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Tumour deposits (TDs) significantly impact colorectal cancer (CRC) prognosis. Integrating TDs into the TNM staging system can enhance individualized disease management. Keeping abreast of evolving TDs research is pivotal for clinical advancement. We comprehensively reviewed both recent and popular literature to grasp the field's essence. Subsequently, a data retrieval sourced articles on TDs in CRC for bibliometric analysis, spanning from 1 January 1935 to 30 April 2023. Bibliometrix software facilitated paper analysis and visualization. Bibliometric indicators, the trends and hotspots were determined. A total of 2147 articles were successfully retrieved. Brown G emerged as the most productive author, and the USA as the most prolific country. Central South University and Memorial Sloan Kettering Cancer Center led productivity. Bradford's law categorized 48 journals into zone 1. Keywords co-occurrence analysis identified three main clusters: the application of TDs in TNM staging, the pathogenesis of TDs, and the assessment of TDs. The trend topic analysis highlighted research focused on refining TDs incorporation into tumour staging. TDs wield enduring medical significance, shaping ongoing research. Much literature focused on confirming TD's prognostic value and optimizing TNM integration. Additionally, it is worth highlighting that TD's enigmatic pathogenesis demands research priority, as it holds the potential to unveil concealed knowledge regarding their development.
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Neoplasias Colorrectales , Estadificación de Neoplasias , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/diagnóstico , Pronóstico , Bibliometría , Toma de Decisiones ClínicasRESUMEN
We present herein a novel cobalt/zinc bimetallic catalysis system for the realization of an efficient and enantioselective alkynylation of isatins and α-ketoesters using terminal alkynes. By using a simple procedure with all commercially available catalysts, including cobalt bromide, a chiral bisphosphine ligand, and zinc triflate, a range of synthetically useful tertiary propargylic alcohols are accessed with high yields and good enantioselectivities. Control reactions showed that this catalytic system proceeds through activation of the terminal alkyne by zinc triflate and a base, transmetalation from zinc to cobalt, and then the enantio-determining alkynylation of ketones.
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Isatina , Alquinos , Estereoisomerismo , Zinc , Alcoholes , Cobalto , CatálisisRESUMEN
To evaluate the effects of donor ages on growth and stress resistance of 6-year-old seedlings propagated from 5-, 2000-, and 3000-year-old Platycladus orientalis donors with grafting, cutting, and seed sowing, growth indicators and physiological and transcriptomic analyses were performed in 6-year-old seedlings in winter. Results showed that basal stem diameters and plant heights of seedlings of the three propagation methods decreased with the age of the donors, and the sown seedlings were the thickest and tallest. The contents of soluble sugar, chlorophyll, and free fatty acid in apical leaves of the three propagation methods were negatively correlated with donor ages in winter, while the opposite was true for flavonoid and total phenolic. The contents of flavonoid, total phenolic, and free fatty acid in cutting seedlings were highest in the seedlings propagated in the three methods in winter. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis of differentially expressed genes showed phenylpropanoid biosynthesis and fatty acid metabolism pathways, and their expression levels were up-regulated in apical leaves from 6-year-old seedlings propagated from 3000-year-old P. orientalis donors. In addition, hub genes analysis presented that C4H, OMT1, CCR2, PAL, PRX52, ACP1, AtPDAT2, and FAD3 were up-regulated in cutting seedlings, and the gene expression levels decreased in seedlings propagated from 2000- and 3000-year-old donors. These findings demonstrate the resistance stability of cuttings of P. orientalis and provide insights into the regulatory mechanisms of seedlings of P. orientalis propagated from donors at different ages in different propagation methods against low-temperature stress.
