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IntroductionHistorically, Multiple Endocrine Neoplasia type 1 (MEN1)-related pituitary adenomas (PAs) were considered more aggressive and treatment-resistant than sporadic PAs. However, recent studies suggest similarities in their behavior. This study aimed to evaluate the long-term outcomes of MEN1 PAs and identify predictive factors.MethodsNationwide multicenter retrospective cohort study of MEN1-related PAs with a minimum 1-year follow-up, collecting patient demographics, germline MEN1 pathogenic variants (PV), PA size, secretory profile, radiological characteristics, treatments, and outcomes.ResultsWe analyzed 84 PAs, 69%in females and 31% in males (P

IntroductionHow to make work life increasingly meaningful and ensuring that business actions aim at improving quality of life is a trending topic. Yet, it has not often been studied within architectural firms, that play a crucial role in achieving sustainable development goals, especially those related to equity, equality, and the creation of pleasant work environments. This study aims to identify whether there are gender differences in the perception and levels of workplace happiness of individuals working within architectural companies in Valencia (Spain).MethodsA mixed methodology based on qualitative and quantitative data has been applied with a sample of 201 workers from 60 practices.ResultsParticipants perceive themselves as flourishing and quite happy at work. Yet, there are gender differences in the factors that motivate workplace happiness. While women prioritize the work environment, their colleagues and teams, men point out to career development. Thus, recognition, appreciation, feeling valued and goals and achievements are among the main drivers of men’s workplace happiness. In addition, women tend to experience negative emotions such as anxiety, anger, or sadness more frequently than men. Given these results, architectural companies face a considerable challenge.DiscussionThe research examines the relationship between workplace happiness and social sustainability in architectural firms, highlighting the importance of human capital for competitiveness. To promote sustainability and well-being at work, it is crucial to understand how organizational decisions impact employee well-being and to know the differences in perceptions of workplace happiness between men and women. This analysis may be of interest to the architectural firms object of this research.

Objectives: Identifying patients with COVID-19 who are at risk of poor evolution is key to early decide on their hospitalization. We evaluated the combined impact of nucleocapsid (N)-antigenemia profiled by a rapid test and antibodies against the S1 subunit of the SARS-CoV S protein (S1) on the hospitalization risk of patients with COVID-19. Methods: N-antigenemia and anti-S1 antibodies were profiled at admission to the emergency department in 146 patients with COVID-19 using the Panbio® antigen Rapid Test and the SARS-CoV-2 immunoglobulin G II Quant/SARS-CoV-2 immunoglobulin G assay from Abbott. A multivariable analysis was used to evaluate the impact of these factors on hospitalization. Results: Patients with a positive N-antigen test in plasma and anti-S1 levels

The mammalian target of rapamycin (mTOR) is a master regulator of the cell metabolism which impacts numerous signaling involved in cell proliferation and death and recycling cell constituents to readapt to new physiological or pathological environments. mTOR is constituted by two structural and functional different complexes, mTORC1 and mTORC2. Both can be independently regulated, which has a great impact on the effectiveness of therapeutic interventions in different clinical and experimental situations. Furthermore, mTORC1 interacts with specific chaperones or immunophilins which are intracellular receptors of the immunosuppressive drugs. Low and high molecular weights of immunophilins have different intracellular functions. The present review updates the molecular structure and signaling of mTOR as well as their regulation by immunophilins and upstream and downstream signaling events, highlighting the potential therapeutic intervention of mTOR in cancer, metabolic disturbances, and aging.

Kanban is a process management system originally developed in the automotive industry that is migrating to other fields such as construction. This article provides a literature review of 53 international scientific contributions that focus on the application of Kanban in the construction sector. The contents has been qualitatively analysed using ATLAS.ti 8.1 software, and interpretative synthesis to summarise the relevant findings. Kanban has been used for supply chain management, Just In Time (JIT) implementation in construction, and the Last Planner® System (LPS) for work management and coordination. In addition, we have detected a progressive evolution to E-Kanban systems and their application in Building Information Management (BIM) environments, as well as the development of new software applications and methods. Kanban's flexibility and its value in terms of improving the performance of construction sites is highlighted. Future research is suggested to explore the implementation of this system in the European and Spanish construction sector.

Summary: Here, we present a protocol for lentiviral delivery of CRISPR-Cas9 to human induced pluripotent stem cell (iPSC)-derived macrophages using co-incubation with VPX virus-like particles (VPX-VLPs). We describe steps for producing polybrene and puromycin kill curves, VPX viral production, and VPX-VLP titration by western blotting. We then detail procedures for iPSC macrophage precursor lentiviral transduction and lentiviral CRISPR-Cas9-based knockout in iPSC-derived macrophages. This protocol uses efficient genome-editing techniques to explore macrophage involvement in immune response, chronic inflammation, neurodegenerative disease, and cancer progression.For complete details on the use and execution of this protocol, please refer to Navarro-Guerrero et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

This work introduces a methodology for the design of X-band microwave absorbers using carbon-graphite powder composites. The reflection loss (RL) is adjusted through variations in sample thickness, mono/bi-slab geometries, and effective dielectric constant. The impact of the particle size of the powders and the volume fraction (v.f.) of the composites on the effective dielectric permittivity has been systematically investigated. The Nicolson-Ross-Weir (NRW) conversion and the Birchak dielectric mixing model were employed. Optimal absorption conditions predicted by RL simulations were validated through experimental waveguide measurements for mono/bi-slab systems of paraffin-carbon composite samples. The mono-slabs with a particle size of 3.5 μm showed the best versatility for tailoring the RL in the X-band through v.f. variations while maintaining a fixed thickness of 2 mm. In addition, a bi-slab system (powder-paraffin/paraffin) for such powder size, at 18.0 % of v.f., showed an enhanced RL with a bandwidth of 2.6 GHz and a minimum of − 40 dB (at 11 GHz). Other dielectrics based on resin:paint mixtures were tested to replace the paraffin-matrix, revealing a strong powder-matrix interaction capable of modulating the effective dielectric permittivity. Finally, experimental antenna RL measurements conducted in free space were corroborated by theoretical simulations based on the waveguide characterizations.

