Black Mesoporous Silicon as a Contrast Agent for LED-Based 3D Photoacoustic Tomography

Mesoporous silicon (PSi) nanoparticles have been widely studied in different biomedical imaging modalities due to their several beneficial material properties. However, they have not been found to be suitable for photoacoustic imaging due to their poor photothermal conversion performance. In the present study, biodegradable black mesoporous silicon (BPSi) nanoparticles with strong light absorbance were developed as superior image contrast agents for photoacoustic tomography (PAT), which was realized with a light-emitting diode (LED) instead of the commonly used laser. LED-based PAT offers the advantages of low cost, compactness, good mobility, and easy operation as compared to the traditional laser-based PAT modality. Nevertheless, the poor imaging sensitivity of the LED-PAT systems has been the main barrier to prevent their wide biomedical application because the LED light has low optical energy. The present study demonstrated that the imaging sensitivity of the LED-PAT system was significantly enhanced with the PEGylated BPSi (PEG–BPSi) nanoparticles. The PEG–BPSi nanoparticles were clearly detectable with a low concentration of 0.05 mg/mL in vitro and with an LED radiation energy of 5.2 μJ. The required concentration of the PEG–BPSi nanoparticles was 10 times lesser than that of the reference gold nanoparticles to reach the corresponding level of the imaging contrast. The ex vivo studies demonstrated that the submillimeter BPSi nanoparticle-based absorbers were distinguishable in chicken breast tissues. The strong contrast provided by the BPSi particles indicated that these particles can be utilized as novel contrast agents in PAT, especially in LED-based systems with low light intensity

Learning how to understand complexity and deal with sustainability challenges : A framework for a comprehensive approach and its application in university education

Sustainability challenges such as climate change, biodiversity loss, poverty and rapid urbanization are complex and strongly interrelated. In order to successfully deal with these challenges, we need comprehensive approaches that integrate knowledge from multiple disciplines and perspectives and emphasize interconnections. In short, they aid in observing matters in a wider perspective without losing an understanding of the details. In order to teach and learn a comprehensive approach, we need to better understand what comprehensive thinking actually is. In this paper, we present a conceptual framework for a comprehensive approach, termed the GHH framework. The framework comprises three dimensions: generalism, holism, and holarchism. It contributes to the academic community's understanding of comprehensive thinking and it can be used for integrating comprehensive thinking into education. Also, practical examples of the application of the framework in university teaching are presented. We argue that an ideal approach to sustainability challenges and complexity in general is a balanced, dialectical combination of comprehensive and differentiative approaches. The current dominance of specialization, or the differentiative approach, in university education calls for a stronger emphasis on comprehensive thinking skills. Comprehensiveness should not be considered as a flawed approach, but should instead be considered as important an aspect in education as specialized and differentiative skills. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

The C-Type Lectin of the Aggrecan G3 Domain Activates Complement

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint

Bone marrow mesenchymal stem cells do not enhance intra-synovial tendon healing despite engraftment and homing to niches within the synovium

Intra-synovial tendon injuries display poor healing, which often results in reduced functionality and pain. A lack of effective therapeutic options has led to experimental approaches to augment natural tendon repair with autologous mesenchymal stem cells (MSCs) although the effects of the intra-synovial environment on the distribution, engraftment and functionality of implanted MSCs is not known. This study utilised a novel sheep model which, although in an anatomically different location, more accurately mimics the mechanical and synovial environment of the human rotator cuff, to determine the effects of intra-synovial implantation of MSCs

RAB24 facilitates clearance of autophagic compartments during basal conditions

Officially accepted for publication August 21, 2015.RAB24 belongs to a family of membrane traffic controlling RAB proteins and has been implicated to function in autophagy. Here we confirm the intracellular localization of RAB24 to autophagic vacuoles with immuno electron microscopy and cell fractionation, and show that prenylation and guanine nucleotide binding are necessary for the targeting of RAB24 to autophagic compartments. Further, we show that RAB24 plays a role in the maturation and/or clearance of autophagic compartments under nutrient-rich conditions, but not during short amino acid starvation. Quantitative electron microscopy showed an increase in the numbers of late autophagic compartments in cells silenced for RAB24, and mRFP-GFP-LC3 probe and autophagy flux experiments indicated that this was due to a hindrance in their clearance. Formation of autophagosomes was shown to be unaffected by RAB24 silencing with siRNA. A defect in aggregate clearance in the absence of RAB24 was also shown in cells forming polyglutamine aggregates. This study places RAB24 function in the termination of the autophagic process under nutrient-rich conditions.Peer reviewe

Learning how to understand complexity and deal with sustainability challenges – A framework for a comprehensive approach and its application in university education

Sustainability challenges such as climate change, biodiversity loss, poverty and rapid urbanization are complex and strongly interrelated. In order to successfully deal with these challenges, we need comprehensive approaches that integrate knowledge from multiple disciplines and perspectives and emphasize interconnections. In short, they aid in observing matters in a wider perspective without losing an understanding of the details. In order to teach and learn a comprehensive approach, we need to better understand what comprehensive thinking actually is. In this paper, we present a conceptual framework for a comprehensive approach, termed the GHH framework. The framework comprises three dimensions: generalism, holism, and holarchism. It contributes to the academic community’s understanding of comprehensive thinking and it can be used for integrating comprehensive thinking into education. Also, practical examples of the application of the framework in university teaching are presented. We argue that an ideal approach to sustainability challenges and complexity in general is a balanced, dialectical combination of comprehensive and differentiative approaches. The current dominance of specialization, or the differentiative approach, in university education calls for a stronger emphasis on comprehensive thinking skills. Comprehensiveness should not be considered as a flawed approach, but should instead be considered as important an aspect in education as specialized and differentiative skills.</p

Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome

During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we per-formed a transcriptomic analysis of the changes induced by phagocytosis in microglia in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (http://www. mineco.gob.es) with FEDER funds to A.S. (BFU2012-32089 and RYC-2013-12817) to A.S. and J.V. (BFU2015-66689); a Leonardo Award from the BBVA Foundation to A.S. (IN16,_BBM_BAS_0260); a Basque Government Department of Education project to A.S. (PI_2016_1_0011; http://www.euskadi.eus/basque-government/department-educa- tion/); Ikerbasque start-up funds to J.V.; a Hungarian Research and Development Fund Grant (K116654) to B.S.; a Hungarian Brain Research Program Grant (2017-1.2.1-NKP-2017-00002) to B.S.; a National Institutes of Health Grant (AG060748) to G.L

The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5 epimerization of glucuronic acid in higher organisms

Dermatan sulfate epimerase 1 DS epi1, EC 5.1.3.19 catalyzes the conversion of D glucuronic acid to L iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS epi1, solved at 2.4 resolution, as well as a model of the full length luminal protein obtained by a combination of macromolecular crystallography and targeted cross linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS epi1, involving a His double Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal coordinating center and pattern of N glycosylation of the protein. Additionally, the structure of DS epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitor

A low COMT activity haplotype is associated with recurrent preeclampsia in a Norwegian population cohort (HUNT2)

The etiology of preeclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Although many candidate genes for preeclampsia have been suggested and studied, the specific causative genes still remain to be identified. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine and estrogen degradation and has recently been ascribed a role in development of preeclampsia. In the present study, we have examined the COMT gene by genotyping the functional Val108/158Met polymorphism (rs4680) and an additional single-nucleotide polymorphism, rs6269, predicting COMT activity haplotypes in a large Norwegian case/control cohort (ncases= 1135, ncontrols= 2262). A low COMT activity haplotype is associated with recurrent preeclampsia in our cohort. This may support the role of redox-regulated signaling and oxidative stress in preeclampsia pathogenesis as suggested by recent studies in a genetic mouse model. The COMT gene might be a genetic risk factor shared between preeclampsia and cardiovascular diseases