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Plantones , Thuja , Plantones/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Perfilación de la Expresión Génica , Clorofila/metabolismo , Thuja/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
BACKGROUND: TREM2 is a microglial receptor genetically linked to the risk for Alzheimer's disease (AD). The cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2) have emerged as a valuable biomarker for the disease progression in AD and higher CSF levels of sTREM2 are linked to slower cognitive decline. Increasing sTREM2 in mouse models of amyloidosis reduces amyloid-related pathology through modulating microglial functions, suggesting a beneficial role of sTREM2 in microglia biology and AD pathology. METHODS: In the current study, we performed serial C- and N-terminal truncations of sTREM2 protein to define the minimal sequence requirement for sTREM2 function. We initially assessed the impacts of sTREM2 mutants on microglial functions by measuring cell viability and inflammatory responses. The binding of the sTREM2 mutants to oligomeric Aß was determined by solid-phase protein binding assay and dot blot assay. We further evaluated the impacts of sTREM2 mutants on amyloid-related pathology by direct stereotaxic injection of sTREM2 proteins into the brain of 5xFAD mice. RESULTS: We found that both sTREM2 fragments 41-81 and 51-81 enhance cell viability and inflammatory responses in primary microglia. However, the fragment 51-81 exhibited impaired affinity to oligomeric Aß. When administrated to the 5xFAD mice brain, the sTREM2 fragment 41-81, but not 51-81, increased the number of plaque-associated microglia and reduced the plaque deposition. Interestingly, the fragment 41-81 was more efficient than the physiological form of sTREM2 in ameliorating Aß-related pathology. CONCLUSIONS: Our results indicate that the interaction of sTREM2 truncated variants with Aß is essential for enhancing microglial recruitment to the vicinity of an amyloid plaque and reducing the plaque load. Importantly, we identified a 41-amino acid sequence of sTREM2 that is sufficient for modulating microglial functions and more potent than the full-length sTREM2 in reducing the plaque load and the plaque-associated neurotoxicity. Taken together, our data provide more insights into the mechanisms underlying sTREM2 function and the minimal active sTREM2 sequence represents a promising candidate for AD therapy.
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Amiloidosis/genética , Amiloidosis/patología , Encéfalo/patología , Glicoproteínas de Membrana/genética , Microglía/patología , Fenotipo , Receptores Inmunológicos/genética , Secuencia de Aminoácidos , Animales , Células Cultivadas , Células HEK293 , Humanos , RatonesRESUMEN
Heat stress during Brassica napus seed filling severely impairs yield and oil content. However, the mechanisms underlying heat-stress effects on B. napus seed photosynthesis and oil accumulation remain elusive. In this study, we showed that heat stress resulted in reduction of seed oil accumulation, whereas the seed sugar content was enhanced, which indicated that incorporation of carbohydrates into triacylglycerols was impaired. Photosynthesis and respiration rates, and the maximum quantum yield of photosystem II in developing seeds were inhibited by heat stress. Transcriptome analysis revealed that heat stress led to up-regulation of genes associated with high light response, providing evidence that photoinhibition was induced by heat stress. BnWRI1 and its downstream genes, including genes involved in de novo fatty acid biosynthesis pathway, were down-regulated by heat stress. Overexpression of BnWRI1 with a seed-specific promoter stabilized both oil accumulation and photosynthesis under the heat-stress condition, which suggested BnWRI1 plays an important role in mediating the effect of heat stress on fatty acid biosynthesis. A number of sugar transporter genes were inhibited by heat stress, resulting in defective integration of carbohydrates into triacylglycerols units. The results collectively demonstrated that disturbances of the seed photosynthesis machinery, impairment of carbohydrates incorporation into triacylglycerols and transcriptional deregulation of the BnWRI1 pathway by heat stress might be the major cause of decreased oil accumulation in the seed.
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Brassica napus/metabolismo , Fotosíntesis , Proteínas de Plantas/metabolismo , Aceite de Brassica napus/metabolismo , Factores de Transcripción/metabolismo , Brassica napus/fisiología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Respuesta al Choque Térmico , Fotosíntesis/fisiología , Proteínas de Plantas/fisiología , Transducción de Señal , Factores de Transcripción/fisiologíaRESUMEN
Multi-frequency Terahertz (THz) detectors have shown great application potentials in THz imaging and sensing systems. For the first time to our knowledge, a novel dual-frequency THz detector with the stacked structure consisting of a silicon-based plasmonic antenna and a metal-based antenna in one compact unit is proposed and fabricated in standard CMOS technology. Compared with the metal antenna, the antenna based on heavy-doped poly-silicon materials enables the detector to excite localized surface plasmon resonance mode, making the effective absorption of the THz waves and thus resulting in the significant responsivity enhancement of the detector. The experimental results show a maximum voltage responsivity up to about 2000 V/W and 450 V/W, while the noise equivalence power is as low as 23 pW/Hz0.5 and 110 pW/Hz0.5 for the silicon antenna and metal antenna at the frequency of 220 GHz and 650 GHz, respectively. The presented dual-frequency detector can be easily implemented in a small size in favor of high-density array integration.
