of the nucleic acid sensor Zbp1 largely prevents lethality in both Ripk1RE and Ripk1REKA embryos. Thus, the RIPK1-FADD interaction prevents Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated embryonic lethality, affected by the kinase activity of RIPK1.

The franciscana dolphin is a small, vulnerable species often caught in artisanal gillnets. This study aims to provide a comprehensive assessment of their acoustic capabilities by using advanced equipment to collect a large dataset of wideband, continuous recordings. We examined the detailed acoustic signals of franciscana dolphins, comparing the sounds from rehabilitated dolphins in captivity with those of wild dolphins near fishing nets. Significant differences in acoustic characteristics were found between neonates and older dolphins, with juvenile and wild dolphins showing similar features. For the first time, repetition patterns in click production were identified, highlighting the importance of understanding the context of these sounds in regards to feeding and communication. This study emphasizes the need for detecting neonates for species protection and suggests the potential for developing acoustic classifiers specific to different age groups. Our findings offer valuable insights for conservation efforts and the development of protection strategies for franciscana dolphins.

Summary: Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene expression. XRN1 deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state.

Abstract Background Uncertainty around the risk of COVID-19 to pregnant women and their babies prompted precautionary restrictions on their health and care during the pandemic. Maternity services had to adapt to changing Government guidance. Coupled with the imposition of national lockdowns in England and restrictions on daily activities, women’s experiences of pregnancy, childbirth and the postpartum period, and their access to services, changed rapidly. This study was designed to understand women’s experiences of pregnancy, labour and childbirth and caring for a baby during this time. Methods This was an inductive longitudinal qualitative study, using in-depth interviews by telephone with women in Bradford, UK, at three timepoints during their maternity journey (18 women at timepoint one, 13 at timepoint two and 14 at timepoint three). Key topics explored were physical and mental wellbeing, experience of healthcare services, relationships with partners and general impact of the pandemic. Data were analysed using the Framework approach. A longitudinal synthesis identified over-arching themes. Results Three longitudinal themes captured what was important to women: (1) women feared being alone at critical points in their maternity journey, (2) the pandemic created new norms for maternity services and women’s care, and (3) finding ways to navigate the COVID-19 pandemic in pregnancy and with a baby. Conclusions Modifications to maternity services impacted significantly on women’s experiences. The findings have informed national and local decisions about how best to direct resources to reduce the impact of COVID-19 restrictions and the longer-term psychological impact on women during pregnancy and postnatally.

El artículo describe las tendencias tecnológicas emergentes utilizadas por los actores ilegales del sistema de drogas ilícitas para dinamizar el narcotráfico; especialmente, la posibilidad del anonimato de la operación criminal, el recaudo y lavado de activos de la actividad ilegal y la entrega de las drogas ilegales a través del ciberespacio. Dicho análisis se construye a partir de la experiencia inicial con la construcción de la Unidad Investigativa en Cibernarcotráfico, adscrita a la Dirección de Antinarcóticos, y la revisión y sistematización del estado del arte de la comercialización de drogas en línea de los últimos cuatro años. En este proceso, y como herramientas del fenómeno criminal del cibernarcotráfico, se identifican tres ejes principales de análisis que se abordarán en este documento: redes sociales, cibercrimen y criptoactivos; todos ellos, elementos que, combinados y analizados con las tendencias que dinamizan el fenómeno y los actores de mayor influencia presentes, permiten proyectar tres escenarios probables a mediano plazo.

Background & Objective: Despite the burden of sudden cardiac arrest (SCA) worldwide, implantable cardioverter-defibrillators (ICDs) are underutilized, particularly in Asia, Latin America, Eastern Europe, the Middle East, and Africa. The Improve SCA trial demonstrated that primary prevention (PP) patients in these regions benefit from an ICD or a cardiac resynchronization therapy defibrillator (CRT-D). We aimed to compare the rate of device therapy and mortality among ischemic and non-ischemic cardiomyopathy (ICM and NICM) PP patients who met guideline indications for ICD therapy and had an ICD/CRT-D implanted. Methods: Improve SCA was a prospective, non-randomized, non-blinded multicenter trial that enrolled patients from the above-mentioned regions. All-cause mortality and device therapy were examined by cardiomyopathy (ICM vs NICM) and implantation status. Cox proportional hazards methods were used, adjusting for factors affecting mortality risk. Results: Of 1848 PP NICM patients, 1007 (54.5%) received ICD/CRT-D, while 303 of 581 (52.1%) PP ICM patients received an ICD/CRT-D. The all-cause mortality rate at 3 years for NICM patients with and without an ICD/CRT-D was 13.1% and 18.3%, respectively (HR 0.51, 95% CI 0.38–0.68, p