Resumen Objetivos: El incremento de la población mayor ha hecho que se eleve el porcentaje de personas con demencia que requieren una atención especializada dirigida a mantener o retrasar su declive cognitivo y físico. El objetivo de esta investigación ha sido analizar si un grupo de personas con demencia mejoran cognitivamente al ser atendidos por cuidadores profesionales que han sido formados en un módulo de estimulación cognitiva del programa CUIDA-2 siguiendo los principios de la atención centrada en la persona. Metodología: La muestra estuvo formada por 47 personas con demencia (divididas en grupo tratamiento y grupo control) y 5 cuidadores formales de un centro de día de personas con demencia de Granada. El grupo tratamiento de personas mayores fue atendido durante 3 meses por cuidadores que recibieron el programa de formación. Todos los participantes fueron evaluados antes y después de la intervención con diversas pruebas de evaluación cognitiva. Resultados: Las personas con demencia que fueron atendidas por los cuidadores formados en el programa mantuvieron o mejoraron sus puntuaciones en todas las pruebas analizadas, si bien estas mejoras solo fueron significativas en diversas subescalas de los test empleados. Conclusiones: Se ha comprobado que el programa de formación de cuidadores aquí analizado produce un efecto positivo para las personas con demencia, ya que ayuda a mejorar y mantener sus funciones cognitivas. Esta investigación abre nuevas líneas de trabajo en el ámbito de la intervención cognitiva en personas con demencia que pueden ser de gran utilidad cuando se trabaje con esta población.

Abstract Background Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A. Methods The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells. Results Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1. Conclusions The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.

BackgroundBehavioral and substance addictions are prevalent health problems that, alongside obesity, are linked to reduced physical activity and increased sedentary time. Similarly, arterial stiffness and vascular aging are processes that begin gradually at an early age and are closely associated with morbidity and mortality from cardiovascular diseases. The main objective of this study is to analyze how addictions are related to obesity and body fat distribution, physical activity, sedentary time, arterial stiffness and vascular aging, as well as sleep quality, cognitive function and gender differences in young adults aged between 18 and 34 years.MethodsThis cross-sectional descriptive observational study will analyze data from 500 subjects (250 men and 250 women) aged 18–34 without cardiovascular disease, selected by simple random sampling with replacement from the urban population of the city center of Salamanca (34,044 people aged 18–34, with 18,450 women and 15,594 men). Behavioral and substance addictions, as well as sleep quality and cognitive impairment will be assessed using questionnaires. The Pittisburg Sleep Quality Index (PSQI) will be used to measure sleep quality and the Ford questionnaire will be used to measure insomnia in response to stress. For obesity, weight, height, waist and hip circumference, body composition will be measured with the Inbody 230® impedance meter. For physical activity and sedentary time, we will use the Actigraph® accelerometer alongside the international physical activity questionnaire (IPAQ) and the Marshall questionnaire. The Sphygmocor System® will be used for pulse wave analysis and carotid-femoral pulse wave velocity (cfPWV), while the Vasera VS-2000® will measure cardio ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV). Vascular aging will be calculated with the 10th and 90th percentiles of cfPWV or baPWV. Demographic, analytical variables will be collected, as will data to assess vascular, cardiac, renal, and brain injury.DiscussionAddictions are on the rise in today’s society, affecting the mental health and well-being of those who suffer from them, generating important social problems such as job loss, family dysfunction, debt and social isolation. Together with obesity, they are prevalent health problems in young adults and are associated with lower physical activity and higher sedentary time. Meanwhile, arterial stiffness and vascular aging are processes that begin gradually at an early age and determine morbidity and mortality caused by cardiovascular diseases. The results of this project will allow us to understand the situation regarding behavioral and substance addictions in young adults. Better understanding of these addictions will in turn facilitate the development of more effective prevention strategies and intervention programs, which can then reduce the negative impact at both the individual and societal levels.Clinical trial registration[ClinicalTrials.gov], identifier [NCT05819840].

Background: Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage disease (aDTC) with reduced overall survival (OS). Objective: The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic management, and prognosis in Spain and Portugal. Methods: A multicentre, longitudinal, retrospective study of adult patients diagnosed with aDTC in the Iberian Peninsula was conducted between January 2007 and December 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors impacting the evolution of advanced disease were evaluated. Results: Two hundred and thirteen patients (median age: 63 years; 57% female) were eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3–15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7–16.2) years; log-rank test P = 0.4737). Age at diagnosis being

Purpose: The arrival of new companies that are more technological and scalable to the real estate sector has caused a revolution in a very conservative and not very innovative industry. The main objective of this research is to characterize the business model of proptech online brokerage companies in home sales in Spain, based on the traditional agency model. Design/methodology: Nine semi-structured interviews were conducted with the CEOs and managers of six proptech online real estate brokerage agencies in Spain. Their content was analyzed by means of the study and comparison of common patterns. Findings: During the digitalization process of the brokerage, a regression was detected back to more classic procedures typically found in traditional agencies, thus establishing an important difference as compared to other more transparent markets. Accordingly, a convergence occurs between the different real estate brokerage models (online and traditional), resulting in a hybrid model. Research limitations: The limited number of agencies that operate in the online mode in Spain makes the sample size quite small. Practical implications: The results contribute greater transparency to a traditional sector characterized by its opacity, and they give visibility to the changes that are currently taking place, facilitating information to both professionals and users. Social implications: It contributes to the fulfillment of Sustainable Development Goal number 9, concerning the promotion of development-oriented policies that support the creation of decent jobs, entrepreneurship, creativity and innovation. Originality/value: It expands the scientific literature dedicated to online real estate brokerage in Spain, given that as of today, we have no knowledge of any other published academic work on this topic. The research contributes to the vision that new sector agents have of it and those changes that are occurring within it.

