3,114 research outputs found
Endoplasmic Reticulum Stress Is Important for the Manifestations of alpha-Synucleinopathy In Vivo
No full textAccumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-synucleinopathy. Using the A53T mutanthuman αS transgenic (A53T αS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperones in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2 α, indicating that α-synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53T αS Tg mouse model and the adeno-associated virus-transduced rat model of A53T αS-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies
Toxic alpha-synuclein oligomer accumulation and endoplasmic reticulum stress is mechanistically linked to alpha-synucleinopathy in vivo
No full textIn Parkinson's disease (PD) and other α-synucleinopathies, prefibrillar α-synuclein (αS) oligomer is implicated in the pathogenesis. However, toxic αS oligomers observed using in vitro systems are not generally seen to be associated with α-synucleinopathy in vivo. Thus, the pathologic significance of αS oligomers to αS neurotoxicity is unknown. Herein, we show that, αS that accumulate within endoplasmic reticulum (ER)/microsome forms toxic oligomers in mouse and human brain with the α-synucleinopathy. In the mouse model of α-synucleinopathy, αS oligomers initially form before the onset of disease and continue to accumulate with the disease progression. Significantly, treatment of αS transgenic mice with Salubrinal, an anti-ER stress compound that delays the onset of disease, reduces ER accumulation of αS oligomers. These results indicate that αS oligomers with toxic conformation accumulate in ER, and αS oligomer-dependent ER stress is pathologically relevant for PD
Accumulation of Toxic alpha-Synuclein Oligomer within Endoplasmic Reticulum Occurs in alpha-Synucleinopathy In Vivo
No full textIn Parkinson's disease (PD) and other α-synucleinopathies, prefibrillar α-synuclein (αS) oligomer is implicated in the pathogenesis. However, toxic αS oligomers observed using in vitro systems are not generally seen to be associated with α-synucleinopathy in vivo. Thus, the pathologic significance of αS oligomers to αS neurotoxicity is unknown. Herein, we show that, αS that accumulate within endoplasmic reticulum (ER)/microsome forms toxic oligomers in mouse and human brain with the α-synucleinopathy. In the mouse model of α-synucleinopathy, αS oligomers initially form before the onset of disease and continue to accumulate with the disease progression. Significantly, treatment of αS transgenic mice with Salubrinal, an anti-ER stress compound that delays the onset of disease, reduces ER accumulation of αS oligomers. These results indicate that αS oligomers with toxic conformation accumulate in ER, and αS oligomerdependent ER stress is pathologically relevant for PD
Perancangan Sistem Informasi Pengelola Barang/Inventaris Di Jc Komp
No full textInventory information system is a system used to enter inventory data into the database, so that there are no errors in input, output data, and reporting based on the desired data. based on surveys and interviews with jc comp personnel, information was obtained that the existing system in the jc comp warehouse section is still manual. therefore, the system that will be created by the author is the result of a replication of the existing system in the jc comp warehouse section. in addition to the process of input and output of goods, this information system is also equipped with features for creating data reports, input and output of goods, and searching for goods data by item name. with the inventory information system is expected to be useful for the warehouse parts jc comp. By implementing this system in the jc comp warehouse, it is hoped that it can reduce errors that may occur. this system is also expected to further speed up the process of input, output, and report generation, which in turn will help the jc comp warehouseSistem Informasi Persediaan Barang adalah sebuah sistem yang digunakan untuk memasukkan data-data persediaan barang ke dalam database, sehinggga tidak terjadi kesalahan dalam input, output data, dan pembuatan laporan berdasarkan data yang diinginkan. Berdasarkan survey dan wawancara dengan bagian personalia Jc Komp, didapatkan informasi bahwa sistem yang ada dibagian gudang Jc Komp masih manual. Oleh karena itu, sistem yang akan dibuat oleh penulis adalah hasil replikasi dari sistem yang telah ada dibagian gudang Jc Comp. Selain proses input dan output barang, pada sistem informasi ini juga dilengkapi fitur pembuatan laporan data, input, dan output barang, dan pencarian data barang berdasarkan nama barang. Dengan adanya Sistem Informasi persediaan barang ini diharapkan dapat bermanfaat bagi bagian gudang Jc Komp. Dengan diterapkannya sistem ini pada bagian gudang Jc Comp, maka diharapkan dapat mengurangi kesalahan-kesalahan yang mungkin terjadi. Sistem ini juga diharapkan dapat lebih mempercepat proses input, output, dan pembuatan laporan yang pada akhirnya dapat membantu bagian gudang Jc Komp
Amenable L-2-Theoretic Methods and Knot Concordance