Summary: In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but their role in longevity is unclear. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered an important role for lipid droplets in proteostasis and longevity. Using genome-wide RNAi screening, we identified several SQST-1 modulators, including lipid droplets-associated and aggregation-prone proteins. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan. Notably, a substantial amount of ubiquitinated proteins were found on lipid droplets. Reducing lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised, and significantly reduced the lifespan of long-lived daf-2 animals. Altogether, our study uncovered a key role for lipid droplets in C. elegans as a proteostatic mediator that modulates ubiquitinated protein accumulation, facilitates autophagy, and promotes longevity.

Combinatorial CRISPR screens can be utilized to identify genetic interactions and functional redundancies of multiple genes. Here, the authors benchmark ten digenic CRISPR technologies and identify novel Cas9 tracrRNA combinations that show superior performance.

Abstract 2-Deoxy-D-glucose (2DG) has recently received emergency approval for the treatment of COVID-19 in India, after a successful clinical trial. SARS-CoV-2 infection of cultured cells is accompanied by elevated glycolysis and decreased mitochondrial function, whereas 2DG represses glycolysis and stimulates respiration, and restricts viral replication. While 2DG has pleiotropic effects on cell metabolism in cultured cells it is not known which of these manifests in vivo. On the other hand, it is known that 2DG given continuously can have severe detrimental effects on the rodent heart. Here, we show that the principal effect of an extended, intermittent 2DG treatment on mice is to augment the mitochondrial respiratory chain proteome in the heart; importantly, this occurs without vacuolization, hypertrophy or fibrosis. The increase in the heart respiratory chain proteome suggests an increase in mitochondrial oxidative capacity, which could compensate for the energy deficit caused by the inhibition of glycolysis. Thus, 2DG in the murine heart appears to induce a metabolic configuration that is the opposite of SARS-CoV-2 infected cells, which could explain the compound’s ability to restrict the propagation of the virus to the benefit of patients with COVID-19 disease.

This article explores the implementation process of a User Acceptance Study to evaluate the feasibility of conducting cultural domain analysis (CDA) online during the COVID-19 pandemic. We conducted 19 cultural domain analysis sessions involving three techniques: free listing, pile sorts, and rank ordering. A diverse set of participants were recruited to help assess requirements and needs that researching online involves. We found that conducting CDA online is a feasible research method that offers benefits such as generating large amounts of data, making participants feel comfortable joining sessions from a safe space, providing anonymity, reducing research costs such as time and travel, and eliciting large numbers of responses. We also identified several factors for consideration when implementing CDA online and provide recommendations for improvement, including the aesthetics of the digital software employed, user accessibility and digital literacy, participants’ environments, Internet connection, and online-specific ethical issues.

Estudios recientes han reportado efectos benéficos de la vitamina D tanto en la prevención, como en el tratamiento de la enfermedad por COVID-19. Esto se ha relacionado principalmente con sus mecanismos de acción dentro del sistema renina angiotensina (SRA), la respuesta inmunitaria y las regulaciones de las citocinas proinflamatorias, ejes de importancia en la fisiopatología de la COVID-19.

Music training has traditionally been a fundamental component of children's education across several cultures. Moreover, music training has been hypothesized to enhance the development of executive functions and improve executive performance in children. In this systematic review, we analyze the available evidence of the effects of music training on executive function performance, evaluated using validated neuropsychologic batteries and classic tasks. To achieve this objective, we performed a systematic search in three databases (PubMed, Ovid MEDLINE, and Scopus) and selected case-control or intervention studies conducted on children with neurotypical development. We analyzed 29 studies that met the inclusion criteria and observed significant heterogeneity among the music interventions and methods for assessing executive functions. The review of the available literature suggests a beneficial effect of music training in core executive function performance, primarily in inhibitory control, and to a lesser extent, in working memory and cognitive flexibility.