Background: SARS-CoV-2 infection affects the vascular endothelium, which mediates the inflammatory and thrombotic cascade. Moreover, alterations in the endothelium are related to arterial stiffness, which has been established as a marker of cardiovascular disease. The objective of this study is to analyse how the structure, vascular function, vascular ageing and endothelial damage are related to the biopsychological situation in adults diagnosed with persistent COVID and the differences by gender.Methods: This cross-sectional, descriptive, observational study will be carried out in the Primary Care Research Unit of Salamanca (APISAL) and in the BioSepsis laboratory of the University of Salamanca. The sample will be selected from the persistent COVID monographic office at the Internal Medicine Service of the University Hospital of Salamanca, and from the population of subjects diagnosed with persistent COVID in the clinical history of Primary Care. Through consecutive sampling, the study will include 300 individuals diagnosed with persistent COVID who meet the diagnosis criteria established by the WHO, after they sign the informed consent. Endothelial damage biomarkers will be measured using ELLA-SimplePlexTM technology (Biotechne). Their vascular structure and function will be analysed by measuring the carotid intima-media thickness (Sonosite Micromax); the pulse wave and carotid-femoral pulse wave velocity (cfPWV) will be recorded with Sphygmocor System®. Cardio Ankle Vascular Index (CAVI), brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index will be analysed with Vasera VS-2000®. The integral assessment of the subjects with persistent COVID will be conducted with different scales that evaluate fatigue, sleep, dyspnea, quality of life, attention, nutrition state, and fragility. We will also evaluate their lifestyles (diet, physical activity, smoking habits and alcohol consumption), psychological factors, and cognitive deterioration, which will be gathered through validated questionnaires; moreover, physical activity will be objectively measured using a pedometer for 7 days. Body composition will be measured through impedance using an Inbody 230. Vascular ageing will be calculated with 10 and 90 percentiles of cfPWV and baPWV. Furthermore, we will analyse the presence of vascular injury in the retina, heart, kidneys and brain, as well as cardiovascular risk. Demographic and analytical variables will also be gathered.Discussion: Arterial stiffness reflects the mechanic and functional properties of the arterial wall, showing the changes in arterial pressure, blood flow, and vascular diameter that occur with each heartbeat. SARS-CoV-2 affects the endothelial cells that are infected with this virus, increasing the production of pro-inflammatory cytokines and pro-thrombotic factors, which can cause early vascular ageing and an increase of arterial stiffness. Persistent COVID is a complex heterogeneous disorder that affects the lives of millions of people worldwide. The identifications of potential risk factors to better understand who is at risk of developing persistent COVID is important, since this would enable early and appropriate clinical support. It is unknown whether vascular alterations caused by COVID-19 resolve after acute infection or remain over time, favouring the increase of arterial stiffness and early vascular ageing. Therefore, it is necessary to propose studies that analyse the evolution of persistent COVID in this group of patients, as well as the possible variables that influence it.Clinical Trial registration:ClinicalTrials.gov, identifier NCT05819840

Cysteine residues can undergo multiple posttranslational modifications with diverse functional consequences, potentially behaving as tunable sensors. The intermediate filament protein vimentin has important implications in pathophysiology, including cancer progression, infection, and fibrosis, and maintains a close interplay with other cytoskeletal structures, such as actin filaments and microtubules. We previously showed that the single vimentin cysteine, C328, is a key target for oxidants and electrophiles. Here, we demonstrate that structurally diverse cysteine-reactive agents, including electrophilic mediators, oxidants and drug-related compounds, disrupt the vimentin network eliciting morphologically distinct reorganizations. As most of these agents display broad reactivity, we pinpointed the importance of C328 by confirming that local perturbations introduced through mutagenesis provoke structure-dependent vimentin rearrangements. Thus, GFP-vimentin wild type (wt) forms squiggles and short filaments in vimentin-deficient cells, the C328F, C328W, and C328H mutants generate diverse filamentous assemblies, and the C328A and C328D constructs fail to elongate yielding dots. Remarkably, vimentin C328H structures resemble the wt, but are strongly resistant to electrophile-elicited disruption. Therefore, the C328H mutant allows elucidating whether cysteine-dependent vimentin reorganization influences other cellular responses to reactive agents. Electrophiles such as 1,4-dinitro-1H-imidazole and 4-hydroxynonenal induce robust actin stress fibers in cells expressing vimentin wt. Strikingly, under these conditions, vimentin C328H expression blunts electrophile-elicited stress fiber formation, apparently acting upstream of RhoA. Analysis of additional vimentin C328 mutants shows that electrophile-sensitive and assembly-defective vimentin variants permit induction of stress fibers by reactive species, whereas electrophile-resistant filamentous vimentin structures prevent it. Together, our results suggest that vimentin acts as a break for actin stress fibers formation, which would be released by C328-aided disruption, thus allowing full actin remodeling in response to oxidants and electrophiles. These observations postulate C328 as a “sensor” transducing structurally diverse modifications into fine-tuned vimentin network rearrangements, and a gatekeeper for certain electrophiles in the interplay with actin.

Background: The harmful effect of alcohol on the immune system may be due to both a direct action of the alcohol or its metabolites on immune cells as an indirect action modifying the different mechanisms of intercellular interaction. The interplay between stimulatory (aKIR) and inhibitory (iKIR) natural killer (NK) cell receptors and their corresponding human leukocyte antigen (HLA) ligands influences the outcome of virus infection. The aim was to analyze the influence of the KIR/HLA pair genetic profile in male alcoholic cirrhosis (AC) patients with and without viral infections to find susceptibility biomarkers that can help establish the risks and prevent viral infections. Methods: A total of 281 male AC patients were analyzed. The sociodemographic characteristics, viral hepatitis C (HCV), hepatitis B (HBV), and cytomegalovirus (CMV) infections were analyzed. Genomic DNA was extracted, and genetic the KIR/HLA profiles were investigated. A total of 6 KIR genes and their corresponding ligands (HLA-C) were analyzed. Patients were grouped into two groups: with and without associated viral infection. Results: A statistically significant increase in the combination of KIR2DL2+/C1C1 was observed in male AC patients with viral infection compared to those without viral infection (45.9% vs. 24.5%, p = 0.021). The analysis of KIR2DL3+/C1+ showed a high frequency comparing healthy controls and male AC patients without virus infection (85% vs. 76.4%; p = 0.026). The analysis of KIR2DL3+/C2C2 frequency showed a statistically significant increase comparing male AC patients without viral infection and healthy controls (23.6% vs. 15%; p = 0.026). Conclusions: The genetic KIR2DL2+/C2C2 profiles may play a significant role in determining the vulnerability of male AC patients to viral infections, providing valuable insights for future research and potential therapeutic interventions.

Abstract Bone is the second most common distant metastasis site in differentiated thyroid cancer (DTC) and is normally associated with the presence of other metastases, which are usually radioiodine‐resistant. The presence of bone metastasis (BM) determines low survival and greater morbidity due to the frequency of skeletal‐related events (SREs), which can be a serious complication of BM. There is evidence that antiresorptive therapy (AT) reduces SREs in other solid tumors, but not yet in DTC BM, for which data are scant. The same is true for systemic therapy with multikinase inhibitors (MKIs). In general, the results for MKI use are well known, although the effect on BM has rarely been evaluated. While MKIs are indicated in current clinical practice guidelines, studies evaluating the benefits and risks of concomitant treatment with MKIs and AT are lacking, and the available data come from small samples in retrospective studies. The objective of this article is to review the latest evidence for concomitant MKIs and AT.

