Degradation of connective tissue matrices by macrophages. III. Morphological and biochemical studies on extracellular, pericellular, and intracellular events in matrix proteolysis by macrophages in culture.

We have shown that macrophages in culture degrade the glycoproteins and amorphous elastin of insoluble extracellular matrices. Ultrastructural observation of the macrophage-matrix interaction revealed that connective tissue macromolecules were solubilized from the matrix extracellularly. At least part of the matrix breakdown was localized to the immediate vicinity of the cells, as shown by morphological and biochemical studies, although the rate of degradation correlated closely with the secretion of proteinases by various inflammatory stimuli in vivo, by glucocorticoids, prostaglandin E2 or colchicine, or by phagocytosis of latex, zymosan, or cholesterol-albumin complexes in culture was reflected in altered rates of glycoprotein and elastin degradation by the macrophages. Alteration of endocytosis and lysosomal digestion by cytochalasin B, NH4Cl, and proteinase inhibitors did not decrease the overall rate of matrix solubilization, but reduced the processing of the matrix fragments to peptides. Therefore, extracellular, pericellular, and lysosomal events each contribute to degradation of extracellular matrix macromolecules by inflammatory macrophages

Challenges in scaling up AAV-based gene therapy manufacturing

Accelerating the scale up of adeno-associated virus (AAV) manufacture is highly desirable to meet the increased demand for gene therapies. However, the development of bioprocesses for AAV gene therapies remains time-consuming and challenging. The quality by design (QbD) approach ensures bioprocess designs that meet the desired product quality and safety profile. Rapid stress tests, developability screens, and scale-down technologies have the potential to streamline AAV product and manufacturing bioprocess development within the QbD framework. Here we review how their successful use for antibody manufacture development is translating to AAV, but also how this will depend critically on improved analytical methods and adaptation of the tools as more understanding is gained on the critical attributes of AAV required for successful therapy

Work addiction, obsessive-compulsive personality disorder, burn-out, and global burden of disease: implications from the ICD-11

Occupational stress and high workload are being increasingly recognized as significant contributors to the diseases and disorders constituting major components of the global burden of disease. A more detailed definition of burnout was recently included by the World Health Organization (WHO) in the eleventh revision of the International Classification of Diseases (ICD-11) which reflects a growing acknowledgment of the role of professional work in mental health. One of the symptoms of obsessive-compulsive personality disorder/anankastic personality disorder (OCPD/APD) is an undue preoccupation with productivity to the exclusion of pleasure and interpersonal relationships. This compulsive overworking is closely related to the concept of work addiction, and OCPD/APD was suggested to be its major risk factor. OCPD/APD is the most prevalent personality disorder and one that appears to produce the highest direct and indirect medical costs. At the same time, it is vastly understudied. In recent years, it has been repeatedly emphasized that it requires consistent conceptualization and clarification of its overlapping with similar conditions. Even though the limited existing studies suggest its strong relationship with burnout and depression among employed individuals, there has been no systematic effort to investigate its role in the consequences of occupational stress and high workload. This paper identifies several substantial gaps in the current understanding of the relationships between work addiction, OCPD/APD, burnout, and the global burden of disease within the context of the WHO's plan of developing evidence-based guidelines on mental wellbeing in the workplace

Steady dark solitary flexural gravity waves

The nonlinear Schrödinger (NLS) equation describes the modulational limit of many surface water wave problems. Dark solitary waves of the NLS equation asymptote to a constant in the far field and have a localized decrease to zero amplitude at the origin, corresponding to water wave solutions that asymptote to a uniform periodic Stokes wave in the far field and decreasing oscillations near the origin. It is natural to ask whether these dark solitary waves can be found in the irrotational Euler equations. In this paper, we find such solutions in the context of flexural-gravity waves, which are often used as a model for waves in ice-covered water. This is a situation in which the NLS equation predicts steadily travelling dark solitons. The solution branches of dark solitons are continued, and one branch leads to fully localized solutions at large amplitudes

Open3D: Crowd-Sourced Distributed Curation of City Models

Detailed, large-scale 3D models of cities are important assets for many applications. While creating such models is difficult and time consuming, keeping them updated is even more challenging. In comparison, in many domains, crowd-sourcing of data is now an established process for expanding the scope or detail of data sets. In this paper, we describe the initial prototype implementation of Open3D, a crowd-sourcing platform for distributed curation of large-scale city models. We present an open architecture with interfaces that clearly separate model storage and indexing from viewing or editing. To support collaborative editing of extremely large models, we propose to use a modeling and model description paradigm that can integrate polygon-based modeling with parametric operations. We demonstrate the main concepts and prototype through an online city model that can be synchronously edited by multiple users, with live changes being propagated among clients. The main implementation consists of a set of web services, which support key functions such as model storage, locks for editing and spatial queries; a light-weight viewer based on the Cesium library, which runs on desktops and mobile devices; and a prototype editor, which clients can install to edit the models

In silico and in vivo investigations using an endocavitary photoplethysmography sensor for tissue viability monitoring

Significance: Colorectal cancer is one of the major causes of cancer-related deaths worldwide. Surgical removal of the cancerous growth is the primary treatment for this disease. A colorectal cancer surgery, however, is often unsuccessful due to the anastomotic failure that may occur following the surgical incision. Prevention of an anastomotic failure requires continuous monitoring of intestinal tissue viability during and after colorectal surgery. To date, no clinical technology exists for the dynamic and continuous monitoring of the intestinal perfusion. Aim: A dual-wavelength indwelling bowel photoplethysmography (PPG) sensor for the continuous monitoring of intestinal viability was proposed and characterized through a set of in silico and in vivo investigations. Approach: The in silico investigation was based on a Monte Carlo model that was executed to quantify the variables such as penetration depth and detected intensity with respect to the sensor–tissue separations and tissue perfusion. Utilizing the simulated information, an indwelling reflectance PPG sensor was designed and tested on 20 healthy volunteers. Two sets of in vivo studies were performed using the driving current intensities 20 and 40 mA for a comparative analysis, using buccal tissue as a proxy tissue-site. Results: Both simulated and experimental results showed the efficacy of the sensor to acquire good signals through the “contact” to a “noncontact” separation of 5 mm. A very slow wavelength-dependent variation was shown in the detected intensity at the normal and hypoxic states of the tissue, whereas a decay in the intensity was found with the increasing submucosal-blood volume. The simulated detected-to-incident-photon-ratio and the experimental signal-to-noise ratio exhibited strong positive correlations, with the Pearson product-moment correlation coefficient R ranging between 0.65 and 0.87. Conclusions: The detailed feasibility analysis presented will lead to clinical trials utilizing the proposed sensor

A novel 3D absorption correction method for quantitative EDX-STEM tomography.

This paper presents a novel 3D method to correct for absorption in energy dispersive X-ray (EDX) microanalysis of heterogeneous samples of unknown structure and composition. By using STEM-based tomography coupled with EDX, an initial 3D reconstruction is used to extract the location of generated X-rays as well as the X-ray path through the sample to the surface. The absorption correction needed to retrieve the generated X-ray intensity is then calculated voxel-by-voxel estimating the different compositions encountered by the X-ray. The method is applied to a core/shell nanowire containing carbon and oxygen, two elements generating highly absorbed low energy X-rays. Absorption is shown to cause major reconstruction artefacts, in the form of an incomplete recovery of the oxide and an erroneous presence of carbon in the shell. By applying the correction method, these artefacts are greatly reduced. The accuracy of the method is assessed using reference X-ray lines with low absorption.The research leading to these results has received funding from the European Union Seventh Framework Programme under Grant Agreement 312483 - ESTEEM2 (Integrated Infrastructure Initiative–I3), as well as from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC grant agreement 291522 - 3DIMAGE. A.N.F. and A.B. acknowledge project MAT2013-42900-P from the Spanish Ministry of Economy and Competitiveness and REGPOT-CT-2011-285895-AlNANOFUNC.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ultramic.2015.09.01

Filter-less WDM for visible light communications using colored pulse amplitude modulation

This paper demonstrates, for the first time, a new wavelength-division multiplexing (WDM) scheme for visible light communications using multi-level coloured pulse amplitude modulation (M-CPAM). Unlike traditional WDM, no optical bandpass filters are required and only a single optical detector is used. We show that, by transmitting n independent sets of weighted on-off keying non-return-to-zero data on separate wavelengths over a line-of-sight transmission path, the resultant additive symbols can be successfully demodulated. Hence, the data rates can be aggregated for a single user or divided into individual colours for multiple user access schemes. The system is empirically tested for M = 4 and 8 using an off-the-shelf red, green and blue (RGB) chip light emitting diode (LED). We demonstrate that for M = 4, using the R and B chips a bit error rate (BER) of ≤10-6 can be achieved for each wavelength at bit rates up to 10 Mbps, limited by the LEDs under test. For M = 8 using R, G and B a BER of ≤10-6 can be achieved for each wavelength at bit rates up to 5 Mbps