Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis.

Multiple sclerosis (MS) is a complex and demyelinating disease of the central nervous system. One of the challenges of the post-genome-wide association studies (GWAS) era is to understand the molecular basis of statistical associations to reveal gene networks and potential therapeutic targets. The L3MBTL3 locus has been associated with MS risk by GWAS. To identify the causal variant of the locus, we performed fine mapping in a cohort of 3440 MS patients and 1688 healthy controls. The variant that best explained the association was rs6569648 (P = 4.13E-10, odds ratio = 0.71, 95% confidence interval (CI) = 0.64-0.79), which tagged rs7740107, located in intron 7 of L3MBTL3. The rs7740107 (A/T) variant has been reported to be the best expression and splice quantitative trait locus (eQTL and sQTL) of the region in up to 35 human genotype-tissue expression (GTEx) tissues. By sequencing RNA from blood of 17 MS patients and quantification by digital qPCR, we determined that this eQTL/sQTL originated from the expression of a novel short transcript starting in intron 7 near rs7740107. The short transcript was translated into three proteins starting at different translation initiation codons. These N-terminal truncated proteins lacked the region where L3MBTL3 interacts with the transcriptional regulator Recombination Signal Binding Protein for Immunoglobulin Kappa J Region which, in turn, regulates the Notch signalling pathway. Our data and other functional studies suggest that the genetic mechanism underlying the MS association of rs7740107 affects not only the expression of L3MBTL3 isoforms, but might also involve the Notch signalling pathway.

Hospital nurses experiencing day-to-day workplace incivility: A diary study on the benefits of daily social support.

AIM: The present study investigated the adverse effects of daily experienced incivility and the positive role of daily social support during the workday in predicting daily emotional exhaustion after work and vitality and positive affect at bedtime. BACKGROUND: Despite the broad knowledge of the impact of experienced incivility in different occupations, little is known about day-to-day nurse incivility, much less in the hospital context. METHOD: After completing a general questionnaire, hospital nurses (n = 96) completed a diary questionnaire twice a day for five consecutive workdays (n = 480 diary observations). The diary design had two levels: 5-day repeated measures (Level 1, day level) nested in persons (Level 2, person level) using an experience-sampling methodology. RESULTS: Multilevel hierarchical analyses showed that incivility during the workday increased emotional exhaustion after work (t = 3.00, p = <0.05) and reduced vitality (t = -2.48, p = 0.05) and positive affect (t = -2.23, p = 0.05) at bedtime. However, daily social support during the workday was a crucial job resource that directly benefited hospital nurses' daily wellbeing (t = 5.19, p = 0.01 vitality; t = 4.89, p = 0.01 positive affect) and buffered the adverse effects of daily workplace incivility (t = -2.33, p = 0.05). CONCLUSION: The within-person approach of our findings suggests that supportive practices can reduce day-to-day incivility spirals. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers can promote a civility culture within their units using in service training programmes at work.

SUMOylated SNF2PH promotes variant surface glycoprotein expression in bloodstream trypanosomes.

SUMOylation is a post-translational modification that positively regulates monoallelic expression of the trypanosome variant surface glycoprotein (VSG). The presence of a highly SUMOylated focus associated with the nuclear body, where the VSG gene is transcribed, further suggests an important role of SUMOylation in regulating VSG expression. Here, we show that SNF2PH, a SUMOylated plant homeodomain (PH)-transcription factor, is upregulated in the bloodstream form of the parasite and enriched at the active VSG telomere. SUMOylation promotes the recruitment of SNF2PH to the VSG promoter, where it is required to maintain RNA polymerase I and thus to regulate VSG transcript levels. Further, ectopic overexpression of SNF2PH in insect forms, but not of a mutant lacking the PH domain, induces the expression of bloodstream stage-specific surface proteins. These data suggest that SNF2PH SUMOylation positively regulates VSG monoallelic transcription, while the PH domain is required for the expression of bloodstream-specific surface proteins. Thus, SNF2PH functions as a positive activator, linking expression of infective form surface proteins and VSG regulation, thereby acting as a major regulator of pathogenicity.