This work focuses on the synthesize of nanostructured (Fe65Co35)100-x (Pr6O11)x (x = 0, 5) powders using high energy ball milling. The influence of Pr6O11 on structural, morphological and magnetic properties of Fe65Co35 nanoparticles were carried out by X-ray diffraction (XRD), scanning electron microscopy (SEM) with a dispersive energy analyzer (EDS), vibratory sample magnetometer (VSM) and differential scanning calorimetry (DSC). Results show that the praseodymium oxide addition increased the decrement rate of the crystallite size with milling time of about 27 % and decreased the increment rate of the internal micro-strain of 50 %. Moreover, because of its high grain fragmentation tendency, Pr6O11 increases the hardness and brittleness of Fe-Co powders. Moreover, it minimized the cold welding between Fe-Co ductile particles leading to a significant decrease in the average particle size (~1�m). The magnetic measurements conducted at room temperature show that the saturation magnetisation (Ms) and the coercivity (Hc) increased with milling time in both compositions. A low Ms and high Hc values were detected in (Fe65Co35)95 (Pr6O11)5 nanoparticles. The results demonstrated a soft ferromagnetic nature in all of the synthesized nanoparticles with Ms in the range 207 � 216 emu/g and Hc is found to be 113 Oe.

Abstract Background Saliva is being increasingly used as a sample for measuring biomarkers in several species and shows a high potential of use to detect and monitor stress. The weaning and grouping in dairy calves are a particularly stressful time. Therefore, the objectives of this study were to evaluate a panel of antioxidant and oxidant biomarkers in the saliva of calves on the day of weaning (W0), 2 days after weaning or milk withdrawal (W + 2), and 4 days after grouping (G + 4). In addition, to verify if cortisol and oxytocin concentrations are related to the biomarkers measured. Results Salivary cupric reducing antioxidant capacity (CUPRAC), ferric reducing ability of saliva (FRAS), Trolox equivalent antioxidant capacity (TEAC), advanced oxidation protein products (AOPP), and ferrous oxidation-xylenol orange (FOX) were significantly higher (P

Teamwork is a fundamental employability skill and, as such, is fostered in professional programmes. This study presents a comparative analysis of higher education students' perceptions, development, and experiences of teamwork at two universities: one in South Africa and the other in Spain. These study sites provided a fruitful opportunity for comparison, given their contextual similarities. Through a survey of 395 3rd and 4th-year students of professional degrees, the authors explored how these students developed the teamwork skills required within their curricula. The findings showed that respondents from both institutions perceive teamwork similarly, but there are significant differences in how these skills are developed. While most South African respondents had participated in courses focused on team functioning, the Spanish had learnt to function in teams during project work. Furthermore, the South African sample was more aware of the impact of socio-cultural factors on team functioning than the Spanish one. The former reported feeling marginalised due to their race, gender and language to a greater extent than the Spanish. The paper outlines the potential benefits of successful teamwork, such as improving social cohesion. The results could be useful to policymakers and lecturers designing context-specific interventions to develop students' teamwork skills.

Nuclear architecture and functions depend on dynamic interactions between nuclear components (such as chromatin) and inner nuclear membrane (INM) proteins. Mutations in INM proteins interfering with these interactions result in disease. However, mechanisms controlling the levels and turnover of INM proteins remain unknown. Here, we describe a mechanism of regulated degradation of the INM SUN domain-containing protein 2 (SUN2). We show that Casein Kinase 2 and the C-terminal domain Nuclear Envelope Phosphatase 1 (CTDNEP1) have opposing effects on SUN2 levels by regulating SUN2 binding to the ubiquitin ligase Skp/Cullin1/F-BoxβTrCP (SCFβTrCP). Upon binding to phosphorylated SUN2, SCFβTrCP promotes its ubiquitination. Ubiquitinated SUN2 is membrane extracted by the AAA ATPase p97 and delivered to the proteasome for degradation. Importantly, accumulation of non-degradable SUN2 results in aberrant nuclear architecture, vulnerability to DNA damage and increased lagging chromosomes in mitosis. These findings uncover a central role of proteolysis in INM protein homeostasis.

This paper explores the key factors influencing mental health professionals' behavioral intention to adopt virtual humans as a means of affect recognition training. Therapies targeting social cognition deficits are in high demand given that these deficits are related to a loss of functioning and quality of life in several neuropsychiatric conditions such as schizophrenia, autism spectrum disorders, affective disorders, and acquired brain injury. Therefore, developing new therapies would greatly improve the quality of life of this large cohort of patients. A questionnaire based on the second revision of the Unified Theory of Acceptance and Use of Technology (UTAUT2) questionnaire was used for this study. One hundred and twenty-four mental health professionals responded to the questionnaire after viewing a video presentation of the system. The results confirmed that mental health professionals showed a positive intention to use virtual reality tools to train affect recognition, as they allow manipulation of social interaction with patients. Further studies should be conducted with therapists from other countries to reach more conclusions.

Abstract Background The possible use of oxytocin in saliva as an indicator of positive emotions in bovine species has been poorly investigated. In the present study, two new assays (one using a monoclonal antibody and the other using a polyclonal antibody) for the measurement of oxytocin in bovine saliva were developed and validated. Also, the changes in oxytocin in saliva were explored in two different situations. One was around parturition, and for this purpose, saliva samples from 13 cows were collected at three different times: 7 days before the parturition, the day of parturition and 7 days after the parturition. The second situation was weaning and grouping of calves, and for this purpose, saliva from 25 calves was collected at three different times: 1 day before weaning, 2 days after weaning or milk withdrawal and 4 days after grouping calves. Results In cows, oxytocin concentrations showed an increase on the day of parturition with both assays, while in calves, oxytocin concentrations showed a decrease 4 days after the grouping. Conclusions The assays validated in this report could be used for the measurement of oxytocin in bovine saliva and detect changes in this analyte that can occur in different physiological or productive situations such as parturition and weaning.

Abstract Genome engineering using CRISPR/Cas9 technology enables simple, efficient and precise genomic modifications in human cells. Conventional immortalized cell lines can be easily edited or screened using genome-wide libraries with lentiviral transduction. However, cell types derived from the differentiation of induced Pluripotent Stem Cells (iPSC), which often represent more relevant, patient-derived models for human pathology, are much more difficult to engineer as CRISPR/Cas9 delivery to these differentiated cells can be inefficient and toxic. Here, we present an efficient, lentiviral transduction protocol for delivery of CRISPR/Cas9 to macrophages derived from human iPSC with efficiencies close to 100%. We demonstrate CRISPR/Cas9 knockouts for three nonessential proof-of-concept genes—HPRT1, PPIB and CDK4. We then scale the protocol and validate for a genome-wide pooled CRISPR/Cas9 loss-of-function screen. This methodology enables, for the first time, systematic exploration of macrophage involvement in immune responses, chronic inflammation, neurodegenerative diseases and cancer progression, using efficient genome editing techniques.

