Refine
Year of publication
- 2019 (565) (remove)
Document Type
- Journal article (565) (remove)
Language
- English (565) (remove)
Keywords
- apoptosis (9)
- inflammation (7)
- boron (6)
- cancer (6)
- children (6)
- Fabry disease (5)
- deep learning (5)
- ischemic stroke (5)
- stem cells (5)
- tissue engineering (5)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (91)
- Medizinische Klinik und Poliklinik II (36)
- Physikalisches Institut (33)
- Neurologische Klinik und Poliklinik (32)
- Medizinische Klinik und Poliklinik I (30)
- Institut für Psychologie (26)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (23)
- Institut für Anorganische Chemie (22)
- Institut für Geographie und Geologie (21)
- Rudolf-Virchow-Zentrum (20)
Sonstige beteiligte Institutionen
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (1)
- Interdisciplinary Center for Clinical Research (1)
- Johns Hopkins School of Medicine (1)
- University of Bari Medical School, Bari, Italy (1)
Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor.
Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.
Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.
Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
Honeybees (Apis mellifera) are threatened by numerous pathogens and parasites. To prevent infections they apply cooperative behavioral defenses, such as allo-grooming and hygiene, or they use antimicrobial plant resin. Resin is a chemically complex and highly variable mixture of many bioactive compounds. Bees collect the sticky material from different plant species and use it for nest construction and protection. Despite its importance for colony health, comparatively little is known about the precise origins and variability in resin spectra collected by honeybees. To identify the botanical resin sources of A. mellifera in Western Europe we chemically compared resin loads of individual foragers and tree resins. We further examined the resin intake of 25 colonies from five different apiaries to assess the effect of location on variation in the spectra of collected resin. Across all colonies and apiaries, seven distinct resin types were categorized according to their color and chemical composition. Matches between bee-collected resin and tree resin indicated that bees used poplar (Populus balsamifera, P. x canadensis), birch (Betula alba), horse chestnut (Aesculus hippocastanum) and coniferous trees (either Picea abies or Pinus sylvestris) as resin sources. Our data reveal that honeybees collect a comparatively broad and variable spectrum of resin sources, thus assuring protection against a variety of antagonists sensitive to different resins and/or compounds. We further unravel distinct preferences for specific resins and resin chemotypes, indicating that honeybees selectively search for bioactive resin compounds.
Background
The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking.
Results
Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1.
Conclusion
This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.
Chronic alcohol use leads to specific neurobiological alterations in the dopaminergic brain reward system, which probably are leading to a reward deficiency syndrome in alcohol dependence. The purpose of our study was to examine the effects of such hypothesized neurobiological alterations on the behavioral level, and more precisely on the implicit and explicit reward learning. Alcohol users were classified as dependent drinkers (using the DSM-IV criteria), binge drinkers (using criteria of the USA National Institute on Alcohol Abuse and Alcoholism) or low-risk drinkers (following recommendations of the Scientific board of trustees of the German Health Ministry). The final sample (n = 94) consisted of 36 low-risk alcohol users, 37 binge drinkers and 21 abstinent alcohol dependent patients. Participants were administered a probabilistic implicit reward learning task and an explicit reward- and punishment-based trial-and-error-learning task. Alcohol dependent patients showed a lower performance in implicit and explicit reward learning than low risk drinkers. Binge drinkers learned less than low-risk drinkers in the implicit learning task. The results support the assumption that binge drinking and alcohol dependence are related to a chronic reward deficit. Binge drinking accompanied by implicit reward learning deficits could increase the risk for the development of an alcohol dependence.
Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384–402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.
Animals must slow or halt locomotion to integrate sensory inputs or to change direction. In Caenorhabditis elegans, the GABAergic and peptidergic neuron RIS mediates developmentally timed quiescence. Here, we show RIS functions additionally as a locomotion stop neuron. RIS optogenetic stimulation caused acute and persistent inhibition of locomotion and pharyngeal pumping, phenotypes requiring FLP-11 neuropeptides and GABA. RIS photoactivation allows the animal to maintain its body posture by sustaining muscle tone, yet inactivating motor neuron oscillatory activity. During locomotion, RIS axonal Ca2+ signals revealed functional compartmentalization: Activity in the nerve ring process correlated with locomotion stop, while activity in a branch correlated with induced reversals. GABA was required to induce, and FLP-11 neuropeptides were required to sustain locomotion stop. RIS attenuates neuronal activity and inhibits movement, possibly enabling sensory integration and decision making, and exemplifies dual use of one cell across development in a compact nervous system.
Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
A new strategy is demonstrated for the synthesis of warped, negatively curved, all‐sp\(^2\)‐carbon π‐scaffolds. Multifold C−C coupling reactions are used to transform a polyaromatic borinic acid into a saddle‐shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X‐ray crystallographic studies and pronounced flexibility of this π‐scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one‐electron oxidations at mild potentials.
Although usually asymptomatically colonizing the human nasopharynx, the Gram-negative bacterium Neisseria meningitidis (meningococcus) can spread to the blood stream and cause invasive disease. For survival in blood, N. meningitidis evades the complement system by expression of a polysaccharide capsule and surface proteins sequestering the complement regulator factor H (fH). Meningococcal strains belonging to the sequence type (ST-) 41/44 clonal complex (cc41/44) cause a major proportion of serogroup B meningococcal disease worldwide, but they are also common in asymptomatic carriers. Proteome analysis comparing cc41/44 isolates from invasive disease versus carriage revealed differential expression levels of the outer membrane protein NspA, which binds fH. Deletion of nspA reduced serum resistance and NspA expression correlated with fH sequestration. Expression levels of NspA depended on the length of a homopolymeric tract in the nspA promoter: A 5-adenosine tract dictated low NspA expression, whereas a 6-adenosine motif guided high NspA expression. Screening German cc41/44 strain collections revealed the 6-adenosine motif in 39% of disease isolates, but only in 3.4% of carriage isolates. Thus, high NspA expression is associated with disease, but not strictly required. The 6-adenosine nspA promoter is most common to the cc41/44, but is also found in other hypervirulent clonal complexes.
Background
High-intensity interval training (HIIT) is frequently employed to improve the endurance of various types of athletes. To determine whether youth soccer players may benefit from the intermittent load and time efficiency of HIIT, we performed a meta-analysis of the relevant scientific literature.
Objectives
Our primary objective was to compare changes in various physiological parameters related to the performance of youth soccer players in response to running-based HIIT to the effects of other common training protocols (i.e., small-sided games, technical training and soccer-specific training, or high-volume endurance training). A secondary objective was to compare specifically running-based HIIT to a soccer-specific form of HIIT known as small-sided games (SSG) in this same respect, since this latter type of training is being discussed extensively by coaches.
Method
A systematic search of the PubMed, SPORTDiscus, and Web of Science databases was performed in August of 2017 and updated during the review process in December of 2018. The criteria for inclusion of articles for analysis were as follows: (1) comparison of HIIT to SSG or some other training protocol employing a pre-post design, (2) involvement of healthy young athletes (≤ 18 years old), and (3) assessment of variables related to endurance or soccer performance. Hedges’ g effect size (dppc2) and associated 95% confidence intervals for the comparison of the responses to HIIT and other interventions were calculated.
Results
Nine studies, involving 232 young soccer players (mean age 16.2 ± 1.6 years), were examined. Endurance training in the form of HIIT or SSG produced similar positive effects on most parameters assessed, including peak oxygen uptake and maximal running performance during incremental running (expressed as Vmax or maximal aerobic speed (MAS)), shuttle runs (expressed as the distance covered or time to exhaustion), and time-trials, as well as submaximal variables such as running economy and running velocity at the lactate threshold. HIIT induced a moderate improvement in soccer-related tests involving technical exercises with the soccer ball and other game-specific parameters (i.e., total distance covered, number of sprints, and number of involvements with the ball). Neuromuscular parameters were largely unaffected by HIIT or SSG.
Conclusion
The present meta-analysis indicates that HIIT and SSG have equally beneficial impacts on variables related to the endurance and soccer-specific performance of youth soccer players, but little influence on neuromuscular performance.
Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
Due to the complexityof research objects, theoretical concepts, and stimuli in media research, researchers in psychology and communications presumably need sophisticated measures beyond self-report scales to answer research questions on media use processes. The present study evaluates stimulus-dependent structure in spontaneous eye-blink behavior as an objective, corroborative measure for the media use phenomenon of spatial presence. To this end, a mixed methods approach is used in an experimental setting to collect, combine, analyze, and interpret data from standardized participant self-report, observation of participant behavior, and content analysis of the media stimulus. T-pattern detection is used to analyze stimulus-dependent blinking behavior, and this structural data is then contrasted with self-report data. The combined results show that behavioral indicators yield the predicted results, while self-report data shows unpredicted results that are not predicted by the underlying theory. The use of a mixed methods approach offered insights that support further theory development and theory testing beyond a traditional, mono-method experimental approach.