Loss of 5hmC identifies a new type of aberrant DNA hypermethylation in glioma.

Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC and 5-methylcytosine (5mC) in human primary samples from 12 non-tumoral brains and 53 gliomas. We found that the levels of 5hmC identified in non-tumoral samples were significantly reduced in gliomas. Strikingly, hypo-hydroxymethylation at 4627 (9.3%) CpG sites was associated with aberrant DNA hypermethylation and was strongly enriched in CpG island shores. The DNA regions containing these CpG sites were enriched in H3K4me2 and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. As this 5mC gain is inversely correlated with loss of 5hmC and has not been identified with classical sodium bisulfite-based technologies, we conclude that our data identifies a novel 5hmC-dependent type of aberrant DNA hypermethylation in glioma.

Observers' reactions to workplace incivility in the masculine domain: How does role congruency explain gender bias in future workers?

Based on Role Congruity Theory, we tested the hypothesis of gender bias by examining gender differences in observers' evaluations of the awareness and acceptability of workplace incivility gender-dyad interaction. Three hundred and ninety-six Spanish high school students (55.3% female) read one scenario of overt incivility (publicly humiliates and openly doubts the employee's judgment) or covert (omits and pays little attention) from a leader (female vs. male) toward a subordinate (female vs. male) in engineering. Results indicated gender differences among observers. From the leader actor of incivility, males were more aware and accepted less the incivility when performed by a female leader in a male domain; whereas females were more aware and accepted less incivility than males in all cases. Regarding the subordinate target of incivility, only females were more aware and accepted less incivility, and both males and females were more aware and accepted less covert incivility. Our results reveal practical implications for interventions from a gender perspective.

Nurse profiles in evaluating incivility: even a slight sexism in employment affects the evaluation.

BACKGROUND: Workplace incivility is a serious concern in the healthcare setting worldwide. Addressing how sexism impacts this, may help administrators take action to reduce this problem and to increase safety at work. METHODS: 557 nurses (63% women) read a hospital scene describing an episode of incivility from a nurse leader towards a nurse employee. They then evaluated the situation regarding their awareness, tolerance, and their beliefs toward sexism by completing a self-report questionnaire. FINDINGS: Two distinct nurse profiles emerged: high-sensitivity and medium-sensitivity. Medium-sensitivity nurses were significantly higher in sexism in employment, and differ in their evaluation of workplace incivility from highly sensitive nurses. CONCLUSIONS: The majority of nurses are sensitive to workplace incivility, but those with sexist tendencies in employment are less aware and tolerate uncivil episodes to a greater extent. APPLICATION TO PRACTICE: Training nurses to be aware of workplace incivility is necessary, especially for those demonstrating sexism.

Work Intensification and Its Effects on Mental Health: The Role of Workplace Curiosity.

Work intensification is a psychosocial risk that has been increasing in recent decades and may have been accentuated after the COVID-19 pandemic. Its effects on health are negative, but they can be moderated by contextual and personal factors. The aim of this study was twofold: to analyze the effect of work intensification on workers' stress, anxiety, and depression and to explore the role of workplace curiosity in these relationships. The study design was cross-sectional, and a total of 766 Spanish workers (58.9% female) with different occupations completed the survey. The results showed that work intensification was associated with the symptomatology of stress, anxiety, and depression, with a medium effect size. Women workers showed higher work intensification, but its association with mental health was equally strong for both genders. Workers with higher levels of the workplace curiosity dimension "stress tolerance" showed less impaired mental health in the presence of work intensification. However, workers with higher levels of the workplace curiosity dimension "deprivation sensitivity" showed more symptoms of stress, anxiety, and depression when faced with high work intensification. The results were discussed in terms of their contributions to the field of study of work intensification, the future research they could inspire, and the prevention and intervention measures they could motivate.