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We present herein an unprecedented enantioselective isomerization of homoallylic and bishomoallylic secondary alcohols, catalyzed by a commercially available rhodium-complex and a base. This catalytic redox-neutral process provides an effective access to chiral ketones in high efficiency and enantioselectivity, without the use of any stoichiometric reagent or generation of any waste. For the reaction of homoallylic alcohols, this system achieved not only a stereoconvergent access to chiral ketones bearing a ß-stereocenter (up to 95%, 86% ee) but also a concomitant oxidative kinetic resolution of the alcohol substrates (S > 20). In the case of bishomoallylic alcohols, an intriguing ligand-induced divergent reactivity was observed. A terminal-to-internal alkene isomerization promoted by Rh/L7 followed by redox isomerization using Rh/BINAP system produced chiral ketones bearing a γ-stereocenter with high yield and enantioselectivity. Mechanistic studies provided strong support for the redox-isomerization pathway with chain walking of the key alkyl-Rh intermediate.
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The first enantioselective formal [5+4] cycloaddition is realized under palladium catalysis to deliver benzofuran-fused nine-membered rings. These medium-sized heterocycles and derivatives undergo unique rearrangements induced by transannular bond formation, resulting in the production of two classes of densely substituted polycyclic heterocycles in excellent efficiency and stereoselectivity.
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We present here an unprecedented cobalt-catalyzed enantioselective vinylation of α-ketoesters, isatins, and imines to deliver a range of synthetically useful allylic alcohols and amines in high enantiopurity. This method employs commercially available and easy to handle catalysts and reagents and exhibits a high degree of practicality. The efficiency, selectivity, and operational simplicity of this catalytic system coupled with the substrate generality render this method a valuable tool in organic synthesis.
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Cobalto/química , Iminas/química , Cetonas/química , Aminas/química , Catálisis , Indoles/química , Propanoles/química , EstereoisomerismoRESUMEN
The allylation of heterobicyclic alkenes is presented for the first time. By using an inexpensive cobalt salt as the catalyst and easy-to-handle potassium allyltrifluoroborate as the reagent, an unprecedented formal hydroallylation of the bicyclic alkenes is realized in high efficiency. When a chiral cobalt/bis(phosphine) complex is used instead, the alternative ring-opening products can be obtained in high yield and excellent enantioselectivity.
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Photosynthesis in "green" seeds, such as rapeseed, soybean, and Arabidopsis, plays a substantial role in the improved efficiency of oil accumulation. However, the molecular mechanism underpinning the coordinated expression of fatty acid (FA) biosynthesis- and photosynthesis-related genes in such developing seeds remains to be elucidated. Here, we found that seed-specific overexpression of BnWRI1, a WRI1 homolog from rapeseed (Brassica napus cv. ZGY2), results in enhanced chlorophyll content in developing seeds and increased oil content and seed mass in matured seeds. BnWRI1 was co-expressed with BnBCCP and BnCAB, two marker genes of FA biosynthesis and photosynthesis during seed development, respectively. Overexpression of BnWRI1 increased expression of both marker genes. Further, the nuclear-localized BnWRI1 protein was found to act as a transcription activator. It could bind to the GT1-element and/or GCC-box, which are widespread in the upstream regions of genes involved in FA biosynthesis and photosynthesis pathways. Accordingly, BnWRI1 could interact with promoters of BCCP2 and LHB1B2 in vivo. These results suggested that BnWRI1 may coordinate FA biosynthesis and photosynthesis pathways in developing seeds via directly stimulating expression of GT1-element and/or GCC-box containing genes.