Background
Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
Methods
We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
Results
We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas.
Conclusions
The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
Depending on the point of view, conceptions of greed range from being a desirable and inevitable feature of a well-regulated, well-balanced economy to the root of all evil - radix omnium malorum avaritia (Tim 6.10). Regarding the latter, it has been proposed that greedy individuals strive for obtaining desired goods at all costs. Here, we show that trait greed predicts selfish economic decisions that come at the expense of others in a resource dilemma. This effect was amplified when individuals strived for obtaining real money, as compared to points, and when their revenue was at the expense of another person, as compared to a computer. On the neural level, we show that individuals high, compared to low in trait greed showed a characteristic signature in the EEG, a reduced P3 effect to positive, compared to negative feedback, indicating that they may have a lack of sensitivity to adjust behavior according to positive and negative stimuli from the environment. Brain-behavior relations further confirmed this lack of sensitivity to behavior adjustment as a potential underlying neuro-cognitive mechanism which explains selfish and reckless behavior that may come at the expense of others.
A new ranking of the world's largest cities—Do administrative units obscure morphological realities?
(2019)
With 37 million inhabitants, Tokyo is the world's largest city in UN statistics. With this work we call this ranking into question. Usually, global city rankings are based on nationally collected population figures, which rely on administrative units. Sprawling urban growth, however, leads to morphological city extents that may surpass conventional administrative units. In order to detect spatial discrepancies between the physical and the administrative city, we present a methodology for delimiting Morphological Urban Areas (MUAs). We understand MUAs as a territorially contiguous settlement area that can be distinguished from low-density peripheral and rural hinterlands. We design a settlement index composed of three indicators (settlement area, settlement area proportion and density within the settlements) describing a gradient of built-up density from the urban center to the periphery applying a sectoral monocentric city model. We assume that the urban-rural transition can be defined along this gradient. With it, we re-territorialize the conventional administrative units. Our data basis are recent mapping products derived from multi-sensoral Earth observation (EO) data – namely the Global Urban Footprint (GUF) and the GUF Density (GUF-DenS) – providing globally consistent knowledge about settlement locations and densities. For the re-territorialized MUAs we calculate population numbers using WorldPop data. Overall, we cover the 1692 cities with >300,000 inhabitants on our planet. In our results we compare the consistently re-territorialized MUAs and the administrative units as well as their related population figures. We find the MUA in the Pearl River Delta the largest morphologically contiguous urban agglomeration in the world with a calculated population of 42.6 million. Tokyo, in this new list ranked number 2, loses its top position. In rank-size distributions we present the resulting deviations from previous city rankings. Although many MUAs outperform administrative units by area, we find that, contrary to what we assumed, in most cases MUAs are considerably smaller than administrative units. Only in Europe we find MUAs largely outweighing administrative units in extent.
Regardless of political boundaries, river basins are a functional unit of the Earth’s land surface and provide an abundance of resources for the environment and humans. They supply livelihoods supported by the typical characteristics of large river basins, such as the provision of freshwater, irrigation water, and transport opportunities. At the same time, they are impacted i.e., by human-induced environmental changes, boundary conflicts, and upstream–downstream inequalities. In the framework of water resource management, monitoring of river basins is therefore of high importance, in particular for researchers, stake-holders and decision-makers. However, land surface and surface water properties of many major river basins remain largely unmonitored at basin scale. Several inventories exist, yet consistent spatial databases describing the status of major river basins at global scale are lacking. Here, Earth observation (EO) is a potential source of spatial information providing large-scale data on the status of land surface properties. This review provides a comprehensive overview of existing research articles analyzing major river basins primarily using EO. Furthermore, this review proposes to exploit EO data together with relevant open global-scale geodata to establish a database and to enable consistent spatial analyses and evaluate past and current states of major river basins.
Objectives
Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia.
Methods
An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95% CI.
Results
Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2= 68%). The prevalence estimate attained by a skin biopsy was 45% (95% CI: 32–59%, I2= 70%) and for corneal confocal microscopy it was 59% (95% CI: 40–78%, I2= 51%).
Conclusion
There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy.
The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in ~1 h and describes the workflow in detail for use by researchers with limited bioinformatics training.
