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Heart and kidney diseases cause high morbidity and mortality. Heart and kidneys have vital functions in the human body and, interestingly, reciprocally influence each other’s behavior: pathological changes in one organ can damage the other. Cardiorenal syndrome (CRS) is a group of disorders in which there is combined dysfunction of both heart and kidney, but its underlying biological mechanisms are not fully understood. This is because complex, multifactorial, and dynamic mechanisms are likely involved. Effective treatments are currently unavailable, but this may be resolved if more was known about how the disease develops and progresses. To date, CRS has actually only been modeled in mice and rats in vivo. Even though these models can capture cardiorenal interaction, they are difficult to manipulate and control. Moreover, interspecies differences may limit extrapolation to patients. The questions we address here are what would it take to model CRS in vitro and how far are we? There are already multiple independent in vitro (human) models of heart and kidney, but none have so far captured their dynamic organ-organ crosstalk. Advanced in vitro human models can provide an insight in disease mechanisms and offer a platform for therapy development. CRS represents an exemplary disease illustrating the need to develop more complex models to study organ-organ interaction in-a-dish. Human induced pluripotent stem cells in combination with microfluidic chips are one powerful tool with potential to recapitulate the characteristics of CRS in vitro. In this review, we provide an overview of the existing in vivo and in vitro models to study CRS, their limitations and new perspectives on how heart-kidney physiological and pathological interaction could be investigated in vitro for future applications.

Loxosceles spider venom contains Sphingomyelinase D (SMase D), the key toxin causing pathology. SMase D hydrolyzes the main component of lipid rafts, sphingomyelin, which changes the membrane microenvironment resulting in the activation of endogenous metalloproteinase from the ADAMs family. Alterations in membrane microenvironment of lipid rafts contribute to the activation of several cell surface molecules. Serine proteinases convertases acting on the pro-domain of membrane metalloproteinases, such as ADAMs, increase the cleavage and the release of proteins ectodomains and receptors located at the cell surface areas containing lipid rafts. We, therefore, investigated the interaction of SMases D with these membrane microdomains (lipid rafts) in human keratinocytes, to better understand the molecular mechanism of SMases D action, and identify the ADAM(s) responsible for the cleavage of cell surface molecules. Using specific inhibitors, we observed that ADAMs 10 and 17 are activated in the cell membrane after SMase D action. Furthermore, proproteins convertases, such as furin, are involved in the SMase D induced ADAMs activation. One of the signaling pathways that may be involved in the activation of these proteases is the MAPK pathway, since phosphorylation of ERK1/2 was observed in cells treated with SMase D. Confocal analysis showed a strong colocalization between SMase D and GM1 ganglioside present in rafts. Analysis of structural components of rafts, such as caveolin-1 and flotillin-1, showed that the action of SMase D on cell membranes leads to a reduction in caveolin-1, which is possibly degraded by toxin-induced superoxide production in cells. The action of the toxin also results in flotilin-1 increased detection in the cell membrane. These results indicate that SMases D from Loxosceles venoms alter membrane rafts structure, leading to the activation of membrane bound proteases, which may explain why the lipase action of this toxin can result in proteolytic cleavage of cell surface proteins, ultimately leading to pathology.

IntroductionBurn-out leads to reduced worker well-being, long-term absenteeism, and high costs for employers and society. Determinants at different levels may affect burn-out in an interrelated and dynamic manner. The aim of the present study was to apply a broader systems perspective by exploring and visualizing the complex system of determinants at different levels (living conditions, working conditions, and societal developments) underlying the prevalence of burn-out in the Netherlands.MethodsDuring three group model building (GMB) sessions with in total eight experts on workers’ mental health, a causal loop diagram (CLD) was developed and relevant feedback loops were identified. For the selection of determinants to be included in the CLD a recently published overview of determinants on burn-out at different levels was used. Experts could also add factors that were not listed in the overview.ResultsThe final CLD consists of 20 factors and depicts a central position of working conditions. Societal developments (e.g., access to mental health care, size of the working population, rougher social climate, etc.) were mostly located at the outside of the CLD and barely integrated in feedback loops. Several reinforcing feedback loops resulting in an increase of the prevalence of burn-out were identified in which the factors (very) high workload, imbalance between work and private life, and insufficient recovery time play an important role. Also, several balancing loops were found that visualize the crucial role of functional support from supervisors to prevent burn-out among workers.DiscussionApplying a broader systems perspective, including determinants at different levels, offers new insights into dynamic feedback loops that contribute to the prevalence of burn-out. Supervisors, amongst others, have a considerable impact on the system underlying the high prevalence of burn-out and may therefore contribute to its prevention. Even though societal developments were less integrated in feedback loops, they might be considered drivers of existing feedback loops. The results from this study confirm that determinants at various levels underly the prevalence of burn-out. To be able to address the diversity of determinants underlying a high prevalence of burn-out, a complex system approach can be helpful.

