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Background: Atypical antipsychotics (AAPs)-induced sexual dysfunction (SD) is a frequent issue in clinical practice, often underestimated by clinicians and not extensively researched. The current study aimed to quantify the strength of association between the use of different AAPs and SD using real-world data from the FDA Adverse Event Reporting System (FAERS), as well as investigate the receptor mechanisms that are involved. Methods: Data from the FAERS database from the first quarter of 2004 to the third quarter of 2023 were queried through OpenVigil 2.1. Disproportionality analysis was estimated using the reporting odds ratio (ROR) and information component (IC) methods, and linear regression was used to investigate the relationship between ROR and receptor occupancy which was estimated using in vitro receptor binding profiles. Results: Our analysis yielded 4839 reports that co-mentioned AAP and SD events, and the findings revealed statistical associations between 12 AAPs and SD. The highest signal value was identified for iloperidone reporting retrograde ejaculation with iloperidone (ROR = 832.09, ROR025 = 552.77; IC = 9.58, IC025 = 6.36), followed by compulsive sexual behavior with aripiprazole (ROR = 533.02, ROR025 = 435.90; IC = 7.30, IC025 = 5.97), and psychosexual disorder for aripiprazole (ROR = 145.80, ROR025 = 109.57; IC025 = 6.47, IC025 = 4.86). Different characteristics of the SD side effects in each AAPs were discovered after further data mining. Regression analysis revealed potential effects for receptor occupancy of D2, D3, and 5-HT1A receptors on ROR. However, no significant correlation persisted following sensitivity analyses. Conclusion: This is the first study to investigate the AAP-SD associations by using FAERS. In this study, we report for the first time a significant association between aripiprazole and SD based on real-world data. The study suggests that different AAPs have varying levels of association with SD, and the D2, D3, and 5-HT1A receptor occupancy may contribute to potential mechanisms. The findings of this study warrant further validation of more studies and clinical causality assessment.
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TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.
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Esclerose Lateral Amiotrófica , Disfunção Cognitiva , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Proteinopatias TDP-43 , Humanos , Animais , Camundongos , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Modelos Animais de Doenças , RNARESUMO
Tau-mediated toxicity is associated with cognitive decline and Alzheimer's disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration.
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H. virescens is a perennial herbaceous plant with highly tolerant to cold weather, but the key genes that respond to low temperature stress still remain unclear. Hence, RNA-seq was performed using leaves of H. virescens treated at 0 °C and 25 °C for 12 h, 36 h, and 60 h, respectively, and a total of 9416 DEGs were significantly enriched into seven KEGG pathways. The LC-QTRAP platform was performed using leaves of H. virescens leaves at 0 °C and 25 °C for 12 h, 36 h, and 60 h, respectively, and a total of 1075 metabolites were detected, which were divided into 10 categories. Additionally, 18 major metabolites, two key pathways, and six key genes were mined using a multi-omics analytical strategy. The RT-PCR results showed that with the extension of treatment time, the expression levels of key genes in the treatment group gradually increased, and the difference between the treatment group and the control group was extremely significant. Notably, the functional verification results showed that the key genes positively regulated cold tolerance of H. virescens. These results can lay a foundation for the in-depth analysis of the mechanism of response of perennial herbs to low temperature stress.
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Perfilação da Expressão Gênica , Transcriptoma , Temperatura , Poaceae , Metabolômica , Temperatura Baixa , Regulação da Expressão Gênica de PlantasRESUMO
Background: GRAS transcription factors play a variety of functions in plant growth and development and are named after the first three transcription factors GAI (GIBBERRELLICACIDINSENSITIVE), RGA (REPRESSOROFGAI), and SCR (SCARECROW) found in this family. Oat (Avena sativa) is one of the most important forage grasses in the world. However, there are few reports on the GRAS gene family in oat. Methods: In order to understand the information and expression pattern of oat GRAS family members, we identified the GRAS members and analyzed their phylogenetic relationship, gene structure, and expression pattern in oat by bioinformatics technology. Results: The results showed that the oat GRAS family consists of 30 members, and most of the AsGRAS proteins were neutral or acidic proteins. The phylogenetic tree divided the oat GRAS members into four subfamilies, and each subfamily has different conservative domains and functions. Chromosome location analysis suggested that 30 GRAS genes were unevenly distributed on five chromosomes of oat. The results of real-time quantitative reverse transcription-PCR (qRT-PCR) showed that some AsGRAS genes (AsGRAS12, AsGRAS14, AsGRAS21, and AsGRAS24) were all up-regulated with increasing stress treatment time.The results of this study provide a theoretical basis for further research into the corresponding stress of oat. Therefore, further studies concentrating on these AsGRAS genes might reveal the many roles played by GRAS genes in oat.
