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Host and environment early-life risk factors are associated with progression of wheezing symptoms over time; however, their individual contribution is relatively small. We hypothesised that the dynamic interactions of these factors with an infant's developing respiratory system are the dominant factor for subsequent wheeze and asthma.

Activin receptor-like kinases 1–7 (ALK1–7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234and MU1700, along with their negative controls. We show that both MU1700and M4K2234efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.

CRISPR–Cas9 genome engineering is a powerful technology for correcting genetic diseases. However, the targeting range of Cas9 proteins is limited by their requirement for a protospacer adjacent motif (PAM), and in vivo delivery is challenging due to their large size. Here, we use phage-assisted continuous directed evolution to broaden the PAM compatibility of Campylobacter jejuniCas9 (CjCas9), the smallest Cas9 ortholog characterized to date. The identified variant, termed evoCjCas9, primarily recognizes N4AH and N5HA PAM sequences, which occur tenfold more frequently in the genome than the canonical N3VRYAC PAM site. Moreover, evoCjCas9 exhibits higher nuclease activity than wild-type CjCas9 on canonical PAMs, with editing rates comparable to commonly used PAM-relaxed SpCas9 variants. Combined with deaminases or reverse transcriptases, evoCjCas9 enables robust base and prime editing, with the small size of evoCjCas9 base editors allowing for tissue-specific installation of A-to-G or C-to-T transition mutations from single adeno-associated virus vector systems.

Im Zuge der Digitalisierung werden neue digitale Ansätze für die Fabrikplanung und den Fabrikbetrieb entwickelt. Die Übergänge zwischen diesen beiden Lebenszyklusphasen und den jeweils verwendeten digitalen Modellen gehen mit Informationsbrüchen einher. In dieser Veröffentlichung wird eine mögliche Konvergenz des Building Information Models und des Digitalen Zwillings aufgezeigt. Anhand eines Anwendungsbeispiels wird demonstriert, wie eine Durchgängigkeit der Informationen erreicht werden kann.

The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma.

Combined hyperlipidaemia results in premature atherosclerosis and a high burden of cardiovascular morbidity and mortality. Early identification of highly affected subjects within this population is of utmost importance to enable informed treatment decisions. The measurement of intima media thickness (IMT) is a readily available, non-invasive method to investigate evidence of early atherosclerosis. To assess the usefulness of this method in pediatric subjects with hypercholesterolemia, we here examined a possible interaction of LDL-C and Lp(a) on IMT.

The work of automation in education is not automatic but needs to be ‘done’. Grounded in an ethnographic study which followed a Grade 9/10 class through their daily activities in a ‘regular’ high school for a year, this paper asks how automation is enacted by students and teachers, and what these practices imply for forms of knowledge and relationality. Inspired by feminist technoscience, and drawing on recent work on everyday automation, the paper suggests that the ‘auto-’ of automation in practice is very often more of a ‘sym-’, a ‘with’, in which students and machines co-produce something that looks like automation. Rather than ‘automation’, observing practices in classrooms shows practices of ‘symmation’. The paper elaborates on symmation scenes of realigning, revising and reworking relations. Automation is, in these scenes, deeply embedded in social relations, involving the processing of ability, difference and hierarchy. Rather than the industry hype of automation, these sets of socio-technical practices alert us to the messy, non-linear, contested, warm realities of education (and not just learning) in schools today. The paper identifies specific aspects of how these socio-technical realities impact knowledge and teacher-student relations.

In diesem Beitrag werden Praktiken im Zusammenhang mit dem Bereitstellen von unterrichtlichen Aufgaben über eine Schulplattform in einer Lerngruppe einer Gesamtschule während der Covid 19-Pandemie untersucht. Die Aufgaben über die Plattform zu prozessieren, wurde im Distanzlernen während der zeitweiligen Schulschließungen eingeführt und im Präsenzunterricht anschließend beibehalten. An ethnographischem Datenmaterial wird aus einer praxistheoretischen, posthumanistischen Perspektive analysiert, wie mit der Bezugnahme auf und durch das Agieren des Aufgabenmoduls verschiedene Interferenzen und insgesamt ein Interferenzmuster des ‚Sich Kümmerns‘ zu Tage tritt. Dieses Sich-Kümmern, das u.a. das Verfügbarmachen von Aufgaben auch dann aufrecht erhält, wenn sich einzelne unterrichtliche Praktiken in und durch die Pandemie verschieben, interferiert mit Annahmen über eine einfache, glatte Entwicklungs- und Effizienzsteigerung durch zunehmende automatisierte Technologien im Unterricht.

