610 Medizin und Gesundheit
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The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced β-catenin binding resulting in increased cytosolic and nuclear β-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/β-catenin signaling.
Our study shows ZP2 to be a new biomarker for diagnosis, best used in combination with other low abundant genes in colon cancer. Furthermore, ZP2 promotes cell proliferation via the ERK1/2-cyclinD1-signaling pathway. We demonstrate that ZP2 mRNA is expressed in a low-abundant manner with high specificity in subsets of cancer cell lines representing different cancer subtypes and also in a significant proportion of primary colon cancers. The potential benefit of ZP2 as a biomarker is discussed. In the second part of our study, the function of ZP2 in cancerogenesis has been analyzed. Since ZP2 shows an enhanced transcript level in colon cancer cells, siRNA experiments have been performed to verify the potential role of ZP2 in cell proliferation. Based on these data, ZP2 might serve as a new target molecule for cancer diagnosis and treatment in respective cancer types such as colon cancer.
Fabry disease (FD) is an X‐linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha‐galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life‐threatening long‐term complications. The complete pathophysiology of chronic kidney disease (CKD) in FD and the role of tubular involvement for its progression are unclear.
We established human renal tubular epithelial cell lines from the urine of male FD patients and male controls. The renal tubular system is rich in mitochondria and involved in transport processes at high energy costs. Our studies revealed fragmented mitochondria with disrupted cristae structure in FD patient cells. Oxidative stress levels were elevated and oxidative phosphorylation was up‐regulated in FD pointing at enhanced energetic needs. Mitochondrial homeostasis and energy metabolism revealed major changes as evidenced by differences in mitochondrial number, energy production and fuel consumption. The changes were accompanied by activation of the autophagy machinery in FD. Sirtuin1, an important sensor of (renal) metabolic stress and modifier of different defense pathways, was highly expressed in FD.
Our data show that lysosomal FD impairs mitochondrial function and results in severe disturbance of mitochondrial energy metabolism in renal cells. This insight on a tissue‐specific level points to new therapeutic targets which might enhance treatment efficacy.
Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re‐evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well‐informed decisions in the context of MMA and PA patient care.
In thyroid carcinoma cells, the soluble βgalactosidespecific lectin, galectin3, is extra and intracellularly expressed and plays a significant role in thyroid cancer diagnosis. The functional relevance of this molecule, particularly in its extracellular environment however, warrants further elucidation. To gain insight into this topic, the present study characterized principal functional properties of galectin3 in 3 commonly used thyroid carcinoma cell lines (BCPAP, Cal62 and FTC133) that express the molecule intra and extracellulary. Cellintrinsic galectin3 harbors a functional carbohydrate recognition domain as determined by affinity purification. Moreover, cell surface expressed galectin3 can be partially removed by treatment with lactose or asialofetuin, but not with sucrose. Thyroid carcinoma cells adhere to substratebound galectin3 in a βgalactosidespecific manner, whereby only cell adhesion, but not cell migration is promoted. Thus, thyroid tumor cells harbor functional active galectin3 that, inter alia, specifically interacts with cell surfaceexpressed molecular ligands in a βgalactosidedependent manner, whereby the molecule can at least interfere with cell adhesion. The modulation of galectin3 expression level or its ligands in such tumor cells could be of therapeutic interest and needs further experimental clarification.
Cysticfibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressiveand life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterized. Our aims were to describe theclinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individu-als harboring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made inprimary human bronchial epithelial cultures (HBEs) andXenopusoocytes. Molecular properties of R751L-CFTR were investigatedin the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotypeassociated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared with non-CF HBEs and asso-ciated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function inXenopusoocytes, together with folding and cell surface transport of R751L-CFTR, was not different from wild-type CFTR. Overall,R751L-CFTR was associated with reduced sodium chloride absorption but had functional properties similar to wild-type CFTR.This is thefirst report of R751L-CFTR that combines clinical phenotype with characterization of functional and biological proper-ties of the mutant channel. Our work will build upon existing knowledge of mutations within this region of CFTR and, importantly,inform approaches for clinical management. Elevated sweat chloride and reduced chloride secretion in HBEs may be due to al-ternative non-CFTR factors, which require further investigation.