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Avena , Genoma de Planta , Avena/genética , Filogenia , Genoma de Planta/genética , Perfilação da Expressão Gênica/métodos , Família Multigênica/genética , Fatores de Transcrição/genética , Estresse Fisiológico/genéticaRESUMO
Helictotrichon virescens is a perennial herbaceous plant with a life expectancy of about 10 years. It has high cold and heat resistance and can successfully survive over winter in the habitats with a temperature range of -25 to 25°C. Therefore, this study aimed to identify the key genes regulating low-temperature stress responses in H. virescens and analyze cold tolerant at molecular level. This study used RNA sequencing (RNA-Seq) and weighted gene co-expression network analysis (WGCNA) to identify the hub genes associated with cold tolerance in H. virescens. RT-PCR was conducted, homologous genes were identified, and related bioinformatics were analyzed to verify the identified hub genes. Moreover, WGCNA analysis showed that only the brown module had the highest correlation with the active-oxygen scavenging enzymes [peroxide (POD), superoxide dismutase (SOD), and catalase (CAT)]. The expression levels of three hub genes in the brown module (Cluster-37118.47362, cluster-37118.47713, and cluster-37118.66740) were significantly higher under low-temperature stress than those under control conditions. Furthermore, gene ontology (GO) and KEGG annotations showed that the three hub genes were mainly enriched in the metabolism pathways of sphingolipids, selenocompounds, glyoxylate, and dicarboxylate, carotenoids biosynthesis, and other biological pathways. The results of this study also showed that the subcellular localization prediction results showed that the cold tolerance hub genes were all localized to the plasma membrane. By constructing a protein interaction network, it was found that the hub gene Cluster-37118.66740 interacted with Sb09g003460.1 and Sb04g020180.1 proteins in Sorghum bicolor. By constructing phylogenetic trees of the four species of H. virescens, Sorghum bicolo, Oryza sativa Japonica, and Arabidopsis thaliana, the results showed that, the hub gene Cluster 37118.66740 (of H. virescens) and Os03g0340500 (of Oryza sativa Japonica) belonged to the same ancestral branch and were in the same subfamily. Thus, this study provides methodology and guidance to identify the cold tolerance genes for other herbage and their cold tolerant molecular mechanisms at molecular level.
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A total of 14 Festuca sinensis seed lots were collected from different geographical locations on the Qinghai-Tibet Plateau to study the seed microbiota and determine the abiotic (temperature, precipitation, and elevation) and biotic (Epichloë sinensis infection rate) factors likely to shape the seed microbiome. The 14 seed lots had different bacterial and fungal structures and significantly different diversities (p < 0.05). The α-diversity indices of the bacteria were significantly correlated with precipitation (p < 0.05), whereas those of the fungi were significantly correlated with temperature (p < 0.05). Microbiota analysis showed that Proteobacteria, Cyanobacteria, and Bacteroidetes were the most abundant bacteria at the phylum level in the seeds, and Ascomycota and Basidiomycota were the most abundant fungi. ß-diversity analysis suggested large differences in the microbial communities of each sample. Redundancy analysis showed that temperature and precipitation were the main environmental factors that drive variations in the microbial community, at the medium-high elevation (3,000-4,500 m), the impact of temperature and precipitation on microbial community is different, and the other elevations that effect on microbial community were basically identical. Spearman's correlation analysis showed that the relative abundances of the most abundant bacterial phyla were significantly correlated with temperature (p < 0.05), whereas those of the most abundant fungal phyla were significantly correlated with precipitation (p < 0.05). E. sinensis infection rates were significantly correlated with elevation and temperature (p < 0.05). These results suggest that temperature and precipitation are the key factors driving the microbial community, that temperature and elevation also had a great influence on the E. sinensis infection rate, and that environmental factors (temperature and elevation) may further affect the microbial community by regulating the E. sinensis infection rate.