Background
Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ.
Methods
Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method.
Results
Median overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47–3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21–3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504).
Conclusions
Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.
Previous magnetic resonance imaging (MRI) studies revealed structural-functional brain reorganization 12 months after gastric-bypass surgery, encompassing cortical and subcortical regions of all brain lobes as well as the cerebellum. Changes in the mean of cluster-wise gray/white matter density (GMD/WMD) were correlated with the individual loss of body mass index (BMI), rendering the BMI a potential marker of widespread surgery-induced brain plasticity. Here, we investigated voxel-by-voxel associations between surgery-induced changes in adiposity, metabolism and inflammation and markers of functional and structural neural plasticity. We re-visited the data of patients who underwent functional and structural MRI, 6 months (n = 27) and 12 months after surgery (n = 22), and computed voxel-wise regression analyses. Only the surgery-induced weight loss was significantly associated with brain plasticity, and this only for GMD changes. After 6 months, weight loss overlapped with altered GMD in the hypothalamus, the brain's homeostatic control site, the lateral orbitofrontal cortex, assumed to host reward and gustatory processes, as well as abdominal representations in somatosensory cortex. After 12 months, weight loss scaled with GMD changes in right cerebellar lobule VII, involved in language-related/cognitive processes, and, by trend, with the striatum, assumed to underpin (food) reward. These findings suggest time-dependent and weight-loss related gray matter plasticity in brain regions involved in the control of eating, sensory processing and cognitive functioning.
Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.
Background
Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response.
Results
Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI.
Conclusions
Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.
Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF‐α is CEACAM1‐dependently upregulated in the aging vasculature. Vice versa, TNF‐α induces CEACAM1 expression. This results in a feed‐forward loop in the aging vasculature that maintains a chronic pro‐inflammatory milieu. Furthermore, we demonstrate that age‐associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age‐dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR‐2 signaling. Consequently, aging‐related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.
Allopolyploid plants are long known to be subject to a homoeolog expression bias of varying degree. The same phenomenon was only much later suspected to occur also in animals based on studies of single selected genes in an allopolyploid vertebrate, the Iberian fish Squalius alburnoides. Consequently, this species became a good model for understanding the evolution of gene expression regulation in polyploid vertebrates. Here, we analyzed for the first time genome-wide allele-specific expression data from diploid and triploid hybrids of S. alburnoides and compared homoeolog expression profiles of adult livers and of juveniles. Co-expression of alleles from both parental genomic types was observed for the majority of genes, but with marked homoeolog expression bias, suggesting homoeolog specific reshaping of expression level patterns in hybrids. Complete silencing of one allele was also observed irrespective of ploidy level, but not transcriptome wide as previously speculated. Instead, it was found only in a restricted number of genes, particularly ones with functions related to mitochondria and ribosomes. This leads us to hypothesize that allelic silencing may be a way to overcome intergenomic gene expression interaction conflicts, and that homoeolog expression bias may be an important mechanism in the achievement of sustainable genomic interactions, mandatory to the success of allopolyploid systems, as in S. alburnoides.
Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 x 10(4)-5 x 10(6) CD3(+) cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0 center dot 3-2 x 10(6) CD3(+) cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.
We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n =187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice.
The membrane protein EsaA is a conserved component of the type VIIb secretion system. Limited proteolysis of purified EsaA from Staphylococcus aureus USA300 identified a stable 48 kDa fragment, which was mapped by fingerprint mass spectrometry to an uncharacterized extracellular segment of EsaA. Analysis by circular dichroism spectroscopy showed that this fragment folds into a single stable domain made of mostly α‐helices with a melting point of 34.5°C. Size‐exclusion chromatography combined with multi‐angle light scattering indicated the formation of a dimer of the purified extracellular domain. Octahedral crystals were grown in 0.2 M ammonium citrate tribasic pH 7.0, 16% PEG 3350 using the hanging‐drop vapor‐diffusion method. Diffraction data were analyzed to 4.0 Å resolution, showing that the crystals belonged to the enantiomorphic tetragonal space groups P41212 or P43212, with unit‐cell parameters a = 197.5, b = 197.5, c = 368.3 Å, α = β = γ = 90°.
