The predominant type of immune cell in the brain is the microglia, a type of tissue-resident macrophage. In a variety of neurodegenerative settings, microglia alter their transcriptional profile, ...morphology and function in similar ways; thus, these activated cells have been called 'degeneration- or disease-associated microglia' (DAM). These activated microglia can perform different functions and exert both positive effects and negative effects in different mouse disease models. In humans, mutations in genes expressed in microglia are linked to various neurodegenerative diseases. Here we provide an overview of the common microglial response to neurodegeneration and key contributing pathways; delineate the multifaceted functions of activated microglia spanning various diseases; and discuss insights from the study of human disease-associated genes. We argue that strong evidence from both mouse models and human genetics causally links the function of activated microglia to neurodegeneration.
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their ...broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.
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•A miniaturized spinning bioreactor for cost-effective culturing of organoids•Generation of brain-region-specific organoids from human iPSCs•ZIKV causes decrease of neuronal cell-layer volume resembling microcephaly•Both African and Asian ZIKV infect neural progenitors in organoids
Zika virus preferentially infects neural progenitors in early stage cortical organoids generated using cost-effective miniaturized spinning bioreactors, resulting in suppressed proliferation, increased cell death, and macroscopic features resembling microcephaly.
The microstructures were observed in C-Mn steel and statistical analysis of the inclusions produced when trace amounts of rare earth were added to the steel. The results show that the content of ...intragranular acicular ferrite decreased in the order of being treated with La+Ce/La/Ce in C-Mn steel after the treatment of different kinds of rare earths. The optimum mass ratio of La and Ce for La+Ce combined treatment is 3:1.The best incubation time after Le+Ce (3:1) treatment is 5 min. The size of inclusion nuclei favouring intragranular acicular ferrite nucleation concentrates in the range of 1-4 μm. The disregistries between rare earth inclusions and α-Fe are small, which plays an important role in rare earth inclusions inducing intragranular acicular ferrite nucleation.
Abstract
Volatile organic compounds (VOCs) are secondary pollutant precursors having adverse impacts on the environment and human health. Although VOC emissions, their sources, and impacts have been ...investigated, the focus has been on large-scale industrial sources or indoor environments; studies on relatively small-scale enterprises (e.g., auto-repair workshops) are lacking. Here, we performed field VOC measurements for an auto-repair painting facility in Korea and analyzed the characteristics of VOCs emitted from the main painting workshop (top coat). The total VOC concentration was 5069–8058 ppb, and 24–35 species were detected. The VOCs were mainly identified as butyl acetate, toluene, ethylbenzene, and xylene compounds. VOC characteristics differed depending on the paint type. Butyl acetate had the highest concentration in both water- and oil-based paints; however, its concentration and proportion were higher in the former (3256 ppb, 65.5%) than in the latter (2449 ppb, 31.1%). Comparing VOC concentration before and after passing through adsorption systems, concentrations of most VOCs were lower at the outlets than the inlets of the adsorption systems, but were found to be high at the outlets in some workshops. These results provide a theoretical basis for developing effective VOC control systems and managing VOC emissions from auto-repair painting workshops.
Members of the genus Aeromonas are opportunistic pathogen of a variety of aquatic animals that exhibits multidrug resistance, phenotypes, virulence genes and virulence. The present study described ...the species distribution and the potential pathogenicity of Aeromonas isolated from healthy Northern snakehead (Channa argus) in China. Molecular identification revealed that A. veronii biovar veronii (69/167; 41·3%) and A. hydrophila (41/167; 24·6%) were the most common species found in Northern snakehead intestine based on sequencing of the 16S rRNA gene and DNA gyrase subunit B protein. The distribution of seven virulence factors including aer (84·4%), act (80·8%), ser (40·1%), Aha (27·5%), lip (23·4%), exu (15·0%) and LuxS (12·6%) were determined exclusively in Aeromonas isolates. All the seven virulence genes were present in 9·6% (16/167), among which 11 strains were identified as A. veronii biovar veronii. For the strains harbouring seven virulence genes, the 50% lethal doses (LD50) of isolates were lower compared to the isolates carrying two virulence genes. The challenge tests revealed that isolate W31 had the lowest lethal dose, causing 50% mortality at 4·5 × 103 colony‐forming units (CFU) per ml. Furthermore, histopathology of Northern snakehead infected with Aeromonas strains showed necrosis and congestion in liver, spleen and kidney and also damage to the intestine. This study confirms that the Aeromonas strains isolated from healthy Northern snakehead may be a cause of concern for public health.
Significance and Impact of the Study
Aeromonas species are widely distributed in aquatic environments and have considerable virulence potential. The aim of this study was to identify Aeromonas strains isolated from healthy Northern snakehead, and to investigate if Aeromonas species isolated from healthy fish potential pathogenicity with special reference to virulence and epidemiology studies.