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Raising crops production via improving photosynthesis has always been focused. Recently excavating and increasing the photosynthetic capacity of non-leaf organs becomes an important approach to crops yield increase. Here we studied the photosynthetic characteristics of the flag leaf and the non-leaf organs including the sheath, the glume and the lemma under greenhouse. The relative water content (RWC), the stomatal characteristics, the photosynthetic pigment contents, the enzyme activities in C3 and C4 pathway and the malate content of the flag leaf and the non-leaf organs on 7, 14, 21, and 28 days after anthesis (denoted by 7DAA, 14DAA, 21DAA, and 28DAA) were determined under well-watered (CK) and water-stressed (D) treatments. Drought stress significantly reduced the RWC of the flag leaf and the non-leaf organs, while the variation of RWC in the glume and the lemma was lower than in the flag leaf. The chlorophyll a content, the chlorophyll b content, the total chlorophyll content and the xanthophyll content in the flag leaf were significantly decreased under D. However, drought stress significantly increased the photosynthetic pigment contents in the glume at the late stage (21DAA and 28DAA). In addition, the induced activities of PEPC, NADP-MDH, NADP-ME, NAD-ME, and PPDK in non-leaf organs under drought stress suggested that the C4 photosynthetic pathway in non-leaf organs compensated the limited C3 photosynthesis in the flag leaf. Non-leaf organs, in particular the glume, showed the crucial function in maintaining the stable photosynthetic performance of oat.
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The posttranslational regulation of the neuronal proteome is critical for brain homeostasis but becomes dysregulated in the aged or diseased brain, in which abnormal posttranslational modifications (PTMs) are frequently observed. While the full extent of modified substrates that comprise the "PTM-ome" are slowly emerging, how the upstream enzymes catalyzing these processes are regulated themselves is not well understood, particularly in the context of neurodegeneration. Here, we describe the reciprocal regulation of a kinase, the microtubule affinity-regulating kinase 2 (MARK2), and an acetyltransferase, CREB-binding protein (CBP), two enzymes known to extensively modify tau proteins in the progression of Alzheimer's disease. We found that MARK2 negatively regulates CBP and, conversely, CBP directly acetylates and inhibits MARK2 kinase activity. These findings highlight a reciprocal negative feedback loop between a kinase and an acetyltransferase, which has implications for how PTM interplay is coordinated on substrates including tau. Our study suggests that PTM profiles occur through the posttranslational control of the master PTM remodeling enzymes themselves.
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Proteína de Ligação a CREB/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Acetiltransferases/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Retroalimentação , Humanos , Camundongos , Microtúbulos/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Kengyilia hirsuta is an important pioneer plant distributed on the desertified grassland of the Qinghai-Tibet Plateau. It has strong adaptability to alpine desert habitats, so it can be used as a sand-fixing plant on sandy alpine land. To study the response mechanisms of root morphological and physiological characteristics of K. hirsuta to sandy soil moisture, 10%, 25% and 40% moisture levels were set up through potted weighing water control method. The biomass, root-shoot ratio, root architecture parameters, and biochemical parameters malondialdehyde, free proline, soluble protein, indole-3-acetic acid, abscisic acid, cytokinin, gibberellin, relative conductivity and antioxidant enzyme activities were measured in the trefoil stage, and the response mechanisms of roots at different moisture levels were analyzed. The results showed that with the increase of soil moisture, root morphological indexes such as root biomass, total root length, total root volume and total root surface increased, while the root topological index decreased continuously. The malondialdehyde content, relative conductivity, superoxide dismutase activity, peroxidase activity, catalase activity, free proline content, soluble protein content, abscisic acid content and cytokinin content at the 25% and 40% moisture levels were significantly decreased compared with the 10% level (P< 0.05). Thus, the root growth of K. hirsuta was restricted by the 10% moisture level, but supported by the 25% and 40% moisture levels. An artificial neural network revealed that total root length, total root surface area, root link average length, relative conductivity, soluble protein, free proline and moisture level were the key factors affecting root development. These research results could contribute to future agricultural sustainability.
