RESUMO
Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 µg or 300/300/300 µg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 µg and 300/300/300 µg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov: NCT04075318 .
RESUMO
INTRODUCTION: Lewy body disease, a frequently observed co-pathology in Alzheimer's disease (AD), can be identified antemortem in cerebrospinal fluid (CSF) by α-synuclein seed amplification assay (αS-SAA). The prevalence and clinical impact of CSF αS-SAA positivity in AD are still unknown. METHODS: αS-SAA was performed on CSF samples from 240 AD patients (preclinical, prodromal, and dementia stages), 85 controls, 84 patients with Parkinson's disease (PD), and 21 patients with PD with dementia or dementia with Lewy bodies. In AD patients, associations between αS-SAA positivity and cognitive changes were also evaluated. RESULTS: In agreement with available neuropathological studies, αS-SAA positivity was observed in 30% of AD patients (vs 9% in controls), and was associated with cognitive decline, visuospatial impairment, and behavioral disturbances. DISCUSSION: αS-SAA positivity in AD patients reflects the prevalence observed in neuropathological series and is associated with a worse clinical outcome. These data confirm the validity of CSF αS-SAA positivity as biomarker of synucleinopathy.
Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Sinucleinopatias , Humanos , alfa-Sinucleína/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
Gadolinium-doped carbon dots (Gd-CDs), as a new class of nanomaterial, has a wide application prospect in targeted imaging and monitoring diagnosis and treatment of liver cancer because of their good fluorescence (FL)-magnetic resonance (MR) imaging properties. First, Gd-CDs were synthesized by hydrothermal method with gadodiamide as gadolinium source, citric acid as carbon source and silane coupling agent (KH-792) as coupling agent with FL quantum yield (QY) of 48.2%. Then, folic acid (FA), which is highly expressed in liver cancer, was used as a targeting component to modify Gd-CDs to obtain targeted imaging agent (Gd-CDs-FA). The results showed that Gd-CDs and Gd-CDs-FA have low cytotoxicity and good biocompatibility, and the targeting and selectivity of Gd-CDs-FA to HepG2 cells could be observed under confocal laser scanning microscope (CLSM). The T1 longitudinal relaxation rates (r1) of Gd-CDs and Gd-CDs-FA are 15.92 mM-1s-1 and 13.56 mM-1s-1, respectively. They showed good MR imaging ability in vitro and in vivo, and MR imaging in nude mice further proved the targeting imaging performance of Gd-CDs-FA. Therefore, Gd-CDs-FA with higher QY showed good FL-MR targeting imaging ability of liver cancer, which broke through the limitations of single molecular imaging probe in sensitivity and soft tissue resolution. This study provides a new idea for the application of Gd-CDs in FL and MR targeting imaging of liver cancer.
Assuntos
Neoplasias Hepáticas , Pontos Quânticos , Animais , Camundongos , Meios de Contraste , Fluorescência , Gadolínio , Carbono , Ácido Fólico , Camundongos Nus , Imageamento por Ressonância Magnética/métodos , Neoplasias Hepáticas/diagnóstico por imagemRESUMO
Haematococcus lacustris is a precious algal species renowned for its ability to simultaneous production of astaxanthin and lipid. However, its slow growth rate necessitates the development of appropriate mutagenesis methodologies to effectively enhance its synchronous production of both astaxanthin and lipid. This study introduced the co-mutation of Atmospheric and Room Temperature Plasma (ARTP) and ethanol. The performance and preliminary mechanisms underlying the combined accumulation of astaxanthin and lipid in H. lacustris under both mutations by ARTP and ethanol were comparatively analyzed. Combined astaxanthin and lipid contents relative to total cell mass in the 110-2 strain reached 54.4%, surpassing that of strain 0-3 and the control by 17.0% and 47.6% respectively. Transcriptome level analysis revealed how both ethanol and ARTP induction promote the expressions of carotenoid and lipid synthesis genes and related enzymatic activities. Upregulation of genes associated with cell activity contributed to lipid and astaxanthin metabolism in multi pathways.