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Brassica napus/metabolismo , Brassica rapa/genética , Ácidos Grasos/biosíntesis , Fotosíntesis , Aceites de Plantas/metabolismo , Proteínas de Plantas/metabolismo , Núcleo Celular/metabolismo , Ácidos Grasos Monoinsaturados , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Datos de Secuencia Molecular , Especificidad de Órganos , Fotosíntesis/genética , Plantas Modificadas Genéticamente , Unión Proteica , Aceite de Brassica napus , Secuencias Reguladoras de Ácidos Nucleicos/genética , Saccharomyces cerevisiae/metabolismo , Semillas/genética , Semillas/crecimiento & desarrollo , Semillas/metabolismo , Semillas/ultraestructura , Transactivadores/metabolismoRESUMEN
We investigated the inter- and intra-species differences of leaf vein traits of three dominant Quercus species, Q. wutaishanica, Q. aliena var. acutiserrata, and Q. variabilis of Niubeiling (subtropical humid climate) and Taohuagou (warm temperate semi-humid climate), located in the eastern and western Qinling Mountains. The nine examined leaf vein traits included primary leaf vein width, secondary leaf vein width, mean fine vein width, primary vein density, fine vein density, vein areole diameter, areole density, 3D fine vein surface area, and fine vein volume. We further elucidated the influencing mechanisms and regulatory pathways of biotic and abiotic factors on leaf vein traits. The results showed that species identity had significant effects on eight out of nine leaf vein traits except 3D fine vein surface area, while habitat had significant effects on primary leaf vein width, secondary leaf vein width, vein areole diameter, fine vein density, and areole density. Altitude had significant effects on primary vein density, mean fine vein width, vein areole diameter, fine vein density and areole density. Habitat, tree species identity, and altitude had significantly interactive effects on primary leaf vein density, 3D fine vein surface area, and fine vein volume. There were significant differences in primary leaf vein width, mean fine vein width, areole density, 3D fine vein surface area, fine vein volume, primary vein density of Q. wutaishanica between the two studied habitats, but the differences were only found in secondary leaf vein width and areole density of Q. aliena var. acutiserrata and Q. variabilis. The examined leaf vein traits were influenced both by biotic and abiotic factors, with varying effect sizes. Among the biotic factors, petiole length, leaf length and width ratio had strong effect on leaf vein traits. Among the abiotic factors, climatic and soil factors had high effect size on vein traits, with the former being higher than the latter. Leaf vein traits were affected directly by biotic factors, but indirectly by abiotic factors (soil and climatic factors) via regulating biotic factors (leaf stoichiometry and leaf phenotypic traits).
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Ecosistema , Hojas de la Planta , Quercus , Quercus/anatomía & histología , Hojas de la Planta/anatomía & histología , China , Especificidad de la Especie , AltitudRESUMEN
OBJECTIVE: To assess whether diet quality and specific dietary components are associated with hypertensive disorders of pregnancy (HDP). STUDY DESIGN: Nested case control study in a prospectively collected cohort of 450 participants with singleton pregnancies who completed the National Institutes of Health Diet Health Questionnaire II (DHQ-II) in the third trimester or within 3 months of delivery. Patients with fetal anomalies, conception by in-vitro fertilization, and deliveries at outside hospitals were excluded from the original prospective cohort study. Cases were patients diagnosed with HDP and controls were patients without HDP. Cases and controls were matched by BMI class in a 1:2 ratio. Exposures of interest were HEI-2015 score components and other DHQ-II dietary components including minerals, caffeine, and water. These dietary components were compared between cohorts using univariate analyses. MAIN OUTCOME MEASURES: HEI-2015 total scores representing diet quality, component scores, and objective background data between patients with HDP and patients without HDP. RESULTS: 150 patients with HDP were matched to 300 controls without HDP. Baseline demographics were similar between groups, including BMI. Patients with HDP were less likely to have high quality diets (HEI ≥ 70) than controls (7.3 % v 15.7 %, P = 0.02). HDP were associated with significantly higher dairy, saturated fat, and sodium intake compared to controls. Other components were similar between groups. CONCLUSION: Patients with HDP are more likely to have lower diet quality and higher consumption of sodium, dairy, and saturated fats. These results can be used to study antenatal diet modification in patients at high risk of HDP.