The number of people aged 60 and above will rise from 46 million in 2015 to 157 in 2050 million, exceeding 30% of the population in many western countries. Consequently, the demand for oncological therapy for elderly patients will increase within the next decades. Currently, sufficient data on neoadjuvant therapy (NTx) of pancreatic cancer in elderly patients are lacking.

ABSTRACTIntroductionConnexin and pannexin (hemi)channels play an important role in paracrine and autocrine signaling pathways. The opening of these cellular pores is linked to a wide range of diseases. Therefore, pharmacological closing of connexin and pannexin (hemi)channels seems a promising therapeutic strategy. However, the currently available inhibitors cope with recurring problems concerning selectivity, specificity, stability and/or solubility.Areas coveredA number of peptides that mimic specific regions in the native sequence of connexins and pannexins have the potential to overcome some of these hurdles. In this paper, an overview is provided on these peptide-based inhibitors of connexin and pannexin (hemi)channels for therapeutic purposes. The authors also provide the reader with their expert perspectives on the future of these peptide-based inhibitors.Expert opinionPeptide mimetics can become valuable tools in the treatment of connexin-related and pannexin-related diseases. This can be made possible provided that available peptides are optimized, and new peptide mimetics are designed based on knowledge of the mechanisms underlying the gating control of connexin and pannexin (hemi)channels.

Inflammasomes can prevent systemic dissemination of enteropathogenic bacteria. As adapted pathogens including SalmonellaTyphimurium (S. Tm) have evolved evasion strategies, it has remained unclear when and where inflammasomes restrict their dissemination. Bacterial population dynamics establish that the NAIP/NLRC4 inflammasome specifically restricts S. Tm migration from the gut to draining lymph nodes. This is solely attributable to NAIP/NLRC4 within intestinal epithelial cells (IECs), while S. Tm evades restriction by phagocyte NAIP/NLRC4. NLRP3 and Caspase-11 also fail to restrict S. Tm mucosa traversal, migration to lymph nodes, and systemic pathogen growth. The ability of IECs (not phagocytes) to mount a NAIP/NLRC4 defense in vivo is explained by particularly high NAIP/NLRC4 expression in IECs and the necessity for epithelium-invading S. Tm to express the NAIP1-6 ligands—flagella and type-III-secretion-system-1. Imaging reveals both ligands to be promptly downregulated following IEC-traversal. These results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.

Inflammasomes can prevent systemic dissemination of enteropathogenic bacteria. As adapted pathogens including SalmonellaTyphimurium (S. Tm) have evolved evasion strategies, it has remained unclear when and where inflammasomes restrict their dissemination. Bacterial population dynamics establish that the NAIP/NLRC4 inflammasome specifically restricts S. Tm migration from the gut to draining lymph nodes. This is solely attributable to NAIP/NLRC4 within intestinal epithelial cells (IECs), while S. Tm evades restriction by phagocyte NAIP/NLRC4. NLRP3 and Caspase-11 also fail to restrict S. Tm mucosa traversal, migration to lymph nodes, and systemic pathogen growth. The ability of IECs (not phagocytes) to mount a NAIP/NLRC4 defense in vivo is explained by particularly high NAIP/NLRC4 expression in IECs and the necessity for epithelium-invading S. Tm to express the NAIP1-6 ligands—flagella and type-III-secretion-system-1. Imaging reveals both ligands to be promptly downregulated following IEC-traversal. These results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.

Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9% ± 5.9% correction of the Eif2b5R191Hvariant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females; however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e., lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivobase-editing approaches for the treatment of VWM or other leukodystrophies.

In water based solutions, electrodeposition of Pd and Pd alloys is complicated due to hydrogen embrittlement. This can be avoided by using non-aqueous solutions like deep eutectic solvents (DES). In this study, the electrodeposition of Pd–Ag films were investigated on Cu from choline chloride/urea based deep eutectic solvents containing sulfosalicylic acid dihydrate (SSS) as an organic additive. The effects of pulse current, an organic additive and different Ag concentrations on the surface morphology and layer thickness were evaluated. Cyclic voltammetry experiments showed that the reduction of Pd(II) occurred prior to that of Ag(I). Scanning electron microscope (SEM) micrographs of the deposits revealed that the surface of the Pd–Ag films were typically granular to nodular and became more compact when the surface active compound was present in the DES solution. X-ray diffraction (XRD) experiments proved the existence of metallic Pd–Ag alloys.