Introduction Antiretroviral treatment turned HIV infection into a chronic disease and improved quality of life for people living with HIV. Dual-drug combinations have been shown to be effective in suppressing viral replication and can potentially reduce long-term drug-associated toxicities. We aim to investigate patients’ perceptions and experiences on the safety, effectiveness, tolerability and unmet needs of the dual-drug combination dolutegravir/lamivudine in Brighton and Hove, UK. In addition, we will conduct a comparative analysis between patients on dolutegravir/lamivudine and patients on other dual-drug and three-drug combinations. Finally, the study aims to provide recommendations to improve doctor–patient communication, knowledge and understanding of the treatment plan, and additional care that ought to be considered in patient-centred, holistic care plans.Methods and analysis Our qualitative methodological framework is based on three main methods: cultural domain analysis, focus group discussions and in-depth interviews. Cultural domain analysis employs a range of techniques (free listing, pile sorts and rankings) to elicit terms from informants regarding specific cultural domains (ie, groups of items that are perceived to be of the same kind). This framework has been codesigned with a patient representative to ensure relevance, suitability and coproduction of knowledge. All methods have been tested to take place online, as an option, via Zoom, Skype or Microsoft Teams. Padlet, an application to create online boards, will be used during the cultural domain analysis session. Data collected will be analysed following the completion of each method embracing an iterative approach through applied thematic analysis.Ethics and dissemination Ethical approval was obtained from the Health Research Authority (Reference 21/NW/0070). Findings will be used to produce recommendations to improve doctor and patient communication by identifying patients’ fears, worries, misconceptions and general concerns of their drug regimen. Conclusions will be disseminated via journal articles, conference papers and discussions through public engagement events.Project registration number IRAS number: 286277. NCT04901728.

Peripheral arterial disease (PAD) is the main cause of mortality in the western population and requires surgical intervention with the use of vascular substitutes, such as autologous veins or Dacron or PTFE prostheses. When this is not possible, it progresses to limb amputation. For cases where there is no autologous vascular substitute, tissue engineering with the production of neovessels may be a promising option. Previous experimental studies have shown in vitro that rabbit vena cava can be decellularized and serve as a scaffold for receiving mesenchymal stem cells (MSC), with subsequent differentiation into endothelial cells. The current study aimed to evaluate the behavior of a 3D product structure based on decellularized rabbit inferior vena cava (IVC) scaffolds seeded with adipose-tissue-derived stem cells (ASCs) and implanted in rabbits dorsally subcutaneously. We evaluated the induction of the inflammatory response in the animal. We found that stem cells were positive in reducing the inflammatory response induced by the decellularized scaffolds.

Abstract Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson’s disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.

Editorial Vol. 26 No. 2

Introducción: El objetivo de este estudio es analizar nuestros resultados clínico-radiológicos con el uso de copas de tantalio trabecular para la reconstrucción de acetábulos complejos, tanto en cirugías primarias como en revisiones, y com- pararlos con series similares de otros autores. Materiales y Métodos: Se llevó a cabo una revisión retrospectiva de una serie de 42 cirugías (29 revisiones y 13 artro- plastias primarias) en 40 pacientes, entre marzo de 2010 y marzo de 2016. La serie incluyó a 20 mujeres y 20 hombres, con una edad promedio de 60 años (rango 27-93). El seguimiento promedio fue de 37 meses (rango 12-84). Todos los pacientes fueron tratados con el mismo tipo de metal trabecular. Resultados: Al promedio de seguimiento mencionado la supervivencia del componente acetabular fue del 97,6%. Un paciente fue tratado con artroplastia de resección debido a una infección persistente. La tasa de complicaciones totales fue del 12% y el promedio del Harris Hip Score posoperatorio fue de 81,54 (rango 63,25-92,75). Conclusiones: Aunque se necesita un seguimiento más prolongado, el uso de copas de metal trabecular logra resultados prometedores para el tratamiento de acetábulos complejos.