Assuntos
Clorofíceas , Etanol , Temperatura , Etanol/metabolismo , Clorofíceas/metabolismo , Mutação/genética , Lipídeos , XantofilasRESUMO
Basal-like breast cancer (BLBC) is the most aggressive subtype with poor prognosis; however, the mechanisms underlying aggressiveness in BLBC remain poorly understood. In this study, we showed that in contrast to other subtypes, inositol monophosphatase 2 (IMPA2) was dramatically increased in BLBC. Mechanistically, IMPA2 expression was upregulated due to copy number amplification, hypomethylation of IMPA2 promoter and MYC-mediated transcriptional activation. IMPA2 promoted MI-PI cycle and IP3 production, and IP3 then elevated intracellular Ca2+ concentration, leading to efficient activation of NFAT1. In turn, NFAT1 up-regulated MYC expression, thereby fulfilling a positive feedback loop that enhanced aggressiveness of BLBC cells. Knockdown of IMPA2 expression caused the inhibition of tumorigenicity and metastasis of BLBC cells in vitro and in vivo. Clinically, high IMPA2 expression was strongly correlated with large tumor size, high grade, metastasis and poor survival, indicating poor prognosis in breast cancer patients. These findings suggest that IMPA2-mediated MI-PI cycle allows crosstalk between metabolic and oncogenic pathways to promote BLBC progression.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Retroalimentação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Regiões Promotoras GenéticasRESUMO
Acute kidney injury (AKI) is a serious disorder associated with significant morbidity and mortality. AKI and ischemia/reperfusion (hypoxia/reoxygenation, H/R) injury can be induced due to several reasons. Paeoniflorin (PF) is a traditional herbal medicine derived from Paeonia lactiflora Pall. It exerts diverse therapeutic effects, including anti-inflammatory, antioxidative, antiapoptotic, and immunomodulatory properties; thus, it is considered valuable for treating several diseases. However, the effects of PF on H/R injury-induced AKI remain unknown. In this study, we established an in vitro H/R model using COCL2 and investigated the functions and underlying mechanisms of PF on H/R injury in HK-2 cells. The cell vitality was evaluated using the cell count kit-8 assay. The DCFH-DA fluorescence probe was used to measure the levels of reactive oxygen species (ROS). Oxidative damage was detected using superoxide dismutase (SOD) and malondialdehyde (MDA) assay kits. Apoptotic relative protein and Keap1/Nrf2/HO-1 signaling were evaluated by Western blotting. Our results indicated that PF increased cell viability and SOD activity and decreased the ROS and MDA levels in HK-2 cells with H/R injury. PF inhibits apoptosis by increasing Bcl-2 and decreasing Bax. Furthermore, PF significantly upregulated the expression of HO-1 and Nrf2, but downregulated the expression of HIF-1α and Keap1. PF considerably increased Nrf2 nuclear translocation and unregulated the HO-1 expression. The Nrf2 inhibitor (ML385) could reverse the abovementioned protective effects of PF, suggesting that Nrf2 can be a critical target of PF. To conclude, we found that PF attenuates H/R injury-induced AKI by decreasing the oxidative damage via the Nrf2/HO-1 pathway and inhibiting apoptosis.
Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Fator 2 Relacionado a NF-E2/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais , Estresse Oxidativo , Apoptose , Hipóxia , Superóxido Dismutase , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
INTRODUCTION: Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example, atypical parkinsonisms like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Seed amplification assays (SAA), developed for the detection of α-synuclein (αSyn) aggregates in CSF, have been successful when used as a biomarker evaluation for synucleinopathies. In this study, we investigated the potential of this assay to not only detect αSyn seeds in CSF, but also discriminate between movement disorders. METHODS: The αSyn-SAA was tested in a Scandinavian cohort composed of 129 CSF samples from patients with PD (n = 55), MSA (n = 27), CBD (n = 7), and PSP (n = 16), as well as healthy controls (HC, n = 24). RESULTS: The αSyn seed amplification assay (αSyn-SAA) was able to correctly identify all PD samples as positive (sensitivity of 100%) while also discriminating the PD group from HC (70.8% specificity, p < 0.0001) and tauopathies [CBD (71% specificity) and PSP (75% specificity), p < 0.0001)]. The αSyn-SAA was also able to identify almost all MSA samples as positive for αSyn aggregation (sensitivity of 92.6%). In general, this assay is able to discriminate between the synucleinopathies and tauopathies analyzed herein (p < 0.0001) despite the overlapping symptoms in these diseases. CONCLUSION: These findings suggest the αSyn-SAA is a useful diagnostic tool for differentiating between different parkinsonian disorders, although further optimization may be needed.
Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Sinucleinopatias , Tauopatias , Humanos , alfa-Sinucleína , Transtornos Parkinsonianos/diagnóstico , Doença de Parkinson/diagnóstico , Atrofia de Múltiplos Sistemas/diagnósticoRESUMO
BACKGROUND: Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson's disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification. METHODS: In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. RESULTS: We found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates. CONCLUSIONS: Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.
Assuntos
Doença de Parkinson , Sinucleinopatias , Humanos , alfa-Sinucleína/química , Doença de Parkinson/diagnóstico , LipoproteínasRESUMO
BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. FINDINGS: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. INTERPRETATION: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts. FUNDING: PPMI is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity.
Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , alfa-Sinucleína/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Estudos Transversais , Anosmia , BiomarcadoresRESUMO
BACKGROUND: Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVES: The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline. METHODS: We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter-single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, and various cognitive and nonmotor scales. RESULTS: αS-SAA detected αSyn-seeds in baseline PD-CSF with 98% accuracy. αSyn-seeds were detected in 93% of the iRBD cases. αS-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-αSyn aggregation disorder. For synucleinopathies, αS-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression. CONCLUSIONS: Our results confirm αS-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. αS-SAA conditions reported here are highly sensitive, enabling the detection of αSyn-seeds in CSF from iRBD just months after the first symptoms, suggesting that αSyn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, αSyn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , alfa-Sinucleína , Humanos , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/química , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Transtorno do Comportamento do Sono REM/diagnóstico , Transtorno do Comportamento do Sono REM/metabolismo , Sinucleinopatias/diagnósticoRESUMO
Terpenes are the largest and most diverse class of plant specialized metabolites. Sesterterpenes (C25), which are derived from the plastid methylerythritol phosphate pathway, were recently characterized in plants. In Arabidopsis thaliana, four genes encoding geranylfarnesyl diphosphate synthase (GFPPS) (AtGFPPS1 to 4) are responsible for the production of GFPP, which is the common precursor for sesterterpene biosynthesis. However, the interplay between sesterterpenes and other known terpenes remain elusive. Here, we first provide genetic evidence to demonstrate that GFPPSs are responsible for sesterterpene production in Arabidopsis. Blockage of the sesterterpene pathway at the GFPPS step increased the production of geranylgeranyl diphosphate (GGPP)-derived terpenes. Interestingly, co-expression of sesterTPSs in GFPPS-OE (overexpression) plants rescued the phenotypic changes of GFPPS-OE plants by restoring the endogenous GGPP. We further demonstrated that, in addition to precursor (DMAPP/IPP) competition by GFPPS and GGPP synthase (GGPPS) in plastids, GFPPS directly decreased the activity of GGPPS through protein-protein interaction, ultimately leading to GGPP deficiency in planta. Our study provides a new regulatory mechanism of the plastidial terpenoid network in plant cells.
