Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical ...regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel–Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1–activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.
Understanding how the brain captures transient experience and converts it into long lasting changes in neural circuits requires the identification and investigation of the specific ensembles of ...neurons that are responsible for the encoding of each experience. We have developed a Robust Activity Marking (RAM) system that allows for the identification and interrogation of ensembles of neurons. The RAM system provides unprecedented high sensitivity and selectivity through the use of an optimized synthetic activity-regulated promoter that is strongly induced by neuronal activity and a modified Tet-Off system that achieves improved temporal control. Due to its compact design, RAM can be packaged into a single adeno-associated virus (AAV), providing great versatility and ease of use, including application to mice, rats, flies, and potentially many other species. Cre-dependent RAM, CRAM, allows for the study of active ensembles of a specific cell type and anatomical connectivity, further expanding the RAM system's versatility.
Rationale, aims, and objectives
Clinical practice guidelines (CPGs) endeavour to incorporate the best available research evidence together with the clinically informed opinions of leading experts in ...order to guide clinical practice when dealing with a given condition. There has been increased interest in CPGs that are evidence based and that promote best practice, a central component of which is incorporating the best available research predicated on strong study designs. Despite this soaring interest, there remains heterogeneity in the methodological quality of many CPGs, which may have an effect on the quality of services that clinicians offer. In light of this, this study examined the quality of the methodology used to develop two CPGs of the Canadian Psychiatric Association (CPA).
Method
The CPA's guidelines for the management of anxiety disorders (2006) and for the treatment of depressive disorders (2001) were assessed by trained raters using the Appraisal of Guidelines for Research and Evaluation II Instrument scale.
Results
The blind ratings of three trained raters demonstrated that the anxiety and depression CPGs had a number of strengths and important weaknesses.
Conclusion
Implications for the development of future CPGs on anxiety and depression, including recommendations to improve guideline quality in psychiatry in particular, are discussed.
Boron carbide is an excellent armor material due to its light weight and ultrahigh hardness. However, high‐rate mechanical behavior can be degraded by stress‐induced amorphization. In this paper, we ...review the progressive advances in the understanding of amorphization in three successive generations of boron carbide: stoichiometric (undoped), B‐rich, and B/Si codoped boron carbides. For each generation of boron carbide, the crystal structure and microstructure are first discussed. Then, we outline the experimental observations of amorphization made by Raman spectroscopy and transmission electron microscopy. The susceptibility of amorphization in each generation of boron carbide will be compared and the fundamental mechanisms that explain the reduction in amorphization for B‐rich and B/Si codoped boron carbides elucidated. Comments on future research directions to further broaden and deepen the understanding of stress‐induced amorphization of boron carbide are also provided.
Compositional analysis of boron carbide on nanometer length scales to examine or interpret atomic mechanisms, for example, solid‐state amorphization or grain‐boundary segregation, is challenging. ...This work reviews advancements in high‐resolution microanalysis to characterize multiple generations of boron carbide. First, ζ‐factor microanalysis will be introduced as a powerful (scanning) transmission electron microscopy ((S)TEM) analytical framework to accurately characterize boron carbide. Three case studies involving the application of ζ‐factor microanalysis will then be presented: (1) accurate stoichiometry determination of B‐doped boron carbide using ζ‐factor microanalysis and electron energy loss spectroscopy, (2) normalized quantification of silicon grain‐boundary segregation in Si‐doped boron carbide, and (3) calibration of a scanning electron microscope X‐ray energy‐dispersive spectroscopy (XEDS) system to measure compositional homogeneity differences of B/Si‐doped arc‐melted boron carbides in the as‐melted and annealed conditions. Overall, the improvement and application of advanced analytical tools have helped better understand processing–microstructure–property relationships and successfully manufacture high‐performance ceramics.
Boron carbide undergoes stress-induced amorphization when subjected to large non-hydrostatic stresses that exceed its elastic limit. This has been proposed as the source for the abrupt loss of shear ...strength in boron carbide which limits its engineering applications. Si/B co-doping was suggested as one of the means to suppress stress-induced amorphization but this has not been experimentally verified. Here, by utilizing arc melting, we prepared Si/B co-doped boron carbide with increased Si content as compared to conventional methods. Through Raman analysis in conjunction with indention and elemental analyses based on SEM and STEM (ζ-factor microanalysis), it is suggested that Si/B co-doping is a promising avenue for suppressing stress-induced amorphization. A comprehensive characterization of microstructure, chemistry, and structural change of boron carbide as a result of Si/B co-doping was elucidated.
Abstract
Objective
We examined features of clinically amyopathic JDM (CAJDM), in which patients have characteristic rashes with little to no evidence of muscle involvement, to determine whether this ...is a distinct phenotype from JDM.
Methods
Demographic, clinical, laboratory and treatment data from 12 (9 hypomyopathic, 3 amyopathic) patients meeting modified Sontheimer criteria for CAJDM and from 60 matched JDM patients meeting Bohan and Peter criteria were examined. Differences were evaluated by Fisher's exact and Mann-Whitney tests, random forests and logistic regression analysis.
Results
Nine (75%) CAJDM patients had anti-p155/140 (transcriptional intermediary factor 1), one (8.3%) anti-melanoma differentiation-associated gene 5 autoantibodies and two (16.7%) were myositis autoantibody negative. CAJDM patients were younger at diagnosis and frequently had mild disease at onset. CAJDM patients had less frequent myalgias, arthritis, contractures, calcinosis, dysphagia, abdominal pain and fatigue. The muscle, skeletal and overall clinical scores were lower in CAJDM. Serum muscle enzymes were less frequently increased in CAJDM, and peak values were lower. CAJDM patients received fewer medications compared with JDM patients. Only 50% of CAJDM patients received oral prednisone, but the maximum dose and treatment duration did not differ from JDM. At a median follow-up of 2.9 years, CAJDM patients had no documented functional disability, and none developed weakness, calcinosis, interstitial lung disease or lipodystrophy. Multivariable modelling revealed a lower skeletal score and less frequent myalgias as the most important factors in distinguishing CAJDM from JDM.
Conclusion
CAJDM may be distinguished from JDM, in that they often have p155/140 (transcriptional intermediary factor 1) autoantibodies, have fewer systemic manifestations and receive less therapy.
The therapeutic goal for peripheral arterial disease and ischemic heart disease is to increase blood flow to ischemic areas caused by hemodynamic stenosis. Vascular surgery is a viable option in ...selected cases, but for patients without indications for surgery such as progression to rest pain, critical limb ischemia, or major disruptions to life or work, there are few possibilities for mitigating their disease. Cell therapy via monocyte-enhanced perfusion through the stimulation of collateral formation is one of a few non-invasive options. Our group examines arteriogenesis after monocyte transplantation into mice using the hindlimb ischemia model. Previously, we have demonstrated improvement in hindlimb perfusion using tetanus-stimulated syngeneic monocyte transplantation. In addition to the effects on the collateral formation, tumor growth could be affected by this therapy as well. To investigate these effects, we use a basement membrane-like matrix mouse model by injecting the extracellular matrix of the Engelbreth-Holm-Swarm sarcoma into the flank of the mouse, after occlusion of the femoral artery. After the artificial tumor studies, we use intravital microscopy to study in vivo tumor-angiogenesis and monocyte homing within collateral arteries. Previous studies have described the histological examination of animal models, which presupposes subsequent analysis to post-mortem artifacts. Our approach visualizes monocyte homing to areas of collateralization in real time sequences, is easy to perform, and investigates the process of arteriogenesis and tumor angiogenesis in vivo.
Analytical electron microscopy was used to examine the grain boundary chemistry in boron carbide containing Al-O-rich phases at triple junctions. In this study, SiO2, Al2O3, and B2O3 additives were ...used to synthesize an aluminoborosilicate glass on the grain boundaries with the long-term goal to enhance fracture resistance. Nanolayer films were not observed using high-angle annular dark field imaging; however, energy-dispersive spectroscopy quantification revealed grain boundaries with varying excess of Si and Al. Overall, it was concluded variations in grain boundary chemistry depend upon the intrinsic grain boundary character and spatial heterogeneity of the oxide additives.
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