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Introduction: Obesity is classified as a global epidemic and judged to be the greatest public health threat in Western countries. The tremendously increasing prevalence rates in children lead to morbidity and mortality in adults. In many countries, prevalence has doubled since the 1980s. Other countries show a continuous increase or stagnate at a very high level. Given these regional differences, this study aims to draw a global world map of childhood obesity research, including regional epidemiological characteristics, to comprehensively assess research influences and needs. Methods: In addition to established bibliometric parameters, this study uses epidemiological data to interpret metadata on childhood obesity research from the Web of Science in combination with state-of-the-art visualization methods, such as density equalizing map projections. Results: It was not until the 1990s that belated recognition of the dangerous effects of childhood obesity led to an increase in the number of publications worldwide. In addition, our findings show that countries’ study output does not correlate with epidemiologic rates of childhood obesity. In contrast, the primary driver of the research efforts on childhood obesity appears to be largely driven government funding structures. Discussion/Conclusion: The geographical differences in the epidemiological background of childhood obesity complicate the implementation of transnational research projects and cross-border prevention programs. Effective realization requires a sound scientific basis, which is facilitated by globally valid approaches. Hence, there is a need for information exchange between researchers, policy makers, and private initiatives worldwide.
Hematopoietic stem cell transplantation (HSCT) has been proposed as a promising therapeutic opportunity to improve immunity and prevent hematologic malignancies in Ataxia-telangiectasia (A-T). However, experience in the transplantation strategy for A-T patients is still scarce. The aim of this study was to investigate whether different approaches of HSCT are feasible in regard to graft versus host response and sufficient concerning functional immune reconstitution. Atm-deficient mice were treated with a clinically relevant non-myeloablative host-conditioning regimen and transplanted with CD90.2-depleted, green fluorescent protein (GFP)-expressing, and ataxia telangiectasia mutated (ATM)-competent bone marrow donor cells in a syngeneic, haploidentical or allogeneic setting. Like syngeneic HSCT, haploidentical HSCT, but not allogeneic HSCT extended the lifespan of Atm-deficient mice through the reduction of thymic tumors and normalized T-cell numbers. Donor-derived splenocytes isolated from transplanted Atm-deficient mice filled the gap of cell loss in the naïve T-cell population and raised CD4 cell functionality up to wild-type level. Interestingly, HSCT using heterozygous donor cells let to a significantly improved survival of Atm-deficient mice and increased CD4 cell numbers as well as CD4 cell functionality equivalent to HSCT using with wild-type donor cells. Our data provided evidence that haploidentical HSCT could be a feasible strategy for A-T, possibly even if the donor is heterozygous for ATM. However, this basic research cannot substitute any research in humans.
Membrane-suspended nanopores in microchip arrays for stochastic transport recording and sensing
(2021)
The transport of nutrients, xenobiotics, and signaling molecules across biological membranes is essential for life. As gatekeepers of cells, membrane proteins and nanopores are key targets in pharmaceutical research and industry. Multiple techniques help in elucidating, utilizing, or mimicking the function of biological membrane-embedded nanodevices. In particular, the use of DNA origami to construct simple nanopores based on the predictable folding of nucleotides provides a promising direction for innovative sensing and sequencing approaches. Knowledge of translocation characteristics is crucial to link structural design with function. Here, we summarize recent developments and compare features of membrane-embedded nanopores with solid-state analogues. We also describe how their translocation properties are characterized by microchip systems. The recently developed silicon chips, comprising solid-state nanopores of 80 nm connecting femtoliter cavities in combination with vesicle spreading and formation of nanopore-suspended membranes, will pave the way to characterize translocation properties of nanopores and membrane proteins in high-throughput and at single-transporter resolution.