Spanish Adaptation of the Intensified Job Demands Scale (IDS).

BACKGROUND: The Intensification of Job Demands Scale (IDS) is a multidimensional instrument designed to capture the phenomenon of work intensification that characterizes modern Western societies. However, in Spain the instrument has not been validated to assess this phenomenon. The aim of this study was to examine the psychometric properties of the IDS adaptation with a heterogeneous sample of Spanish workers. METHOD: The sample consisted of 722 Spanish workers (57.8% female, 42.2% male) who completed a survey between January and April 2022. RESULTS: A five-factor correlated model, as in the original IDS, had an optimal fit with 15 items, and displayed invariance across gender, level of education, and organizational tenure. Reliability coefficients were all satisfactory, and scale adaptation showed evidence of convergent, discriminant, and incremental validity. CONCLUSIONS: The Spanish adaptation of the IDS is a valid, reliable measure for analyzing the phenomenon of work intensification and intensified job demands in Spain.

Associations between Motives for Physical Exercise, Body Composition and Cardiorespiratory Fitness: A Cross-Sectional Study.

Adolescents' need for some minimum amount of daily physical exercise has been widely studied so as to assist better health outcomes and to reduce future obesity rates. However, the motivations of adolescents to exercise are less well-known. This manuscript aims to analyze the motives that explain the practice of physical exercise in adolescents and the possible associations with elements of body composition and cardiorespiratory fitness. For this purpose, the Self-Report of Motives for the Practice of Physical Exercise questionnaire (AMPEF) was administered to 917 students between 13-16 years of age (50.1% girls, 49.9% boys, M age = 14.82) from Seville, Spain. Subscales Ill-Health Avoidance and Positive Health, Revitalization and Enjoyment, Strength and Endurance, and Challenge represent the participants' main reasons for practicing physical exercise. Associations between BMI and FAT % with the subscales Weight Management and Appearance (direct association) and Revitalization and Enjoyment (inverse association) were found. A direct association between cardiorespiratory fitness and Revitalization and Enjoyment, Competition, Strength, and Endurance and Challenge subscales was found for both genders. Conclusions emphasize the practice of physical exercise in adolescents due to intrinsic motives based on improving their state of health, increasing their levels of strength and endurance (boys), and achieving short-term objectives (girls).

Identification of sequence-specific promoters driving polycistronic transcription initiation by RNA polymerase II in trypanosomes.

Protein-coding genes in trypanosomes occur in polycistronic transcription units (PTUs). How RNA polymerase II (Pol II) initiates transcription of PTUs has not been resolved; the current model favors chromatin modifications inducing transcription rather than sequence-specific promoters. Here, we uncover core promoters by functional characterization of Pol II peaks identified by chromatin immunoprecipitation sequencing (ChIP-seq). Two distinct promoters are located between divergent PTUs, each driving unidirectional transcription. Detailed analysis identifies a 75-bp promoter that is necessary and sufficient to drive full reporter expression and contains functional motifs. Analysis of further promoters suggests transcription initiation is regulated and promoters are either focused or dispersed. In contrast to the previous model of unregulated and promoter-independent transcription initiation, we find that sequence-specific promoters determine the initiation of Pol II transcription of protein-coding genes PTUs. These findings in Trypanosoma brucei suggest that in addition of chromatin modifications, promoter motifs-based regulation of gene expression is deeply conserved among eukaryotes.

Daily Beneficial Effects of Work-to-Family Facilitation on Employees' Recovery and General Health: Is More Work Engagement Always Better?