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Hipertensión Inducida en el Embarazo , Humanos , Femenino , Embarazo , Adulto , Estudios de Casos y Controles , Factores de Riesgo , Hipertensión Inducida en el Embarazo/epidemiología , Estudios Prospectivos , Dieta/efectos adversos , Dieta SaludableRESUMEN
Low temperature is one of the major factors affecting rice germination, and low temperature germination (LTG) is an important agronomic trait. Although significant progress has been made in the study of rice LTG, the molecular mechanism of LTG remains poorly understood. To explore more rice LTG gene resources, we first demonstrated that weedy rice WR04-6 (Oryza sativa f. spontanea) had significantly higher LTG ability at 10 °C than the cultivated rice Qishanzhan (QSZ Oryza sativa L. ssp. indica). RNA-seq was used to investigate the gene expression of WR04-6 and QSZ at 10 °C for 10, 12 and 14 days after imbibition (DAI) of seed germination. The results of Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed that the differentially expressed genes (DEGs) between WR04-6 and QSZ were mainly concentrated on the response to starch catabolic processes and the response to abscisic acid (ABA). This is consistent with the results of α-amylase activity, ABA and gibberellins (GA) treatment. A recombinant inbred line (RIL) population derived from a cross between WR04-6 and QSZ and its high-density SNP genetic map were used to detect quantitative trait loci (QTL) for LTG rates. The results showed that two new QTLs were located on chromosome 3 and chromosome 12. Combined with the mapped QTLs and RNA-seq DEGs, sixteen candidate genes potentially associated with LTG were identified. Validation of the expression of the candidates by qRT-PCR were consistent with the RNA-seq data. These results will enable us to understand the genetic basis of LTG in weedy rice and provide new genetic resources for the generation of rice germplasm with improved LTG.
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We examined species composition, community characteristics, diversity, and community similarity of five Quercus communities composed of three Quercus species (Q. variabilis, Q. aliena var. acutiserrata, Q. wutaishanica) on the altitudinal gradient on the south and north slopes of Taibai Mountain. The results showed that there was an altitudinal transition pattern from Q. variabilis pure forest to Q. variabilis-Q. aliena var. acutiserrata mixed forest, Q. aliena var. acutiserrata pure forest, Q. aliena var. acutiserrata-Q. wutaishanica mixed forest and Q. wutaishanica pure forest on the south and north slopes of Taibai Mountain. The main companion species of Quercus community on the north slope were Pinus armandii, Castanea seguinii, and Sorbus alnifolia, and were Pinus tabuliformis, C. seguinii, Carpinus cordata, and Q. spinosa on the south slope. Species richness, woody plant density, and Quercus species dominance on the north slope of Taibai Mountain were higher than those on the south slope. α diversity of tree layer in Quercus community on the south and north slopes of Taibai Mountain increased first, then decreased and then increased with altitude. α diversity of tree layer was higher in mixed forests than pure forests. α diversity of shrub layer was higher than that of tree layer and herb layer in Quercus community on south and north slopes. ß diversity fluctuated greatly along the altitudinal gradient on the south and north slopes, indicating that species composition changed greatly with altitude. Results of redundancy analysis showed that mean warmest month temperature, altitude and tree height accounted for 79.0% of the community diversity on the north slope, and that soil water content, tree height, canopy density and mean annual temperature accounted for 79.6% of the community diversity on the south slope. Overall, Quercus dominance was higher on the north slope of Taibai Mountain, and the substitution distribution pattern of Quercus species was clearer than that on the south slope. Environmental factors related to temperature and precipitation jointly affected α diversity of Quercus communities.