Introduction: Ischemic and hemorrhagic strokes in the brainstem and cerebellum with injury to the functional loop of the Guillain-Mollaret triangle (GMT) can trigger a series of events that result in secondary trans-synaptic neurodegeneration of the inferior olivary nucleus. In an unknown percentage of patients, this leads to a condition called hypertrophic olivary degeneration (HOD). Characteristic clinical symptoms of HOD progress slowly over months and consist of a rhythmic palatal tremor, vertical pendular nystagmus, and Holmes tremor of the upper limbs. Diffusion Tensor Imaging (DTI) with tractography is a promising method to identify functional pathway lesions along the cerebello-thalamo-cortical connectivity and to generate a deeper understanding of the HOD pathophysiology. The incidence of HOD development following stroke and the timeline of clinical symptoms have not yet been determined in prospective studies—a prerequisite for the surveillance of patients at risk. Methods and Analysis: Patients with ischemic and hemorrhagic strokes in the brainstem and cerebellum with a topo-anatomical relation to the GMT are recruited within certified stroke units of the Interdisciplinary Neurovascular Network of the Rhine-Main. Matching lesions are identified using a predefined MRI template. Eligible patients are prospectively followed up and present at 4 and 8 months after the index event. During study visits, a clinical neurological examination and brain MRI, including high-resolution T2-, proton-density-weighted imaging, and DTI tractography, are performed. Fiberoptic endoscopic evaluation of swallowing is optional if palatal tremor is encountered. Study Outcomes: The primary endpoint of this prospective clinical multicenter study is to determine the frequency of radiological HOD development in patients with a posterior fossa stroke affecting the GMT at 8 months after the index event. Secondary endpoints are identification of (1) the timeline and relevance of clinical symptoms, (2) lesion localizations more prone to HOD occurrence, and (3) the best MR-imaging regimen for HOD identification. Additionally, (4) DTI tractography data are used to analyze individual pathway lesions. The aim is to contribute to the epidemiological and pathophysiological understanding of HOD and hereby facilitate future research on therapeutic and prophylactic measures.
Co-design of a trustworthy AI system in healthcare: deep learning based skin lesion classifier
(2021)
This paper documents how an ethically aligned co-design methodology ensures trustworthiness in the early design phase of an artificial intelligence (AI) system component for healthcare. The system explains decisions made by deep learning networks analyzing images of skin lesions. The co-design of trustworthy AI developed here used a holistic approach rather than a static ethical checklist and required a multidisciplinary team of experts working with the AI designers and their managers. Ethical, legal, and technical issues potentially arising from the future use of the AI system were investigated. This paper is a first report on co-designing in the early design phase. Our results can also serve as guidance for other early-phase AI-similar tool developments.
Predator-induced plasticity in life-history and antipredator traits during the larval period has been extensively studied in organisms with complex life-histories. However, it is unclear whether different levels of predation could induce warning signals in aposematic organisms. Here, we investigated whether predator-simulated handling affects warning coloration and life-history traits in the aposematic wood tiger moth larva, Arctia plantaginis. As juveniles, a larger orange patch on an otherwise black body signifies a more efficient warning signal against predators but this comes at the costs of conspicuousness and thermoregulation. Given this, one would expect that an increase in predation risk would induce flexible expression of the orange patch. Prior research in this system points to plastic effects being important as a response to environmental changes for life history traits, but we had yet to assess whether this was the case for predation risk, a key driver of this species evolution. Using a full-sib rearing design, in which individuals were reared in the presence and absence of a non-lethal simulated bird attack, we evaluated flexible responses of warning signal size (number of orange segments), growth, molting events, and development time in wood tiger moths. All measured traits except development time showed a significant response to predation. Larvae from the predation treatment developed a more melanized warning signal (smaller orange patch), reached a smaller body size, and molted more often. Our results suggest plasticity is indeed important in aposematic organisms, but in this case may be complicated by the trade-off between costly pigmentation and other life-history traits.
Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity.
Epoxides and diols of polyunsaturated fatty acids (PUFAs) are bioactive and can influence processes such as tumor cell proliferation and angiogenesis. Studies with inhibitors of the soluble epoxide hydrolase (sEH) in animals overexpressing cytochrome P450 enzymes or following the systemic administration of specific epoxides revealed a markedly increased incidence of tumor metastases. To determine whether PUFA epoxides increased metastases in a model of spontaneous breast cancer, sEH-/- mice were crossed onto the polyoma middle T oncogene (PyMT) background. We found that the deletion of the sEH accelerated the growth of primary tumors and increased both the tumor macrophage count and angiogenesis. There were small differences in the epoxide/diol content of tumors, particularly in epoxyoctadecamonoenic acid versus dihydroxyoctadecenoic acid, and marked changes in the expression of proteins linked with cell proliferation and metabolism. However, there was no consequence of sEH inhibition on the formation of metastases in the lymph node or lung. Taken together, our results confirm previous reports of increased tumor growth in animals lacking sEH but fail to substantiate reports of enhanced lymph node or pulmonary metastases.
Objectives: Bladder neck contracture (BNC) is a bothersome complication following endoscopic treatment for benign prostatic hyperplasia (BPH). The objective of our study was to give a more realistic insight into contemporary endoscopic BNC treatment and to evaluate and identify risk factors associated with inferior outcome. Material and Methods: We identified patients who underwent transurethral treatment for BNC secondary to previous endoscopic therapy for BPH between March 2009 and October 2016. Patients with vesico-urethral anastomotic stenosis after radical prostatectomy were excluded. Digital charts were reviewed for re-admissions and re-visits at our institutions and patients were contacted personally for follow-up. Our non-validated questionnaire assessed previous urologic therapies (including radiotherapy, endoscopic, and open surgery), time to eventual further therapy in case of BNC recurrence, and the modality of recurrence management. Results: Of 60 patients, 49 (82%) and 11 (18%) underwent transurethral bladder neck resection and incision, respectively. Initial BPH therapy was transurethral resection of the prostate (TURP) in 54 (90%) and holmium laser enucleation of the prostate (HoLEP) in six (10%) patients. Median time from prior therapy was 8.5 (IQR 5.3–14) months and differed significantly in those with (6.5 months; IQR 4–10) and those without BNC recurrence (10 months; IQR 6–20; p = 0.046). Thirty-three patients (55%) underwent initial endoscopic treatment, and 27 (45%) repeated endoscopic treatment for BNC. In initially-treated patients, time since BPH surgery differed significantly between those with a recurrence (median 7.5 months; IQR 6–9) compared to those treated successfully (median 12 months; IQR 9–25; p = 0.01). In patients with repeated treatment, median time from prior BNC therapy did not differ between those with (4.5 months; IQR 2–12) and those without a recurrence (6 months; IQR 6–10; p = 0.6). Overall, BNC treatment was successful in 32 patients (53%). The observed success rate of BNC treatment was significantly higher after HoLEP compared to TURP (100% vs. 48%; p = 0.026). Type of BNC treatment, number of BNC treatment, and age at surgery did not influence the outcome. Conclusions: A longer time interval between previous BPH therapy and subsequent BNC incidence seems to favorably affect treatment success of endoscopic BNC treatment, and transurethral resection and incision appear equally effective. Granted the relatively small sample size, BNC treatment success seems to be higher after HoLEP compared to TURP, which warrants validation in larger cohorts.
The current state of research about ancient settlements within the Nile Delta allows the hypothesizing of fluvial connections to ancient settlements all over the Nile Delta. Previous studies suggest a larger Nile branch close to Kom el-Gir, an ancient settlement hill in the northwestern Nile Delta. To contribute new knowledge to this little-known site and prove this hypothesis, this study aims at using small-scale paleogeographic investigations to reconstruct an ancient channel system in the surroundings of Kom el-Gir. The study pursues the following: (1) the identification of sedimentary environments via stratigraphic and portable X-ray fluorescence (pXRF) analyses of the sediments, (2) the detection of fluvial elements via electrical resistivity tomography (ERT), and (3) the synthesis of all results to provide a comprehensive reconstruction of a former fluvial network in the surroundings of Kom el-Gir. Therefore, auger core drillings, pXRF analyses, and ERT were conducted to examine the sediments within the study area. Based on the evaluation of the results, the study presents clear evidence of a former channel system in the surroundings of Kom el-Gir. Thereby, it is the combination of both methods, 1-D corings and 2-D ERT profiles, that derives a more detailed illustration of previous environmental conditions which other studies can adopt. Especially within the Nile Delta which comprises a large number of smaller and larger ancient settlement hills, this study's approach can contribute to paleogeographic investigations to improve the general understanding of the former fluvial landscape.