pyFBS is an open-source Python package for frequency-based substructuring. The package implements an object-oriented approach for dynamic substructuring. This tutorial is intended to introduce structural dynamics and NVH engineers to the research toolbox in order to overcome vibration challenges in the future. The focus will be on experimental modeling and post-processing of datasets in the context of dynamic substructuring applications. The state-of-the-art methods of frequency-based substructuring, such as the virtual point transformation, the singular vector transformation, and system-equivalent model mixing, are available in pyFBS and will be presented. Furthermore, basic and application examples, as well as numerical and experimental datasets that are provided, are intended to familiarize users with the workflow of the package. pyFBS is demonstrated with two example structures. First, a simple beam-like structure is used to demonstrate how to start with the experimental modeling, FRF synthesis, virtual point transformation, and mixing of system equivalence models. Second, an automotive test structure is used to demonstrate the use of the pyFBS on a complex structure where in-situ transfer path analysis is used to characterize the blocked forces. This tutorial is intended to provide an informal overview of how research can be powered by open-source tools.
Lightweight design for gears is becoming increasingly important for efficient, sustainable drive trains. Innovative lightweight designs can be achieved by the additive manufacturing process of P.B.F.-L.B./M. (powder bed fusion by laser beam of metals). This contribution presents lightweight hub designs for gears manufactured by P.B.F.-L.B./M. Helical as well as spur gears are 3D-printed out of the case-hardening steel 16MnCr5. After the PBF-LB/M-process, the gears are case-carburized, shot blasted for mechanical cleaning. The gears with lightweight hubs are analyzed concerning their density, microstructure, roughness. The gears are tested regarding their static, dynamic load carrying capacity, the influence of the lightweight hub on the load carrying capacity is analyzed, evaluated. In conclusion, this contribution enables aprofound understanding, prospective evolution of lightweight hub designs for gears.
Shared vehicles architectures for fuel cell and battery electric vehicles offer a high potential for cost reduction by enabling economies of scale in engineering and production. The efficient integration of hydrogen storages in flat box-shaped battery design spaces represents one of the essential basic requirements. As state-of-the-art cylindrical pressure vessels do not allow a high volumetric efficiency in the installation space, two concepts of box-shaped pressure vessels with tension struts are investigated with regard to manufacturability. The first concept focuses on the integration of aramid fibers in a carbon fiber tank by tufting. In a second concept 3D weaving is analyzed with regard to the construction of a pressure vessel with inner tension struts. For both tank designs manufacturing technologies are developed and the concepts are validated using prototypes. Considering technologies for series production of the textile sector possible paths for industrialization are identified.
The human gastrointestinal tract is home to trillions of microbes. Gut microbial communities have a significant regulatory role in the intestinal physiology, such as gut motility. Microbial effect on gut motility is often evoked by bioactive molecules from various sources, including microbial break down of carbohydrates, fibers or proteins. In turn, gut motility regulates the colonization within the microbial ecosystem. However, the underlying mechanisms of such regulation remain obscure. Deciphering the inter-regulatory mechanisms of the microbiota and bowel function is crucial for the prevention and treatment of gut dysmotility, a comorbidity associated with many diseases. In this review, we present an overview of the current knowledge on the impact of gut microbiota and its products on bowel motility. We discuss the currently available techniques employed to assess the changes in the intestinal motility. Further, we highlight the open challenges, and incorporate biophysical elements of microbes-motility interplay, in an attempt to lay the foundation for describing long-term impacts of microbial metabolite-induced changes in gut motility.
The refractory diabetic wound has remained a worldwide challenge as one of the major health problems. The impaired angiogenesis phase during diabetic wound healing partly contributes to the pathological process. MicroRNA (miRNA) is an essential regulator of gene expression in crucial biological processes and is a promising nucleic acid drug in therapeutic fields of the diabetic wound. However, miRNA therapies have limitations due to lacking an effective delivery system. In the present study, we found a significant reduction of miR-31-5p expression in the full-thickness wounds of diabetic mice compared to normal mice. Further, miR-31-5p has been proven to promote the proliferation, migration, and angiogenesis of endothelial cells. Thus, we conceived the idea of exogenously supplementing miR-31-5p mimics to treat the diabetic wound. We used milk-derived exosomes as a novel system for miR-31-5p delivery and successfully encapsulated miR-31-5p mimics into milk exosomes through electroporation. Then, we proved that the miR-31-5p loaded in exosomes achieved higher cell uptake and was able to resist degradation. Moreover, our miRNA-exosomal formulation demonstrated dramatically improved endothelial cell functions in vitro, together with the promotion of angiogenesis and enhanced diabetic wound healing in vivo. Collectively, our data showed the feasibility of milk exosomes as a scalable, biocompatible, and cost-effective delivery system to enhance the bioavailability and efficacy of miRNAs.