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The prion-like spread of tau pathology could underlie a spectrum of clinical syndromes including Alzheimer's disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau seeds are processed in neurons. Here, we analyze fibrillar wild-type and disease-associated P301L tau seeds by using in vitro and neuronal assays. We show that P301L seeds are uniquely modified by post-translational modifications (PTMs) within the microtubule-binding region (MTBR). Although these modifications do not alter tau seed trafficking or localization, acetylated tau variants show accelerated tau aggregation, enhanced tau PTM priming, and prion-like templating. To explain the enhanced tau seed acetylation, we demonstrate that P301L seeds undergo auto-acetylation. Moreover, tau acts generally to inhibit HDAC6 deacetylase activity by preventing HDAC6 phosphorylation, leading to increased substrate acetylation. Our study highlights complex post-translational regulation of transmissible tau seeds and provides insight into the biological properties of tau strains in AD and other tauopathies.
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Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Animais , Humanos , CamundongosRESUMO
Salix cupularis is a common shrub for ecological restoration of the desertified alpine meadow on the Tibetan Plateau. However, the effect of S. cupularis on spatial heterogeneity of soil resources (i.e., resource islands effect) has not been systematically evaluated, and the influence of shrub patches on the rehabilitation of understory herbs has also been unknown. In this study, we randomly selected S. cupularis individuals in the early restoration stage of desertified alpine meadow, where the three native forages (Elymus nutans, Elymus sibiricus and Festuca sinensis) were sown at different microsites around S. cupularis to explore the effects of S. cupularis on soil resources and emergence rates of the native forages. The results showed that S. cupularis significantly increased SWC (soil water content), C (carbon) and N (nitrogen) nutrients (p < 0.01) and enzyme activities (p < 0.05) under canopy compared with the bare land, and the improvement performed better in the topsoil (0-5 cm) than in the subtop-soil (5-15 cm). Moreover, the soil properties were affected significantly by microsites around S. cupularis, resulting in regular changes of SWC, nutrients and enzyme activities in different microsites (Shrub center > Middle of canopy radius > Bare land). In addition, there are significant regression relationships between emergence rates and enriching soil water, C and N nutrients, so the emergence rates of native forages under canopy may be improved significantly with the enriched soil resources, especially for E. nutans. As a result, S. cupularis is a suitable pioneer shrub for the vegetation restoration of desertified alpine meadow on the Tibetan Plateau, because it could not only shape the enrichment of soil resources under canopy, but also facilitate emergence of companion forages in the process of vegetation restoration.
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Pradaria , Salix , Ecossistema , Humanos , Ilhas , Nitrogênio/análise , Plântula/química , Solo , TibetRESUMO
The rhizosheath is a critical interface supporting the exchange of resources between plants and their associated environment of soil. Favorable microenvironment of rhizosphere soil provides the rhizosheath formed and then promotes desert plant survival. However, it remains unclear how rhizosheath benefits the colonization of pioneer plants in alpine desert under changing environment. In this study, we investigated the effect of different soil moisture and sterilization treatments (three moisture levels and unsterilized or sterilized soil) on rhizosheath forming process of Kengyilia hirsuta (K. hirsuta), a sand-inhabiting and drought-resistant pioneer plant of the Tibetan Plateau desert. The results showed that in both unsterilized and sterilized soil, increasing soil moisture first increased and then decreased rhizosheath weight, with the highest value is 25%. During rhizosheath formation, developing rhizosheaths were selectively enriched in the bacterial genera Massilia and Arthrobacter. These suggest the existence of a highly specialized signal recognition system during rhizosheath formation that involves the accumulation of bacteria. These bacterial species exhibited different roles in the process of rhizosheath formation and is an advantageous strategy for K. hirsuta.
