Publications

<p>Interactions literature references</p>

Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding organoids can be grown directly from multiple somatic tissues, yet to date, brain organoids can solely be established from pluripotent stem cells. Here, we show that healthy human fetal brain in vitro self-organizes into organoids (FeBOs), phenocopying aspects of in vivo cellular heterogeneity and complex organization. FeBOs can be expanded over long time periods. FeBO growth requires maintenance of tissue integrity, which ensures production of a tissue-like extracellular matrix (ECM) niche, ultimately endowing FeBO expansion. FeBO lines derived from different areas of the central nervous system (CNS), including dorsal and ventral forebrain, preserve their regional identity and allow to probe aspects of positional identity. Using CRISPR-Cas9, we showcase the generation of syngeneic mutant FeBO lines for the study of brain cancer. Taken together, FeBOs constitute a complementary CNS organoid platform.

This study among a sample of 204 German nurses tested the hypothesis that an imbalance of high extrinsic efforts spent (i.e. job demands) and low extrinsic rewards obtained (e.g. poor promotion prospects) are associated with the burnout syndrome: the depletion of nurses' emotional resources. The results of a series of analyses of variances confirmed this hypothesis, by showing that those nurses who experienced an effort-reward imbalance (ERI) reported higher levels on two of the three core dimensions of burnout (i.e. emotional exhaustion and depersonalization) than those who did not experience such an imbalance. Moreover - as additionally hypothesized - significant interaction effects indicated that burnout (i.e. emotional exhaustion and reduced personal accomplishment) was particularly prevalent among those nurses who experienced ERI and put relatively high intrinsic effort into their jobs, as reflected by their strong tendency to be personally in control over job conditions.

RESUMOO workaholism caracteriza-se por um estado mental em que os profissionais trabalham excessiva e compulsivamente.Este estudo objetivou avaliar as propriedades psicométricas das versões extensa (DUWAS-16) e reduzida (DUWAS-10) da Dutch Work Addiction Scale (DUWAS) para o contexto brasileiro.Participaram da pesquisa 571 trabalhadores (65,5% do sexo feminino) com idade média de 36,4 anos (DP = 10,8).A análise fatorial confirmatória (AFC) da DUWAS-16 evidenciou que a escala pode ser utilizada adotando uma estrutura de dois fatores oblíquos (Trabalhar Excessivamente e Trabalhar Compulsivamente) ou uma estrutura unidimensional (Adição).A AFC da versão reduzida DUWAS-10 sugere que tanto a estrutura unidimensional (Adição) ou de dois fatores oblíquos (Trabalhar Excessivamente e Trabalhar Compulsivamente) são adequadas.Os resultados indicaram que a DUWAS-10 pode ser considerada superior a DUWAS-16 para avaliar as dimensões de workaholism no contexto brasileiro.

Abstract Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components ( Odontogenic ameloblast-associated protein ) and dentin dysplasia targets ( Dentin matrix acidic phosphoprotein 1 ). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2 −/− mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2 −/− mutants, reducing matrix metalloprotease (Mmp)9 . Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.

<div>Abstract<p>Inactivation of the <i>Apc</i> gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in <i>Apc<sup>Min/+</sup></i> mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from <i>Apc<sup>Min/+</sup></i> mice. Taken together, these results indicate that cyclin D–CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC. Cancer Res; 70(20); 8149–58. ©2010 AACR.</p></div>

The efficacy of VIR-7831, a class 3 anti-SARS-CoV-2 monoclonal antibody (mAb), was demonstrated repeatedly in clinical trials; yet, reduced neutralization against Omicron variants in cell-line-based neutralization assays led to its withdrawal from clinical use. We developed organoid-based neutralization assays to measure mAb potency. We found that most class 3 mAbs, especially those not blocking receptor-binding domain-ACE2 binding, including VIR-7831, were substantially underestimated in cell-line-based assays. Nasal organoids adequately recapitulated the real-world effectiveness of VIR-7831 because of biologically relevant low ACE2 expression, and exclusively reproduced the in vivo protection of S2 mAbs due to the high TMPRSS2 expression, reminiscent of native human respiratory epithelial cells. Collectively, the robust organoid culture system and biologically relevant expression profiles of ACE2 and TMPRSS2 make nasal organoids present a correlate of in vivo protection of neutralizing mAbs exclusively. The organoid-based neutralization assays, superior to conventional cell-line-based assays, can recapitulate and predict the real-world efficacy of mAbs.

High involvement work systems (HIWS) have been found to be improve employee well‐being. The underlying processes through which HIWS influence employee well‐being and the conditions under which these practices work are not fully understood. This study draws on job demands‐resources theory to address this gap by theorising two novel mediators, that is, work pressure and bonding social capital, to explain how HIWS influence emotional exhaustion. We further proposed that engaging leadership as a proxy of line manager implementation of HIWS would strengthen these relationships. An integrated model is presented on how, why, and when HIWS influence employee well‐being. Using data collected from 97 employees in a pharmaceutical company via a general survey and then a diary survey for 5 working days, this study found that HIWS alleviated day‐level emotional exhaustion through their experience of higher day‐level bonding social capital and lower day‐level work pressure and these relationships were stronger under high level of engaging leadership.

Organoids are a major new tool to study tissue renewal. However, characterizing the underlying differentiation dynamics remains challenging. Here, we developed TypeTracker, which identifies cell fates by AI-enabled cell tracking and propagating end point fates back along the branched lineage trees. Cells that ultimately migrate to the villus commit to their new type early, when still deep inside the crypt, with important consequences: (i) Secretory cells commit before terminal division, with secretory fates emerging symmetrically in sister cells. (ii) Different secretory types descend from distinct stem cell lineages rather than an omnipotent secretory progenitor. (iii) The ratio between secretory and absorptive cells is strongly affected by proliferation after commitment. (iv) Spatial patterning occurs after commitment through type-dependent cell rearrangements. This “commit-then-sort” model contrasts with the conventional conveyor belt picture, where cells differentiate by moving up the crypt-villus axis and hence raises new questions about the underlying commitment and sorting mechanisms.

Disorders of isolated mineralocorticoid deficiency, which cause potentially life-threatening salt-wasting crisis early in life, have been associated with gene variants of aldosterone biosynthesis or resistance; however, in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone-producing adrenal zona glomerulosa (zG). Herein, we describe a highly consanguineous family with multiple perinatal deaths and infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex-specific ablation of Lgr4, using Lgr4fl/fl mice mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG, and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling, which results in abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

This study aims to gain insight in the motivational process of the Job Demands-Resources (JD-R) model by examining whether daily fluctuations in colleague support (i.e., a typical job resource) predict day-levels of job performance through self-efficacy and work engagement. Forty-four flight attendants filled in a questionnaire and a diary booklet before and after consecutive flights to three intercontinental destinations. Results of multilevel analyses revealed that colleague support had unique positive effects on self-efficacy and work engagement. Self-efficacy did not mediate the relationship between support and engagement, but work engagement mediated the relationship between self-efficacy and (in-role and extra-role) performance. In addition, colleague support had an indirect effect on in-role performance through work engagement. These findings shed light on the motivational process as outlined in the JD-R model, and suggest that colleague support is an important job resource for flight attendants helping them reach their work-related goals.