There is a growing debate about the involvement of the gut microbiome in COVID-19, although it is not conclusively understood whether the microbiome has an impact on COVID-19, or vice versa, especially as analysis of amplicon data in hospitalized patients requires sophisticated cohort recruitment and integration of clinical parameters. Here, we analyzed fecal and saliva samples from SARS-CoV-2 infected and post COVID-19 patients and controls considering multiple influencing factors during hospitalization. 16S rRNA gene sequencing was performed on fecal and saliva samples from 108 COVID-19 and 22 post COVID-19 patients, 20 pneumonia controls and 26 asymptomatic controls. Patients were recruited over the first and second corona wave in Germany and detailed clinical parameters were considered. Serial samples per individual allowed intra-individual analysis. We found the gut and oral microbiota to be altered depending on number and type of COVID-19-associated complications and disease severity. The occurrence of individual complications was correlated with low-risk (e.g., Faecalibacterium prausznitzii) and high-risk bacteria (e.g., Parabacteroides ssp.). We demonstrated that a stable gut bacterial composition was associated with a favorable disease progression. Based on gut microbial profiles, we identified a model to estimate mortality in COVID-19. Gut microbiota are associated with the occurrence of complications in COVID-19 and may thereby influencing disease severity. A stable gut microbial composition may contribute to a favorable disease progression and using bacterial signatures to estimate mortality could contribute to diagnostic approaches. Importantly, we highlight challenges in the analysis of microbial data in the context of hospitalization.
Introduction: Although evidence-based treatments for posttraumatic stress disorder (PTSD) in adolescents and young adults exist, affected youth do not have sufficient access to these treatments due to structural and attitudinal barriers. Internet- and mobile-based interventions (IMIs) can help fill this healthcare gap, but such programmes have not yet been sufficiently evaluated in youth with PTSD. Aim: This study aims to investigate the feasibility of an IMI for youth with PTSD in a one-arm, non-randomised, prospective proof-of-concept feasibility study. Methods: We aim to recruit 32 youth between 15 and 21 years old with clinically relevant posttraumatic stress symptoms (CATS ≥ 21), who will receive access to the IMI. The IMI consists of nine sessions involving psychoeducation, emotion regulation and coping skills, written-based imaginal exposure, cognitive restructuring and relapse prevention. Participants will be guided by an eCoach, who provides weekly semi-standardised written feedback on completed sessions and adherence reminders. We will use a formal feasibility framework to assess different dimensions of feasibility: (1) recruitment capability and resulting sample characteristics, (2) data collection procedures and outcome measures, (3) acceptability of the IMI and study procedures, (4) resources and ability to manage and implement the study and IMI and (5) participants' responses to the IMI in terms of symptom severity and satisfaction. Additionally, potential negative effects related to the intervention will be assessed. Assessments take place pre-, mid- and post-intervention and at follow-up, including semi-structured clinical telephone interviews for PTSD diagnostics at pre- and post-intervention assessment. Qualitative interviews will be conducted to investigate the youth perspectives on the IMI. Discussion: This study aims to determine the feasibility of a guided IMI for youth with PTSD to adapt the IMI as closely as possible to youth needs and to inform the design, procedure and safety management of a large-scale efficacy RCT. Trial registration: German Clinical Trials Register identifier: DRKS00023341. Highlights: Evidence-based care for adolescents after trauma is not widely available.• This study evaluates the feasibility of a guided trauma-focused Internet intervention as a time- and location-independent low-threshold treatment option for adolescents and young adults with posttraumatic stress disorder.
An amendment to this paper has been published and can be accessed via the original article.
