Enzyme-Responsive Nanoparticles and Coatings Made from Alginate/Peptide Ciprofloxacin Conjugates as Drug Release System

Infection-controlled release of antibacterial agents is of great importance, particularly for the control of peri-implant infections in the postoperative phase. Polymers containing antibiotics bound via enzymatically cleavable linkers could provide access to drug release systems that could accomplish this. Dispersions of nanogels were prepared by ionotropic gelation of alginate with poly-L-lysine, which was conjugated with ciprofloxacin as model drug via a copper-free 1,3-dipolar cy-cloaddition (click reaction). The nanogels are stable in dispersion and form films which are stable in aqueous environments. However, both the nanogels and the layers are degraded in the presence of an enzyme and the ciprofloxacin is released. The efficacy of the released drug against Staphylococcus aureus is negatively affected by the residues of the linker. Both the acyl modification of the amine nitrogen in ciprofloxacin and the sterically very demanding linker group with three annel-lated rings could be responsible for this. However the basic feasibility of the principle for enzyme-triggered release of drugs was successfully demonstrated

Report on current state of the art & understanding of the circular economy : CICERONE D1.2

The key objective of this deliverable is to gain insights on and assess how CE is being implemented and R&I is being funded at regional level, e.g., via the RIS3 strategy and Structural Funds. As such it sets the scope for the project and provides the background against which programmes and measures can be understood, assessed, developed and recommended in succinct tasks and work packages. The objective of this report is to provide a concise overview of the current R&I priorities, as expressed in running and newly introduced funding and legislative measures with respect to Circular Economy in European countries and regions

Early Predictability of Grasping Movements by Neurofunctional Representations: A Feasibility Study

Human grasping is a relatively fast process and control signals for upper limb prosthetics cannot be generated and processed in a sufficiently timely manner. The aim of this study was to examine whether discriminating between different grasping movements at a cortical level can provide information prior to the actual grasping process, allowing for more intuitive prosthetic control. EEG datasets were captured from 13 healthy subjects who repeatedly performed 16 activities of daily living. Common classifiers were trained on features extracted from the waking-state frequency and total-frequency time domains. Different training scenarios were used to investigate whether classifiers can already be pre-trained by base networks for fine-tuning with data of a target person. A support vector machine algorithm with spatial covariance matrices as EEG signal descriptors based on Riemannian geometry showed the highest balanced accuracy (0.91 ± 0.05 SD) in discriminating five grasping categories according to the Cutkosky taxonomy in an interval from 1.0 s before to 0.5 s after the initial movement. Fine-tuning did not improve any classifier. No significant accuracy differences between the two frequency domains were apparent (p > 0.07). Neurofunctional representations enabled highly accurate discrimination of five different grasping movements. Our results indicate that, for upper limb prosthetics, it is possible to use them in a sufficiently timely manner and to predict the respective grasping task as a discrete category to kinematically prepare the prosthetic hand

On-tissue dataset-dependent MALDI-TIMS-MS2^{2} bioimaging

Trapped ion mobility spectrometry (TIMS) adds an additional separation dimension to mass spectrometry (MS) imaging, however, the lack of fragmentation spectra (MS$^{2}$) impedes confident compound annotation in spatial metabolomics. Here, we describe spatial ion mobility-scheduled exhaustive fragmentation (SIMSEF), a dataset-dependent acquisition strategy that augments TIMS-MS imaging datasets with MS$^{2}$ spectra. The fragmentation experiments are systematically distributed across the sample and scheduled for multiple collision energies per precursor ion. Extendable data processing and evaluation workflows are implemented into the open source software MZmine. The workflow and annotation capabilities are demonstrated on rat brain tissue thin sections, measured by matrix-assisted laser desorption/ionisation (MALDI)-TIMS-MS, where SIMSEF enables on-tissue compound annotation through spectral library matching and rule-based lipid annotation within MZmine and maps the (un)known chemical space by molecular networking. The SIMSEF algorithm and data analysis pipelines are open source and modular to provide a community resource

Requirement of β1 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia

An acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase (eNOS). A long-term increase in blood flow chronically enlarges the arterial lumen, a process called arteriogenesis. In several common human diseases, these processes are disrupted for as yet unknown reasons. Here, we asked whether β1 integrin, a mechanosensory protein in endothelial cells, is required for FMD and arteriogenesis in the ischemic hindlimb. Permanent ligation of the femoral artery in C57BL/6J mice enlarged pre-existing collateral arteries and increased numbers of arterioles in the thigh. In the lower leg, the numbers of capillaries increased. Notably, injection of β1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for β1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that β1 integrin-blocking antibody or endothelial cell-specific depletion of β1 integrin attenuated FMD of the femoral artery, and blocking of β1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial β1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS

Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth

Vascular endothelial growth factor receptor-3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell-specific depletion of integrin-linked kinase (ILK) in mouse embryos hyper-activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)-specific deletion of Ilk in adult mice initiates lymphatic vascular expansion in different organs, including cornea, skin and myocardium. Knockdown of ILK in human LECs triggers VEGFR3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR3 and β1 integrin in vitro and in vivo, and endothelial cell-specific deletion of an Itgb1 allele rescues the excessive lymphatic vascular growth observed upon ILK depletion. Finally, mechanical stimulation disrupts the assembly of ILK and β1 integrin, releasing the integrin to enable its interaction with VEGFR3. Our data suggest that ILK facilitates mechanically regulated VEGFR3 signalling via controlling its interaction with β1 integrin and thus ensures proper development of lymphatic vessels

Author Correction: Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2.

Abstract: Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH

Precise mass determination for the keystone sub-Neptune planet transiting the mid-type M dwarf G 9-40

Context. Despite being a prominent subset of the exoplanet population discovered in the past three decades, the nature and provenance of sub-Neptune-sized planets is still one of the open questions in exoplanet science. Aims. For planets orbiting bright stars, precisely measuring the orbital and planet parameters of the system is the best approach to distinguish between competing theories regarding their formation and evolution. Methods. We obtained 69 new radial velocity observations of the mid-M dwarf G 9-40 with the CARMENES instrument to measure for the first time the mass of its transiting sub-Neptune planet, G 9-40 b, discovered in data from the K2 mission. Results. Combined with new observations from the TESS mission during Sectors 44, 45, and 46, we are able to measure the radius of the planet to an uncertainty of 3.4% (R-b = 1.900 +/- 0.065 R-circle plus) and determine its mass with a precision of 16% (M-b = 4.00 +/- 0.63 M-circle plus). The resulting bulk density of the planet is inconsistent with a terrestrial composition and suggests the presence of either a water-rich core or a significant hydrogen-rich envelope. Conclusions. G 9-40 b is referred to as a keystone planet due to its location in period-radius space within the radius valley. Several theories offer explanations for the origin and properties of this population and this planet is a valuable target for testing the dependence of those models on stellar host mass. By virtue of its brightness and small size of the host, it joins L 98-59 d as one of the two best warm (T-eq similar to 400 K) sub-Neptunes for atmospheric characterization with JWST, which will probe cloud formation in sub-Neptune-sized planets and break the degeneracies of internal composition models