No full textWe reveal new structures in the topological knot concordance group. As a key ingredient, we develop obstructions using L-2-theoretic methods for amenable groups in Strebel's class recently introduced by Orr and the author. Concerning (h)-solvable knots, which are defined in terms of certain Whitney towers of height h in bounding 4-manifolds, we show the following: for any n>1, there are (n)-solvable but non-(n. 5)-solvable (and therefore nonslice) knots, which are not detected by prior methods using Cochran-Orr-Teichner L-2-signature obstructions as well as Levine algebraic obstructions and Casson-Gordon invariants.X1197sciescopu
Dynamics of Network Formation Processes in the Co-Author Model
No full textThis article studies the dynamics in the formation processes of a mutual consent network in game theory setting: the Co-Author Model. In this article, a limited observation is applied and analytical results are derived. Then, 2 parameters are varied: the number of individuals in the network and the initial probability of the links in the network in its initial state. A simulation result shows a finding that is consistent with an analytical result for a state of equilibrium while it also shows different possible equilibria.Dynamics, Network, Game Theory, Model,Simulation, Equilibrium, Complexity
High-level polyomavirus JC viruria following long-term steroid therapy
No full textCASE REPORT JC virus is a highly seroprevalent ubiquitous polyomavirus which is acquired at an early age through respiratory or oral route, Thereafter JCV establishes persistent, but mainly asymptomatic, infections in various tissues, including the genitourinary tract and brain Corresponding author Cristina Costa, MD S.C.D.U. Virologia Azienda Ospedaliero-Universitaria San Giovanni Battista di Torino Via Santena, 9 -10126 Torino E-mail: [email protected] increasing with age, with adult prevalence rate often between 15% and 60
Engineering Framework to Utilize Miniaturized Charpy Type SE(B) Specimens to Predict Jc of Full Sized Specimens
No full textAbstractThis paper introduces our experience of using miniature Charpy type SE(B) specimen in obtaining fracture toughness Jc of a material in the ductile to brittle transition temperature (DBTT) region. Width W x thickness B of 2 x 2 mm, 3 x 3 mm and 10 x 10 mm were chosen as miniature specimens and 25 x 25 mm were chosen as full sized specimen. 0.55% carbon steel JIS S55C, whose tensile to yield stress ratio σTS/σYS was equal to 1.8 was chosen as a material to simulate a degraded (embrittled) material in the DBTT region. Focus was placed on whether cleavage fracture could be predicted for these miniaturized specimens. Another focus was placed on whether the Jc of full sized specimen is predictable from the test results of the miniature sized specimens, in case cleavage fracture were observed. The results showed that the modified Ritch-Knott-Rice (RKR) failure criterion (which predicts the onset of cleavage fracture when the crack opening stress measured at 4 times the crack-tip opening displacement exceeds this σ22c) could predict whether cleavage fracture would occur or not. Another finding was that, in case cleavage fracture was observed though, the critical value σ22c in the modified RKR failure criterion was independent of specimen size, and thus, Jc of the full sized specimen is predictable from the miniature specimen test results, though M = (W-a)σYS/Jc was smaller than ASTM E1921 requirement of 30. Here, a and σYS are crack length and yield strength, respectively
One-day-ahead electricity demand forecasting in holidays using discrete-interval moving seasonalities
No full text[EN] Transmission System Operators provide forecasts of electricity demand to the electricity system. The producers and sellers use this information to establish the next day production units planning and prices. The results obtained are very accurate. However, they have a great deal with special events forecasting. Special events produce anomalous load conditions, and the models used to provide predictions must react properly against these situations. In this article, a new forecasting method based on multiple seasonal Holt-Winters modelling including discrete-interval moving seasonalities is applied to the Spanish hourly electricity demand to predict holidays with a 24-h prediction horizon. It allows the model to integrate the anomalous load within the model. The main results show how the new proposal outperforms regular methods and reduces the forecasting error from 9.5% to under 5% during holidays.The authors would like to thank the Spanish Ministry of Science, Innovation and Universities for the support under the project TIN201788209C2; and Red Electrica de Espana S.A. for providing the data used in this article.Trull, O.; García-Díaz, JC.; Troncoso, A. (2021). One-day-ahead electricity demand forecasting in holidays using discrete-interval moving seasonalities. Energy. 231:1-12. https://doi.org/10.1016/j.energy.2021.120966S11223
Clinicopathologic features of frontotemporal dementia with progranulin sequence variation
No full textBACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A→G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A→G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS
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