Significance and Impact of the Study: Aeromonas species are widely distributed in aquatic environments and have considerable virulence potential. The aim of this study was to identify Aeromonas strains isolated from healthy Northern snakehead, and to investigate if Aeromonas species isolated from healthy fish potential pathogenicity with special reference to virulence and epidemiology studies.
Persistent significant tricuspid regurgitation (TR) after successful left-sided valve surgery is frequently reported.
To evaluate the incidence, risk factors and clinical impact of development of ...late significant TR after successful left-sided valve surgery.
638 patients (356 men, mean age 52 (SD 14) years) who had mild (<or=grade 2/4) TR and underwent successful surgery without any procedure for TR were analysed. Development of significant TR was defined as a TR increase by more than one grade and final TR grade >or=3/4 at follow-up echocardiography. Clinical events were defined as cardiovascular death, repeated open-heart surgery, and congestive heart failure requiring hospital admission. The overall incidence of late significant TR was 7.7% (49/638). Age (hazard ratio (HR), 1.0, 95% CI, 1.0 to 1.1; p = 0.005), female gender (HR, 5.0; 95% CI 2.0 to 12.7; p = 0.001), rheumatic aetiology (HR, 3.8; 95% CI 1.4 to 10.3; p = 0.011), atrial fibrillation (Af) (HR, 2.6; 95% CI 1.1 to 6.4; p = 0.035) and peak pressure gradient of TR at follow-up (HR, 1.1; 95% CI 1.0 to 1.1; p<0.001) were independent factors associated with development of late significant TR. During clinical follow-up of 101 (24) months, patients who developed late significant TR showed a significantly lower 8-year clinical event-free survival rate (76 (6) vs 91 (1)%, p<0.001).
Several clinical variables were independent risk factors for development of late significant TR. Early surgical intervention for TR in selected patients with these risk factors may be justified, even though they have only mild TR.
Although many high-entropy alloys (HEAs) possess excellent mechanical properties, they are not exempt from the common dilemma of strength–ductility trade-off in most cases, which limits their ...potential applications. Herein, rotationally accelerated shot peening was used to introduce different gradient hierarchical microstructures, including gradients in twin and dislocation densities, and hierarchical nanotwin, into a CoCrFeNiMn HEA by adjusting the processing parameters. The resulting gradient structures and their effect on hardening behaviour and mechanical properties were systematically explored. Quantitative analysis indicates that deformation twinning, including hierarchical nanotwinning could be more important than dislocation slip in terms of their contribution to hardness and strain hardening capability, depending on the gradient structure profile. It was found that simultaneous improvement of strength and ductility can be achieved in a gradient structure with a thin deformed layer and an undeformed core. Based on our experimental results, we propose that a gradient structure with a largest possible strength difference between the surface layer and the undeformed core would maximize the strength–ductility synergy.
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•Gradient hierarchical microstructures to simultaneously enhance strength and ductility of CoCrFeNiMn high entropy alloy.•This structure include: thin gradient layer of deformation twins with undeformed core, and fully deformed gradient layer.•Larger strain gradient promotes accumulation of geometrically necessary dislocations to sustain strain hardening.•Two-order hierarchical nanotwin contributes to higher strain hardening due to twin-twin and dislocation-twin interactions.•Appropriate gradient thickness for the effectiveness of hierarchical nanotwin induced strength-ductility synergy.
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse ...AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β-induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction.
Neurotrophic factors, a family of secreted proteins that support the growth, survival and differentiation of neurons, have been intensively studied for decades due to the powerful and diverse effects ...on neuronal physiology, as well as their therapeutic potential. Such efforts have led to a detailed understanding on the molecular mechanisms of neurotrophic factor signaling. One member, brain-derived neurotrophic factor (BDNF) has drawn much attention due to its pleiotropic roles in the central nervous system and implications in various brain disorders. In addition, recent advances linking the rapid-acting antidepressant, ketamine, to BDNF translation and BDNF-dependent signaling, has re-emphasized the importance of understanding the precise details of BDNF biology at the synapse. Although substantial knowledge related to the genetic, epigenetic, cell biological and biochemical aspects of BDNF biology has now been established, certain aspects related to the precise localization and release of BDNF at the synapse have remained obscure. A recent series of genetic and cell biological studies have shed light on the question-the site of BDNF release at the synapse. In this Perspectives article, these new insights will be placed in the context of previously unresolved issues related to BDNF biology, as well as how BDNF may function as a downstream mediator of newer pharmacological agents currently under investigation for treating psychiatric disorders.
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of ...disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n
C4b
reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
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