The fibrillins, large extracellular matrix molecules, are polymerized to form “microfibrils.” The fibrillin microfibril scaffold is populated by microfibril-associated proteins and by growth factors, ...which are likely to be latent. The scaffold, associated proteins, and bound growth factors, together with cellular receptors that can sense the microfibril matrix, constitute the fibrillin microenvironment. Activation of TGFβ signaling is associated with the Marfan syndrome, which is caused by mutations in fibrillin-1. Today we know that mutations in fibrillin-1 cause the Marfan syndrome as well as Weill-Marchesani syndrome (and other acromelic dysplasias) and result in opposite clinical phenotypes: tall or short stature; arachnodactyly or brachydactyly; joint hypermobility or stiff joints; hypomuscularity or hypermuscularity. We also know that these different syndromes are associated with different structural abnormalities in the fibrillin microfibril scaffold and perhaps with specific cellular receptors (mechanosensors). How does the microenvironment, framed by the microfibril scaffold and populated by latent growth factors, work? We must await future investigations for the molecular and cellular mechanisms that will answer this question. However, today we can appreciate the importance of the fibrillin microfibril niche as a contextual environment for growth factor signaling and potentially for mechanosensation.
•The fibrillin microenvironment consists of a fibrillin microfibril scaffold, associated microfibril proteins, bound growth factors, and cells that interact with this microenvironment.•Studies in human and mouse indicate that fibrillins control TGFβ and BMP signaling.•Genetic evidence from the fibrillinopathies demonstrate that fibrillins control musculoskeletal growth.•Genetic disorders are associated with distinct structural abnormalities in fibrillin microfibrils and with distinct cellular receptors that can sense the fibrillin microenvironment.•The fibrillin microfibril niche provides an important contextual environment for growth factor signaling and potentially for mechanosensation.
Summary
Kawasaki disease (KD) is an acute systemic vasculitis of childhood that does not have a known cause or aetiology. The epidemiological features (existence of epidemics, community outbreaks and ...seasonality), unique age distribution and clinical symptoms and signs of KD suggest that the disease is caused by one or more infectious environmental triggers. However, KD is not transmitted person‐to‐person and does not occur in clusters within households, schools or nurseries. KD is a self‐limited illness that is not associated with the production of autoantibodies or the deposition of immune complexes, and it rarely recurs. Regarding the underlying pathophysiology of KD, innate immune activity (the inflammasome) is believed to play a role in the development of KD vasculitis, based on the results of studies with animal models and the clinical and laboratory findings of KD patients. Animal studies have demonstrated that innate immune pathogen‐associated molecular patterns (PAMPs) can cause vasculitis independently of acquired immunity and have provided valuable insights regarding the underlying mechanisms of this phenomenon. To validate this concept, we recently searched for KD‐specific PAMPs and identified such molecules with high specificity and sensitivity. These molecules have structures similar to those of microbe‐associated molecular patterns (MAMPs), as shown by liquid chromatography‐tandem mass spectrometry. We propose herein that KD is an innate immune disorder resulting from the exposure of a genetically predisposed individual to microbe‐derived innate immune stimulants and that it is not a typical infectious disease.
Based on the results of epidemiological, clinical, laboratory and animal studies, we have concluded that KD is not an infectious disease but an innate immune disorder. We propose that KD results from the exposure of a genetically predisposed individual to PAMPs from microbes growing under biofilm‐like conditions, as well as DAMPs.
Fibrillin-1 and fibrillin-2 are large cysteine-rich glycoproteins that serve two key physiological functions: as supporting structures that impart tissue integrity and as regulators of signaling ...events that instruct cell performance. The structural role of fibrillins is exerted through the temporal and hierarchical assembly of microfibrils and elastic fibers, whereas the instructive role reflects the ability of fibrillins to sequester transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) complexes in the extracellular matrix. Characterization of fibrillin mutations in human patients and in genetically engineered mice has demonstrated that perturbation of either function manifests in disease. More generally, these studies have indicated that fibrillins are integral components of a broader biological network of extracellular, cell surface, and signaling molecules that orchestrate morphogenetic and homeostatic programs in multiple organ systems. They have also suggested that the relative composition of fibrillin-rich microfibrils imparts contextual specificity to TGFβ and BMP signaling by concentrating the ligands locally so as to regulate cell differentiation within a spatial context during organ formation (positive regulation) and by restricting their bioavailability so as to modulate cell performance in a timely fashion during tissue remodeling/repair (negative regulation). Correlative evidence suggests functional coupling of the cell-directed assembly of microfibrils and targeting of TGFβ and BMP complexes to fibrillins. Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals, with TGFβ and BMPs as the nodal points that convert extracellular inputs into discrete and context-dependent cellular responses.
Graphical abstract Highlights ► hASCs were differentiated to Schwann cell-like cells with a mixture of growth factors. ► Differentiated hASCs secreted neurotrophic factors and promoted neurite ...outgrowth. ► hASCs transplanted into nude rats survived and formed myelin on regenerating axons. ► In vitro differentiation improved survival and myelin-forming rates of hASCs in vivo.
Through numerical simulations, it is predicted that the gravitational waves (GWs) reflect the characteristics of the core-collapse supernova (CCSN) explosion mechanism. There are multiple GW ...excitation processes that occur inside a star before its explosion, and it is suggested that the GWs originating from the CCSN have a mode for each excitation process in terms of time-frequency representation. Therefore, we propose an application of the Hilbert-Huang transform (HHT), which is a high-resolution time-frequency analysis method, to analyze these GW modes for theoretically probing and increasing our understanding of the explosion mechanism. The HHT defines frequency as a function of time, and is not bound by the trade-off between time and frequency resolutions. In this study, we analyze a gravitational waveform obtained from a three-dimensional general-relativistic CCSN model that showed a vigorous activity of the standing-accretion-shock-instability (SASI). We succeed in extracting the SASI induced GWs with high resolution on a time-frequency representation using the HHT and we examine their instantaneous frequencies.
Extracellular matrix (ECM) proteins are biosynthesized in the rough endoplasmic reticulum (rER) and transported via the Golgi apparatus to the extracellular space. The coat protein complex II (COPII) ...transport vesicles are approximately 60–90 nm in diameter. However, several ECM molecules are much larger, up to several hundreds of nanometers. Therefore, special COPII vesicles are required to coat and transport these molecules. Transmembrane Protein Transport and Golgi Organization 1 (TANGO1) facilitates loading of collagens into special vesicles. The Src homology 3 (SH3) domain of TANGO1 was proposed to recognize collagen molecules, but how the SH3 domain recognizes various types of collagen is not understood. Moreover, how are large noncollagenous ECM molecules transported from the rER to the Golgi? Here we identify heat shock protein (Hsp) 47 as a guide molecule directing collagens to special vesicles by interacting with the SH3 domain of TANGO1. We also consider whether the collagen secretory model applies to other large ECM molecules.
Background
Previous studies have reported that patients undergoing oesophagectomy in high‐volume hospitals experience lower mortality rates. However, there has been ongoing discussion regarding the ...validity of evidence for this association. The purpose of this study was to investigate the relationship between hospital volume and risk‐adjusted mortality following oesophagectomy in Japan, using a nationwide web‐based database.
Methods
The study included patients registered in the database as having undergone oesophagectomy with reconstruction between 2011 and 2013. Outcome measures were 30‐day and operative mortality rates. Logistic regression analysis was used to adjust for hospital volume, surgeon volume and risk factors for mortality after oesophagectomy.
Results
A total of 16 556 oesophagectomies at 988 hospitals were included; the overall unadjusted 30‐day and operative mortality rates were 1·1 and 3·0 per cent respectively. The unadjusted operative mortality rate in hospitals performing fewer than ten procedures per year (5·1 per cent) was more than three times higher than that in hospitals conducting 30 or more procedures annually (1·5 per cent). Multivariable models indicated that hospital volume had a significant effect on 30‐day (odds ratio 0·88 per 10‐patient increase; P = 0·012) and operative (odds ratio 0·86 per 10‐patient increase; P < 0·001) mortality.
Conclusion
In Japan, high‐volume hospitals had lower risk‐adjusted 30‐day and operative mortality rates following oesophagectomy compared with low‐volume hospitals.
Volume outcome effect evident in Japan
Higher-value chemicals can be produced from methane with small exergy losses by partial oxidation if the chemical conversion proceeds in an internal combustion engine (ICE) as a polygeneration ...process (Gossler and Deutschmann, 2015). Kinetics models are not sufficiently validated for the very fuel-rich and high-pressure conditions relevant for this process. Therefore, ignition delay times of fuel-rich methane/(additive)/air mixtures were measured in a shock tube at about 30 bar and temperatures between 600 and 1650 K. n-heptane and diethylether were used as additives to increase the reactivity of the fuel so that the polygeneration process can be realized in an ICE at HCCI conditions at lower compression temperatures. At ϕ = 2, measured ignition delay times agree well with simulations using different mechanisms from literature. Synthesis gas (CO, H2) is the main product at these conditions (Sen et al., 2016). For the production of higher hydrocarbons, the equivalence ratio must be increased. Very fuel-rich mixtures (ϕ = 10) were used because the temperature increase during the reaction of these mixtures is quite low (<450 K), so that post-ignition temperatures stay below the lower limit of soot formation. Only for mixtures with n-heptane as additive, good agreement of measured and simulated ignition delay times is found. The other mixtures show strong deviations with all mechanisms. As a further parameter to improve and validate the mechanisms at ϕ = 10, product distributions after ignition were determined by sampling in the cooling phase with a fast-opening valve and GC/MS analysis. Besides H2 and H2O, CO and higher hydrocarbons like C2H2, C2H4, C2H6, and C6H6 were detected as main products. About half of the carbon of the consumed methane is converted to CO, the other half to higher hydrocarbons. The product distributions are well predicted by simulations.
To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan.
We conducted a nationwide survey and collected clinical data on ...children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007.
Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval CI, 0.34-0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58-0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04-0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group.
Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.
•Tabs do not only enhance but also suppress jet entrainment and diffusion.•Tabs generally decreases entrainment velocity represented by velocity gradient.•Entrainment area significantly affects the ...entrainment rate.•Directional characteristics of jet diffusion can be controlled by optimizing tabs.
Effects of half delta-wing tabs on mixing and diffusion in an axisymmetric jet are experimentally investigated. The tabs are installed at the jet exit circumferentially with an equal interval. The number of the tab is varied from 1 to 6. The jet Reynolds number is set to 20,000. Instantaneous streamwise and radial (vertical or horizontal) velocities and temperature are mainly measured by a composite probe which consists of an X-type hot-wire and an I-type cold-wire. The results show that mixing with the ambient fluid is more enhanced with increasing the number of the tab near the jet exit. However, in the downstream region, it is suppressed in the cases with 4, 5, and 6 tabs and most suppressed in the case with 6 tabs, while it is most enhanced in the case with 3 tabs. The analysis based on the mean velocity distribution indicates that, although the spatially-averaged entrainment velocity is basically decreased by the tabs, the mixing and entrainment can be enhanced when the entrainment area is significantly increased. Thermal diffusion is more enhanced with increasing the number of the tab near the jet exit but, in the downstream region, it is equivalent or suppressed in the cases with the tabs. These results are caused by the mixed effects of the tabs: enhancement of not only mixing and diffusion but also the energy dissipation. The present study suggests that it is feasible to both promote and suppress mixing of the jet by the half delta-wing tabs, and directional characteristics of the jet diffusion can be controlled by optimizing configuration of the tabs.
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