RESUMO
Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (GLA). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 GLA variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems. We have analyzed four different male subject-derived cell types for alpha-galactosidase A enzyme (GLA) activity and intracellular Gb3 load. Additionally, Gb3 load in skin tissue as well as clinical data were studied for correlates of disease manifestations. A reduction of GLA activity was observed in cells carrying p.A143T compared with controls (p < 0.05). In cells carrying the p.D313Y variant, a reduced GLA activity was found only in endothelial cells (p < 0.01) compared with controls. No pathological changes were observed in cells carrying the p.S126G variant. None of the VUS investigated caused intracellular Gb3 accumulation in any cell type. Our data of aberrant GLA activity in cells of p.A143T hemizygotes and overall normal cellular phenotypes in cells of p.D313Y and p.S126G hemizygotes contribute a basic science perspective to the clinically highly relevant discussion on VUS in GLA.
Assuntos
Doença de Fabry , Fenótipo , alfa-Galactosidase , Humanos , Doença de Fabry/genética , Doença de Fabry/patologia , Doença de Fabry/enzimologia , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismo , Masculino , Adulto , Variação Genética , Triexosilceramidas/metabolismo , Pessoa de Meia-Idade , Pele/patologia , Células Endoteliais/patologia , Células Endoteliais/metabolismo , Mutação , Glicolipídeos/metabolismo , EsfingolipídeosRESUMO
This study investigated the developmental profiles of perceived early career insecurity (ECI) and their outcomes among adolescents (n = 1416) during a critical educational transition from basic education to upper secondary education. We found three distinct latent profiles with varying amounts of ECI: Profile 1: Moderate and decreasing ECI before the transition (57%); Profile 2: Low-decreasing ECI before the transition but increasing ECI after the transition (31%); and Profile 3: High and stable ECI during the transition (12%). Moreover, the ECI profiles related to school and life satisfaction as well as to school stress and dropout intentions in a meaningful way consistent with the stressor hypothesis. Chronically high and increasing ECI was related to negative outcomes.
Assuntos
Intenção , Instituições Acadêmicas , Humanos , Adolescente , Estudos Longitudinais , Escolaridade , Satisfação PessoalRESUMO
Fabry disease (FD) is caused by α-galactosidase A (AGAL) enzyme deficiency, leading to globotriaosylceramide accumulation (Gb3) in several cell types. Pain is one of the pathophysiologically incompletely understood symptoms in FD patients. Previous data suggest an involvement of hypoxia and mitochondriopathy in FD pain development at dorsal root ganglion (DRG) level. Using immunofluorescence and quantitative real-time polymerase chain reaction (qRT PCR), we investigated patient-derived endothelial cells (EC) and DRG tissue of the GLA knockout (KO) mouse model of FD. We address the question of whether hypoxia and mitochondriopathy contribute to FD pain pathophysiology. In EC of FD patients (P1 with pain and, P2 without pain), we found dysregulated protein expression of hypoxia-inducible factors (HIF) 1a and HIF2 compared to the control EC (p < 0.01). The protein expression of the HIF downstream target vascular endothelial growth factor A (VEGFA, p < 0.01) was reduced and tube formation was hampered in the P1 EC compared to the healthy EC (p < 0.05). Tube formation ability was rescued by applying transforming growth factor beta (TGFß) inhibitor SB-431542. Additionally, we found dysregulated mitochondrial fusion/fission characteristics in the P1 and P2 EC (p < 0.01) and depolarized mitochondrial membrane potential in P2 compared to control EC (p < 0.05). Complementary to human data, we found upregulated hypoxia-associated genes in the DRG of old GLA KO mice compared to WT DRG (p < 0.01). At protein level, nuclear HIF1a was higher in the DRG neurons of old GLA KO mice compared to WT mice (p < 0.01). Further, the HIF1a downstream target CA9 was upregulated in the DRG of old GLA KO mice compared to WT DRG (p < 0.01). Similar to human EC, we found a reduction in the vascular characteristics in GLA KO DRG compared to WT (p < 0.05). We demonstrate increased hypoxia, impaired vascular properties, and mitochondrial dysfunction in human FD EC and complementarily at the GLA KO mouse DRG level. Our data support the hypothesis that hypoxia and mitochondriopathy in FD EC and GLA KO DRG may contribute to FD pain development.
