Cooperative effects enhance the transport properties of molecular spider teams

Molecular spiders are synthetic molecular motors based on DNA nanotechnology. While natural molecular motors have evolved towards very high efficiency, it remains a major challenge to develop efficient designs for man-made molecular motors. Inspired by biological motor proteins such as kinesin and myosin, molecular spiders comprise a body and several legs. The legs walk on a lattice that is coated with substrate which can be cleaved catalytically. We propose a molecular spider design in which n spiders form a team. Our theoretical considerations show that coupling several spiders together alters the dynamics of the resulting team significantly. Although spiders operate at a scale where diffusion is dominant, spider teams can be tuned to behave nearly ballistic, which results in fast and predictable motion. Based on the separation of time scales of substrate and product dwell times, we develop a theory which utilizes equivalence classes to coarse-grain the microstate space. In addition, we calculate diffusion coefficients of the spider teams, employing a mapping of an n-spider team to an n-dimensional random walker on a confined lattice. We validate these results with Monte Carlo simulations and predict optimal parameters of the molecular spider team architecture which makes their motion most directed and maximally predictable

VOM LASERSCAN ZUM PLANUNGSTAUGLICHEN PRODUKTMODELL

Im Bereich der Altbausanierung und der Bestandserfassung im Bauwesen ist es häufig notwendig, bestehende Pläne hinsichtlich des Bauwerkszustandes zu aktualisieren oder, wenn diese Pläne nicht (mehr) zugänglich sind, gänzlich neue Planunterlagen des Ist-Zustandes zu erstellen. Ein komfortabler Weg, diese Bauwerksdaten zu erheben, eröffnet die Technologie der Laservermessung. Der vorliegende Artikel stellt in diesem Zusammenhang Ansätze zur Teilautomatisierung der Generierung eines dreidimensionalen Computermodells eines Bauwerkes vor. Als Ergebnis wird ein Volumenmodell bereitgestellt, in dem zunächst die geometrischen und topologischen Informationen über Flächen, Kanten und Punkte im Sinne eines B-rep Modells beschrieben sind. Die Objekte dieses Volumenmodells werden mit Verfahren aus dem Bereich der künstlichen Intelligenz analysiert und in Bauteilklassen systematisch kategorisiert. Die Kenntnis der Bauteilsemantik erlaubt es somit, aus den Daten ein Bauwerks-Produktmodell abzuleiten und dieses einzelnen Fachplanern – etwa zur Erstellung eines Energiepasses – zugänglich zu machen. Der Aufsatz zeigt den erfolgreichen Einsatz virtueller neuronaler Netze im Bereich der Bestandserfassung anhand eines komplexen Beispiels

Toward optical coherence tomography on a chip: in vivo three-dimensional human retinal imaging using photonic integrated circuit-based arrayed waveguide gratings

In this work, we present a significant step toward in vivo ophthalmic optical coherence tomography and angiography on a photonic integrated chip. The diffraction gratings used in spectral-domain optical coherence tomography can be replaced by photonic integrated circuits comprising an arrayed waveguide grating. Two arrayed waveguide grating designs with 256 channels were tested, which enabled the first chip-based optical coherence tomography and angiography in vivo three-dimensional human retinal measurements. Design 1 supports a bandwidth of 22 nm, with which a sensitivity of up to 91 dB (830 µW) and an axial resolution of 10.7 µm was measured. Design 2 supports a bandwidth of 48 nm, with which a sensitivity of 90 dB (480 µW) and an axial resolution of 6.5 µm was measured. The silicon nitride-based integrated optical waveguides were fabricated with a fully CMOS-compatible process, which allows their monolithic co-integration on top of an optoelectronic silicon chip. As a benchmark for chip-based optical coherence tomography, tomograms generated by a commercially available clinical spectral-domain optical coherence tomography system were compared to those acquired with on-chip gratings. The similarities in the tomograms demonstrate the significant clinical potential for further integration of optical coherence tomography on a chip system

A serological biomarker of type I collagen degradation is related to a more severe, high neutrophilic, obese asthma subtype

BACKGROUND: Asthma is a heterogeneous disease; therefore, biomarkers that can assist in the identification of subtypes and direct therapy are highly desirable. Asthma is a chronic inflammatory disease that leads to changes in the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) degradation causing fragments of type I collagen that is released into circulation. OBJECTIVE: Here, we asked if MMP-generated type I collagen (C1M) was associated with subtypes of asthma. METHODS: C1M was serologically assessed at baseline in the adult participants of the All Age Asthma study (ALLIANCE) (n = 233), and in The Prospective Epidemiological Risk Factor study (PERF) (n = 283). In addition, C1M was assessed in mice sensitized to ovalbumin (OVA) and challenged with OVA aerosol. C1M was evaluated in mice with and without acute neutrophilic inflammation provoked by poly(cytidylic-inosinic) acid and mice treated with CP17, a peptide inhibiting neutrophil accumulation. RESULTS: Serum C1M was significantly increased in asthmatics compared to healthy controls (p = 0.0005). We found the increased C1M levels in asthmatics were related to blood neutrophil and body mass index (BMI) in the ALLIANCE cohort, which was validated in the PERF cohort. When patients were stratified into obese (BMI > 30) asthmatics with high neutrophil levels and uncontrolled asthma, this group had a significant increase in C1M compared to normal-weight (BMI < 25) asthmatics with low neutrophil levels and controlled asthma (p = 0.0277). C1M was significantly elevated in OVA mice with acute neutrophilic inflammation compared to controls (P = 0.0002) and decreased in mice treated with an inhibitor of neutrophil infiltration (p = 0.047). CONCLUSION & CLINICAL RELEVANCE: C1M holds the potential to identify a subtype of asthma that relates to severity, obesity, and high neutrophils. These data suggest that C1M is linked to a subtype of overall inflammation, not only derived from the lung. The link between C1M and neutrophils were further validated in in vivo model. TRIAL REGISTRATION: (ALLIANCE, NCT02419274). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40733-022-00084-6

COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy.

BACKGROUND Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3). OBJECTIVE To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response. METHODS The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (pediatric cases/controls: 134/35; adult cases/controls: 149/31). Exacerbation of allergic airway disease in mice was induced by sensitising to OVA, challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor, Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (CF, n=14) and CF with allergic broncho-pulmonary aspergillosis (ABPA, n=9) as well as severe allergic, uncontrolled asthmatics (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed by the Asthma Control Test. RESULTS Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in CF plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic odds ratio 31.5). CONCLUSION C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response

The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1

The post-translational modification poly(ADPribosyl)ation (PARylation) plays key roles in genome maintenance and transcription. Both non-covalent poly(ADP-ribose) binding and covalent PARylation control protein functions, however, it is unknown how the two modes of modification crosstalk mechanistically. Employing the tumor suppressor p53 as a model substrate, this study provides detailed insights into the interplay between noncovalent and covalent PARylation and unravels its functional significance in the regulation of p53. We reveal that the multifunctional Cterminal domain (CTD) of p53 acts as the central hub in the PARylation-dependent regulation of p53. Specifically, p53 bound to auto-PARylated PARP1 via highly specific non–covalent PAR-CTD interaction, which conveyed target specificity for its covalent PARylation by PARP1. Strikingly, fusing the p53-CTD to a protein that is normally not PARylated, renders this a target for covalent PARylation as well. Functional studies revealed that the p53–PAR interaction had substantial implications on molecular and cellular levels. Thus, PAR significantly influenced the complex p53–DNA binding properties and controlled p53 functions, with major implications on the p53-dependent interactome, transcription, and replication-associated recombination. Remarkably, this mechanism potentially also applies to other PARylation targets, since a bioinformatics analysis revealed that CTD-like regions are highly enriched in the PARylated proteome