In this paper, a methodology for optimal decision making for electrical systems is addressed. This methodology seeks to identify and to prioritize the replacement and maintenance of a power asset fleet optimizing the return of investment. It fulfills this objective by considering the risk index, the replacement and maintenance costs, and the company revenue. The risk index is estimated and predicted for each asset using both its condition records and by evaluating the consequence of its failure. The condition is quantified as the probability of failure of the asset, and the consequence is determined by the impact of the asset failure on the whole system. Failure probability is estimated using the health index as scoring of asset condition. The consequence is evaluated considering a failure impact on the objectives of reliability (energy not supplied -ENS), environment, legality, and finance using Monte Carlo simulations for an assumed period of planning. Finally, the methodology was implemented in an open-source library called PywerAPM for assessing optimal decisions, where the proposed mathematical optimization problem is solved. As a benchmark, the power transformer fleet of the New England IEEE 39 Bus System was used. Condition records were provided by a local utility to compute the health index of each transformer. Subsequently, a Monte Carlo contingency simulation was performed to estimate the energy not supplied for a period of analysis of 10 years. As a result, the fleet is ranked according to risk index, and the optimal replacement and maintenance are estimated for the entire fleet.

Voltage-gated calcium (Cav) channels are a prerequisite for signal transmission at the first olfactory sensory neuron (OSN) synapse within the glomeruli of the main olfactory bulb (MOB). We showed previously that the N-type Cav channel subunit Cav2.2 is present in the vast majority of glomeruli and plays a central role in presynaptic transmitter release. Here, we identify a distinct subset of glomeruli in the MOB of adult mice that is characterized by expression of the P/Q-type channel subunit Cav2.1. Immunolocalization shows that Cav2.1+ glomeruli reside predominantly in the medial and dorsal MOB, and in the vicinity of the necklace glomerular region close to the accessory olfactory bulb. Few glomeruli are detected on the ventral and lateral MOB. Cav2.1 labeling in glomeruli colocalizes with the presynaptic marker vGlut2 in the axon terminals of OSNs. Electron microscopy shows that Cav2.1+ presynaptic boutons establish characteristic asymmetrical synapses with the dendrites of second-order neurons in the glomerular neuropil. Cav2.1+ glomeruli receive axonal input from OSNs that express molecules of canonical OSNs: olfactory marker protein, the ion channel Cnga2, and the phosphodiesterase Pde4a. In the main olfactory epithelium, Cav2.1 labels a distinct subpopulation of OSNs whose distribution mirrors the topography of the MOB glomeruli, that shows the same molecular signature, and is already present at birth. Together, these experiments identify a unique Cav2.1+ multiglomerular domain in the MOB that may form a previously unrecognized olfactory subsystem distinct from other groups of necklace glomeruli that rely on cGMP signaling mechanisms.

We previously demonstrated endocytosis of KCa2.3 is caveolin-1-, dynamin II- and Rab5-dependent. KCa2.3 then enters Rab35/EPI64C- and RME-1-containing recycling endosomes and is returned to the plasma membrane (PM). Herein, we report on the mechanism by which KCa2.3 is inserted into the PM during recycling and following exit from the Golgi. We demonstrate KCa2.3 colocalizes with SNAP-23 and Syntaxin-4 in the PM of HEK and endothelial cells by confocal immunofluorescence microscopy. We further show KCa2.3 can be co-immunoprecipitated with SNAP-23 and Syntaxin-4. Overexpression of either Syntaxin-4 or SNAP-23 increased PM expression of KCa2.3, whereas shRNA-mediated knockdown of these SNARE proteins significantly decreased PM KCa2.3 expression, as assessed by cell surface biotinylation. Whole-cell patch clamp studies confirmed knockdown of SNAP-23 significantly decreased the apamin sensitive, KCa2.3 current. Using standard biotinylation/stripping methods, we demonstrate shRNA mediated knockdown of SNAP-23 inhibits recycling of KCa2.3 following endocytosis, whereas scrambled shRNA had no effect. Finally, using biotin ligase acceptor peptide (BLAP)-tagged KCa2.3, coupled with ER-resident biotin ligase (BirA), channels could be biotinylated in the ER after which we evaluated their rate of insertion into the PM following Golgi exit. We demonstrate knockdown of SNAP-23 significantly slows the rate of Golgi to PM delivery of KCa2.3. The inhibition of both recycling and PM delivery of newly synthesized KCa2.3 channels likely accounts for the decreased PM expression observed following knockdown of these SNARE proteins. In total, our results suggest insertion of KCa2.3 into the PM depends upon the SNARE proteins, Syntaxin-4 and SNAP-23.

