VEGF188 promotes corneal reinnervation after injury

Vascular endothelial growth factor A (VEGF) induces angiogenesis and vascular hyperpermeability in ocular tissues and is therefore a key therapeutic target for eye conditions in which these processes are dysregulated. In contrast, the therapeutic potential of VEGF's neurotrophic roles in the eye has remained unexploited. In particular, it is not known whether modulating levels of any of the 3 major alternatively spliced VEGF isoforms might provide a therapeutic approach to promote neural health in the eye without inducing vascular pathology. Here, we have used a variety of mouse models to demonstrate differences in overall VEGF levels and VEGF isoform ratios across tissues in the healthy eye. We further show that VEGF isoform expression was differentially regulated in retinal versus corneal disease models. Among the 3 major isoforms - termed VEGF120, VEGF164, and VEGF188 - VEGF188 was upregulated to the greatest extent in injured cornea, where it was both necessary and sufficient for corneal nerve regeneration. Moreover, topical VEGF188 application further promoted corneal nerve regeneration without inducing pathological neovascularization. VEGF isoform modulation should therefore be explored further for its potential in promoting neural health in the eye

Data segmentation based on the local intrinsic dimension

One of the founding paradigms of machine learning is that a small number of variables is often sufficient to describe high-dimensional data. The minimum number of variables required is called the intrinsic dimension (ID) of the data. Contrary to common intuition, there are cases where the ID varies within the same data set. This fact has been highlighted in technical discussions, but seldom exploited to analyze large data sets and obtain insight into their structure. Here we develop a robust approach to discriminate regions with different local IDs and segment the points accordingly. Our approach is computationally efficient and can be proficiently used even on large data sets. We find that many real-world data sets contain regions with widely heterogeneous dimensions. These regions host points differing in core properties: folded versus unfolded configurations in a protein molecular dynamics trajectory, active versus non-active regions in brain imaging data, and firms with different financial risk in company balance sheets. A simple topological feature, the local ID, is thus sufficient to achieve an unsupervised segmentation of high-dimensional data, complementary to the one given by clustering algorithms

Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis

Background There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion. Methods One hundred patients with pulmonary tuberculosis (65% HIV-co-infected) were intensively sampled to determine rifampicin, isoniazid and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and pharmacokinetic parameters determined using non-linear-mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 and 5-6 months. Minimum inhibitory concentrations (MIC) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 24-hour-area-under-the-curve (AUC0-24), peak concentration (Cmax), AUC0-24/MIC, Cmax/MIC and % time that concentrations persisted above MIC (%TMIC). Results 26% of patients had Cmax (mg/L) of rifampicin4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion. Conclusions PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion

Manufacturing of PAV-ONE, a Permeator against Vacuum Mock-Up with Niobium Membrane

The Permeator Against Vacuum (PAV) is one of the proposed technologies for the Tritium Extraction System of the WCLL BB (Water-Cooled Lithium-Lead Breeding Blanket) of the EU DEMO reactor. In this paper, the manufacturing of the first PAV mock-up with a niobium membrane with a cylindrical configuration is presented. This work aimed to demonstrate the possibility of manufacturing a relevant-size PAV to be later tested in the TRIEX-II facility. The adopted prototypical solutions are described in detail, starting with the methodology developed to join the Nb tubes with a 10CrMo9-10 (A182 F22) plate. Dedicated manufacturing and welding procedures, based on vacuum brazing with a nickel-based brazing alloy, were developed to solve the problem. This new kind of brazing was first analyzed to check the morphology of the joint and then tested to check its capability to withstand the TRIEX-II operative conditions. In parallel, the compatibility with a lithium-lead environment was analyzed by exposing samples of niobium and 10CrMo9-10 (A335 P22) to a flow of the eutectic alloy at 500 °C up to 4000 h. Finally, the PAV mock-up was installed in the TRIEX-II facility

Effects of build orientation and element partitioning on microstructure and mechanical properties of biomedical Ti-6Al-4V alloy produced by laser sintering

Direct Metal Laser Sintering (DMLS) technology was used to produce tensile and flexural samples based on the Ti-6Al-4V biomedical composition. Tensile samples were produced in three different orientations in order to investigate the effect of building direction on the mechanical behavior. On the other hand, flexural samples were submitted to thermal treatments to simulate the firing cycle commonly used to veneer metallic devices with ceramics in dental applications. Roughness and hardness measurements as well as tensile and flexural mechanical tests were performed to study the mechanical response of the alloy while X-ray diffraction (XRD), electron microscopy (SEM, TEM, STEM) techniques and microanalysis (EDX) were used to investigate sample microstructure. Results evidenced a difference in the mechanical response of tensile samples built in orthogonal directions. In terms of microstructure, samples not submitted to the firing cycle show a single phase acicular α’ (hcp) structure typical of metal parts subject to high cooling rates. After the firing cycle, samples show a reduction of hardness and strength due to the formation of laths of the β (bcc) phase at the boundaries of the primary formed α’ plates as well as to lattice parameters variation of the hcp phase. Element partitioning during the firing cycle gives rise to high concentration of V atoms (up to 20 wt%) at the plate boundaries where the β phase preferentially forms

Brownian motion of graphene.

Brownian motion is a manifestation of the fluctuation-dissipation theorem of statistical mechanics. It regulates systems in physics, biology, chemistry, and finance. We use graphene as prototype material to unravel the consequences of the fluctuation-dissipation theorem in two dimensions, by studying the Brownian motion of optically trapped graphene flakes. These orient orthogonal to the light polarization, due to the optical constants anisotropy. We explain the flake dynamics in the optical trap and measure force and torque constants from the correlation functions of the tracking signals, as well as comparing experiments with a full electromagnetic theory of optical trapping. The understanding of optical trapping of two-dimensional nanostructures gained through our Brownian motion analysis paves the way to light-controlled manipulation and all-optical sorting of biological membranes and anisotropic macromolecules

Effect of powder recycling in laser-based powder bed fusion of Ti-6Al-4V

Additive manufacturing (AM) has shown promise to process parts for end-use applications, however stringent requirements must be fulfilled in terms of reliability and predictability. The expensiveness of raw materials for AM, especially for metal-based Powder Bed Fusion (PBF), brings about the need for a careful recycling of powder, but the effect of powder reuse on both processing conditions and final part performance is still the focus of intensive research in the open literature. Although ASTM F2924-14 specifies the virgin-to-used powder ratio to be introduced to manufacture titanium-6aluminum-4vanadium (Ti-6Al-4V) components by PBF, a deeper understanding of the effect of powder recycling on the mechanical properties of finished parts is expected to foster a more efficient and safe reuse. The present contribution is therefore addressed to investigate the consequence of Ti- 6Al-4V powder recycling on the flowability, particle size distribution and morphology of the feedstock material as well as on the density and tensile performance of built parts. In order to quantify the recyclability of powders, a new "average usage time" (AUT) parameter is defined to account for both the real usage time of the powder and the virgin-to-used powder mixing ratio. The new parameter, whose applicability can be readily extended to any kind of feedstock powder, offers a significant contribution to achieve a more consistent and economical recycling of raw materials for PBF processing