Introducción: el sistema español de farmacovigilancia se basa en la notificación espontánea de sospechas de Reacciones Adversas a Medicamentos (RAM) por parte de los pacientes, la industria farmacéutica y los profesionales sanitarios mediante la tarjeta amarilla. La farmacovigilancia es una de las actividades que puede desarrollar la farmacia comunitaria y que, además, está contemplada en la legislación como una labor obligatoria para todos los profesionales sanitarios. El objetivo de este artículo es describir y analizar las sospechas de RAM detectadas por el equipo farmacéutico de una farmacia comunitaria y comunicadas al Centro Andaluz de Farmacovigilancia desde el año 2002 al año 2018. Métodos: estudio observacional longitudinal realizado en una farmacia comunitaria de Benalmádena (Málaga) con las sospechas de RAM detectadas y notificadas mediante tarjeta amarilla al Centro Andaluz de Farmacovigilancia desde el año 2002 hasta el año 2018. Resultados: el número total de sospechas de RAM comunicadas al Centro Andaluz de Farmacovigilancia desde el año 2002 ha sido de 329. La edad media de los pacientes que presentaron una RAM ha sido de 59,3 años (DE: 16,8). Los grupos farmacológico implicados en las RAM con una mayor frecuencia han sido los agentes modificadores de los lípidos (9,4 %), agentes que actúan sobre el sistema renina-angiotensina (9,4 %), antibacterianos (6,9 %), antiinflamatorios (6,9 %) y psicoanalépticos (6,4 %). Las RAM detectadas han afectado principalmente al sistema nervioso (31,7 %), al tracto gastrointestinal (22,4 %) y a la piel (14,3 %). Conclusiones: más de la mitad de las sospechas comunicadas se han registrado en pacientes mayores de 65 años. El equipo farmacéutico debe seguir atento a la detección de sospechas de RAM en este grupo de pacientes, especialmente en los medicamentos de nueva comercialización. El análisis de las sospechas de RAM detectadas permite disponer de un conocimiento más completo de la seguridad del medicamento en nuestra actividad.

(1) Introduction: With older adults, cognitive intervention programs are most often used for preventing or reversing a decline in cognitive functions, but it has been recently noted that there are insufficient high-quality research studies that report the effects of cognitive intervention on the cognitive functioning of older adults. (2) Objective: To analyze the available evidence concerning the effect of cognitive interventions for improving or maintaining the general cognitive status of older adults who present different cognitive levels. (3) Method: a review of studies published between 2010 and 2019 using the following databases: PubMed, PsycINFO, Cochrane, Google Scholar, ProQuest and Medline. (4) Results: We selected 13 systematic reviews and/or meta-analyses. The results showed that the cognitive intervention programs improved general cognitive functioning and specific cognitive functions regardless of the initial cognitive level; that cognitive decline was slowed in older persons with dementia; and there was improvement in activities of daily living. Regarding duration of the results, benefits were maintained for periods of 2 months to 5 years. (5) Conclusion: Cognitive interventions have proven effective for maintaining and/or improving cognitive functioning in older adults regardless of their initial cognitive status. Even so, there are few studies that follow up these results to see whether they are maintained in the long term and whether there is transfer to other skills of daily life. However, we were able to observe in the present review how the participants’ cognitive level varied according to sociodemographic differences, and to identify which components of cognitive programs make them more effective. Based on the results found, we highlight the importance of designing cognitive intervention programs that meet these effectiveness criteria, in order to maximize the positive effects of such programs when working with a population of older adults.

Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway involved in self-renewal and quality control processes to maintain cellular homeostasis. The alteration of autophagy has been implicated in numerous diseases such as cancer where it plays a dual role. Autophagy serves as a tumor suppressor in the early phases of cancer formation with the restoration of homeostasis and eliminating cellular altered constituents, yet in later phases, autophagy may support and/or facilitate tumor growth, metastasis and may contribute to treatment resistance. Key components of autophagy interact with either pro- and anti-apoptotic factors regulating the proximity of tumor cells to apoptotic cliff promoting cell survival. Autophagy is regulated by key cell signaling pathways such as Akt (protein kinase B, PKB), mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) involved in cell survival and metabolism. The expression of critical members of upstream cell signaling, as well as those directly involved in the autophagic and apoptotic machineries are regulated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Consequently, non-coding RNAs play a relevant role in carcinogenesis and treatment response in cancer. The review is an update of the current knowledge in the regulation by miRNA and lncRNA of the autophagic components and their functional impact to provide an integrated and comprehensive regulatory network of autophagy in cancer.

Background: Brief interventions (BI) for risky drinkers in primary healthcare have been demonstrated to be cost-effective but they are still poorly implemented. Digital BI seems to be a complementary strategy to overcome some barriers to implementation but there is a scarcity of studies in clinical environments. We present the results of a randomized controlled non-inferiority trial which tests the non-inferiority of facilitated access to a digital intervention (experimental condition) for risky drinkers against a face-to-face BI (control condition) provided by primary healthcare professionals. Method: In a non-inferiority randomized controlled trial, unselected primary healthcare patients (≥ 18 years old) were given a brief introduction and asked to log on to the study website to fill in the 3-item version of the Alcohol Use Disorders Identification Test. Positively screened patients (4+ for women and 5+ for men) received further online assessment (AUDIT, socio-demographic characteristics and EQ-5D-5L) and were automatically randomized to either face-to-face or digital BI (1:1). The primary outcome was the proportion of patients classified as risky drinkers by the digitally administered AUDIT at month 3. A multiple imputation approach for the missing data was performed. Results: Of the 4499 patients approached by 115 healthcare professionals, 1521 completed the AUDIT-C. Of the 368 positively screened patients, 320 agreed to participate and were randomized to either intervention. At month 3, there were more risky drinkers in the experimental group (59.8%) than in the control group (52%), which was similar to the distribution at baseline and less than the pre-specified margin of 10%. The difference was not significant when accounting for possible confounders. Conclusion: Digital BI was not inferior to face-to-face BI, in line with previous findings and the a priori hypothesis. However, the low power of the final sample, due to the low recruitment and loss to follow-up, limits the interpretation of the findings. New approaches in this field are required to ensure the effective implementation of digital interventions in actual practice.

BackgroundChromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs).MethodsKMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis.ResultsChaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation, and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death.ConclusionKMT inhibitors could function as sensitizers to DNA damage-based therapies and be used in novel synthetic lethality strategies for sarcoma treatment.

Primary hyperparathyroidism is the most frequent manifestation of multiple endocrine neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). Eighty-nine patients (49 men and 40 women, 34.2 ± 13 years old) were included. Sixty-four out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs 7/12, P < 0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypopar athyroidism and patients with different mutated exons, but a second surgery was more freq uent after a less than subtotal parathyroidectomy.

The intermediate filament vimentin reorganizes during mitosis, but its molecular regulation and impact on the cell during cell division is unclear. Here, the authors show that vimentin filaments redistribute to the cell cortex during mitosis intertwining with and affecting actin organization.

Abstract Background Biomarkers of oxidative stress in pigs have been measured in serum/plasma samples. However, blood collection in pigs can be highly stressful to the animals. Saliva is a biological fluid with several advantages in pigs over blood, since it can be easily collected without stress to the animals, being therefore an ideal sample in this species. The objective of this study was the validation of assays for the evaluation of oxidative stress status in saliva of pigs. For this purpose, three assays commonly used to evaluate the total antioxidant capacity (TAC): trolox equivalent antioxidant capacity (TEAC), cupric reducing antioxidant capacity (CUPRAC), and ferric reducing ability of plasma (FRAP)), one individual antioxidant (uric acid) and two assays to evaluate oxidant concentrations (advanced oxidation protein products (AOPP) and hydrogen peroxide (H2O2)) were measured and validated in porcine saliva. In addition, the possible changes of these assays in sows’ saliva during lactation were be studied. Results The methods had intra- and inter-assays coefficient of variation lower than 15%. They also showed an adequate linearity and recovery, and their detection limits were low enough to detect the analytes in saliva of pigs. Overall the analytical validation tests showed that the assays used in our study are valid and reliable for the evaluation of oxidative stress in porcine saliva. In addition, it was observed that these salivary biomarkers can change in a situation of oxidative stress such as lactation in sows. Conclusions All assays for salivary biomarkers of oxidative stress evaluated in this study have demonstrated a high analytical accuracy and low imprecision. In addition, it has been observed that these biomarkers showed significant changes in a situation of oxidative stress such as lactation in sows. Therefore, this study opens a new possibility of using saliva as a non-invasive sample to evaluate oxidative stress in pigs.

Resumen La aplicación del Método de la Cadena Crítica en la dirección y gestión de proyectos suscita abiertos debates sobre qué procedimiento de dimensionado del búfer se ha de utilizar y cuál ha de ser la duración de las actividades en la realización del cronograma. Se ha realizado una comparativa entre 4 métodos de dimensionado de búfers, empleando dos tipos de estimaciones de la duración de las tareas. Se ha determinado la probabilidad de cumplimiento de la fecha de finalización del proyecto obtenida con cada método a través de una simulación Monte Carlo. Tomando como criterio la probabilidad de cumplimiento, se ha demostrado que la duración media de las actividades tiene mayor efecto que un procedimiento específico de dimensionado del búfer. Aunque cada método de dimensionado genera una planificación diferente, el tamaño del búfer siempre aumenta la confiabilidad de la fecha de finalización del proyecto. Abstract Critical Chain Method application in Project Management generates open discussions about which buffer’s sizing procedure should be used and what tasks duration should be considered in the realization of the timeline. A comparison has been carried out between 4 buffers' sizing methods, using two types of estimates for tasks duration. By means of a Monte Carlo simulation, each probability of project deadline compliance has been determined. Taking the probability of compliance as a criterion, it has been found that the use of average tasks durations has a greater effect than a specific sizing buffer's method. Although each sizing method generates a different planning, the buffer size always increases the reliability of the project's end date

BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.

Many factors can lead to an inadequate development of piglets during their first days of life, including poor maternal behavior, which can be due to pain caused by farrowing, and reduced colostrum ingestion. This study investigates the action of meloxicam administered orally at farrowing on piglet weight gain and immunity transfer. Thirty-five multiparous sows were divided into two groups and treated with 0.4 mg/kg of oral meloxicam (oral meloxicam group; n = 18) or with a mock administration (control group; n = 17). A total of 382 piglets were individually weighed on the farrowing day (day 0), as well as on days +9 and +20. Immunoglobulin G (IgG) and A (IgA) concentrations in piglet serum and in sow's saliva, colostrum and milk were measured. Additionally, Interleukin-2 (IL-2), Interleukin-4 (IL-4) and Interferon gamma (IFN-⋎) in serum of piglets and in sow's milk or colostrum were studied. All samples were obtained on days +1, +9, and +20. Piglets from sows in the oral meloxicam group tended to grow faster from day +9 to day +20 than did piglets from control sows (p = 0.059), and this difference was also observed in piglets with low body weight (BW) at birth (p = 0.056). The oral meloxicam group sows tended to increase the colostrum levels of IgA and IgG, as compared with control sows on day +1 (p = 0.068 and p = 0.072, respectively). IgA levels in piglet serum from the oral meloxicam group were significantly higher than in the control group on day +1 and +9 (p = 0.019 and p = 0.011 respectively). Furthermore, IL-2 and IL-4 levels in the serum of piglets from sows in the oral meloxicam group tended to be higher than that in the control group on day +9 (p = 0.078 and 0.056, respectively). The administration of meloxicam orally at the beginning of farrowing in multiparous sows increased immunoglobin and cytokine concentrations in colostrum, improving both humoral and cellular immune response of piglets. Pre-weaning growth of piglets born with a low BW improved in the meloxicam-treated group.

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages.There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.

Ferromagnetic films down to thicknesses of tens of nanometers and composed by polycrystalline Fe and Fe2O3 nanopillars are grown in large areas by glancing angle deposition with magnetron sputtering (MS-GLAD). The morphological features of these films strongly depend on the growth conditions. Vertical or tilted nanopillars have been fabricated depending on whether the substrate is kept rotating azimuthally during deposition or not, respectively. The magnetic properties of these nanopillars films, such as hysteresis loops squareness, adjustable switching fields, magnetic anisotropy and coercivity, can be tuned with the specific morphology. In particular, the growth performed through a collimator mask mounted onto a not rotating azimuthally substrate produces almost isolated well-defined tilted nanopillars that exhibit a magnetic hardening. The first-order reversal curves diagrams and micromagnetic simulations revealed that a growth-induced uniaxial anisotropy, associated with an anisotropic surface morphology produced by the glancing angle deposition in the direction perpendicular to the atomic flux, plays an important role in the observed magnetic signatures. These results demonstrate the potential of the MS-GLAD method to fabricate nanostructured films in large area with tailored structural and magnetic properties for technological applications.

