Publications

A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels

Current methods of culturing human epithelial organoids from adult stem cells may not be compatible with clinical applications as they rely on xenogeneic, chemically undefined or non-standardized components such as the basement membrane extract Matrigel. Matrigel provides a source of extracellular matrix molecules, including laminins and collagen IV, which interact with β1 integrins expressed on organoid cells. Here we describe a single-chain (sc) version of antibody TS2/16 that allosterically activates integrin β1 function in organoids. The addition of monomeric scTS2/16 to organoid medium results in up to a fivefold increase in the yield of all gastrointestinal organoids grown in Matrigel. Moreover, scTS2/16 supports a six- to sevenfold increase in the yield of these organoids when cultured in collagen I hydrogels, both in 3D and 2D. Collagen I is well defined, available in clinical-grade formulations and, when combined with scTS2/16, may support the clinical application of epithelial organoids derived from gastrointestinal tissues and other epithelial sources.

A Human Organoid Model of Aggressive Hepatoblastoma for Disease Modeling and Drug Testing

Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/β-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments.

Lactate controls cancer stemness and plasticity through epigenetic regulation

Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

Burnout among Dutch Teachers: An Mbi-Validity Study

The study investigates the internal consistency as well as the factorial and discriminant validity of the Maslach Burnout Inventory (MBI) in a sample of 326 Dutch secondary teachers. Compared to other teacher samples, the internal consistency of the three subscales (Emotional Exhaustion-EEX, Depersonalization-DEP, Reduced Personal Accomplishment-PAC) is relatively high. Using confirmatory maximum likelihood factor analysis with LISREL, it is shown that the three-factor oblique model fits relatively well compared to various alternative models. As in some other studies, one ambiguous item was identified ("I feel very energetic") that loads on two factors simultaneously (i.e., EEX and PAC). Moreover, burnout can be distinguished successfully from self-reported psychological strain as well as from somatic complaints. Nevertheless, EEX is substantially related to these more general symptoms. Finally, levels of EEX, psychological strain, and somatic complaints are significantly higher compared to Dutch reference groups, whereas levels of DEP and reduced PAC are significantly lower. It is concluded that the MBI is a valid and reliable self-report instrument to assess burnout in a non-English-speaking country like the Netherlands.

Tubuloid culture enables long-term expansion of functional human kidney tubule epithelium from iPSC-derived organoids

Kidney organoids generated from induced pluripotent stem cells (iPSC) have proven valuable for studies of kidney development, disease, and therapeutic screening. However, specific applications have been hampered by limited expansion capacity, immaturity, off-target cells, and inability to access the apical side. Here, we apply recently developed tubuloid protocols to purify and propagate kidney epithelium from d7+18 (post nephrogenesis) iPSC-derived organoids. The resulting ‘iPSC organoid-derived (iPSCod)’ tubuloids can be exponentially expanded for at least 2.5 mo, while retaining expression of important tubular transporters and segment-specific markers. This approach allows for selective propagation of the mature tubular epithelium, as immature cells, stroma, and undesirable off-target cells rapidly disappeared. iPSCod tubuloids provide easy apical access, which enabled functional evaluation and demonstration of essential secretion and electrolyte reabsorption processes. In conclusion, iPSCod tubuloids provide a different, complementary human kidney model that unlocks opportunities for functional characterization, disease modeling, and regenerative nephrology.

Introduction

No abstract is provided for this article.

Werkverslaving, stress en gezondheid: ontwikkeling en validatie van een Nederlandse workaholisme-schaal

No abstract is provided for this article.

Additional file 7 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Additional file 7. Table S6

ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

Significance Sex determination involves antagonistic interactions between the testis-determining (SRY-SOX9-FGF9) and ovary-promoting (RSPO1-WNT/β-catenin-FOXL2) pathways, but the underlying molecular mechanisms remain unclear. We show that ZNRF3, an E3 ubiquitin ligase that inhibits WNT signaling and is a direct target of RSPO1-mediated membrane clearance, is testis-determining in mice. Testis determination defects in the absence of ZNRF3 arise due to ectopic canonical WNT signaling in XY gonads at the sex-determining stage. We identify human ZNRF3 sequence variants in cases of 46,XY disorders of sex development with XY female presentation. In vitro functional assays show that these variants disrupt ZNRF3 function. Our data reveal a sex-determining role for ZNRF3 and indicate that interactions between ZNRF3 and RSPO1 regulate mammalian sex determination.

List of Contributors

DRA002711

List of DRA (http://trace.ddbj.nig.ac.jp/dra/index_e.html) accession numbers of the FANTOM5 samples, sequences and genomic coordinations. Files are in tab-delimited format, which includes * Library ID * FFID * BioSamples accession number * DRA experiment accession number * DRA run accession numbers * DRA analysis accession number for genomic coordination (BAM file) * DRA analysis accession number for CTSS (BED file) * Experiment method (CAGE/RNA-Seq/sRNA-Seq)

The role of attributions in the cognitive appraisal of work-related stressful events: An event-recording approach

This paper describes a micro-analysis of the cognitive appraisal of daily stressful events in a sample of correctional officers (COs). More specifically, the authors examined whether three attribution dimensions mediated the relationship between the occurrence of stressful events and the 'significance' of these events, and whether the latter functioned as a mediator between the attribution dimensions on the one hand and negative affect (outcome variable) on the other. Convincing indications were found for the mediating role of the 'significance' of a stressful event, while weak indications were found for the mediating role of the attribution dimensions. Finally, the strengths and weaknesses of daily event-recording methods are discussed at length.

Synergistic action of A23187 and phorbol ester on human B cell activation.

Abstract We have investigated the existence of a synergy occurring between the calcium ionophore A23187 and phorbol myristic acetate (PMA) with respect to human B cell proliferation and differentiation. The combination of A23187 (250 to 500 nM) with nonmitogenic concentrations of PMA (1 to 3 ng/ml) resulted in a strong proliferative response in human tonsillar, spleen, and peripheral blood B cells. This proliferation could not be blocked by anti-Tac antibody at concentrations that effectively inhibited T cell proliferation under similar culture conditions, suggesting that IL 2 and its receptor are not involved in B cell proliferation in this system. During a 3-day culture period, A23187 (500 nM) did not activate B cells in terms of changes in cell size or in the expression of transferrin receptor, HLA-DR, and Tac antigen. PMA at a nonmitogenic concentration (3 ng/ml) enhanced the expression of the first two markers. Combination of the ionophore with PMA induced the occurrence of Tac and further increased the expression of transferrin receptor and HLA-DR. A23187 similarly enhanced the PMA-mediated increase in cell size. PMA and A23187 did not induce differentiation to lg production. However, when cells were prestimulated with a combination of the two agents and were recultured in the presence of a preparation containing B cell differentiation factor, a strong increase in IgM, IgG, and IgA production was found. We conclude that PMA and A23187 synergistically trigger intracellular events in human B cells, leading to proliferation and to responsiveness to differentiation factors.

The Effect of a Nation-Specific Stressor on Well-Being: Guanxi in Chinese Workplace

No abstract is provided for this article.

Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation

The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkβ(EE) IEC transgenic mice expressing constitutively active IκB kinase β (IKKβ) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkβ(EE) IEC mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli ( Apc ) tumor suppressor locus, Ikkβ(EE) IEC mice exhibited more β-catenin + early lesions and visible small intestinal and colonic tumors relative to Apc +/ΔIEC mice, and their survival was severely compromised. IEC of Ikkβ(EE) IEC mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkβ(EE) IEC / Apc +/ΔIEC mice with an iNOS inhibitor decreased DNA damage markers and reduced early β-catenin + lesions and tumor load. The results suggest that persistent NF-κB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.

Job crafting in changing organizations: Antecedents and implications for exhaustion and performance.

The present study addressed employee job crafting behaviors (i.e., seeking resources, seeking challenges, and reducing demands) in the context of organizational change. We examined predictors of job crafting both at the organizational level (i.e., perceived impact of the implemented changes on the working life of employees) and the individual level (i.e., employee willingness to follow the changes). Job crafting behaviors were expected to predict task performance and exhaustion. Two-wave longitudinal data from 580 police officers undergoing organizational changes were analyzed with structural equation modeling. Findings showed that the degree to which changes influence employees' daily work was linked to reducing demands and exhaustion, whereas employee willingness to change was linked to seeking resources and seeking challenges. Furthermore, while seeking resources and seeking challenges were associated with high task performance and low exhaustion respectively, reducing demands seemed to predict exhaustion positively. Our findings suggest that job crafting can act as a strategy of employees to respond to organizational change. While seeking resources and seeking challenges enhance employee adjustment and should be encouraged by managers, reducing demands seems to have unfavorable implications for employees.

Личностные ресурсы и выгорание у сотрудников библиотек Московской области

Цель. В предлагаемой работе целью исследования стало изучение профессионального выгорания и его взаимосвязи с личностными ресурсами на выборке библиотекарей Московской области. Метод. Выборка включала 504 респондента в возрасте от 17 до 72 лет. Подавляющее большинство участников исследования - женщины (96%). Для измерения выгорания была использована модель, предложенная В. Шауфели и Ш. Дезарт. Основными конструктами для описания личностных ресурсов выступили оптимизм, жизнестойкость и самоэффективность. В качестве основного метода анализа использовалась многоуровневая регрессия, которая является оптимальной при анализе сгруппированных данных, чтобы не происходила переоценка вклада каких-либо переменных. В качестве предварительного анализа была проведена валидизация измерительной модели выгорания с помощью конфирматорного факторного анализа (с факторами первого и второго порядка). Результаты. Было показано,что уровень выгорания у испытуемых достаточно низкий, личностные ресурсы связаны с выгоранием тесно и отрицательно (rs = - .64, p < .01). Эффект личностных ресурсов различается в среднем по библиотекам (β = - .08, 95% CI[- .04; - .12]), но одинаков у работников сельских и городских библиотек (β = .03, 95% CI[- .15; .21]). Помимо личностных ресурсов, значимым предиктором уровня выгорания выступил возраст (β = - .10, 95% CI[- .18; - .02]), при этом вклад стажа работы оказался незначим. Выводы. Впервые было показано, что эффект личностных ресурсов изменяется по группам: чем выше отклонение по уровню выгорания, тем ниже вклад личностных ресурсов. В заключение обсуждаются результаты этой работы с ранее проведёнными исследованиями, а также говорится о возможности профессионального развития библиотекарей с учётом психологического состояния.

Perfectionism Scale