Assuntos
Doença de Fabry , Doenças Vasculares , Humanos , Animais , Camundongos , Doença de Fabry/complicações , Doença de Fabry/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , alfa-Galactosidase/genética , Doenças Vasculares/metabolismo , Dor/metabolismo , Camundongos Knockout , Hipóxia/complicações , Hipóxia/genética , Hipóxia/metabolismoRESUMO
PURPOSE: Individual differences in the development of perceived job insecurity among young workers may be influenced by characteristics of the first job (contract type and sector) and individual background (education and previous unemployment), and can have implications for subsequent health and well-being. The aim of this study was to investigate the development of perceived job insecurity during the early career, as well as associations between different patterns of development (i.e., trajectories), predictors and outcomes. METHODS: We conducted a latent class growth analysis to identify trajectories of perceived job insecurity and investigated their respective associations with predictors and outcomes across 6 years in a sample of 1711 German labor market entrants. RESULTS: Six trajectories were identified: three showed stable job insecurity perceptions (stable moderate, 36%; stable low, 32%; stable high, 5%), two showed decrease (moderate to low, 12%; high to moderate, 3%), and one showed increasing job insecurity perceptions (low to moderate, 13%). Temporary contracts and previous unemployment predicted trajectories characterized by increasing, higher initial or higher overall levels of perceived job insecurity. In contrast, public sector employees and university graduates were less likely to experience persisting or increasing job insecurity. The trajectories differed in their overall levels of self-rated health and job satisfaction, but not with respect to change in these outcomes. Instead, increasing perceived job insecurity was associated with decreasing life satisfaction. CONCLUSIONS: The findings suggest that an insecure career start and individual risk factors may predispose young workers to an unfavorable development of both job insecurity perceptions and levels of well-being.
Assuntos
Emprego/psicologia , Desemprego/psicologia , Adulto , Contratos/estatística & dados numéricos , Escolaridade , Emprego/economia , Feminino , Alemanha/epidemiologia , Nível de Saúde , Humanos , Satisfação no Emprego , Estudos Longitudinais , Masculino , Setor PúblicoRESUMO
Verticillium dahliae is a prominent generator of plant vascular wilting disease and sulfur (S)-enhanced defense (SED) mechanisms contribute to its in-planta elimination. The accumulation of S-containing defense compounds (SDCs) including elemental S (S(0) ) has been described based on the comparison of two near-isogenic tomato (Solanum lycopersicum) lines differing in fungal susceptibility. To better understand the effect of S nutrition on V. dahliae resistance both lines were supplied with low, optimal or supraoptimal sulfate-S. An absolute quantification demonstrated a most effective fungal elimination due to luxury plant S nutrition. High-pressure liquid chromatography (HPLC) showed a strong regulation of Cys levels and an S-responsive GSH pool rise in the bulk hypocotyl. High-frequency S peak accumulations were detected in vascular bundles of resistant tomato plants after fungal colonization by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Global transcriptomic analysis suggested that early steps of the primary S metabolism did not promote the SDCs synthesis in the whole hypocotyl as gene expression was downregulated after infection. Enhanced S fertilization mostly alleviated the repressive fungal effect but did not reverse it. Upregulation of glutathione (GSH)-associated genes in bulk hypocotyls but not in vascular bundles indicated a global antioxidative role of GSH. To finally assign the contribution of S metabolism-associated genes to high S(0) accumulations exclusively found in the resistant tomato line, a spatial gene expression approach was applied. Laser microdissection of infected vascular bundles revealed a switch toward transcription of genes connected with cysteine (Cys) synthesis. The upregulation of LeOASTLp1 suggests a role for Cys as key precursor for local S accumulations (possibly S(0) ) in the vascular bundles of the V. dahliae-resistant tomato line.