ABSTRACTIn water based solutions, electrodeposition of Pd and Pd alloys is complicated due to hydrogen embrittlement. This can be avoided by using non-aqueous solutions like deep eutectic solvents (DES). In this study, the electrodeposition of Pd–Ag films were investigated on Cu from choline chloride/urea based deep eutectic solvents containing sulfosalicylic acid dihydrate (SSS) as an organic additive. The effects of pulse current, an organic additive and different Ag concentrations on the surface morphology and layer thickness were evaluated. Cyclic voltammetry experiments showed that the reduction of Pd(II) occurred prior to that of Ag(I). Scanning electron microscope (SEM) micrographs of the deposits revealed that the surface of the Pd–Ag films were typically granular to nodular and became more compact when the surface active compound was present in the DES solution. X-ray diffraction (XRD) experiments proved the existence of metallic Pd–Ag alloys.

Smart Home technologies have the potential to increase the quality of life, home security and facilitate elderly care. Therefore, they require access to a plethora of data about the users’ homes and private lives. Resulting security and privacy concerns form a relevant barrier to adopting this promising technology. Aiming to support end users’ informed decision-making through addressing the concerns we first conducted semi-structured interviews with 42 potential and little-experienced Smart Home users. Their diverse concerns were clustered into four themes that center around attacks on Smart Home data and devices, the perceived loss of control, the trade-off between functionality and security, and user-centric concerns as compared to concerns on a societal level. Second, we discuss measures to address the four themes from an interdisciplinary perspective. The paper concludes with recommendations for addressing user concerns and for supporting developers in designing user-centered Smart Home technologies.

Cryo-ET structures of HeLa nucleosomes were mapped back into their in situ context, revealing basic principles of higher-order heterochromatin organization.

The physicochemical characteristics, fatty acid, tocopherol, stigmasterol, β-sitosterol, and 1H NMR profiles of Citrullus lanatusand Acanthosicyos horridusmelon seed oils were determined and compared among different extraction methods (cold pressing, traditional, and Soxhlet). The oil content was 40.2 ± 3.45 and 37.8 ± 7.26% for C. lanatusand A. horridus, respectively. Significant differences (p< 0.05) were observed among the different extraction methods in the characteristics studied. Physicochemical characteristics of the melon seed oils were saponification value, 180.48–189.86 mg KOH/g oil; iodine value, 108.27–118.62 g I2/100 g oil; acid value, 0.643–1.63 mg KOH/g oil; peroxide value; 1.69–2.98 mequiv/kg oil; specific gravity, 0.901–0.922; and refractive indices, 1.4676–1.4726. The dominant tocopherol was γ-tocopherol with total tocopherol in the range 27.61–74.39 mg/100 g. The dominant fatty acid was linoleic acid in the range 52.57–56.96%. The favorable oil yield, physicochemical characteristics, tocopherol, and fatty acid composition have the potential to replace or improve major commercial vegetable oils and to be used for various applications in the food industry and nutritive medicines.

This paper presents requirements and front-end solutions for low-cost communication systems with data rates of 100 Gbit/s. Link budget analyses in different mass-market applications are conducted for that purpose. It proposes an implementation of the front-end as an active antenna array with support for beam steering and polarization multiplexing over the full W-band. The critical system components are investigated and presented. This applies to a transformer coupled power amplifier (PA) in 40 nm bulk CMOS. It shows saturated output power of more than 10 dBm and power-added-efficiency of more than 10 % over the full W-band. Furthermore, the performance of microstrip-to-waveguide transitions is shown exemplarily as an important part of the active antenna as it interfaces active circuitry and antenna in a polymer-and-metal process. The transition test design shows less than 0.9 dB insertion loss and more than 12 dB return loss for the differential transition over the full W-band.

This paper presents a path following control concept for elastic joint robots. A controller is designed using transverse feedback linearization and a parallel transport frame that is suitable for regular paths with parametrized fivefold continuously differentiable representation. Systematic application of the singular perturbation theory makes this concept also applicable to elastic joint robots with a larger number of degrees of freedom. A simulation example for a six-axis industrial robot shows the feasibility of the proposed approach and the advantages compared to classical trajectory tracking control.

For the automation of certain industrial tasks, like the handling of deformable materials, force/torque sensors are frequently employed in robotic manipulators. This work investigates different signal processing strategies for a force sensor mounted on the end-effector of a biaxial gantry robot. For this, a suitable mathematical model of the manipulator is derived and analyzed. The merits and limitations of the proposed signal processing strategies are compared and validated by a number of experimental results.

Time is a crucial factor in the transport business. Besides the duration of the transport itself, also the loading and unloading of the goods is expected to be done as fast as possible to save valuable time and money. Amongst others, this holds true for container ships where the containers are usually loaded and unloaded by means of ship-to-shore gantry cranes. This scenario exemplarily motivates the investigations in this paper. Different methods are proposed for generating a trajectory for the load based on a geometric path connecting the loading and unloading position. As the path is usually just known right before the task has to begin, special emphasis lies on a fast calculation of the trajectory. The overall goal is to traverse the geometric path as fast as possible under the consideration of constraints for the gantry crane system. The optimal solution is calculated and serves as a reference for comparison reasons as the required computing time is usually rather large. Therefore, tailored methods for a fast calculation of the trajectory are developed. All the different approaches are evaluated and compared by means of representative test paths.