Background:
Employees insured in pension insurance, who are incapable of working due to ill health, are entitled to a disability pension. To assess whether an individual meets the medical requirements to be considered as disabled, a work capacity evaluation is conducted. However, there are no official guidelines on how to perform an external quality assurance for this evaluation process. Furthermore, the quality of medical reports in the field of insurance medicine can vary substantially, and systematic evaluations are scarce. Reliability studies using peer review have repeatedly shown insufficient ability to distinguish between high, moderate and low quality. Considering literature recommendations, we developed an instrument to examine the quality of medical experts’reports.
Methods:
The peer review manual developed contains six quality domains (formal structure, clarity, transparency, completeness, medical-scientific principles, and efficiency) comprising 22 items. In addition, a superordinate criterion (survey confirmability) rank the overall quality and usefulness of a report. This criterion evaluates problems of innerlogic and reasoning. Development of the manual was assisted by experienced physicians in a pre-test. We examined the observable variance in peer judgements and reliability as the most important outcome criteria. To evaluate inter-rater reliability, 20 anonymous experts’ reports detailing the work capacity evaluation were reviewed by 19 trained raters (peers). Percentage agreement and Kendall’s W, a reliability measure of concordance between two or more peers, were calculated. A total of 325 reviews were conducted.
Results:
Agreement of peer judgements with respect to the superordinate criterion ranged from 29.2 to 87.5%. Kendall’s W for the quality domain items varied greatly, ranging from 0.09 to 0.88. With respect to the superordinate criterion, Kendall’s W was 0.39, which indicates fair agreement. The results of the percentage agreement revealed systemic peer preferences for certain deficit scale categories.
Conclusion:
The superordinate criterion was not sufficiently reliable. However, in comparison to other reliability studies, this criterion showed an equivalent reliability value. This report aims to encourage further efforts to improve evaluation instruments. To reduce disagreement between peer judgments, we propose the revision of the peer review instrumentand the development and implementation of a standardized rater training to improve reliability.
The heterotrimeric protein kinase SNF1 plays a key role in the metabolic adaptation of the pathogenic yeast Candida albicans. It consists of the essential catalytic α-subunit Snf1, the γ-subunit Snf4, and one of the two β-subunits Kis1 and Kis2. Snf4 is required to release the N-terminal catalytic domain of Snf1 from autoinhibition by the C-terminal regulatory domain, and snf4Δ mutants cannot grow on carbon sources other than glucose. In a screen for suppressor mutations that restore growth of a snf4Δ mutant on alternative carbon sources, we isolated a mutant in which six amino acids between the N-terminal kinase domain and the C-terminal regulatory domain of Snf1 were deleted. The deletion was caused by an intragenic recombination event between two 8-bp direct repeats flanking six intervening codons. In contrast to truncated forms of Snf1 that contain only the kinase domain, the Snf4-independent Snf1\(^{Δ311 − 316}\) was fully functional and could replace wild-type Snf1 for normal growth, because it retained the ability to interact with the Kis1 and Kis2 β-subunits via its C-terminal domain. Indeed, the Snf4-independent Snf1\(^{Δ311 − 316}\) still required the β-subunits of the SNF1 complex to perform its functions and did not rescue the growth defects of kis1Δ mutants. Our results demonstrate that a preprogrammed in-frame deletion event within the SNF1 coding region can generate a mutated form of this essential kinase which abolishes autoinhibition and thereby overcomes growth deficiencies caused by a defect in the γ-subunit Snf4.
A series of seven unusual dimeric naphthylisoquinoline alkaloids was isolated from the leaves of the tropical liana Ancistrocladus ealaensis J. Léonard, named cyclombandakamine A (1), 1-epi-cyclombandakamine A (2), and cyclombandakamines A3–7 (3–7). These alkaloids have a chemically thrilling structural array consisting of a twisted dihydrofuran-cyclohexenone-isochromene system. The 1′″-epimer of 4, cyclombandakamine A1 (8), had previously been discovered in an unidentified Ancistrocladus species related to A. ealaensis. Both lianas produce the potential parent precursor, mbandakamine A (9), but only A. ealaensis synthesizes the corresponding cyclized form, along with a broad series of slightly modified analogs. The challenging isolation required, besides multi-dimensional chromatography, the use of a pentafluorophenyl stationary phase. Featuring up to six stereocenters and two types of chiral axes, their structures were elucidated by means of 1D and 2D NMR, HRESIMS, in combination with oxidative chemical degradation experiments as well as chiroptical (electronic circular dichroism spectroscopy) and quantum chemical calculations. Compared to the ‘open-chain’ parent compound 9, these dimers displayed rather moderate antiplasmodial activities.