Assuntos
Cisteína/metabolismo , Regulação da Expressão Gênica de Plantas , Hipocótilo/genética , Feixe Vascular de Plantas/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/microbiologia , Enxofre/metabolismo , Verticillium/fisiologia , Transporte Biológico/efeitos dos fármacos , Contagem de Colônia Microbiana , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genes de Plantas , Estudos de Associação Genética , Genótipo , Hipocótilo/efeitos dos fármacos , Solanum lycopersicum/efeitos dos fármacos , Solanum lycopersicum/imunologia , Microdissecção , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Feixe Vascular de Plantas/efeitos dos fármacos , Feixe Vascular de Plantas/genética , Feixe Vascular de Plantas/microbiologia , Espectrofotometria Atômica , Sulfatos/farmacologia , Compostos de Sulfidrila/metabolismo , Verticillium/efeitos dos fármacos , Verticillium/crescimento & desenvolvimento , Xilema/microbiologiaRESUMO
Fabry disease (FD) is a life-limiting disorder characterized by intracellular globotriaosylceramide (Gb3) accumulations. The underlying α-galactosidase A (α-GAL A) deficiency is caused by variants in the gene GLA. Variants of unknown significance (VUS) are frequently found in GLA and challenge clinical management. Here, we investigated a 49-year old man with cryptogenic lacunar cerebral stroke and the chance finding of the VUS S126G, who was sent to our center for diagnosis and initiation of a costly and life-long FD-specific treatment. We combined clinical examination with in vitro investigations of dermal fibroblasts (HDF), induced pluripotent stem cells (iPSC), and iPSC-derived sensory neurons. We analyzed α-GAL A activity in iPSC, Gb3 accumulation in all three cell types, and action potential firing in sensory neurons. Neurological examination and small nerve fiber assessment was normal except for reduced distal skin innervation. S126G iPSC showed normal α-GAL A activity compared to controls and no Gb3 deposits were found in all three cell types. Baseline electrophysiological characteristics of S126G neurons showed no difference compared to healthy controls as investigated by patch-clamp recordings. We pioneer multi-level cellular characterization of the VUS S126G using three cell types derived from a patient and provide further evidence for the benign nature of S126G in GLA, which is of great importance in the management of such cases in clinical practice.
RESUMO
Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the α-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain in both sexes as an early FD symptom of unknown pathophysiology. We aimed at elucidating the link between skin cells and nociceptor sensitization contributing to FD pain in a sex-associated manner. We used cultured keratinocytes and fibroblasts of 27 adult FD patients and 20 healthy controls. Epidermal keratinocytes and dermal fibroblasts were cultured and immunoreacted to evaluate Gb3 load. Gene expression analysis of pain-related ion channels and pro-inflammatory cytokines was performed in dermal fibroblasts. We further investigated electrophysiological properties of induced pluripotent stem cell (iPSC) derived sensory-like neurons of a man with FD and a healthy man and incubated the cells with interleukin 8 (IL-8) or fibroblast supernatant as an in vitro model system. Keratinocytes displayed no intracellular, but membrane-bound Gb3 deposits. In contrast, fibroblasts showed intracellular Gb3 and revealed higher gene expression of potassium intermediate/small conductance calcium-activated potassium channel 3.1 (KCa 3.1, KCNN4) in both, men and women with FD compared to controls. Additionally, cytokine expression analysis showed increased IL-8 RNA levels only in female FD fibroblasts. Patch-clamp studies revealed reduced rheobase currents for both iPSC neuron cell lines incubated with IL-8 or fibroblast supernatant of women with FD. We conclude that Gb3 deposition in female FD patient skin fibroblasts may lead to increased KCa3.1 activity and IL-8 secretion. This may result in cutaneous nociceptor sensitization as a potential mechanism contributing to a sex-associated FD pain phenotype.
Assuntos
Doença de Fabry , Adulto , Feminino , Humanos , Masculino , alfa-Galactosidase/genética , Citocinas , Doença de Fabry/complicações , Doença de Fabry/genética , Doença de Fabry/diagnóstico , Fibroblastos/metabolismo , Interleucina-8/genética , Dor , Pele/metabolismoRESUMO
Fabry disease is a rare monogenetic, X-linked lysosomal storage disorder with neuropathic pain as one characteristic symptom. Impairment of the enzyme alpha-galactosidase A leads to an accumulation of globotriaosylceramide in the dorsal root ganglia. Here, we investigate novel dorsal root ganglia MR imaging biomarkers and their association with Fabry genotype and pain phenotype. In this prospective study, 89 Fabry patients were examined using a standardized 3â T MRI protocol of the dorsal root ganglia. Fabry pain was assessed through a validated Fabry pain questionnaire. The genotype was determined by diagnostic sequencing of the alpha-galactosidase A gene. MR imaging end-points were dorsal root ganglia volume by voxel-wise morphometric analysis and dorsal root ganglia T2 signal. Reference groups included 55 healthy subjects and Fabry patients of different genotype categories without Fabry pain. In patients with Fabry pain, T2 signal of the dorsal root ganglia was increased by +39.2% compared to healthy controls (P = 0.001) and by +29.4% compared to painless Fabry disease (P = 0.017). This effect was pronounced in hemizygous males (+40.7% compared to healthy; P = 0.008 and +29.1% compared to painless; P = 0.032) and was consistently observed across the genotype spectrum of nonsense (+38.1% compared to healthy, P < 0.001) and missense mutations (+39.2% compared to healthy; P = 0.009). T2 signal of dorsal root ganglia and globotriaosylsphingosine levels were the only independent predictors of Fabry pain (P = 0.047; P = 0.002). Volume of dorsal root ganglia was enlarged by +46.0% in Fabry males in the nonsense compared to missense genotype category (P = 0.005) and by +34.5% compared to healthy controls (P = 0.034). In painful Fabry disease, MRI T2 signal of dorsal root ganglia is increased across different genotypes. Dorsal root ganglion MRI T2 signal as a novel in vivo imaging biomarker may help to better understand whether Fabry pain is modulated or even caused by dorsal root ganglion pathology.
RESUMO
Acral burning pain triggered by fever, thermal hyposensitivity and skin denervation are hallmarks of small fibre neuropathy in Fabry disease, a life-threatening X-linked lysosomal storage disorder. Variants in the gene encoding alpha-galactosidase A may lead to impaired enzyme activity with cellular accumulation of globotriaosylceramide. To study the underlying pathomechanism of Fabry-associated small fibre neuropathy, we generated a neuronal in vitro disease model using patient-derived induced pluripotent stem cells from three Fabry patients and one healthy control. We further generated an isogenic control line via gene editing. We subjected induced pluripotent stem cells to targeted peripheral neuronal differentiation and observed intra-lysosomal globotriaosylceramide accumulations in somas and neurites of Fabry sensory neurons using super-resolution microscopy. At functional level, patch-clamp analysis revealed a hyperpolarizing shift of voltage-gated sodium channel steady-state inactivation kinetics in isogenic control neurons compared with healthy control neurons (P < 0.001). Moreover, we demonstrate a drastic increase in Fabry sensory neuron calcium levels at 39°C mimicking clinical fever (P < 0.001). This pathophysiological phenotype was accompanied by thinning of neurite calibres in sensory neurons differentiated from induced pluripotent stem cells derived from Fabry patients compared with healthy control cells (P < 0.001). Linear-nonlinear cascade models fit to spiking responses revealed that Fabry cell lines exhibit altered single neuron encoding properties relative to control. We further observed mitochondrial aggregation at sphingolipid accumulations within Fabry sensory neurites utilizing a click chemistry approach together with mitochondrial dysmorphism compared with healthy control cells. We pioneer pilot insights into the cellular mechanisms contributing to pain, thermal hyposensitivity and denervation in Fabry small fibre neuropathy and pave the way for further mechanistic in vitro studies in Fabry disease and the development of novel treatment approaches.
RESUMO
Using human dermal fibroblasts (hdF) derived from a patient carrying a c.1678C>G variant located in the TRPA1 gene, induced pluripotent stem cells (iPSC) were generated. Cells were reprogrammed via non-modified (NM) RNA-based transfection resulting in three clones. All three clones showed typical embryonic stem cell-like properties including expression of pluripotency markers, morphology, normal karyotype, and potential differentiation in all three germ layers. With this novel cell line, we offer an in vitro option to study TRPA1 gene variant c.1678C>G and its potential involvement in the development of neuropathic pain as a symptom of small fiber neuropathy (SFN).
Assuntos
Células-Tronco Pluripotentes Induzidas , Neuropatia de Pequenas Fibras , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neuropatia de Pequenas Fibras/metabolismo , Diferenciação Celular , Linhagem Celular , Transfecção , Mutação , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismoRESUMO
The link between leadership and employee well-being is long established. In particular, health-oriented leadership is discussed as a leadership style specifically promoting employee well-being. However, the preconditions of health-oriented leadership remain largely unexplored. From the perspective of conservation of resources theory, leaders can only provide resources when receiving some themselves. We propose that organizational health climate (OHC) is an important organization-based resource for a health-oriented leadership style. More specifically, we hypothesize that the relationship between OHC and employee job satisfaction and emotional exhaustion is mediated by health-oriented leadership. We thereby differentiate two levels of analysis: a within-team level and a between-team level. We examined 74 teams with 423 employees of childcare centers at three time points, each 6 months apart. By means of multilevel structural equation modeling, we found OHC to be a significant antecedent of health-oriented leadership at the between-team level. The relationship between OHC and employee job satisfaction was mediated by health-oriented leadership at the between-team level, but not at the within-team level. The relationship between OHC and employee exhaustion showed another pattern of relationships at the different levels of analysis, while it was not significantly mediated by health-oriented leadership. This indicates the value of differentiating between levels of analysis. We discuss the implications for theory and practice that can be drawn from our findings.