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Six perennial herbs (Plantago asiatica, Polygonum viviparum, Anaphalis lactea, Kobresia humilis, Leontopodium nanum and Potentilla chinensis) widely distributed in alpine meadows were reciprocally transplanted at two sites in eastern edge of Qinghai-Tibetan Plateau, Hongyuan (3434 m, 2.97 °C, 911 mm) and Qilian (3701 m, 2.52 °C, 472 mm), aiming to evaluate the responses of alpine plants to changing environments. When plants were transplanted from Hongyuan to Qilian, most plant species showed a decrease of total wax coverage in first year and reverse trend was observed for some plant species in second year. However, when plants were transplanted from Qilian to Hongyuan, the response of total wax coverage differed greatly between plant species. When compared with those in first year, plasticity index of average chain length of alkane decreased whereas carbon preference index of alkane increased at both Hongyuan and Qilian in second year. The total wax coverage differed between local and transplanted plants, suggesting both environmental and genetic factors controlled the wax depositions. Structural equation modeling indicated that co-variations existed between leaf cuticular waxes and leaf functional traits. These results suggest that alpine herbs adjust both wax depositions and chain length distributions to adapt to changing environment, showing climate adaptations.
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Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.
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Disfunção Cognitiva/patologia , Desacetilase 6 de Histona/metabolismo , Tauopatias/patologia , Proteínas tau/metabolismo , Acetilação , Idoso , Idoso de 80 Anos ou mais , Animais , Encéfalo/patologia , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Desacetilase 6 de Histona/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação , Processamento de Proteína Pós-Traducional , Tauopatias/genética , Proteínas tau/genéticaRESUMO
The prediction of the potential distribution of invasive alien species is key for the control of their proliferation. This study developed ensemble niche models to explore the distribution patterns of Cecropia peltata and Ulex europaeus under baseline and future conditions, as well as the factors that regulate them. The models were based on occurrence records as well as climate, land-use and topography datasets. Climatic factors played a stronger role than land-use and topographical factors in their distribution patterns. Additionally, temperature seasonality and temperature annual range were the optimal predictor for the global distributions of C. peltata and U. europaeus, respectively. Under the baseline-RCP 8.5 scenario in 2070, significant increases in habitat suitability for C. peltata were generally detected in tropical regions, while for U. europaeus under the same condition, significant increases in habitat suitability were generally observed in west coast of South America and Europe, suggesting the impacts of climate changes on species distribution may be species specific. The contrast changes of suitable habitat areas for U. europaeus under the baseline-2.6 and 8.5 scenarios may suggest that the scenarios of climate changes may modify its distribution patterns and variations in suitable habitats. The double-edged effects of global warming on plant invasions may be a result of the scenario specific climate change and the species-specific responses to changes in climate. Our findings highlight the importance of climate change scenario specific and species-specific research on the impact of climate change on plant invasions.
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Mudança Climática , Espécies Introduzidas , Ecossistema , Europa (Continente) , América do SulRESUMO
BACKGROUND: Accumulation of somatic mutations caused by both endogenous and exogenous exposures is a high risk for human health, in particular, cancer. Efficient detection of somatic mutations is crucial for risk assessment of different types of exposures. Due to its requirement in the process of attaching glycosylphatidylinositol- (GPI-) anchored proteins to the cell surface, the PIG-A gene located on the X-chromosome is used in both in vivo and in vitro mutation assays. Loss-of-function mutations in PIG-A lead to the elimination of GPI-anchored proteins such that they can no longer be detected on the cell surface by antibodies. Historically, mutation assays based on the PIG-A gene rely on the staining of these cell-surface proteins by antibodies; however, as with any antibody-based assay, there are major limitations, especially in terms of variability and lack of specific antibodies. RESULTS: In the current study, we developed a modified PIG-A mutation assay that uses the expression of GPI-anchored fluorescent proteins (henceforth referred to as a GPI-sensor), whereby the presence of fluorescence on the cell membrane is dependent on the expression of wild-type PIG-A. Using our modified PIG-A mutation assay, we have achieved complete separation of wild type cells and spontaneously mutated cells, in which the presence of PIG-A mutations has been confirmed via proaerolysin resistance and gene sequencing. CONCLUSION: This study establishes a novel PIG-A mutation assay using GPI-anchored fluorescent protein expression that eliminates the need for antibody-based staining. This GPI-sensor PIG-A mutation assay should be widely applicable for accurate and efficient testing of genotoxicity for use in many mammalian and vertebrate cells.