One of the primary current astrobiological goals is to understand the limits of microbial resistance to extraterrestrial conditions. Much attention is paid to ionizing radiation, since it can prevent the preservation and spread of life outside the Earth. The aim of this research was to study the impact of accelerated He ions (150 MeV/n, up to 1 kGy) as a component of the galactic cosmic rays on the black fungus C. antarcticus when mixed with Antarctic sandstones—the substratum of its natural habitat—and two Martian regolith simulants, which mimics two different evolutionary stages of Mars. The high dose of 1 kGy was used to assess the effect of dose accumulation in dormant cells within minerals, under long-term irradiation estimated on a geological time scale. The data obtained suggests that viable Earth-like microorganisms can be preserved in the dormant state in the near-surface scenario for approximately 322,000 and 110,000 Earth years within Martian regolith that mimic early and present Mars environmental conditions, respectively. In addition, the results of the study indicate the possibility of maintaining traces within regolith, as demonstrated by the identification of melanin pigments through UltraViolet-visible (UV-vis) spectrophotometric approach.
This volume of the series Springer Briefs in Space Life Sciences explains the physics and biology of radiation in space, defines various forms of cosmic radiation and their dosimetry, and presents a range of exposure scenarios. It also discusses the effects of radiation on human health and describes the molecular mechanisms of heavy charged particles’ deleterious effects in the body. Lastly, it discusses countermeasures and addresses the vital question: Are we ready for launch?
Written for researchers in the space life sciences and space biomedicine, and for master’s students in biology, physics, and medicine, the book will also benefit all non-experts endeavoring to understand and enter space.
Results from the EU-project iStoppFalls : feasibility, effectiveness, approach for fall prevention
(2016)
This paper presents the outcomes of an exploratory field study that examined the social impact of an ICT-based suite of exergames for people with dementia and their caregivers. Qualitative data was collected over a period of 8 months, during which time we studied the daily life of 14 people with dementia and their informal and professional caregivers. We focus on the experiential aspects of the system and examine its social impact when integrated into the daily routines of both people with dementia themselves and their professional and family caregivers. Our findings indicate that relatives were able to regain leisure time, whilst people with dementia were able to recapture certain aspects of their social and daily activities that might otherwise have been lost to them. Results suggest that the system enhanced social-interaction, invigorated relationships, and improved the empowerment of people with dementia and their caregivers to face daily challenges.
Are There Extended Cognitive Improvements from Different Kinds of Acute Bouts of Physical Activity?
(2020)
Acute bouts of physical activity of at least moderate intensity have shown to enhance cognition in young as well as older adults. This effect has been observed for different kinds of activities such as aerobic or strength and coordination training. However, only few studies have directly compared these activities regarding their effectiveness. Further, most previous studies have mainly focused on inhibition and have not examined other important core executive functions (i.e., updating, switching) which are essential for our behavior in daily life (e.g., staying focused, resisting temptations, thinking before acting), as well. Therefore, this study aimed to directly compare two kinds of activities, aerobic and coordinative, and examine how they might affect executive functions (i.e., inhibition, updating, and switching) in a test-retest protocol. It is interesting for practical implications, as coordinative exercises, for example, require little space and would be preferable in settings such as an office or a classroom. Furthermore, we designed our experiment in such a way that learning effects were controlled. Then, we tested the influence of acute bouts of physical activity on the executive functioning in both young and older adults (young 16–22 years, old 65–80 years). Overall, we found no differences between aerobic and coordinative activities and, in fact, benefits from physical activities occurred only in the updating tasks in young adults. Additionally, we also showed some learning effects that might influence the results. Thus, it is important to control cognitive tests for learning effects in test-retest studies as well as to analyze effects from physical activity on a construct level of executive functions.
The present thesis elucidates the development of (i) a series of small molecule inhibitors reacting in a covalent-irreversible manner with the targeted proteases and (ii) a fluorescently labeled activity-based probe as a pharmacological tool compound for investigation of specific functions of the mentioned enzymes in vitro. Herein, the rational design, organic synthesis and quantitative structure-activity-relationships are described extensively.
There has been increasing interest in designing for dementia in recent years. Empirical investigation is now needed of the long-term role of caregivers in appropriating ICTs into the complex daily life of people with dementia (PwD). We present here the outcomes of a 4-month evaluation of the individual, social and institutional impact of a videogame-based training system. The everyday behavior and interactions of 52 PwD and 25 caregivers was studied qualitatively, focusing on the role played by caregivers in integrating the system into daily routines. Our results indicate that the successful appropriation of ICT for PwD depends partly on the physical, cognitive and social benefits for PwD, but especially on the added value perceived by their social care-network. We discuss the need for design in dementia to develop more socially embedded innovations that can address the social actors involved and thus contribute to practical solutions for professional and private care.