Centromeres are unique chromosomal loci that form the anchorage point for the mitotic spindle during mitosis and meiosis. Their position and function are specified by a unique chromatin domain featuring the histone H3 variant CENP-A. While typically formed on centromeric satellite arrays, CENP-A nucleosomes are maintained and assembled by a strong self-templated feedback mechanism that can propagate centromeres even at non-canonical sites. Central to the epigenetic chromatin-based transmission of centromeres is the stable inheritance of CENP-A nucleosomes. While long-lived at centromeres, CENP-A can turn over rapidly at non-centromeric sites and even erode from centromeres in non-dividing cells. Recently, SUMO modification of the centromere complex has come to the forefront as a mediator of centromere complex stability, including CENP-A chromatin. We review evidence from different models and discuss the emerging view that limited SUMOylation appears to play a constructive role in centromere complex formation, while polySUMOylation drives complex turnover. The deSUMOylase SENP6/Ulp2 and the proteins segregase p97/Cdc48 constitute the dominant opposing forces that balance CENP-A chromatin stability. This balance may be key to ensuring proper kinetochore strength at the centromere while preventing ectopic centromere formation.

End stage renal disease is an increasing problem worldwide driven by aging of the population and increased prevalence of metabolic disorders and cardiovascular disease. Currently, kidney transplantation is the only curative option, but donor organ shortages greatly limit its application. Regenerative medicine has the potential to solve the shortage by using stem cells to grow the desired tissues, like kidney tissue. Immune rejection poses a great threat towards the implementation of stem cell derived tissues and various strategies have been explored to limit the immune response towards these tissues. However, these studies are limited by targeting mainly T cell mediated immune rejection while the rejection process also involves innate and humoral immunity. In this study we investigate whether inhibition of the complement system in human induced pluripotent stem cells (iPSC) could provide protection from such immune injury. To this end we created knock-in iPSC lines of the membrane bound complement inhibitor CD55 to create a transplant-specific protection towards complement activation. CD55 inhibits the central driver of the complement cascade, C3 convertase, and we show that overexpression is able to decrease complement activation on both iPSCs as well as differentiated kidney organoids upon stimulation with anti-HLA antibodies to mimic the mechanism of humoral rejection.

Background and Objectives: Early identification of child mental health problems (MHPs) is important to provide adequate, timely treatment. Dutch preventive youth healthcare monitors all aspects of a child's healthy development. We explored the usefulness of their electronic health records (EHRs) in scientific research and aimed to develop prediction models for child MHPs.Methods: Population-based cohort study with anonymously extracted electronic healthcare data from preventive youth healthcare centers in the Leiden area, the Netherlands, from the period 2005–2015. Data was analyzed with respect to its continuity, percentage of cases and completeness. Logistic regression analyses were conducted to develop prediction models for the risk of a first recorded concern for MHPs in the next scheduled visit at age 3/4, 5/6, 10/11, and 13/14 years.Results: We included 26,492 children. The continuity of the data was low and the number of concerns for MHPs varied greatly. A large number of determinants had missing data for over 80% of the children. The discriminatory performance of the prediction models were poor.Conclusions: This is the first study exploring the usefulness of EHRs from Dutch preventive youth healthcare in research, especially in predicting child MHPs. We found the usefulness of the data to be limited and the performance of the developed prediction models was poor. When data quality can be improved, e.g., by facilitating accurate recording, or by data enrichment from other available sources, the analysis of EHRs might be helpful for better identification of child MHPs.