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Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches.
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Tauopatias/patologia , Proteínas tau/metabolismo , Acetilação , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Estimativa de Kaplan-Meier , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Fosforilação , Receptores de N-Metil-D-Aspartato/metabolismo , Tauopatias/metabolismo , Tauopatias/mortalidade , Proteínas tau/genéticaRESUMO
Heterozygous mutations in PTEN, which encodes a negative regulator of the mTOR and ß-catenin signaling pathways, cause macrocephaly/autism syndrome. However, the neurobiological substrates of the core symptoms of this syndrome are poorly understood. Here, we investigate the relationship between cerebral cortical overgrowth and social behavior deficits in conditional Pten heterozygous female mice (Pten cHet) using Emx1-Cre, which is expressed in cortical pyramidal neurons and a subset of glia. We found that conditional heterozygous mutation of Ctnnb1 (encoding ß-catenin) suppresses Pten cHet cortical overgrowth, but not social behavioral deficits, whereas conditional heterozygous mutation of Mtor suppresses social behavioral deficits, but not cortical overgrowth. Neuronal activity in response to social cues and excitatory synapse markers are elevated in the medial prefrontal cortex (mPFC) of Pten cHet mice, and heterozygous mutation in Mtor, but not Ctnnb1, rescues these phenotypes. These findings indicate that macroscale cerebral cortical overgrowth and social behavioral phenotypes caused by Pten haploinsufficiency can be dissociated based on responsiveness to genetic suppression of Ctnnb1 or Mtor. Furthermore, neuronal connectivity appears to be one potential substrate for mTOR-mediated suppression of social behavioral deficits in Pten haploinsufficient mice. Autism Res 2019, 12: 1463-1471. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A subgroup of individuals with autism display overgrowth of the head and the brain during development. Using a mouse model of an autism risk gene, Pten, that displays both brain overgrowth and social behavioral deficits, we show here that that these two symptoms can be dissociated. Reversal of social behavioral deficits in this model is associated with rescue of abnormal synaptic markers and neuronal activity.
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Comportamento Animal , Haploinsuficiência/genética , PTEN Fosfo-Hidrolase/genética , Supressão Genética/genética , Sinapses/genética , Serina-Treonina Quinases TOR/genética , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Transdução de Sinais/genéticaRESUMO
Angelica dahurica is a widely grown plant species with multiple uses, especially in the medical field. However, the frequent introduction of A. dahurica to new areas has made it difficult to distinguish between varieties. Simple sequence repeats (SSRs) detected based on transcriptome analyses are very useful for constructing genetic maps and analyzing genetic diversity. They are also relevant for the molecular marker-assisted breeding of A. dahurica. We identified 33,724 genic SSR loci based on transcriptome sequencing data. A total of 114 primer pairs were designed for the SSR loci and were tested for their specificity and diversity. Ten SSR loci in untranslated regions were ultimately selected. Subsequently, 56 A. dahurica ecotypes collected from different regions were analyzed. The SSR loci comprised 2-8 alleles, with a mean of 5.2 alleles per locus. The polymorphic information content value and Shannon's information index were 0.6274-0.2702 (average of 0.4091) and 1.3040-0.5618 (average of 0.8475), respectively. Thus, the 10 novel SSRs identified in this study were almost in accordance with Harvey-Weinberg equilibrium and will be useful for analyzing A. dahurica genetic relationships. The results of this study confirm the potential value of transcriptome databases for the development of new SSR markers.