Abstract Objective Although tailored implementation methods are touted as superior to standardized, few researchers have directly compared the two and little guidance regarding the specific details of each method exist. Our study compares these methods in a dynamic cluster randomized trial seeking to optimize implementation of measurement based care (MBC) for depression in community behavioral health. This specific manuscript provides a detailed, replicable account of the components of each multi-faceted implementation method. Results The standardized best practice method includes training, consultation, a clinical guideline, and electronic health record enhancements with the goal to optimize the delivery of MBC with fidelity. Conversely, the tailored, customized and collaborative method is informed by recent implementation science advancements and begins with a needs assessment, followed by tailored training that feeds back barriers data to clinicians, the formation of an implementation team, a clinician-driven clinic-specific guideline, and the use of fidelity data to inform implementation team activities; the goal of the tailored condition is to ensure the intervention and implementation strategies address unique factors of the context. The description of these methods will inform others seeking to implement MBC, as well as those planning to use standardized or tailored implementation methods for interventions beyond behavioral health.

To measure is to know: The diagnosis is a prerequisite to solve any problem. In this paper the situation of the UPV’s faculty is analized in order to establish the degree of masculinisation of the teaching and research staff in its schools and departments. This quantitative description of the «de facto» situation at the time of the study shows the current imbalance at the institution: in addition to horizontal segregation, significant vertical segregation is evident. The drastic decline in women´s proportion as one moves up to the academic hierarchy makes incidental their presence in some of the higher academic ranks. The existence of the glass ceiling in women’s academic careers at the UPV is undeniable. This study constitutes a first step for the future development of strategies, programmes and plans to achieve a balanced composition of its faculty.

Summary: Adult stem cell plasticity, or the ability of somatic stem cells to cross boundaries and differentiate into unrelated cell types, has been a matter of debate in the last decade. Neural-crest-derived stem cells (NCSCs) display a remarkable plasticity during development. Whether adult populations of NCSCs retain this plasticity is largely unknown. Herein, we describe that neural-crest-derived adult carotid body stem cells (CBSCs) are able to undergo endothelial differentiation in addition to their reported role in neurogenesis, contributing to both neurogenic and angiogenic processes taking place in the organ during acclimatization to hypoxia. Moreover, CBSC conversion into vascular cell types is hypoxia inducible factor (HIF) dependent and sensitive to hypoxia-released vascular cytokines such as erythropoietin. Our data highlight a remarkable physiological plasticity in an adult population of tissue-specific stem cells and could have impact on the use of these cells for cell therapy. : Annese et al. find that neural-crest-derived stem cells residing in the adult carotid body are multipotent. These cells have the capacity to contribute to both neurogenesis and angiogenesis during organ acclimatization to hypoxia. Endothelial fate specification is achieved by intrinsic (HIF2α) and extrinsic (EPO) mechanisms. Keywords: angiogenesis and neurogenesis, neural-crest-derived adult stem cell plasticity and multipotency, carotid body physiology, hypoxia

Type 2 diabetes (T2D) is a global pandemic with a strong genetic component, but most causal genes influencing the disease risk remain unknown. It is clear, however, that the pancreatic beta cell is central to T2D pathogenesis. In vitro gene-knockout (KO) models to study T2D risk genes have so far focused on rodent beta cells. However, there are important structural and functional differences between rodent and human beta cell lines. With that in mind, we have developed a robust pipeline to create a stable CRISPR/Cas9 KO in an authentic human beta cell line (EndoC-βH1). The KO pipeline consists of a dual lentiviral sgRNA strategy and we targeted three genes (INS, IDE, PAM) as a proof of concept. We achieved a significant reduction in mRNA levels and complete protein depletion of all target genes. Using this dual sgRNA strategy, up to 94 kb DNA were cut out of the target genes and the editing efficiency of each sgRNA exceeded >87.5%. Sequencing of off-targets showed no unspecific editing. Most importantly, the pipeline did not affect the glucose-responsive insulin secretion of the cells. Interestingly, comparison of KO cell lines for NEUROD1 and SLC30A8 with siRNA-mediated knockdown (KD) approaches demonstrate phenotypic differences. NEUROD1-KO cells were not viable and displayed elevated markers for ER stress and apoptosis. NEUROD1-KD, however, only had a modest elevation, by 34%, in the pro-apoptotic transcription factor CHOP and a gene expression profile indicative of chronic ER stress without evidence of elevated cell death. On the other hand, SLC30A8-KO cells demonstrated no reduction in KATP channel gene expression in contrast to siRNA silencing. Overall, this strategy to efficiently create stable KO in the human beta cell line EndoC-βH1 will allow for a better understanding of genes involved in beta cell dysfunction, their underlying functional mechanisms and T2D pathogenesis.

The following work addresses new configurations of sensing array platforms that are composed of Co-based amorphous ferromagnetic microwires (MWs) to obtain an enhanced modulation of the microwave scattering effects through the application of low strength DC or AC magnetic fields. An amorphous MW is an ultrasoft ferromagnetic material (coercivity ~0.2 Oe) with a circumferential magnetic anisotropy that provides a high surface sensitivity when it is subjected to an external magnetic field. Firstly, microwave scattering experiments are performed as a function of the length and number of MWs placed parallel to each other forming an array. Subsequently, three array configurations are designed, achieving high S21 scattering coefficients up to about −50 dB. The influence of DC and AC magnetic fields on S21 has been analyzed in frequency and time domains representation, respectively. In addition, the MWs sensing array has been overlapped by polymeric surfaces and the variations of their micrometric thicknesses also cause strong changes in the S21 amplitude with displacements in the frequency that are associated to the maximum scattering behavior. Finally, a new concept for amplifying microwave scattering is provided by intercalating Cu MWs into the linear Co-based arrays. The designed mixed system that is composed by Co-based and Cu MWs exhibits a higher S21 coefficient when compared to a single Co-based MW system because of higher electrical conductivity of Cu. However, the ability to modulate the resulting electromagnetic scattering is conferred by the giant magneto-impedance (GMI) effects coming from properties of the ultrasoft amorphous MWs. The mixed array platform covers a wide range of sensor applications, demonstrating the feasibility of tuning the S21 amplitude over a wide scattering range by applying AC or DC magnetic fields and tuning the resonant frequency position according to the polymeric slab thickness.