ABSTRACTUsing Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3–11 times more hyper- than hypo-methylated sites. Reduced NRSF/RESTexpression due to upregulation of DYRK1A(on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L(on chromosome 21q22.4) could lead to de novomethylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3Aand DNMT3Bbecome downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHGsubfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHGexpression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHGand other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.

Analysen von Social Media-Daten haben gerade in den letzten Jahren stark an Aufmerksamkeit unter Entscheidern in Unternehmen gewonnen und werden immer häufiger als Instrument zur Steuerung wesentlicher Unternehmensfunktionen, insbesondere der kundenorientierten Marktbearbeitung, eingesetzt. Die Frage, wie sich konkrete Handlungsempfehlungen und Maßnahmen in Entscheidungsprozesse miteinbeziehen lassen, bleibt dabei jedoch häufig ungelöst. Hinzu kommt ein stetiges Abwägen, zwischen vollautomatisierten Reports und einer aufwändigen, manuellen und kostenintensiven Detailauswertung. Der Artikel beschreibt anhand von konkreten, beispielhaften Anwendungen aktuelle Auswertungsverfahren, die sowohl auf einer deskriptiven Ebene, aber auch mit Methoden aus dem Data Mining gesammelte Daten aus den Plattformen Facebook und Twitter analysieren und verschiedene exemplarische Fragestellungen beantworten. Dies kann im einfachsten Fall eine Übersicht zu aktuell häufig diskutierten Themen sein, aber auch deutlich detaillierte und komplexere Sachverhalte, wie die mitschwingende Emotion, die Vernetzung der mit dem Inhalt interagierenden Nutzer oder Zusammenhänge zwischen einzelnen Themen, umfassen. Um für ein Unternehmen und insbesondere für Entscheider einen Mehrwert zu schaffen, müssen die Analysen durch eine strategische Vorgehensweise geleitet sein sowie an Zielen ausgerichteter Fragestellungen und Ziel-Maßnahmen-Systeme Anwendung finden, um Erkenntnisse systematisch in konkrete Handlungsempfehlungen zu überführen. Abschließend diskutiert der Artikel mögliche Potentiale, die durch die Anwendung von komplexeren Analysemethoden entstehen, reflektiert aber auch konzeptionelle und technische sowie ethische Herausforderungen und Limitierungen. Analyses of social media data have recently gained a lot of attention from decision makers in companies, and are used more and more as a steering instrument of essential business operations, especially the customer oriented marketing actions. However, the question how practical recommendations for actions and measures can be integrated in decision making processes, often remains unresolved. Additionally, there is a constant need to weigh up automatized reports against a time-consuming, manual and cost-intensive detail analysis. This article describe from concrete and exemplary applications, current analysis methods, which are analyzing data from the platforms Facebook and Twitter with both descriptive but also advanced data mining methods to answer to different, exemplary questions. This can be for the simplest case an overview of current frequently discussed topics, but also include considerably more detailed and complex issues, like emotions, the interconnectedness between users, who are interacting with a certain content, or the interdependencies between individual topics. Analyses have to be led by a strategic approach, as well as to be applied to objectives which orient on business questions and to objective measure systems to systematically translate insights into concrete recommended actions. This ensures to add value for companies and especially decision makers. The article concludes with possible potentials, which arise from the use of complex analysis methods, but also reflects conceptual and technical as well as ethical challenges and limitations.

Astma wieku dziecięcego dzieli się na astmę alergiczną (AA) i astmę niealergiczną (NA), jednak leczenie w obu przypadkach jest identyczne i tylko częściowo skuteczne.

This paper investigates and compares some approaches to trajectory generation for an articulated robot with six degrees of freedom. The trajectory to be planned consists of geometrically predetermined segments and phases where the geometry is free. The overall goal is to minimize the time needed for traversing the whole trajectory from a specified start to a terminal configuration. Constraints for the joint angles, velocities, accelerations, and jerks as well as for the joint torques of the robot are taken into account. The optimal solution of this task is calculated as reference. However, this requires considerable computing time. In view of this fact, different parameterizations are investigated. The resulting trajectories require slightly more time for traversing than the optimal one, but they can be calculated more efficiently. Based on four different exemplary trajectories, the proposed approaches are tested and compared on an industrial robot.

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