RESUMO
Leadership plays an important role in employee well-being. In light of a growing research interest in leaders' resources as determinants of healthy leadership, it is not yet clear how leaders' behavior regarding their own health (self-care) may trickle down to employees. Drawing on Conservation of Resources Theory and the model of Health-Oriented Leadership, this study tests two mechanisms through which employees may benefit from self-caring leaders: (a) through staff care, that is, concern for their employees' health (improved leadership hypothesis); and (b) through a direct relationship between leaders' and employees' self-care (role-modeling hypothesis). In turn, both staff care and employee self-care would relate positively to employee health. Multilevel path models based on a sample of N = 46 supervisors and 437 employees revealed that leader self-care was positively related to leader-rated staff care at Level 2, which was positively related to employee-rated staff care at Level 1. In turn, employee-rated staff care was positively related to employee health. The findings support the improved leadership hypothesis and underline the importance of leader self-care as a determinant of healthy leadership.
Assuntos
Liderança , Autocuidado , Humanos , Análise MultinívelRESUMO
It is widely acknowledged that leadership is crucial for follower health. Under stress, positive leader behaviors such as transformational leadership may decrease and the risk of negative behaviors such as abusive leadership may increase. Followers experience these discrepancies in leadership between routine and stressful periods as inconsistent. While positive and negative leadership is generally associated with follower strain, inconsistency may be stressful by itself, because it entails insecurity and unpredictability in the leader-follower relationship. We suggest that the level of perceived inconsistency and volatility in leaders' behavior across situations is an additional risk factor for follower health. Moreover, we expect perceived inconsistency to be stronger when leaders are strained. This survey study with N = 304 employees examines the relationships between leadership inconsistency and leader as well as follower strain from a followers' perspective. Participants rated their leaders' transformational and abusive leadership separately for routine and stressful conditions, their leaders' strain and their own strain. Employees who experienced stronger discrepancies in leadership between routine and stressful conditions, i.e., more inconsistency, experienced more strain. Moreover, from a followers' perspective, inconsistencies were stronger when leaders were strained. The findings provide evidence that leadership is less stable and consistent than generally assumed and that inconsistency is an additional risk factor. Leader strain may threaten the consistency of leadership and thereby negatively affect follower health.
RESUMO
Human dermal fibroblasts (HDF) were obtained by skin punch biopsy from a 51-year old man with suspected Fabry disease (FD), carrying the hemizygous c.376A > G variant in the α-galactosidase A gene (GLA). Cultured HDF were reprogrammed to induced pluripotent stem cells (iPSC) using a non-modified RNA-based transfection protocol. GLA-S126G-iPSC exhibit typical embryonic stem cell-like morphology, normal karyotype, expression of all tested pluripotency markers, and three germ layer differentiation potential. We provide a novel patient-specific cell line that can be used to investigate a genetic variation of yet unknown significance.
Assuntos
Doença de Fabry , Células-Tronco Pluripotentes Induzidas , Doença de Fabry/genética , Doença de Fabry/patologia , Galactosidases/genética , Galactosidases/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , VirulênciaRESUMO
ABSTRACT: Peripheral denervation and pain are hallmarks of small fiber neuropathy (SFN). We investigated the contribution of skin cells on nociceptor degeneration and sensitization. We recruited 56 patients with SFN and 31 healthy controls and collected skin punch biopsies for immunohistochemical and immunocytochemical analysis of netrin-1 (NTN1) and proinflammatory and anti-inflammatory cytokine expression patterns. We further applied coculture systems with murine dorsal root ganglion (DRG) neurons for skin cell-nerve interaction studies and patch-clamp analysis. Human keratinocytes attract murine DRG neuron neurites, and the gene expression of the axon guidance cue NTN1 is higher in keratinocytes of patients with SFN than in controls. NTN1 slows and reduces murine sensory neurite outgrowth in vitro, but does not alter keratinocyte cytokine expression. In the naive state, keratinocytes of patients with SFN show a higher expression of transforming growth factor-ß1 (P < 0.05), while fibroblasts display higher expression of the algesic cytokines interleukin (IL)-6 (P < 0.01) and IL-8 (P < 0.05). IL-6 incubation of murine DRG neurons leads to an increase in action potential firing rates compared with baseline (P < 0.01). Our data provide evidence for a differential effect of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in SFN compared with healthy controls and further supports the concept of cutaneous nociception.