Assuntos
Arabidopsis , Dimetilaliltranstransferase , Terpenos/metabolismo , Dimetilaliltranstransferase/genética , Dimetilaliltranstransferase/metabolismo , Sesterterpenos/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Plastídeos/metabolismoRESUMO
Terpenoids are the most diverse class of plant primary and specialized metabolites, and trans-prenyltransferases (trans-PTs) are the first branch point to synthesize precursors of various chain lengths for further metabolism. Whereas the catalytic mechanism of the enzyme is known, there is no reliable method for precisely predicting the functions of trans-PTs. With the exponentially increasing number of available trans-PTs genes in public databases, an in silico functional prediction method for this gene family is urgently needed. Here, we present PTS-Pre, a web tool developed on the basis of the "three floors" model, which shows an overall 86% prediction accuracy for 141 experimentally determined trans-PTs. The method was further validated by in vitro enzyme assays for randomly selected trans-PTs. In addition, using this method, we identified nine new GFPPSs from different plants which are beyond the previously reported Brassicaceae clade, suggesting these genes may have occurred via convergent evolution and are more likely lineage-specific. The high accuracy of our blind prediction validated by enzymatic assays suggests that PTS-Pre provides a convenient and reliable method for genome-wide functional prediction of trans-PTs enzymes and will surely benefit the elucidation and metabolic engineering of terpenoid biosynthetic pathways.
Assuntos
Brassicaceae , Dimetilaliltranstransferase , Vias Biossintéticas , Brassicaceae/genética , Dimetilaliltranstransferase/genética , Dimetilaliltranstransferase/metabolismo , Terpenos/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to determine the sensitivity and specificity of α-synuclein seed amplification assay (αSyn-SAA) in antemortem and postmortem cerebrospinal fluid (CSF) of autopsy-confirmed patients with different distributions of pathological αSyn, co-pathologies, and clinical diagnoses. METHODS: The αSyn-SAA was used to test antemortem CSF samples from 119 subjects with a variety of clinical syndromes and standardized neuropathological examinations from Oregon Health and Science University (OHSU) and University of California San Diego (UCSD; 56 additional postmortem CSF samples available). The αSyn-SAA was also applied to frontal cortex and amygdala homogenates. Sensitivity and specificity were compared across distributions of αSyn pathology. Clinical data and co-pathologies were compared across αSyn-SAA positive and negative groups. RESULTS: Fifty-three individuals without and 66 with αSyn-pathology (neocortical [n = 38], limbic [n = 7], and amygdala-predominant [n = 21]) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the αSyn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue αSyn-SAA analyses also showed higher assay positivity in samples from limbic/neocortical cases. INTERPRETATION: CSF αSyn-SAA reliably identifies αSyn seeds in patients with diffuse αSyn pathology in the context of co-pathology and non-Lewy body disease (LBD) diagnoses. The analysis of brain homogenates suggests that pathological αSyn in the amygdala might differ from pathological αSyn in the frontal cortex. The αSyn-SAA might facilitate the differential diagnosis of dementias with mixed pathologies. ANN NEUROL 2022;92:650-662.
Assuntos
Encéfalo , alfa-Sinucleína , Encéfalo/patologia , Humanos , Sensibilidade e Especificidade , alfa-Sinucleína/metabolismoRESUMO
With the rapid growth of China's economy, the increase in water demand has threatened the sustainable development of groundwater. Construction of the South-to-North Water Diversion Project alleviated this problem. Zhengzhou, with a large population and high-intensity energy consumption, is a water-receiving city of the South-to-North Water Diversion Central Line Project (CLP). A series of ecological risks caused by the excessive exploitation of groundwater have been exposed. It is urgent to strengthen the assessment and management of groundwater to ensure sustainable development. In this study, the multi-criteria decision analysis (MCDA) underpinned the assessment of the sustainable groundwater development (ASGD) framework. Eight assessment factors were established based on the resource supply function (RSF) and eco-environment stability function (ESF). The novelty of this study lies in the integration of ASGD results with the impact of the CLP on the evolution of groundwater levels in Zhengzhou. Thus, more comprehensive and scientific management suggestions for groundwater development in Zhengzhou were obtained. GIS technology was integrated with the ASGD framework to identify five visualized areas: centralized groundwater supply area (8.61%), decentralized groundwater supply area (27.91%), vulnerable eco-environment area (14.34%), recharge protection area (45.67%), and unsuitable exploitation area (3.47%). The CLP changed the groundwater evolution pattern in Zhengzhou. The results showed that the operation of the CLP effectively slowed the decline in groundwater levels, thus confirming that the CLP has a positive impact on the rational utilization of groundwater. The disuse of two groundwater sources (G1 and G9) were able to enhance sustainable groundwater development. Meanwhile, five groundwater sources in the plain area proved unsuitable. Overall, this study provides a scientific basis for groundwater management in Zhengzhou City, while generating new ideas for sustainable groundwater development in cities affected by large-scale hydraulic projects worldwide.