This study of 104 Chilean employees examines the process of WFF-recovery-general health on a daily basis. Drawing on the work-home resources (W-HR) model, we hypothesized that daily work-to-family facilitation and work engagement predict recovery experiences during off-job time in the evening (i.e., detachment from work and relaxation) and subsequent general health at night. Furthermore, we explored whether daily work engagement moderates the relationships between daily work-to-family facilitation and recovery experiences during off-job time in the evening and general health at night. In addition, we expected employees' detachment from work to have a lagged effect on next-day general health at night. Participants completed a survey and a diary booklet over 5 consecutive working days (N = 520 occasions). Multilevel analyses show that, as expected, daily work-to-family facilitation predicted recovery experiences during off-job time in the evening (i.e., detachment from work and relaxation). However, contrary to our expectations, daily work engagement only predicted general health at night. Moreover, as expected, a moderation effect of daily work engagement shows that on days that employees experience low levels of daily work engagement, daily work-to-family facilitation is strongly related to detachment from work and relaxation during off-job time in the evening and to general health at night. Unexpectedly, on days on which employees experienced high levels of daily work engagement, daily work-to-family facilitation was weakly related to these outcomes. Finally, in accordance with our expectations, detachment from work had a lagged effect on next-day general health at night. These findings offer support for the W-HR model and have theoretical and practical implications for research and organizations.

Safety in Dermatologic Procedures: Anaphylaxis, Vasovagal Reaction, and Hyperventilation. / Seguridad en procedimientos dermatológicos: anafilaxia, reacción vasovagal e hiperventilación.

This article, part of a the series on safety in dermatologic procedures, covers the diagnosis, prevention, management, and treatment of 3 situations or conditions. The first condition we address is anaphylaxis, an uncommon but severe and potentially fatal reaction that must be recognized quickly so that urgent management coordinated with an anesthesiologist can commence. The second is the vasovagal reaction, which is the most common complication in dermatologic surgery. This event, which occurs in 1 out of every 160 procedures, usually follows a benign course and resolves on its own. However, in patients susceptible to vasovagal reactions, syncope may lead to asystole and cardiac arrest. The third is acute hyperventilation syndrome, which is an anomalous anxiety-related increase in breathing rate beyond metabolic requirements. Brief practical recommendations for managing all 3 events are included.

Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia.

B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL-specific gene expression-correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient-derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.

Arousing the Sound: A Field Study on the Emotional Impact on Children of Arousing Sound Design and 3D Audio Spatialization in an Audio Story.

Sound from media increases the immersion of the audience in the story, adding credibility to the narration but also generating emotions in the spectator. A study on children aged 9-13 years (N = 253), using an audio story, investigated the emotional impact of arousal vs. neutral treatment of sound and 3D vs. stereo mix spatialization. The emotional impact was measured combining three different measures: physiological (Electrodermal activity), self-report (pre-post exposition), and richness of mental images elicited by the story (using Think-aloud technique after exposition). Results showed higher emotional impact of the arousal and 3D audio conditions with different patterns according to the age of the participants and distinctive types of interaction when both variables were combined.

Social and Emotional Competences in Spain: A Comparative Evaluation Between Spanish Needs and an International Framework Based on the Experiences of Researchers, Teachers, and Policymakers.

Critical aspects in the field of education are currently related to low levels of socioemotional competences and high rates of school dropouts. However, there are no standard practices or guidelines for helping countries to assess and train social and emotional competences. To overcome this limitation, the project Learning to be (L2B) aims to propose a comprehensive model of the assessment and development of social and emotional competences that bring together policymakers, researchers, teachers, school authorities and learners from different participating countries: Finland, Italy, Latvia, Lithuania, Portugal, Slovenia, and Spain. The project attempts to create an international framework for regulating activities and supporting teachers working on the social and emotional competences of the students and to provide tools which can be used across countries. The aim of the paper is to describe how L2B has been developed in Spain by analyzing the contributions of the international framework and extracting the specific needs in the Spanish context. Specifically, we describe two products of the project: (a) the process for creating a toolkit, a tool focused on creating activities and materials for helping teachers develop social and emotional competences of students and (b) the results of an exploratory study in Spain in which social and emotional competences are assessed and compared to the international framework. First, we explain the definition of social and emotional competences used for creating the toolkit. Second, we analyze responses of Spanish students to questionnaires administered before applying the toolkit in the schools. The paper describes social and emotional competences in Spain and evaluates the overlap between relevant variables in Spain and those used for developing the toolkit, the international tool. Specific needs in Spain are discussed, as well as the contribution of the project for promoting the improved development of students' social and emotional competences, improving learning outcomes and stronger social cohesion in schools and local communities, as well as the utility of the results for creating new educational policies.

Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation.

AIM: Epigenetic regulation plays an important role in cellular development and differentiation. A detailed map of the DNA methylation dynamics that occur during cell differentiation would contribute to decipher the molecular networks governing cell fate commitment. METHODS: Illumina MethylationEPIC BeadChip platform was used to describe the genome-wide DNA methylation changes observed throughout hematopoietic maturation by analyzing multiple myeloid and lymphoid hematopoietic cell types. RESULTS: We identified a plethora of DNA methylation changes that occur during human hematopoietic differentiation. We observed that T lymphocytes display substantial enhancement of de novo CpG hypermethylation as compared with other hematopoietic cell populations. T-cell-specific hypermethylated regions were strongly associated with open chromatin marks and enhancer elements, as well as binding sites of specific key transcription factors involved in hematopoietic differentiation, such as PU.1 and TAL1. CONCLUSION: These results provide novel insights into the role of DNA methylation at enhancer elements in T-cell development.

DNA methylation changes in human lung epithelia cells exposed to multi-walled carbon nanotubes.

Humans are increasingly exposed to nanoparticles and, although many of their physiological effects have been described, the molecular mechanisms underlying them are still largely unknown. The present study aimed to determine the possible role of certain epigenetic mechanisms in the cellular response of human lung epithelial cells that are triggered by long-term exposure to titanium dioxide nanoparticles (TiO2NPs) and multi-walled carbon nanotubes (MWCNTs). The results showed that exposure to TiO2NPs had only minor effects on genome-wide DNA methylation. However, we identified 755 CpG sites showing consistent DNA hypomethylation in cells exposed to MWCNTs. These sites were mainly located at low density CpG regions and enhancers, and very frequently on the X chromosome. Our results thus suggest that long-term MWCNT exposure may have important effects on the epigenome.

Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.

Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.

Positive benefits of caring on nurses' motivation and well-being: a diary study about the role of emotional regulation abilities at work.

BACKGROUND: Recent research reveals that not all job demands have negative effects on workers' well-being and suggests that the negative or positive effects of specific job demands depend on the occupational sector. Specifically, emotional job demands form the heart of the work for nurses and for this reason they can be interpreted by nurses as a challenge that promotes motivation and well-being among these professionals, especially if personal and job resources become available. OBJECTIVES: The study had two objectives. First, to examine whether daily emotional demands within a nursing work context have a positive effect on nurses' daily motivation at work (vigour) and well-being at home (vitality and positive affect). Second, to explore whether this positive effect could be enhanced by nurses' emotional regulation abilities. DESIGN: This research used a diary design to explore daily experiences and to analyze how variations in specific job or personal characteristics can affect levels of motivation and well-being across days. PARTICIPANTS: Fifty-three nurses working in different Spanish hospitals and primary health care centres completed a general questionnaire and a diary booklet over 5 consecutive working days in two different moments, after work and at night (N=53 participants and N=265 observations). RESULTS: In line with our hypotheses, multi-level analyses revealed that, on the one hand, day-level emotional demands at work had a positive effect on vigour at work and on vitality at home. On the other hand, analyses showed that nurses with higher emotional regulation abilities have more motivation at work and well-being at home when they have to face high emotional demands at work, showing a spill over effect after work. CONCLUSIONS: These findings support the idea that emotional demands from the nursing profession can act as challenges which promote motivation and well-being, especially if internal emotional resources become available.