Background:
Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125g dosed every 2weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6years was shown.
Main text
In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted.
Conclusions
This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience.
In mammals the melanocortin 4 receptor (Mc4r) signaling system has been mainly associated with the regulation of appetite and energy homeostasis. In fish of the genus Xiphophorus (platyfish and swordtails) puberty onset is genetically determined by a single locus, which encodes the mc4r. Wild populations of Xiphophorus are polymorphic for early and late-maturing individuals. Copy number variation of different mc4r alleles is responsible for the difference in puberty onset. To answer whether this is a special adaptation of the Mc4r signaling system in the lineage of Xiphophorus or a more widely conserved mechanism in teleosts, we studied the role of Mc4r in reproductive biology of medaka (Oryzias latipes), a close relative to Xiphophorus and a well-established model to study gonadal development. To understand the potential role of Mc4r in medaka, we characterized the major features of the Mc4r signaling system (mc4r, mrap2, pomc, agrp1). In medaka, all these genes are expressed before hatching. In adults, they are mainly expressed in the brain. The transcript of the receptor accessory protein mrap2 co-localizes with mc4r in the hypothalamus in adult brains indicating a conserved function of modulating Mc4r signaling. Comparing growth and puberty between wild-type and mc4r knockout medaka revealed that absence of Mc4r does not change puberty timing but significantly delays hatching. Embryonic development of knockout animals is retarded compared to wild-types. In conclusion, the Mc4r system in medaka is involved in regulation of growth rather than puberty.
Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin-conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.
A unique series of six biaryl natural products displaying four different coupling types (5,10 , 7,10 , 7,80 , and 5,80) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A–D (12–14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and entdioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A–D (12–14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical ‘Ancistrocladaceae-type’ compounds. Ancistrobreveine C (14), is the first – and so far only – example of a 7,80-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrugresistant subline, CEM/ADR5000.
In plants, antimicrobial immune responses involve the cellular release of anions and are responsible for the closure of stomatal pores. Detection of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) induces currents mediated via slow-type (S-type) anion channels by a yet not understood mechanism. Here, we show that stomatal closure to fungal chitin is conferred by the major PRRs for chitin recognition, LYK5 and CERK1, the receptor-like cytoplasmic kinase PBL27, and the SLAH3 anion channel. PBL27 has the capacity to phosphorylate SLAH3, of which S127 and S189 are required to activate SLAH3. Full activation of the channel entails CERK1, depending on PBL27. Importantly, both S127 and S189 residues of SLAH3 are required for chitin-induced stomatal closure and anti-fungal immunity at the whole leaf level. Our results demonstrate a short signal transduction module from MAMP recognition to anion channel activation, and independent of ABA-induced SLAH3 activation.
In the treatment of bone non-unions, an alternative to bone autografts is the use of bone morphogenetic proteins (BMPs), e.g., BMP–2, BMP–7, with powerful osteoinductive and osteogenic properties. In clinical settings, these osteogenic factors are applied using absorbable collagen sponges for local controlled delivery. Major side effects of this strategy are derived from the supraphysiological doses of BMPs needed, which may induce ectopic bone formation, chronic inflammation, and excessive bone resorption. In order to increase the efficiency of the delivered BMPs, we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic) or trabecular bone (random distributed porosity, isotropic). We hypothesize that an anisotropic structure would enhance the osteoconductive properties of the scaffolds by increasing the regenerative performance of the provided rhBMP–2. In vitro, both scaffolds presented similar mechanical properties, rhBMP–2 retention and delivery capacity, as well as scaffold degradation time. In vivo, anisotropic scaffolds demonstrated better bone regeneration capabilities in a rat femoral critical-size defect model by increasing the defect bridging. In conclusion, anisotropic cryostructured collagen scaffolds improve bone regeneration by increasing the efficiency of rhBMP–2 mediated bone healing.
o build, run, and maintain reliable manufacturing machines, the condition of their components has to be continuously monitored. When following a fine-grained monitoring of these machines, challenges emerge pertaining to the (1) feeding procedure of large amounts of sensor data to downstream processing components and the (2) meaningful analysis of the produced data. Regarding the latter aspect, manifold purposes are addressed by practitioners and researchers. Two analyses of real-world datasets that were generated in production settings are discussed in this paper. More specifically, the analyses had the goals (1) to detect sensor data anomalies for further analyses of a pharma packaging scenario and (2) to predict unfavorable temperature values of a 3D printing machine environment. Based on the results of the analyses, it will be shown that a proper management of machines and their components in industrial manufacturing environments can be efficiently supported by the detection of anomalies. The latter shall help to support the technical evangelists of the production companies more properly.
Icefishes (suborder Notothenioidei; family Channichthyidae) are the only vertebrates that lack functional haemoglobin genes and red blood cells. Here, we report a high-quality genome assembly and linkage map for the Antarctic blackfin icefish Chaenocephalus aceratus, highlighting evolved genomic features for its unique physiology. Phylogenomic analysis revealed that Antarctic fish of the teleost suborder Notothenioidei, including icefishes, diverged from the stickleback lineage about 77 million years ago and subsequently evolved cold-adapted phenotypes as the Southern Ocean cooled to sub-zero temperatures. Our results show that genes involved in protection from ice damage, including genes encoding antifreeze glycoprotein and zona pellucida proteins, are highly expanded in the icefish genome. Furthermore, genes that encode enzymes that help to control cellular redox state, including members of the sod3 and nqo1 gene families, are expanded, probably as evolutionary adaptations to the relatively high concentration of oxygen dissolved in cold Antarctic waters. In contrast, some crucial regulators of circadian homeostasis (cry and per genes) are absent from the icefish genome, suggesting compromised control of biological rhythms in the polar light environment. The availability of the icefish genome sequence will accelerate our understanding of adaptation to extreme Antarctic environments.
The green synthesis of silver nanoparticles (SNPs) using plant extracts is an eco-friendly method. It is a single step and offers several advantages such as time reducing, cost-effective and environmental non-toxic. Silver nanoparticles are a type of Noble metal nanoparticles and it has tremendous applications in the field of diagnostics, therapeutics, antimicrobial activity, anticancer and neurodegenerative diseases. In the present work, the aqueous extracts of aerial parts of Lampranthus coccineus and Malephora lutea F. Aizoaceae were successfully used for the synthesis of silver nanoparticles. The formation of silver nanoparticles was early detected by a color change from pale yellow to reddish-brown color and was further confirmed by transmission electron microscope (TEM), UV–visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), and energy-dispersive X-ray diffraction (EDX). The TEM analysis of showed spherical nanoparticles with a mean size between 12.86 nm and 28.19 nm and the UV- visible spectroscopy showed λ\(_{max}\) of 417 nm, which confirms the presence of nanoparticles. The neuroprotective potential of SNPs was evaluated by assessing the antioxidant and cholinesterase inhibitory activity. Metabolomic profiling was performed on methanolic extracts of L. coccineus and M. lutea and resulted in the identification of 12 compounds, then docking was performed to investigate the possible interaction between the identified compounds and human acetylcholinesterase, butyrylcholinesterase, and glutathione transferase receptor, which are associated with the progress of Alzheimer’s disease. Overall our SNPs highlighted its promising potential in terms of anticholinesterase and antioxidant activity as plant-based anti-Alzheimer drug and against oxidative stress.
Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model
(2019)
Background:
Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown.
Methods:
In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison.
Results:
Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1.
Conclusions:
Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.
From the leaves of a botanically and phytochemically as yet unexplored Ancistrocladus liana discovered in the rainforests of the Central region of the Democratic Republic of the Congo in the vicinity of the town of Ikela, six new naphthylisoquinoline alkaloids were isolated, viz., two constitutionally unsymmetric dimers, the mbandakamines B\(_3\) (3) and B\(_4\) (4), and four related 5,8′-linked monomeric alkaloids, named ikelacongolines A–D (5a, 5b, 6, and 7). The dimers 3 and 4 are structurally unusual quateraryls comprising two 5,8′-coupled monomers linked via a sterically strongly constrained 6′,1′′-connection between their naphthalene units. These compounds contain seven elements of chirality, four stereogenic centers and three consecutive chiral axes. They were identified along with two known related compounds, the mbandakamines A (1) and B\(_2\) (2), which had so far only been detected in two Ancistrocladus species indigenous to the Northwestern Congo Basin. In addition, five known monomeric alkaloids, previously found in related Central African Ancistrocladus species, were isolated from the here investigated Congolese liana, three of them belonging to the subclass of 5,8′-coupled naphthylisoquinoline alkaloids, whereas two compounds exhibited a less frequently occurring 7,8′-biaryl linkage. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR), chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. The mbandakamines B\(_3\) (3) and B\(_4\) (4) displayed pronounced activities in vitro against the malaria parasite Plasmodium falciparum and the pathogen of African sleeping sickness, Trypanosoma brucei rhodesiense.