El concepto de envejecimiento exitoso ha dado lugar a una amplia literatura dirigida a la definición del mismo, características asociadas, factores predictores y programas que promueven o mantienen este tipo de envejecer. El objetivo del trabajo que se presenta ha sido hacer un análisis comparativo entre dos grupos de ancianos clasificados como con envejecimiento exitoso versus no exitoso en función de su puntuación en una prueba de screening cognitivo. En el estudio han participado un total de 324 personas mayores con una edad media de 78.22 años que han sido evaluados con una amplia batería de evaluación psicológica y una entrevista semi-estructurada sobre variables socio-económicas. Los resultados muestran diferencias significativas en variables relacionadas con aspectos socioeconómicos, funcionamiento cognitivo y nivel de independencia y calidad de vida entre grupos a favor de las personas con envejecimiento exitoso. Los datos encontrados muestran que envejecimiento no es sinónimo de deterioro y declive y que aún en población mayor podemos encontrar altos niveles de funcionamiento cognitivo y físico.

La industria de la construcción en Europa y América Latina, al igual que en otras partes del mundo, se caracteriza por la escasa participación de la mujer y por su bajo índice de feminización. El análisis del estado actual de la investigación internacional sobre barreras de carrera en dicha industria a lo largo del periodo 2000-2014 nos permite identificar y analizar las barreras que afectan al desarrollo profesional de las mujeres, y a la vez explican su baja participación. Para el análisis y presentación de los resultados de la revisión bibliográfica, se diferencia entre las barreras percibidas por personas que aún no están empleadas, y aquellas otras identificadas por quienes se encuentran trabajando en la industria. El artículo ofrece un estudio de las organizaciones de la construcción desde el constructo del género, presentando entre sus resultados aquellas barreras identificadas en diferentes países. Se demuestra que, hasta la fecha, el tema ha sido apenas investigado en España y en América Latina.

Changes in facial expression have been shown to be a useful tool to assess pain severity in humans and animals, but facial scales have not yet been developed for all species. A facial expression scale in sows was developed using farrowing as a pain model. Five potential facial zones were identified: (i) Tension above eyes, (ii) Snout angle, (iii) Neck tension, (iv) Temporal tension and ear position (v), and Cheek tension. Facial zones were examined through 263 images of a total of 21 sows at farrowing, characterizing moments of non-pain (19 days post-farrowing; score 0), moderate pain (time interval between the delivery of two consecutive piglets; score 1) and severe pain (during active piglet delivery; score 2). Images were evaluated by a “Silver Standard” observer with experience in sows’ facial expressions, and by a group of eight animal welfare scientists, without experience in it, but who received a one-hour training session on how to assess pain in sows’ faces. Intra- and inter-observer reliability of the facial expression ranged from moderate to very good for all facial expression zones, with Tension above eyes, Snout angle, and Neck tension showing the highest reliability. In conclusion, monitoring facial expressions seems to be a useful tool to assess pain caused by farrowing.

The application of satellite single-pass interferometric data to crop-type mapping is demonstrated for the first time in this work. A set of nine TanDEM-X dual-pol pairs of images acquired during its science phase, from June to August 2015, is exploited for this purpose. An agricultural site located in Sevilla (Spain), composed of fields of 13 different crop species, is employed for validation. Sets of input features formed by polarimetric and interferometric observables are tested for crop classification, including single-pass coherence and repeat-pass coherence formed by consecutive images. The backscattering coefficient at HH and VV channels and the correlation between channels form the set of polarimetric features employed as a reference set upon which the added value of interferometric coherence is evaluated. The inclusion of single-pass coherence as feature improves by 2% the overall accuracy (OA) with respect to the reference case, reaching 92%. More importantly, in single-pol configurations OA increases by 10% for the HH channel and by 8% for the VV channel, reaching 87% and 88%, respectively. Repeat-pass coherence also improves the classification performance, but with final scores slightly worse than with single-pass coherence. However, it improves the individual performance of the backscattering coefficient by 6–7%. Furthermore, in products evaluated at field level the dual-pol repeat-pass coherence features provide the same score as single-pass coherence features (overall accuracy above 94%). Consequently, the contribution of interferometry, both single-pass and repeat-pass, to crop-type mapping is proved.

BackgroundImpairments in social cognition have been described in several psychiatric and neurological disorders. Given the importance of the relationship between social cognition and functioning and quality of life in these disorders, there is a growing interest in social cognition remediation interventions. The aim of this study was to carry out a systematic mapping review to describe the state of the art in social cognition training and remediation interventions.MethodsPublications from 2006 to 2016 on social cognition interventions were reviewed in four databases: Scopus, PsycINFO, PubMed and Embase. From the initial result set of 3229 publications, a final total of 241 publications were selected.ResultsThe study revealed an increasing interest in social cognition remediation interventions, especially in the fields of psychiatry and psychology, with a gradual growth in the number of publications. These were frequently published in high impact factor journals and underpinned by robust scientific evidence. Most studies were conducted on schizophrenia, followed by autism spectrum disorders. Theory of mind and emotional processing were the focus of most interventions, whilst a limited number of studies addressed attributional bias and social perception. Targeted interventions in social cognition were the most frequent practice in the selected papers, followed by non-specific treatment interventions and broad-based interventions.ConclusionsResearch in social cognition remediation interventions is growing. Further studies are needed on attributional bias and social perception remediation programs, while the comparative efficacy of different interventions also remains unclear.

ABSTRACT: Objective: To describe the diagnosis of a patient with thyroid metastasis from a bronchial carcinoid tumor, initially mistaken for a medullary thyroid carcinoma. Methods: We present the clinical, laboratory, and imaging findings, along with a literature review. Results: Typical bronchial carcinoids are well-differentiated neoplasms, which usually have a good prognosis. However, 15% of the cases may metastasize. This report describes the case of a 36-year-old woman with a history of a surgically removed bronchial carcinoid tumor, which did not relapse after a 4-year follow-up. Nine years later, the patient consulted for a thyroid nodule, and the anatomic pathology report showed a diagnosis of medullary thyroid carcinoma. Subsequently, immunohistochemistry showed that it was a thyroid metastasis from the bronchial carcinoid tumor, which completely changed the treatment and prognosis. Conclusion: This case highlights the importance of adequate surgery, as well as a detailed review of the past medical history and a proper immunochemistry as part of the histopathologic examination. This will facilitate the distinction between medullary thyroid carcinomas and primary extrathyroid neuroendocrine tumors that have metastasized into the thyroid gland.