Assuntos
Água Subterrânea , Desenvolvimento Sustentável , China , Cidades , Engenharia , Monitoramento Ambiental/métodos , Água Subterrânea/análise , Água/análiseRESUMO
Plants belonging to the genus Taraxacum are widespread all over the world, which contain rubber-producing and non-rubber-producing species. However, the genomic basis underlying natural rubber (NR) biosynthesis still needs more investigation. Here, we presented high-quality genome assemblies of rubber-producing T. kok-saghyz TK1151 and non-rubber-producing T. mongolicum TM5. Comparative analyses uncovered a large number of genetic variations, including inversions, translocations, presence/absence variations, as well as considerable protein divergences between the two species. Two gene duplication events were found in these two Taraxacum species, including one common ancestral whole-genome triplication and one subsequent round of gene amplification. In genomes of both TK1151 and TM5, we identified the genes encoding for each step in the NR biosynthesis pathway and found that the SRPP and CPT gene families have experienced a more obvious expansion in TK1151 compared to TM5. This study will have large-ranging implications for the mechanism of NR biosynthesis and genetic improvement of NR-producing crops.
Assuntos
Genoma de Planta , Borracha/metabolismo , Taraxacum/genética , Vias Biossintéticas , Elementos de DNA Transponíveis , Taraxacum/metabolismoRESUMO
Terpenes, the largest group of plant-specialized metabolites, have received considerable attention for their highly diverse biological activities. Monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and triterpenes (C30) have been extensively investigated at both the biochemical and molecular levels over the past two decades. Sesterterpenes (C25), an understudied terpenoid group, were recently described by plant scientists at the molecular level. This review summarizes the plant species that produce sesterterpenes and describes recent developments in the field of sesterterpene biosynthesis, placing a special focus on the catalytic mechanism and evolution of geranylfarnesyl diphosphate synthase and sesterterpene synthase. Finally, we propose several questions to be addressed in future studies, which may help to elucidate sesterterpene metabolism in plants.
Assuntos
Plantas/metabolismo , Sesterterpenos/metabolismoRESUMO
Class I terpene synthase (TPS) generates bioactive terpenoids with diverse backbones. Sesterterpene synthase (sester-TPS, C25), a branch of class I TPSs, was recently identified in Brassicaceae. However, the catalytic mechanisms of sester-TPSs are not fully understood. Here, we first identified three nonclustered functional sester-TPSs (AtTPS06, AtTPS22, and AtTPS29) in Arabidopsis thaliana. AtTPS06 utilizes a type-B cyclization mechanism, whereas most other sester-TPSs produce various sesterterpene backbones via a type-A cyclization mechanism. We then determined the crystal structure of the AtTPS18-FSPP complex to explore the cyclization mechanism of plant sester-TPSs. We used structural comparisons and site-directed mutagenesis to further elucidate the mechanism: (1) mainly due to the outward shift of helix G, plant sester-TPSs have a larger catalytic pocket than do mono-, sesqui-, and di-TPSs to accommodate GFPP; (2) type-A sester-TPSs have more aromatic residues (five or six) in their catalytic pocket than classic TPSs (two or three), which also determines whether the type-A or type-B cyclization mechanism is active; and (3) the other residues responsible for product fidelity are determined by interconversion of AtTPS18 and its close homologs. Altogether, this study improves our understanding of the catalytic mechanism of plant sester-TPS, which ultimately enables the rational engineering of sesterterpenoids for future applications.
Assuntos
Sesterterpenos/metabolismo , Terpenos/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Domínio Catalítico , Redes e Vias Metabólicas , FilogeniaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.