Objective
To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms.
Methods
Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays.
Results
Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti–NF-155 IgG4 were directed against the NF-155–specific Fn3Fn4 domain. The description of a second phenotype of anti–NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year.
Conclusions
Our results indicate that anti–pan-NF-associated neuropathy differs from anti–NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti–NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.
Predation on pest organisms is an essential ecosystem function supporting yields in modern agriculture. However, assessing predation rates is intricate, and they can rarely be linked directly to predator densities or functions. We tested whether sentinel prey aphid cards are useful tools to assess predation rates in the field. Therefore, we looked at aphid cards of different sizes on the ground level as well as within the vegetation. Additionally, by trapping ground‐dwelling predators, we examined whether obtained predation rates could be linked to predator densities and traits. Predation rates recorded with aphid cards were independent of aphid card size. However, predation rates on the ground level were three times higher than within the vegetation. We found both predatory carabid activity densities as well as community weighted mean body size to be good predictors for predation rates. Predation rates obtained from aphid cards are stable over card type and related to predator assemblages. Aphid cards, therefore, are a useful, efficient method for rapidly assessing the ecosystem function predation. Their use might especially be recommended for assessments on the ground level and when time and resource limitations rule out more elaborate sentinel prey methods using exclosures with living prey animals.
Bulb, leaf, scape and flower samples of British bluebells (Hyacinthoides non-scripta) were collected regularly for one growth period. Methanolic extracts of freeze-dried and ground samples showed antitrypanosomal activity, giving more than 50% inhibition, for 20 out of 41 samples. High-resolution mass spectrometry was used in the dereplication of the methanolic extracts of the different plant parts. The results revealed differences in the chemical profile with bulb samples being distinctly different from all aerial parts. High molecular weight metabolites were more abundant in the flowers, shoots and leaves compared to smaller molecular weight ones in the bulbs. The anti-trypanosomal activity of the extracts was linked to the accumulation of high molecular weight compounds, which were matched with saponin glycosides, while triterpenoids and steroids occurred in the inactive extracts. Dereplication studies were employed to identify the significant metabolites via chemotaxonomic filtration and considering their previously reported bioactivities. Molecular networking was implemented to look for similarities in fragmentation patterns between the isolated saponin glycoside at m/z 1445.64 [M + formic-H](-) equivalent to C64H104O33 and the putatively found active metabolite at m/z 1283.58 [M + formic-H](-) corresponding to scillanoside L-1. A combination of metabolomics and bioactivity-guided approaches resulted in the isolation of a norlanostane-type saponin glycoside with antitrypanosoma I activity of 98.9% inhibition at 20 mu M.
Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy.
Approaches to mimic the complexity of the skeletal mesenchymal stem/stromal cell niche in vitro
(2019)
Mesenchymal stem/stromal cells (MSCs) are an essential element of most modern tissue engineering and regenerative medicine approaches due to their multipotency and immunoregulatory functions. Despite the prospective value of MSCs for the clinics, the stem cells community is questioning their developmental origin, in vivo localization, identification, and regenerative potential after several years of far-reaching research in the field. Although several major progresses have been made in mimicking the complexity of the MSC niche in vitro, there is need for comprehensive studies of fundamental mechanisms triggered by microenvironmental cues before moving to regenerative medicine cell therapy applications. The present comprehensive review extensively discusses the microenvironmental cues that influence MSC phenotype and function in health and disease – including cellular, chemical and physical interactions. The most recent and relevant illustrative examples of novel bioengineering approaches to mimic biological, chemical, and mechanical microenvironmental signals present in the native MSC niche are summarized, with special emphasis on the forefront techniques to achieve bio-chemical complexity and dynamic cultures. In particular, the skeletal MSC niche and applications focusing on the bone regenerative potential of MSC are addressed. The aim of the review was to recognize the limitations of the current MSC niche in vitro models and to identify potential opportunities to fill the bridge between fundamental science and clinical application of MSCs.
Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL).
Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values.
Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95% CI 1.12–11.18, p = 0.03), female sex (OR 3.11, 95% CI 1.19–8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95% CI 1.16–6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95% CI 0.93–5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs.
Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.