Caspase-8 or cellular FLICE-like inhibitor protein (cFLIP) deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8−/− and receptor-interacting protein kinase-3 (RIPK3)−/−, but not cFLIP−/− and RIPK3−/−, double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here, we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis, and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption, and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. However, acute loss of cFLIP in the skin produces a similar phenotype that is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype.

O artigo não apresenta resumo em português.

Olfactory sensory neurons (OSNs) project their axons from the olfactory epithelium toward the olfactory bulb (OB) in a heterogeneous and unsorted arrangement. However, as the axons approach the glomerular layer of the OB, axons from OSNs expressing the same odorant receptor (OR) sort and converge to form molecularly homogeneous glomeruli. Axon guidance cues, cell adhesion molecules, and OR induced activity have been implicated in the final targeting of OSN axons to specific glomeruli. Less understood, and often controversial, are the mechanisms used by OSN axons to initially navigate from the OE toward the OB. We previously demonstrated a role for Wnt and Frizzled (Fz) molecules in OSN axon extension and organization within the olfactory nerve. Building on that we now turned our attention to the downstream signaling cascades from Wnt-Fz interactions. Dishevelled (Dvl) is a key molecule downstream of Fz receptors. Three isoforms of Dvl with specific as well as overlapping functions are found in mammals. Here, we show that Dvl-1 expression is restricted to OSNs in the dorsal recess of the nasal cavity, and labels a unique subpopulation of glomeruli. Dvl-2 and Dvl-3 have a widespread distribution in both the OE and OB. Both Dvl-1 and Dvl-2 are associated with intra-glomerular pre-synaptic OSN terminals, suggesting a role in synapse formation/stabilization. Moreover, because Dvl proteins were observed in all OSN axons, we hypothesize that they are important determinants of OSN cell differentiation and axon extension.

Aims: To determine the impact of permanent cardiac pacing after transcatheter aortic valve implantation (TAVI) with the CoreValveTM prosthesis in terms of all-cause mortality and morbidity [rehospitalizations for heart failure (HF) or stroke] at the long-term follow-up.Methods and results: The prospective analysis comprised 259 patients (138 women, 53.3%, age 78 ± 6 years) treated by a CoreValveTM prosthesis from April 2008 to December 2015. Forty-two patients were excluded for analysis: 9 with pre-existing permanent pacemaker (PPM) implantation, 19 who required a PPM during the follow-up and 14 patients because of hospital mortality during or after the CoreValveTM prosthesis implantation procedure. The remaining 217 patients were divided in two groups: Group-1 included those patients who required a PPM immediately after TAVI, and Group-2 included those patients who did not require permanent cardiac pacing at the long-term follow-up. Patients received follow-up at 1-month, 6-months, 12-months, and yearly thereafter. A total of 39 patients required a PPM immediately after TAVI (15.0%), but 178 patients (68.7%) did not. The mean follow-up was 37 ± 27 months (range 3-99 months) in both groups. There was no difference between the two groups in terms of all-cause mortality (52.6% vs. 56.8%, P = 0.125; HR 1.22 [0.87-1.77, 95% CI]), or stroke (13.3% vs. 15.1% P = 0.842; HR 1.12 [0.37-3.32, 95% CI]). However, patients who underwent PPM implantation developed an increase in readmissions for HF (21.1% vs. 31.9%, P = 0.015; HR 1.82 [1.23-3.92, 95% CI]).Conclusion: Patients requiring a PPM after TAVI did not have an increase in mortality, or an increase in the likelihood of developing a stroke at a long-term follow-up. However, this subgroup of patients showed an increase in rehospitalization due to HF at medium- and long-term follow-up. [ABSTRACT FROM AUTHOR]

