Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Recent genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild-type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant (from the Jackson laboratories). The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of LPS pro-inflammatory or IL4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype, whether treated with RNAi or performed with microglia carrying the R47H variant. In particular, Trem2 knockdown decreased levels of the transcription factor STAT6. STAT6 is the key mediator downstream from IL4 and controls expression of genes including Arg1, which also showed decreased IL4-induced expression when Trem2 expression was decreased. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2's anti-inflammatory drive. The importance of Trem2 activity in regulating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease

Consensus-based technical recommendations for clinical translation of renal ASL MRI

OBJECTIVES: This study aimed at developing technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5 T and 3 T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-centre clinical studies. METHODS: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting. RESULTS: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labelling with a single-slice spin-echo EPI readout with background suppression and a simple but robust quantification model. DISCUSSION: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data become available, since the renal ASL literature is rapidly expanding

Digital design and fabrication: Case study: seashell

Computational aspects of architectural design have revolutionized actual process, and have made a new platform for cooperation that spans across all disciplines. The focus of this study is to understand how the seashell form can be applicable in design process of human architectures. Our approach will show the act of choosing an inspirational natural form and its application into the virtual world, then digitalization, transformation, and evaluation of the form that are suitable for human architecture. 3D model generating would be performed by doing the scan of a selected seashell form. Further action would be to import the object as a tool in the Zbrush application, and continued modeling transformations. This phase would include other parameters that need to be integrated during the architectural design process since architecture usually exists in a radically different environment in comparison with the seashell

The effect of treatment regimens on salivary cortisol levels in patients with chronic musculoskeletal disorders

Background: Increased levels of circulating cortisol have been associated with pain severity in patients with chronic musculoskeletal disorders (CMD). Little is known about the potential association between pain management and salivary cortisol alterations in CPM patients treated with different regimens. Objectives: This prospective feasibility study aimed to determine the effect of two treatment regimens in comparison with sham therapy on pain intensity and disability and salivary cortisol concentration (SCC) in patients with CMD. Methods: Thirty patients were randomly assigned to 3 groups of 10: two experimental groups (A and B) and a control group (C). The experimental groups followed physiotherapy treatment (A) or acupuncture (B), while the control group (C) followed a sham therapy for 10 sessions. Pain data were collected using the Chronic Pain Grade (CPG) questionnaire and SCC was measured by enzyme-linked immunosorbent assay at pre- and posttreatment. Results: Repeated-measures analysis of variance showed that patients treated with acupuncture experienced greater decreases in pain intensity/pain disability (P < 0.05) than the physiotherapy and sham therapy groups. No statistical differences were found between the three groups for the SCC outcome variable. Bonferroni adjustments showed that the mean values of SCC were significantly decreased at posttreatment (P < 0.05) across the three groups. Conclusion: There was a significant decrease in both pain and cortisol outcomes at posttreatment in patients with CMD. Because of the limitations of this study, we cannot draw conclusions regarding whether the lower SCC could be an indication of pain reduction in patients with CMD. © 2019 Elsevier Lt

The effects of muscle cell aging on myogenesis

The process of myogenesis gradually deteriorates as the skeletal muscle ages, contributing to muscle mass loss. The aim of this study is to investigate the effect of senescence/aging on skeletal myogenesis, in vitro. A model of multiple cell divisions of C2C12 myoblasts was used to replicate cell senescence. Control and aged myoblasts were investigated during myogenesis, i.e., at days 0, 2, and 6of differentiation. SA-β-gal activity and comet assay were used as markers of aging and DNA damage. Flow cytometry was performed to characterize potential differences in cell cycle between control and aged cells. Alterations in the mRNA and/or protein expression of myogenic regulatory factors (MRFs), IGF-1 isoforms, apoptotic, atrophy, inflammatory, metabolic and aging-related factors were evaluated. Compared with the control cells, aged myoblasts exhibited G0/G1 cell cycle arrest, DNA damage, increased SA-β-gal activity, and increased expression of aging-related factors p16 and p21 during differentiation. Moreover, aged myoblasts showed a reduction in the expression of MRFs and metabolic/anabolic factors, along with an increased expression of apoptotic, atrophy and inflammatory factors. A diminished differentiation capacity characterized the aged myoblasts which, in combination with the induction of apoptotic and atrophy factors, indicated a disrupted myogenic lineage in the senescent muscle cells. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of LPS pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a programme of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease

Consensus‑based technical recommendations for clinical translation of renal ASL MRI

Objectives This study aimed at developing technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5 T and 3 T feld strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-centre clinical studies. Methods An international panel of 23 renal ASL experts followed a modifed Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting. Results Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or fow-sensitive alternating inversion recovery (FAIR) labelling with a single-slice spin-echo EPI readout with background suppression and a simple but robust quantifcation model. Discussion This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data become available, since the renal ASL literature is rapidly expanding