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Background The ability of overstory tree species to regenerate successfully is important for the preservation of tree species diversity and its associated flora and fauna. This study investigated forest regeneration dynamics in the Cat Ba National Park, a biodiversity hotspot in Vietnam. Data was collected from 90 sample plots (500 m ² ) and 450 sub-sample plots (25 m ² ) in regional limestone forests. We evaluated the regeneration status of tree species by developing five ratios relating overstory and regeneration richness and diversity. By examining the effect of environmental factors on these ratios, we aimed to identify the main drivers for maintaining tree species diversity or for potential diversity gaps between the regeneration and the overstory layer. Our results can help to increase the understanding of regeneration patterns in tropical forests of Southeast Asia and to develop successful conservation strategies. Results We found 97 tree species in the regeneration layer compared to 136 species in the overstory layer. The average regeneration density was 3764 ± 1601 per ha. Around 70% of the overstory tree species generated offspring. According to the International Union for Conservation of Nature’s Red List, only 36% of threatened tree species were found in the regeneration layer. A principal component analysis provided evidence that the regeneration of tree species was slightly negatively correlated to terrain factors (percentage of rock surface, slope) and soil properties (cation exchange capacity, pH, humus content, soil moisture, soil depth). Contrary to our expectations, traces of human impact and the prevailing light conditions (total site factor, gap fraction, openness, indirect site factor, direct site factor) had no influence on regeneration density and composition, probably due to the small gradient in light availability. Conclusion We conclude that the tree species richness in Cat Ba National Park appears to be declining at present. We suggest similar investigations in other biodiversity hotspots to learn whether the observed trend is a global phenomenon. In any case, a conservation strategy for the threatened tree species in the Cat Ba National Park needs to be developed if tree species diversity is to be maintained.
Rationale Multiple myeloma (MM) cells synthesize large amounts of paraproteins, making radiolabeled amino acids promising candidates for PET imaging of MM patients. Methods We compare tumor uptake of the two amino acid analogs [ ¹⁸ F]-fluoroethyltyrosine and [ ¹⁸ F]-FACBC in a MM xenograft model and show the feasibility of PET imaging with [ ¹⁸ F]-FACBC in a MM patient. Results Preclinically [ ¹⁸ F]-FACBC showed superior performance, mainly due to the uptake via the ASC-system. In a subsequent proof-of-concept investigation [ ¹⁸ F]-FACBC PET was performed in a MM patient. It allowed identification of both lesions with and without CT correlate (SUVmean 8.0 or 7.9) based on higher uptake compared to normal bone marrow (SUVmean 5.7). Bone signal was elevated compared to non-MM patients, and, thus [ ¹⁸ F]-FACBC potentially allows the assessment of bone marrow infiltration. Conclusion The FDA/EMA approved PET agent [ ¹⁸ F]-FACBC is promising for imaging MM and should be further evaluated in prospective clinical studies.
[This corrects the article DOI: 10.1016/j.ailsci.2021.100020.].
The majority of risk loci identified by genome-wide association studies (GWAS) are in non-coding regions, hampering their functional interpretation. Instead, transcriptome-wide association studies (TWAS) identify gene-trait associations, which can be used to prioritize candidate genes in disease-relevant tissue(s). Here, we aimed to systematically identify susceptibility genes for coronary artery disease (CAD) by TWAS. We trained prediction models of nine CAD-relevant tissues using EpiXcan based on two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these prediction models, we imputed gene expression of respective tissues from individual-level genotype data on 37,997 CAD cases and 42,854 controls for the subsequent gene-trait association analysis. Transcriptome-wide significant association (i.e. P < 3.85e−6) was observed for 114 genes. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel. Stepwise analyses were performed to study their plausibility, biological function, and pathogenicity in CAD, including analyses for colocalization, damaging mutations, pathway enrichment, phenome-wide associations with human data and expression-traits correlations using mouse data. Finally, CRISPR/Cas9-based gene knockdown of two newly identified TWAS genes, RGS19 and KPTN , in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Our CAD TWAS work (i) prioritized candidate causal genes at known GWAS loci, (ii) identified 18 novel genes to be associated with CAD, and iii) suggested potential tissues and pathways of action for these TWAS CAD genes.
In response to acute urban mobility and livability challenges, city street experiments have emerged as a way to explore possible solutions for alternative futures. While the added value of these experiments to improve urban living conditions is widely acknowledged, their potential to stimulate larger system change remains unknown. This paper uses the defining characteristics of transition experiments and a multi-level perspective of transitions in order to assess the transitional capacity of city street experiments. We devise an assessment framework to systematically assess six case studies in Amsterdam and Munich, revealing emerging patterns of experimentation within urban mobility systems.
Members of the gut microbiota genus Bifidobacterium are widely distributed human and animal symbionts believed to exert beneficial effects on their hosts. However, in-depth genomic analyses of animal-associated species and strains are somewhat lacking, particularly in wild animal populations. Here, to examine patterns of host specificity and carbohydrate metabolism capacity, we sequenced whole genomes of Bifidobacterium isolated from wild-caught small mammals from two European countries (UK and Lithuania). Members of Bifidobacterium castoris , Bifidobacterium animalis and Bifodobacterium pseudolongum were detected in wild mice ( Apodemus sylvaticus , Apodemus agrarius and Apodemus flavicollis ), but not voles or shrews. B. castoris constituted the most commonly recovered Bifidobacterium (78% of all isolates), with the majority of strains only detected in a single population, although populations frequently harboured multiple co-circulating strains. Phylogenetic analysis revealed that the mouse-associated B. castoris clades were not specific to a particular location or host species, and their distribution across the host phylogeny was consistent with regular host shifts rather than host-microbe codiversification. Functional analysis, including in vitro growth assays, suggested that mouse-derived B. castoris strains encoded an extensive arsenal of carbohydrate-active enzymes, including putative novel glycosyl hydrolases such as chitosanases, along with genes encoding putative exopolysaccharides, some of which may have been acquired via horizontal gene transfer. Overall, these results provide a rare genome-level analysis of host specificity and genomic capacity among important gut symbionts of wild animals, and reveal that Bifidobacterium has a labile relationship with its host over evolutionary time scales.
Background Spirometry and conventional chest x-ray have limitations in investigating early emphysema, while computed tomography, the reference imaging method in this context, is not part of routine patient care due to its higher radiation dose. In this work, we investigated a novel low-dose imaging modality, dark-field chest x-ray, for the evaluation of emphysema in patients with alpha1-antitrypsin deficiency. Methods By exploiting wave properties of x-rays for contrast formation, dark-field chest x-ray visualises the structural integrity of the alveoli, represented by a high signal over the lungs in the dark-field image. We investigated four patients with alpha1-antitrypsin deficiency with a novel dark-field x-ray prototype and simultaneous conventional chest x-ray. The extent of pulmonary function impairment was assessed by pulmonary function measurement and regional emphysema distribution was compared with CT in one patient. Results We show that dark-field chest x-ray visualises the extent of pulmonary emphysema displaying severity and regional differences. Areas with low dark-field signal correlate with emphysematous changes detected by computed tomography using a threshold of -950 Hounsfield units. The airway parameters obtained by whole-body plethysmography and single breath diffusing capacity of the lungs for carbon monoxide demonstrated typical changes of advanced emphysema. Conclusions Dark-field chest x-ray directly visualised the severity and regional distribution of pulmonary emphysema compared to conventional chest x-ray in patients with alpha1-antitrypsin deficiency. Due to the ultra-low radiation dose in comparison to computed tomography, dark-field chest x-ray could be beneficial for long-term follow-up in these patients.
Background: Even an ultraprotective ventilation strategy in severe acute respiratory distress syndrome (ARDS) patients treated with extracorporeal membrane oxygenation (ECMO) might induce ventilator-induced lung injury and apneic ventilation with the sole application of positive end-expiratory pressure may, therefore, be an alternative ventilation strategy. We, therefore, compared the effects of ultraprotective ventilation with apneic ventilation on oxygenation, oxygen delivery, respiratory system mechanics, hemodynamics, strain, air distribution and recruitment of the lung parenchyma in ARDS patients with ECMO. Methods: In a prospective, monocentric physiological study, 24 patients with severe ARDS managed with ECMO were ventilated using ultraprotective ventilation (tidal volume 3 ml/kg of predicted body weight) with a fraction of inspired oxygen (FiO2) of 21%, 50% and 90%. Patients were then treated with apneic ventilation with analogous FiO2. The primary endpoint was the effect of the ventilation strategy on oxygenation and oxygen delivery. The secondary endpoints were mechanical power, stress, regional air distribution, lung recruitment and the resulting strain, evaluated by chest computed tomography, associated with the application of PEEP (apneic ventilation) and/or low VT (ultraprotective ventilation). Results: Protective ventilation, compared to apneic ventilation, improved oxygenation (arterial partial pressure of oxygen, p < 0.001 with FiO2 of 50% and 90%) and reduced cardiac output. Both ventilation strategies preserved oxygen delivery independent of the FiO2. Protective ventilation increased driving pressure, stress, strain, mechanical power, as well as induced additional recruitment in the non-dependent lung compared to apneic ventilation. Conclusions: In patients with severe ARDS managed with ECMO, ultraprotective ventilation compared to apneic ventilation improved oxygenation, but increased stress, strain, and mechanical power. Apneic ventilation might be considered as one of the options in the initial phase of ECMO treatment in severe ARDS patients to facilitate lung rest and prevent ventilator-induced lung injury. Trial registration: German Clinical Trials Register (DRKS00013967). Registered 02/09/2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013967 .
Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs’ cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.
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