ObjectivesPhysical activity is key to improve the prognosis of chronic obstructive pulmonary disease (COPD). To help to tailor future interventions we aimed to identify the baseline characteristics of COPD patients which predict 12-month completion and response to a behavioral physical activity intervention.MethodsThis is a 12-month cohort study of the intervention arm of the Urban Training randomized controlled trial (NCT01897298), an intervention proven to be efficacious to increase physical activity. We considered baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics as potential determinants of completion and response. We defined completion as attending the 12-month study visit. Among completers, we defined response as increasing physical activity ≥1100 steps/day from baseline to 12 months, measured by accelerometer. We estimated the factors independently for completion and response using multivariable logistic regression models.ResultsOf a total of 202 patients (m (SD) 69 (9) years, 84% male), 132 (65%) completed the study. Among those, 37 (28%) qualified as responders. Higher numbers of baseline steps/day (OR [95% CI] 1.11 [1.02-1.21] per increase of 1000 steps, pConclusionsThis study found that 12-month completion of a behavioral physical activity intervention was generally determined by previous physical activity habits as well as interpersonal and environmental physical activity facilitators while response was related to diverse factors thought to modify the individual motivation to change to an active lifestyle.

PURPOSE:Accessible interventions to train patients with chronic obstructive pulmonary disease (COPD) are needed. We designed urban trails of different intensities (low, moderate and high) in different types of public spaces (boulevard, beach and park). We aimed to validate the trails' design by assessing the physiological response to unsupervised walking trails of: (1) different intensities in COPD patients, and (2) same intensity from different public spaces in healthy adults. METHODS:On different days and under standardized conditions, 10 COPD patients walked the three intensity trails designed in a boulevard space, and 10 healthy subjects walked the three intensity trails in three different spaces. We measured physiological response and energy expenditure using a gas analyzer. We compared outcomes across trails intensity and/or spaces using mixed-effects linear regression. RESULTS:In COPD patients, physiological response and energy expenditure increased significantly according to the trails intensity: mean (SD) peak V̇O2 15.9 (3.5), 17.4 (4.7), and 17.7 (4.4) mL/min/kg (p-trend = 0.02), and MET-min 60 (23), 64 (26), 72 (31) (p-trend

Apenas un 15% de la población no se encuentra en redes sociales. Las redes sociales se han convertido en plataformas sociales de uso diario y cotidiano que permite a las personas estar interactuando entre sí y con sus marcas preferidas. Como consecuencia de ello, el presente estudio pretende conocer la evolución del número de seguidores de los clubes de la Liga Asobal entre las temporadas 2020/21-2022/23, analizar si existe algún tipo de relación entre la clasificación y el número de seguidores y, averiguar cuál ha sido la plataforma con mayor crecimiento. En el presente estudio participaron 16 clubes de la Liga Asobal (excepcionalmente en la temporada 2020/21, en lugar de competir 16 clubes, participaron 18 equipos en la primera división española de balonmano por motivos del COVID-19). Los resultados indican el aumento considerable del número de seguidores en todos los clubes que han participado en la muestra y es Instagram la red social que ha reflejado un mayor crecimiento. Palabras clave: Social media, marketing, comunicación online, deporte, balonmano. Abstract. Only 15% of the population is not on social networks. Social networks have become social platforms for daily and everyday use that allow people to interact with each other and with their favorite brands. As a consequence, the present study aims to know the evolution of the number of followers of the Asobal League clubs between the 2020/21-2023/24 seasons, examine whether there is any type of relationship between the classification and the number of followers and, find out which has been the platform with the greatest growth. 16 clubs from the Asobal League participated (exceptionally in the 2020/21 season, instead of 16 clubs competing, 18 teams participated in the Spanish first handball division due to COVID-19), using descriptive analyzes and the Wilcoxon test and the Spearman correlation test. The results indicate a considerable increase in the number of followers in all the clubs that have participated in the sample and Instagram is the social network that has reflected the greatest growth. Keywords: Social media, marketing, online communication, sport, handball.

It has been a longstanding goal to promote the propagation of functional mitochondrial DNAs at the expense of pathological molecules in cells where the two species coexist. Here, the authors show that restricting the availability of glucose and glutamine can achieve this outcome.

Abstract Background Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT. Methods This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms. Results Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices. Conclusions This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs.