Excessive consumption of diets high in sugars and saturated fat, frequently known as western diet (WD), may lead to obesity and metabolic syndrome. Recent evidence shows that WD-induced obesity ...impairs cardiac function, but the underlying mechanisms are not fully understood. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of specific dietary nutrients, has emerged as a key contributor to cardiovascular disease pathogenesis. We tested the hypothesis that elevated circulating TMAO levels contribute to cardiac dysfunction in WD-induced obesity. CD1 mice were fed a normal diet (ND) or a WD, without or with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) in drinking water for 8 weeks. Compared with mice fed a ND, mice fed a WD showed a significant increase in body weight and dyslipidemia, and had markedly higher plasma TMAO levels at the end of the feeding protocol. Echocardiography revealed that cardiac systolic and diastolic function was impaired in mice fed a WD. DMB treatment had no effects on body weight and dyslipidemia, but significantly reduced plasma TMAO levels and prevented cardiac dysfunction in mice fed a WD. In addition, mice fed a WD had elevated expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin IL-1β, decreased expression of anti-inflammatory cytokine IL-10, and increased interstitial fibrosis in the hearts, all of which were prevented by DMB treatment. Notably, DMB treatment also reduced plasma TMAO levels in mice fed a ND but did not alter other parameters. These results suggest that consumption of a WD increases circulating TMAO levels, which lead to cardiac inflammation and fibrosis, contributing to cardiac dysfunction. Interventions that reduce circulating TMAO levels may be a novel therapeutic strategy for prevention and treatment of WD-induced cardiac dysfunction.
With rapid economic growth, industrialization, and urbanization, various ecological and environmental problems occur, which threaten and undermine the sustainable development and domestic survival of ...China. On the national scale, our progress remains in a state of qualitative or semi-quantitative evaluation, lacking a quantitative evaluation and a spatial visualization of ecological and environmental security. This study collected 14 indictors of water, land, air, and biodiversity securities to compile a spatial evaluation of ecological and environmental security in terrestrial ecosystems of China. With area-weighted normalization and scaling transformations, the veto aggregation (focusing on the limit indicator) and balanced aggregation (measuring balanced performance among different indicators) methods were used to aggregate security evaluation indicators. Results showed that water, land, air, and biodiversity securities presented different spatial distributions. A relatively serious ecological and environmental security crisis was found in China, but presented an obviously spatial variation of security evaluation scores. Hotspot areas at the danger level, which are scattered throughout the entirety of the country, were identified. The spatial diversities and causes of ecological and environmental problems in different regions were analyzed. Spatial integration of regional development and proposals for improving the ecological and environmental security were put forward.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neuroinflammation is an important host defense response to secondary brain injury after intracerebral hemorrhage (ICH). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong ...neuroprotective effects by attenuating neuroinflammation in experimental ischemic stroke. Recent studies suggest that apolipoprotein E (apoE) is a novel, high-affinity ligand of TREM2. This study aimed to investigate the effects of TREM2 activation on neuroinflammation and neuronal apoptosis in a mouse model of ICH.
Adult male CD1 mice (n = 216) were subjected to intrastriatal injection of bacterial collagenase. The TREM2 ligand, apoE-mimetic peptide COG1410 was administered intranasally at 1 h after ICH induction. To elucidate the underlying mechanism, TREM2 small interfering RNA (siRNA) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were administered intracerebroventricularly prior to COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, western blotting, and Fluoro-Jade C- and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed.
Endogenous TREM2 expression was increased and peaked at 24 h after ICH. TREM2 was expressed on microglia, astrocytes, and neurons. COG1410 improved both short-term and long-term neurological functions, reduced brain edema, inhibited microglia/macrophage activation and neutrophil infiltration, and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Knockdown of endogenous TREM2 by TREM2 siRNA aggravated neurological deficits and decreased the expression of TREM2 in naïve and ICH mice. COG1410 was associated with upregulation of TREM2, PI3K, phosphorylated-Akt, and Bcl-2 and downregulation of TNF-α, IL-1β, and Bax after ICH. The neuroprotective effects of COG1410 were abolished by both TREM2 siRNA and PI3K inhibitor LY294002.
Our finding demonstrated that TREM2 activation improved neurological functions and attenuated neuroinflammation and neuronal apoptosis after ICH, which was, at least in part, mediated by activation of PI3K/Akt signaling pathway. Therefore, activation of TREM2 may be a potential therapeutic strategy for the management of ICH patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
STUDY QUESTION
Do platelets play any role in the development of adenomyosis?
SUMMARY ANSWER
As in endometriosis, adenomyotic lesions show significantly increased platelet aggregation, ...increased expression of transforming growth factor (TGF)-β1, phosphorylated Smad3, markers of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), and smooth muscle metaplasia (SMM), in conjunction with increased fibrosis as compared with normal endometrium.
WHAT IS KNOWN ALREADY
Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis. SMM is universally seen in endometriosis and also in adenomyosis, and is correlated positively with the extent of fibrosis. However, there has been no published study on the role of platelets in fibrogenesis in adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which suggests the involvement of platelets and their possible roles in fibrogenesis.
STUDY DESIGN, SIZE, DURATION
Cross-sectional studies of ectopic endometrial and control endometrial tissue samples from three sets of women with and without adenomyosis (n= 34 and 20, 12 and 10, and 8 and 8, respectively) were carried out from 2014 to 2015.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Immunohistochemistry analysis of ectopic endometrial tissues from women with (n= 34) and without (n= 20) adenomyosis with respect to biomarkers of EMT, FMT and highly differentiated smooth muscle cells as well as TGF-β1, phosphorylated Smad3, markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits. Masson trichrome staining, Van Gieson staining and Pico-Sirius staining were performed to evaluate and quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. In addition, CD42b-positive platelets in ectopic (n= 12) and control (n= 10) endometrium were counted by confocal microscopy and compared. The protein expression levels of TGF-β1 and phosphorylated Smad3 in both ectopic (n= 8) and control (n= 8) endometrium were measured by western blot analysis. Immunofluorescent staining of both platelets and hepatocyte growth factor (HGF) was also performed for adenomyotic tissue samples (n= 10).
MAIN RESULTS AND THE ROLE OF CHANCE
Adenomyotic lesions had a significantly higher extent of platelet aggregation and increased staining for TGF-β1 and phosphorylated Smad3 (both P-values <0.001 versus control). In addition, E-cadherin staining was decreased while vimentin staining in adenomyotic epithelial cells was increased, along with increased staining of proliferating cell nuclear antigen, vascular endothelial growth factor and CD31 (all P-values <0.001), markers of proliferation and angiogenesis. Staining for α-SMA, a marker for myofibroblast, desmin, smooth muscle myosin heavy chain and oxytocin receptor was significantly increased in adenomyotic lesions versus control, concomitant with increased staining of collagen I and lysyl oxidase (all P-values <0.001). Histochemistry analysis indicates that the extent of fibrosis is high in adenomyotic lesions (P < 0.001), and the extent appeared to correlate negatively with the microvessel density (P < 0.05). PR-B staining was significantly decreased in adenomyotic lesion as compared with control endometrium (P < 0.001). Platelets and HGF were co-localized mostly in the stromal component of adenomyotic lesions, near the glandular epithelium.
LIMITATIONS, REASONS FOR CAUTION
The results are limited by the cross-sectional nature of the study and the use of histochemistry and immunohistochemistry analyses only, but nonetheless is a validation of our previous finding in mouse experiments.
WIDER IMPLICATIONS OF THE FINDINGS
The data presented are consistent with the notion that platelet-induced activation of the TGF-β/Smad signaling pathway may be a driving force in EMT, FMT and SMM in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and, as such, platelets play critical roles in the development of adenomyosis by promoting proliferation, angiogenesis, increasing ECM deposits, and SMM, resulting in fibrosis. Platelets may also be involved in uterine hyperactivity and myometrial hyperinnervation. Our results provide one explanation as to why adenomyosis is a challenge for medical treatment, and shed new light onto the pathophysiology of adenomyosis.
STUDY FUNDING/COMPETING INTERESTS
Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.
To evaluate the corrective effect of posterior hemivertebra resection and short-segment fusion surgery on pediatric patients and to assess the impact of short-segment fixation surgery on vertebral ...development during follow-up, a retrospective analysis was performed on 28 pediatric patients who underwent posterior hemivertebra resection surgery. The corrective effect was evaluated by comparing indicators such as segmental scoliosis Cobb angle, upper and lower compensatory curves and trunk balance at different time points. Meanwhile, the vertebral and spinal canal diameters of instrumented vertebrae and adjacent noninstrumented vertebrae were measured and compared to assess vertebral and spinal canal development. The correction rate of segmental scoliosis was 72.2%. The estimated mean vertebral volume of the instrumented vertebra was slightly lower than that of the unfused segment at the final follow-up, but the difference was not statistically significant. The growth rate of the spinal canal during follow-up was much smaller than that of the vertebral body. In summary, internal fixation at a young age shows no significant inhibitory effects on spinal development within the fusion segment. Posterior hemivertebra resection and short-segment fusion surgery are safe and effective.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The genetic basis of many brain and spinal arteriovenous malformations is unclear. Hong et al. reveal a causative role for somatic tumour-related mutations in KRAS/BRAF in the majority of patients ...tested. This homogeneity supports therapeutic targeting of the RAS/RAF/MAPK pathway without the need for tissue genetic diagnosis.
Abstract
Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.
10.1093/brain/awy307_video1
awy307media1
5978667388001
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•Developed a quantified evaluation scheme of production-living-ecology (PLE) functions.•Realized the spatialization at a fine grid scale by big data mining and data ...fusion.•Variable-boundary spatialized approach was developed to depict human activity extent.•Explored spatial characteristics of PLE functions between the global and local scales.
Demands for increasing production and living functions often threaten ecological functions. Reliable quantification of land use multifunctionality (LUMF) contributes to identify and coordinate these conflicts. However, the comprehensive LUMF indicator system and fine spatial resolutions restricted each other. Previous assessments were limited to coarse grids or administrative units, thus failing to provide detailed spatial information and causing scale biases, particularly in landscapes with strong heterogeneity. Combining big data mining and fusion techniques, this study built a comprehensive and quantitative evaluation scheme of production-living-ecology (PLE) land functions with spatial detail. The scheme was applied in the karst region of southwestern China as a case study. Data on socioeconomic status, remote sensing, and location points were fused using a variable-boundary spatialized approach to quantify human activity extent and degree of convenience. Specific environmental characteristics, such as topography and karst rocky desertification, were integrated into the spatialized PLE functions. The results showed that the global distribution of the production and living functions presented some similarity, yet the high production and living functions were not completely aligned. Also, the spatial patterns of the living and production functions usually showed opposite formations to the ecology function. Unlike the global relationship, the enlarged PLE relationships in the study regions validated the importance and necessity of fine spatial information. Local relationships between the production-living and production-ecology functions were significantly different in areas with various economic development levels, particularly in built-up areas. Regions with strong synergistic relationships of PLE functions were rare and were usually found in sightseeing areas of ecology and agriculture. These results demonstrated the effectiveness of our proposed method of spatializing PLE functions with spatial detail. The findings provide detailed spatial information on local anthropogenic and physical differences and support for balancing PLE functions and policy-making about land use optimization in practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The transfer of magnetic chirality in solar active regions is related to the emerging magnetic flux ropes generated in the subatmosphere. This analysis has been presented based on the calculation of ...the injection of magnetic helicity at the solar surface. As the long-term evolution of the accumulated magnetic helicity is followed, it is found that the transfer of reversal magnetic helicity of active regions is a complex process, and is not monotonic with the same sign. It is found that the dominant contribution of helicity occurs mainly in the fast-developing stage of active regions.
By considering the hemispheric trends of magnetic helicity, it is proposed that the reversal helicity in solar active regions has two possible causes: local generation in the convection zone, and trans-equatorial processes in the subatmosphere. In addition to the mirror-symmetrical reverse of twisted magnetic field in the convection zone, the possibility of a trans-equatorial process is discussed in this paper.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Optimizing the allocation schemes of post-disaster recovery resources can promote the sustainable development of a regional economy. However, previous studies determined the inputs and ...allocation schemes of recovery resources based on direct economic (DE) loss while neglecting indirect economic (IDE) loss, which restricted economic recovery. This study considered DE and IDE loss, and used a dynamic disastrous computable general equilibrium (CGE) model to simulate multiple scenarios with different inputs and allocation schemes to identify a better economic recovery strategy. Taking Super Typhoon Mangkhut’s landing in Guangdong Province in 2018 as an example, the results showed that the IDE loss had a long-term impact and dynamic accumulation without post-disaster recovery, reaching 15.25 times the DE loss by 2022. In the baseline scenario, the recovery resource inputs, including relief funds, reconstruction funds, and natural disaster commercial insurance, were limited, leading to a cumulative loss recovery rate of less than 2% in 2018–2022. According to our findings, recovery resources needed a 15-fold increase to recover to pre-disaster levels. Considering the impacts of sector connections on IDE loss, six allocation schemes were established based on DE loss, IDE loss, and industrial structure. Compared with the typical allocation scheme based on DE loss, allocating recovery resources according to the diffusion coefficient substantially improved the loss recovery rate and recovery resource utilization efficiency. The dynamic disastrous CGE model conducted multi-scenario simulations to identify the optimal recovery resource allocation scheme that supported rapid and efficient post-disaster economic recovery.
Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for ...osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer-functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
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