Assuntos
Neuropatia de Pequenas Fibras , Animais , Fibroblastos , Gânglios Espinais , Humanos , Queratinócitos , Camundongos , NociceptoresRESUMO
OBJECTIVE: Investigate organizational, intrapersonal (expectations, risk, strain, self-care), and interpersonal (health-oriented leadership) factors as predictors for employees' participation in occupational health promotion (OHP) and the mediating effect of intention. Identifying moderators that strengthen the relationship between intention and participation. METHODS: Two cross-sectional studies using moderated mediation and moderator analyses analyzed data from Nâ=â269 to Nâ=â503 employees. RESULTS: Study 1 showed that favorable expectations and a supportive context predict participation via intention and strengthen the effect of intention on participation. The relationship between intention and participation was also stronger if leaders' staff-care was higher. Study 2 showed that the relationship between intention and participation was stronger, if employees' self-care was higher, and strain, neuroticism, and agreeableness was lower. CONCLUSIONS: Findings provide suggestions how organizations may increase participation by supporting employees in building intention and turning their intention into participation.
Assuntos
Promoção da Saúde/organização & administração , Intenção , Saúde Ocupacional/educação , Engajamento no Trabalho , Adolescente , Adulto , Estudos Transversais , Feminino , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Liderança , Masculino , Pessoa de Meia-Idade , Neuroticismo , Estresse Ocupacional/psicologia , Medição de Risco , Autocuidado , Adulto JovemRESUMO
Health-oriented leadership consists of three dimensions that contribute to employee health: staff care, i.e., health-specific follower-directed leadership, as well as both leaders' and followers' self care, i.e., health-specific self-leadership. This study explores profiles of follower self care, leader self care and staff care, and investigates the relationships with follower health in two samples. We identified four patterns of health-oriented leadership: A consistently positive profile (high care), a consistently negative profile (low care), and two profiles showing inconsistencies between follower self care, leader self care, and staff care (leader sacrifice and follower sacrifice). The high care profile reported the best health compared to both the low care profile and the inconsistent profiles. The follower sacrifice profile reported more strain than the leader sacrifice profile, while strain and health levels were the least favorable in the low care profile. Findings reveal that (in-)consistency between follower-directed leadership and self-leadership contributes to follower strain and health.
RESUMO
Induced pluripotent stem cells (iPSC) were derived from human dermal fibroblasts (HDF) of two siblings with small fiber neuropathy (SFN) potentially based on the same variation in SCN10A but exhibiting diverse disease phenotypes. HDF were reprogrammed using a non-integrating mRNA approach and showed robust expression of pluripotency markers. iPSC displayed no chromosomal aberrations and were differentiated into all three germ-layers. These two cell lines with a familial genetic background may provide a useful in vitro tool to investigate the underlying mechanisms leading to different phenotypes caused by the same variation.
Assuntos
Linhagem Celular , Variação Genética , Células-Tronco Pluripotentes Induzidas , Canal de Sódio Disparado por Voltagem NAV1.8 , Neuropatia de Pequenas Fibras , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neuropatia de Pequenas Fibras/genética , Neuropatia de Pequenas Fibras/metabolismo , Neuropatia de Pequenas Fibras/patologiaRESUMO
In this study, we report the human induced pluripotent stem cell line (iPSC) HSAN5-T203â¯M-iPSC, generated from human dermal fibroblasts (HDF) of a woman carrying a heterozygous c.608Câ¯>â¯T mutation in the nerve growth factor gene potentially associated with hereditary sensory and autonomic neuropathy type 5 (HSAN5). HDF were reprogrammed using transient expression of key transcription factors for pluripotency and immune evasion via transfection of synthetic mRNA and miRNA. HSAN5-T203â¯M-iPSC retained the disease-associated genotype c.608Câ¯>â¯T, while maintaining a normal karyotype, showed robust and abundant expression of pluripotency-associated markers and could be differentiated into cells of all three germ layers.