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Pinus , Quercus , Bosques , Árboles , Madera , ChinaRESUMEN
Picea koraiensis is major silvicultural and timber species in northeast China, and its distribution area is an important transition zone for genus spruce migration. The degree of intraspecific differentiation of P. koraiensis is high, but population structure and differentiation mechanisms are not clear. In this study, 523,761 single nucleotide polymorphisms (SNPs) were identified in 113 individuals from 9 populations of P. koraiensis by genotyping-by-sequencing (GBS). Population genomic analysis showed that P. koraiensis was divided into three geoclimatic regions: Great Khingan Mountains climatic region, Lesser Khingan Mountains climatic region, and Changbai Mountain climatic region. Mengkeshan (MKS) population on the northern edge of the distribution area and Wuyiling (WYL) population located in the mining area are two highly differentiated groups. Selective sweep analysis showed that MKS and WYL populations had 645 and 1126 selected genes, respectively. Genes selected in the MKS population were associated with flowering and photomorphogenesis, cellular response to water deficit, and glycerophospholipid metabolism; genes selected in the WYL population were associated with metal ion transport, biosynthesis of macromolecules, and DNA repair. Climatic factors and heavy metal stress drives divergence in MKS and WYL populations, respectively. Our findings provide insights into adaptive divergence mechanisms in Picea and will contribute to molecular breeding studies.
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Quantitative Trait Loci (QTL) for oil content has been previously analyzed in a SG-DH population from a cross between a Chinese cultivar and a European cultivar of Brassica napus. Eight QTL with additive and epistatic effects, and with environmental interactions were evaluated. Here we present an integrated linkage map of this population predominantly based on informative markers derived from Brassica sequences, including 249 orthologous A. thaliana genes, where nearly half (112) are acyl lipid metabolism related genes. Comparative genomic analysis between B. napus and A. thaliana revealed 33 colinearity regions. Each of the conserved A. thaliana segments is present two to six times in the B. napus genome. Approximately half of the mapped lipid-related orthologous gene loci (76/137) were assigned in these conserved colinearity regions. QTL analysis for seed oil content was performed using the new map and phenotypic data from 11 different field trials. Nine significant QTL were identified on linkage groups A1, A5, A7, A9, C2, C3, C6 and C8, together explaining 57.79% of the total phenotypic variation. A total of 14 lipid related candidate gene loci were located in the confidence intervals of six of these QTL, of which ten were assigned in the conserved colinearity regions and felled in the most frequently overlapped QTL intervals. The information obtained from this study demonstrates the potential role of the suggested candidate genes in rapeseed kernel oil accumulation.
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Arabidopsis/genética , Brassica napus/genética , Mapeo Cromosómico , Fenotipo , Aceites de Plantas/análisis , Sitios de Carácter Cuantitativo/genética , Brassica napus/química , Estudios de Asociación Genética , Marcadores Genéticos/genética , Especificidad de la EspecieRESUMEN
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aß. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
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Enfermedad de Alzheimer/terapia , Potenciación a Largo Plazo/efectos de los fármacos , Glicoproteínas de Membrana/genética , Microglía/efectos de los fármacos , Placa Amiloide/terapia , Receptores Inmunológicos/genética , Memoria Espacial/efectos de los fármacos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inyecciones Intraventriculares , Potenciación a Largo Plazo/fisiología , Masculino , Glicoproteínas de Membrana/administración & dosificación , Glicoproteínas de Membrana/metabolismo , Ratones , Microglía/metabolismo , Microglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Fenotipo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Cultivo Primario de Células , Proteolisis , Receptores Inmunológicos/administración & dosificación , Receptores Inmunológicos/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Memoria Espacial/fisiología , Técnicas EstereotáxicasRESUMEN
The original version of this Article omitted the following from the end of the Acknowledgements: 'X.C. also received funding from the Shenzhen Basic Research Program JCYJ20170818140904167.' This has now been corrected in both the PDF and HTML versions of the Article.
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BACKGROUND: TREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer's disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined. METHODS: Potential binding of oligomeric amyloid-ß 1-42 (oAß1-42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAß1-42 to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAß1-42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAß1-42-bearing brain areas in vivo. RESULTS: We found that oAß1-42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aß bound to TREM2 supporting a specific interaction between oAß and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAß1-42. Furthermore, we identified several positively charged amino acids within residues 31-91 of TREM2 that were crucial for its interaction with oAß1-42. Importantly, oAß1-42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner. CONCLUSIONS: Our data establish a critical link between oAß1-42, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses.