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1.
Sci Rep ; 14(1): 12690, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830916

RESUMO

A random initialization of the search particles is a strong argument in favor of the deployment of nature-inspired metaheuristic algorithms when the knowledge of a good initial guess is lacked. This article analyses the impact of the type of randomization on the working of algorithms and the acquired solutions. In this study, five different types of randomizations are applied to the Accelerated Particle Swarm Optimization (APSO) and Squirrel Search Algorithm (SSA) during the initializations and proceedings of the search particles for selective harmonics elimination (SHE). The types of randomizations include exponential, normal, Rayleigh, uniform, and Weibull characteristics. The statistical analysis shows that the type of randomization does impact the working of optimization algorithms and the fittest value of the objective function.

2.
Cesk Slov Oftalmol ; 80(Ahead of print): 1-6, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38925893

RESUMO

AIM: To compare functional and anatomical outcomes between the inverted flap technique and conventional removal of the internal limiting membrane (ILM) in the surgical management of idiopathic macular hole (IMH). MATERIAL AND METHODS: We retrospectively evaluated the anatomical and functional results in 67 eyes of 65 patients operated on for IMH. The patients were operated on either using the conventional ILM peeling technique (first group) or with the inverted ILM flap technique (second group). 43 eyes of 41 patients were included in the first group, 24 eyes of 24 patients in the second group. We indicated for surgery only patients with IMH stage 2-4 according to the Gasse classification. Best corrected visual acuity (VA) was always determined before and two months after surgery. Furthermore, a comparison of both techniques was made according to the average letter gain after surgery, and the effect of surgery was evaluated using OCT with regard to whether IMH closure succeeded. For both techniques, 25G PPV with SF6 tamponade was performed. RESULTS: Hole closure took place in 41 eyes with conventional ILM removal. In one eye, the hole did not close even after reoperation with the same technique. Median ETDRS letter gain was 7.0. VA remained the same in 2 eyes (4.7%), worsened in 7 cases (16.2%), and improved in all other cases (79.0%). In 16 eyes (37.2%), VA improved by 2 or more lines of ETDRS charts. Using the inverted flap technique, the hole was closed in all 24 monitored eyes. Median ETDRS letter gain was 9.5. VA remained the same in 2 eyes (8.3%), worsened in 2 cases (8.3%), and improved in all other cases (83.3%). In 12 eyes (50.0%), VA improved by 2 or more lines of ETDRS charts. There were no serious complications intraoperatively or postoperatively. CONCLUSION: Our study demonstrated the safety and efficacy of both methods. Although the results were not statistically significant, the inverted flap technique recorded a greater ETDRS letter gain (9.5 vs. 7.0) and proportion of closed holes (100% vs. 95.3%) compared to the conventional ILM peeling technique in our set of eyes.


Assuntos
Perfurações Retinianas , Retalhos Cirúrgicos , Acuidade Visual , Vitrectomia , Humanos , Estudos Retrospectivos , Perfurações Retinianas/cirurgia , Vitrectomia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso
3.
Sci Rep ; 14(1): 8614, 2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38616206

RESUMO

This paper presents a naïve back propagation (NBP) based i cos ∅ technique implemented to a cascaded multilevel inverter (MLI) based shunt active power filter (SAPF). The recommended control algorithm is applied to extract the fundamental component of load current and to decide the compensating current reference for harmonic elimination. The performance of the SAPF using the proposed NBP-based i cos ∅ technique is compared with another two classical control techniques, such as, i d - i q technique and i cos ∅ technique. The accuracy of the proposed control technique depends on the tuned estimation of active and reactive weights. The performance study of the proposed SAPF with the proposed control technique is investigated under non-linear conditions, with balanced and unbalanced loading conditions. The results reveal that the recommended SAPF is efficient enough to reduce the harmonics from the source current with smooth variation in DC link voltage. The effectiveness of the proposed method is validated by simulation using MATLAB Simulink, and the real-time results are also validated by the experimental setup.

4.
Transl Neurodegener ; 13(1): 13, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438877

RESUMO

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. METHODS: Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3-6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression. RESULTS: Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers. CONCLUSIONS: This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.


Assuntos
Encéfalo , Neurônios Dopaminérgicos , Animais , Humanos , Camundongos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Corpos de Lewy , Camundongos Transgênicos , Mutação/genética
5.
Sci Rep ; 14(1): 7016, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528052

RESUMO

The Multilevel inverter (MLI) plays a pivotal role in Renewable Energy (RE) systems by offering a cost-effective and highly efficient solution for converting DC from Photovoltaic (PV) sources into AC at high voltages. In addition, an innovative technology holds immense significance as it not only enables the seamless integration of PV systems into the grid but also ensures optimal power generation, thereby contributing to the widespread adoption of RE and fostering a sustainable future. This paper presents a modified sinusoidal pulse width modulation (SPWM) control scheme for a three-phase half-bridge cascaded MLI-powered PV sources. The selection of the MLI configuration is motivated by its reduced number of switching components, which enhances system reliability and simplifies experimental implementation. Compared to the SPWM schemes which require (m-1) carriers that make the generation of the pulse circuit very complex, the proposed control scheme requires only three signals: a carrier signal, a triangular waveform, and a modulating signal. This approach significantly reduces the complexity of control and facilitates practical implementation. The proposed control scheme simulation is verified using MATLAB/SIMULINK Software. The grey wolf optimization (GWO) algorithm is implemented to determine the optimal switching angles of the proposed control scheme. The Total Harmonic Distortion (THD) objective is selected to be the fitness function to be minimized for improving the quality of the output waveforms. For verification, the results of the proposed GWO-based modified SPWM control scheme are compared with those obtained using both the Particle swarm Optimization (PSO) and Genetic algorithm (GA) used in the literature. Simulation results declared that the proposed control scheme improves performance, especially THD which is minimized to 6.8%. Experimental validation has been conducted by building a laboratory prototype of the proposed system. The experimental and simulation results gave acceptable and limited convergent results considering the experimental difficulties.

6.
ISA Trans ; 143: 707-722, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37696735

RESUMO

In the conventional multilevel inverters, occurrence of a fault in one or more power switches can cause abnormal changes in the output waveforms. Besides, increasing the applied power switches results to an increase in the possibility of fault on the power switches. Accordingly, providing a comprehensive structure with high fault-tolerant capability is one of the vital requirements and critical challenges. To tackle these issues, this study first presents and explores a new basic unit and staircase module (SM) and then extends and optimizes it to yield a reconfigurable multi-level inverter (MLI) with more levels and different goals. The proposed MLI can continue to operate when open-circuit faults in switches. This advantage of the proposed structure is achieved without any redundant legs or switches. For further investigation, a comparison is made in terms of the number of power switches, drivers, dc sources, and reliability between the proposed and similar structures. To control the output voltage levels, the strategy of fundamental frequency switching triggers the configured topology. The carrier signals are reconfigured under fault conditions based on levels to be generated by bypassing the faulted switch. The validity of the established MLI with its fault-tolerant capability is certified through both computer simulations using the MATLAB/Simulink platform and laboratory prototype implementations.

7.
bioRxiv ; 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37745519

RESUMO

Introduction: Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene cause autosomal dominant Parkinson's disease (PD) with the most common causative mutation being the LRRK2 p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggest involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4 resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known. Methods: Here, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S knock-in mice by RNA-Sequencing analysis. Results: We observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate Genome-Wide Association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated respectively with zymosan treatment while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed the top twenty most significantly differentially expressed genes in LRRK2 p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress. Discussion: Overall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.

8.
Bioorg Med Chem Lett ; 94: 129449, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37591317

RESUMO

The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. Furthermore, LRRK2 function as a scaffolding protein in several pathways has been implicated as a plausible mechanism underlying neurodegeneration caused by LRRK2 mutations. Given that both the kinase activity and scaffolding function of LRRK2 have been linked to neurodegeneration, we developed proteolysis-targeting chimeras (PROTACs) targeting LRRK2. The degrader molecule JH-XII-03-02 (6) displayed high potency and remarkable selectivity for LRKK2 when assessed in a of 468 panel kinases and serves the dual purpose of eliminating both the kinase activity as well as the scaffolding function of LRRK2.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Animais , Modelos Animais , Mutação , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Fosforilação , Quimera de Direcionamento de Proteólise , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores
9.
Micromachines (Basel) ; 14(5)2023 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-37241550

RESUMO

The utilization of Fiber Bragg Grating (FBG) sensors in innovative optical sensor networks has displayed remarkable potential in providing precise and dependable thermal measurements in hostile environments on Earth. Multi-Layer Insulation (MLI) blankets serve as critical components of spacecraft and are employed to regulate the temperature of sensitive components by reflecting or absorbing thermal radiation. To enable accurate and continuous monitoring of temperature along the length of the insulative barrier without compromising its flexibility and low weight, FBG sensors can be embedded within the thermal blanket, thereby enabling distributed temperature sensing. This capability can aid in optimizing the thermal regulation of the spacecraft and ensuring the reliable and safe operation of vital components. Furthermore, FBG sensors offer sev eral advantages over traditional temperature sensors, including high sensitivity, immunity to electromagnetic interference, and the ability to operate in harsh environments. These properties make FBG sensors an excellent option for thermal blankets in space applications, where precise temperature regulation is crucial for mission success. Nevertheless, the calibration of temperature sensors in vacuum conditions poses a significant challenge due to the lack of an appropriate calibration reference. Therefore, this paper aimed to investigate innovative solutions for calibrating temperature sensors in vacuum conditions. The proposed solutions have the potential to enhance the accuracy and reliability of temperature measurements in space applications, which can enable engineers to develop more resilient and dependable spacecraft systems.

10.
Cells ; 13(1)2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38201257

RESUMO

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause autosomal dominant Parkinson's disease (PD), with the most common causative mutation being the LRRK2 p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggests involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4, resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known. Here, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S knock-in mice by RNA-sequencing analysis. We observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate genome-wide association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated, respectively, with zymosan treatment, while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed that the top twenty most significantly differentially expressed genes in LRRK2 p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress. Overall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.


Assuntos
Microglia , Doença de Parkinson , Humanos , Animais , Camundongos , Zimosan/farmacologia , Estudo de Associação Genômica Ampla , Receptor 2 Toll-Like/genética , Doença de Parkinson/genética , Expressão Gênica , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética
11.
BMC Neurosci ; 23(1): 39, 2022 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-35754033

RESUMO

BACKGROUND: Corticotropin-releasing factor (CRF) is the major neuromodulator orchestrating the stress response, and is secreted by neurons in various regions of the brain. Cerebellar CRF is released by afferents from inferior olivary neurons and other brainstem nuclei in response to stressful challenges, and contributes to modulation of synaptic plasticity and motor learning behavior via its receptors. We recently found that CRF modulates facial stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission via CRF type 1 receptor (CRF-R1) in vivo in mice, suggesting that CRF modulates sensory stimulation-evoked MLI-PC synaptic plasticity. However, the mechanism of how CRF modulates MLI-PC synaptic plasticity is unclear. We investigated the effect of CRF on facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological methods. RESULTS: Facial stimulation at 1 Hz induced LTD of MLI-PC synaptic transmission under control conditions, but not in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by application of a selective CRF-R1 antagonist, BMS-763,534 (200 nM), but it was not restored by application of a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-triggered MLI-PC long-term potentiation (LTP) via CRF-R1. Notably, either inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca2+ with cyclopiazonic acid (100 µM), completely prevented CRF-triggered MLI-PC LTP in mouse cerebellar cortex in vivo. CONCLUSIONS: The present results indicated that CRF blocked sensory stimulation-induced opioid-dependent MLI-PC LTD by triggering MLI-PC LTP through CRF-R1/PKC and intracellular Ca2+ signaling pathway in mouse cerebellar cortex. These results suggest that activation of CRF-R1 opposes opioid-mediated cerebellar MLI-PC plasticity in vivo in mice.


Assuntos
Hormônio Liberador da Corticotropina , Células de Purkinje , Analgésicos Opioides/farmacologia , Animais , Córtex Cerebelar/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Interneurônios/metabolismo , Camundongos , Plasticidade Neuronal/fisiologia , Células de Purkinje/metabolismo , Receptor CB1 de Canabinoide/metabolismo
12.
Biomedicines ; 10(4)2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35453631

RESUMO

The G2019S mutation in leucine rich-repeat kinase 2 (LRRK2) is a major cause of familial Parkinson's disease. We previously reported that G2019S knock-in mice manifest dopamine transporter dysfunction and phosphoSerine129 α-synuclein (pSer129 α-syn) immunoreactivity elevation at 12 months of age, which might represent pathological events leading to neuronal degeneration. Here, the time-dependence of these changes was monitored in the striatum of 6, 9, 12, 18 and 23-month-old G2019S KI mice and wild-type controls using DA uptake assay, Western analysis and immunohistochemistry. Western analysis showed elevation of membrane dopamine transporter (DAT) levels at 9 and 12 months of age, along with a reduction of vesicular monoamine transporter 2 (VMAT2) levels at 12 months. DAT uptake was abnormally elevated from 9 to up to 18 months. DAT and VMAT2 level changes were specific to the G2019S mutation since they were not observed in LRRK2 kinase-dead or knock-out mice. Nonetheless, dysfunctional DAT uptake was not normalized by acute pharmacological inhibition of LRRK2 kinase activity with MLi-2. Immunoblot analysis showed elevation of pSer129 α-syn levels in the striatum of 12-month-old G2019S KI mice, which, however, was not confirmed by immunohistochemical analysis. Instead, total α-syn immunoreactivity was found elevated in the striatum of 23-month-old LRRK2 knock-out mice. These data indicate mild changes in DA transporters and α-syn metabolism in the striatum of 12-month-old G2019S KI mice whose pathological relevance remains to be established.

13.
Neurobiol Dis ; 162: 105579, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34871735

RESUMO

The G2019S mutation of LRRK2 represents a risk factor for idiopathic Parkinson's disease. Here, we investigate whether LRRK2 kinase activity regulates susceptibility to the environmental toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). G2019S knock-in mice (bearing enhanced kinase activity) showed greater nigro-striatal degeneration compared to LRRK2 knock-out, LRRK2 kinase-dead and wild-type mice following subacute MPTP treatment. LRRK2 kinase inhibitors PF-06447475 and MLi-2, tested under preventive or therapeutic treatments, protected against nigral dopamine cell loss in G2019S knock-in mice. MLi-2 also rescued striatal dopaminergic terminal degeneration in both G2019S knock-in and wild-type mice. Immunoblot analysis of LRRK2 Serine935 phosphorylation levels confirmed target engagement of LRRK2 inhibitors. However, MLi-2 abolished phosphoSerine935 levels in the striatum and midbrain of both wild-type and G2019S knock-in mice whereas PF-06447475 partly reduced phosphoSerine935 levels in the midbrain of both genotypes. In vivo and ex vivo uptake of the 18-kDa translocator protein (TSPO) ligand [18F]-VC701 revealed a similar TSPO binding in MPTP-treated wild-type and G2019S knock-in mice which was consistent with an increased GFAP striatal expression as revealed by Real Time PCR. We conclude that LRRK2 G2019S, likely through enhanced kinase activity, confers greater susceptibility to mitochondrial toxin-induced parkinsonism. LRRK2 kinase inhibitors are neuroprotective in this model.


Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Animais , Corpo Estriado/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Camundongos , Mutação , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/metabolismo , Fosforilação
14.
ISA Trans ; 119: 41-51, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33627256

RESUMO

This paper proposes new indices of cascaded multilevel inverters (MLIs) in order to compare the conventional topology with 10-existed new topologies. Reduction in the number of power switches is the main target of these new topologies. This aim is to reduce the total cost of designed inverters, though the mentioned aim is not enough to design new inverters. Thus, in this study, four comparative indices including sources power uniform distribution index (SPUDI), switches current uniform distribution index (SCUDI), switches loss uniform distribution index (SLUDI), and switches voltage uniform distribution index (SVUDI), are proposed. In addition, it is shown that in most of the new topologies, reducing the number of switches can lead to lowered values of the proposed indices, after which non-uniform power, current, loss, and voltage pattern are obtained. The results prove that mere emphasis on the number of switches, along with the exclusion of either of the proposed indices will cause significant problems, where cost reduction may be underachieved. Based on new indices, the advantages of conventional topology over new ones are presented in this study.

15.
Neurobiol Dis ; 159: 105487, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34419621

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease. LRRK2 modulates the autophagy-lysosome pathway (ALP), a clearance process subserving the quality control of cellular proteins and organelles. Since dysfunctional ALP might lead to α-synuclein accumulation and, hence, Parkinson's disease, LRRK2 kinase modulation of ALP, its age-dependence and relation with pSer129 α-synuclein inclusions were investigated in vivo. Striatal ALP markers were analyzed by Western blotting in 3, 12 and 20-month-old LRRK2 G2019S knock-in mice (bearing enhanced kinase activity), LRRK2 knock-out mice, LRRK2 D1994S knock-in (kinase-dead) mice and wild-type controls. The lysosomotropic agent chloroquine was used to investigate the autophagic flux in vivo. Quantitative Real-time PCR was used to quantify the transcript levels of key ALP genes. The activity of the lysosomal enzyme glucocerebrosidase was measured using enzymatic assay. Immunohistochemistry was used to co-localize LC3B puncta with pSer129 α-synuclein inclusion in striatal and nigral neurons. No genotype differences in ALP markers were observed at 3 months. Conversely, increase of LC3-I, p62, LAMP2 and GAPDH levels, decrease of p-mTOR levels and downregulation of mTOR and TFEB expression was observed in 12-month-old kinase-dead mice. The LC3-II/I ratio was reduced following administration of chloroquine, suggesting a defective autophagic flux. G2019S knock-in mice showed LAMP2 accumulation and downregulation of ALP key genes MAP1LC3B, LAMP2, mTOR, TFEB and GBA1. Subacute administration of the LRRK2 kinase inhibitor MLi-2 in wild-type and G2019S knock-in mice did not replicate the pattern of kinase-dead mice. Lysosomal glucocerebrosidase activity was increased in 3 and 12-month-old knock-out and kinase-dead mice. LC3B puncta accumulation and pSer129 α-synuclein inclusions were dissociated in striatal neurons of kinase-dead and G2019S knock-in mice. We conclude that constitutive LRRK2 kinase silencing results in early deregulation of GCase activity followed by late impairment of macroautophagy and chaperone-mediated autophagy.


Assuntos
Envelhecimento/genética , Autofagia/genética , Glucosilceramidase/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Neostriado/metabolismo , Neurônios/metabolismo , Doença de Parkinson/genética , alfa-Sinucleína/metabolismo , Envelhecimento/metabolismo , Animais , Técnicas de Introdução de Genes , Inativação Gênica , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos , Camundongos , Camundongos Knockout , Doença de Parkinson/metabolismo
16.
Dokl Biochem Biophys ; 494(1): 219-221, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33119820

RESUMO

In the present study, we assessed the role of annexin 13 membrane-binding protein (ANXA13) in the intracellular transport of vesicles containing type II ribosome-inactivating proteins (RIP-IIs). A modified human intestinal epithelial cell line HT29 was used, in which the expression of ANXA13 was significantly reduced. The cytotoxic effect of ricin and viscumin was evaluated by modification of 28S ribosome RNA. The observed differences in the activity of toxins on the parental and modified HT29 lines indicate that ANXA13 plays a different role in the intracellular transport of vesicles containing the RIP-IIs.


Assuntos
Anexinas/metabolismo , Substâncias para a Guerra Química/farmacologia , Neoplasias do Colo/patologia , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Proteínas Inativadoras de Ribossomos/metabolismo , Ribossomos/efeitos dos fármacos , Ricina/farmacologia , Toxinas Biológicas/farmacologia , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Células HT29 , Humanos
17.
Dokl Biochem Biophys ; 493(1): 198-200, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32894464

RESUMO

The role of proteasome proteins and proteins of the ERAD system in the cytotoxicity of type II ribosome-inactivating proteins ricin and viscumin was investigated. For this, the cell line of colorectal adenocarcinoma HT29, as well as the HT29-sh002 line obtained on its basis, were used. On the basis on the proteome analysis of these lines and the estimation of the proportion of inactivated ribosomes, it was shown that the contribution of the proteasome to the degradation of the catalytic subunits of toxins is different. The role of the Cdc37 co-chaperone in maintaining the stability of A subunit of viscumin in the cytoplasm is shown.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Chaperoninas/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/biossíntese , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Ricina/farmacologia , Toxinas Biológicas/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteínas de Ciclo Celular/genética , Chaperoninas/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citoplasma/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ribossomos/metabolismo , Células Tumorais Cultivadas
18.
Braz J Anesthesiol ; 70(2): 118-124, 2020.
Artigo em Português | MEDLINE | ID: mdl-32482361

RESUMO

BACKGROUND: Obesity causes various difficulties in intubation and ventilation, which are confronted due to increased fat tissue in the upper airway and diminished compliance in the chest wall. Videolaryngoscopes and Intubating Laryngeal Mask Airway (ILMA) are good options as recommended by the American Society of Anesthesologists (ASA) difficult airway guidelines. We aimed to compare ILMA and Airtraq (a channeled videolaryngoscope) in obese patients. METHODS: Eighty patients with ASA physical status I-III, aged between 18 and 65 years and with a body mass index greater than 35 kg.m-2, who were undergoing elective surgery requiring orotracheal intubation, were included in the study. Patients were intubated with one of the devices cited. RESULTS: There was no difference between the number of intubation attempts, insertion times and need for optimisation manoeuvres of Airtraq and ILMA. The intubation with Airtraq was accomplished in a shorter period of time than in that in the ILMA group (29.9±22.1s vs. 50.7±21.2s; p<0.001). A significant difference was found when the times of total intubation were compared (29.9±22.1s vs. 97.4±42.7s; p<0.001). The mean arterial pressure statistically increased after device insertion in the ILMA group (p<0.05). CONCLUSIONS: Airtraq appears to be superior to ILMA in obese patients, with a total of time intubation of less than 60 seconds and with low mean arterial pressure changes. However, ILMA is still a useful tool that provides both ventilation and intubation throughout the whole intubation process.


Assuntos
Intubação Intratraqueal/instrumentação , Máscaras Laríngeas , Laringoscópios , Laringoscopia/instrumentação , Obesidade , Cirurgia Vídeoassistida , Adolescente , Adulto , Idoso , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
19.
Rev. bras. anestesiol ; 70(2): 118-124, Mar.-Apr. 2020. tab, graf
Artigo em Inglês, Português | LILACS | ID: biblio-1137150

RESUMO

Abstract Background: Obesity causes various difficulties in intubation and ventilation, which are confronted due to increased fat tissue in the upper airway and diminished compliance in the chest wall. Videolaryngoscopes and Intubating Laryngeal Mask Airway (ILMA) are good options as recommended by the American Society of Anesthesologists (ASA) difficult airway guidelines. We aimed to compare ILMA and Airtraq (a channeled videolaryngoscope) in obese patients. Methods: Eighty patients with ASA physical status 1-3, aged between 18 and 65 years and with a body mass index greater than 35 kg.m-2, who were undergoing elective surgery requiring orotracheal intubation, were included in the study. Patients were intubated with one of the devices cited. Results: There was no difference between the number of intubation attempts, insertion times and need for optimisation manoeuvres of Airtraq and ILMA. The intubation with Airtraq was accomplished in a shorter period of time than in that in the ILMA group (29.9 ± 22.1s vs. 50.7 ± 21.2s; p < 0.001). A significant difference was found when the times of total intubation were compared (29.9 ± 22.1s vs. 97.4 ± 42.7s; p < 0.001). The mean arterial pressure statistically increased after device insertion in the ILMA group (p < 0.05). Conclusions: Airtraq appears to be superior to ILMA in obese patients, with a total of time intubation of less than 60 seconds and with low mean arterial pressure changes. However, ILMA is still a useful tool that provides both ventilation and intubation throughout the whole intubation process.


Resumo Justificativa: A obesidade dificulta a ventilação manual e intubação traqueal devido ao acúmulo de tecido adiposo na via aérea superior e a complacência diminuída na caixa torácica. Os videolaringoscópios e as Máscaras Laríngeas para Intubação (MLI) são alternativas boas para o manuseio da via aérea difícil, de acordo com as diretrizes da Sociedade Americana de Anestesologia (ASA). O objetivo do estudo foi comparar o uso da MLI e do Airtraq, um videolaringoscópio com canal, em pacientes obesos. Método: Estudamos 80 pacientes com classificação ASA I-III, com idades entre 18 e 65 anos e índice de massa corporal acima de 35 kg.m-2, submetidos a cirurgia eletiva com indicação de intubação orotraqueal. Os pacientes foram intubados empregando-se um dos seguintes dispositivos: MLI ou Airtraq. Resultados: Não houve diferença entre o número de tentativas de intubação, tempo de inserção do dispositivo e necessidade de manobras de otimização para o Airtraq e MLI. A intubação com Airtraq foi realizada mais rapidamente do que no Grupo MLI (29,9 ± 22,1 s vs. 50,7 ± 21,2 s; p < 0,001). Houve diferença significante na comparação do tempo total para intubação (29,9 ± 22,1 s vs. 97,4 ± 42,7 s; p < 0,001). Houve aumento estatisticamente significante da pressão arterial média após a inserção do dispositivo no Grupo MLI (p < 0,05). Conclusões: Airtraq parece ser superior a MLI em pacientes obesos, apresentando tempo total de intubação abaixo de 60 segundos e com menor variação na pressão arterial média. Todavia, a MLI ainda é ferramenta útil que propicia tanto ventilação quanto intubação durante todo o processo de manejo da via aérea.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Idoso , Adulto Jovem , Máscaras Laríngeas , Cirurgia Vídeoassistida , Laringoscópios , Intubação Intratraqueal/instrumentação , Obesidade , Estudos Prospectivos , Desenho de Equipamento , Laringoscopia/instrumentação , Pessoa de Meia-Idade
20.
Med Phys ; 47(4): 1827-1835, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31930516

RESUMO

PURPOSE: The feasibility of low-dose megavoltage cone-beam acquisition (MVCBCT) using a novel, high detective quantum efficiency (DQE) multi-layer imager (MLI) was investigated. The aim of this work was to reconstruct MVCBCT images using the MLI at different total dose levels, and assess Hounsfield Unit (HU) accuracy, noise and contrast-to-noise ratio (CNR) for low-dose megavoltage cone-beam acquisition. METHODS: The MLI has four stacked layers; each layer contains a combination of copper filter/converter, gadolinium oxysulfide (GOS) scintillator and a-Si detector array. In total, 720 projections of a CATPHAN® phantom were acquired over 360° at 2.5, 6, and 6 MV flattening filter free (FFF) beam energies on a Varian TrueBeam LINAC. The dose per projection was 0.01, 0.0167, and 0.05 MU for 2.5, 6, and 6 MV FFF, respectively. MVCBCT images were reconstructed with varying numbers of projections to provide a range of doses for evaluation. Hounsfield Unit uniformity, accuracy, noise and CNR were estimated. Improvements were quantified relative to the standard AS1200 single-layer imager. RESULTS: Average HU uniformity for the MLI reconstructions was within a range of 95%-99% for all of the energies studied. Relative electron density estimation from HU values was within 0.4% ± 1.8% from nominal values. The CNR for MVCBCT based on MLI projections was 2-4× greater than from AS1200 projections. The 2.5 MV beam acquisition with the MLI exhibited the lowest noise and the best balance between CNR and dose for low-dose reconstructions. CONCLUSIONS: Megavoltage cone-beam acquisition imaging with a novel MLI prototype mounted on a clinical linear accelerator demonstrated substantial improvement over the standard AS1200 EPID. Further optimization of MVCBCT reconstruction, particularly for 2.5 MV acquisitions, will improve image metrics. Overall, the MLI improves CNR at substantially lower doses than currently required by conventional detectors. This new high DQE detector could provide high-quality MVCBCT at clinically acceptable doses.


Assuntos
Tomografia Computadorizada de Feixe Cônico/métodos , Doses de Radiação , Algoritmos , Estudos de Viabilidade , Processamento de Imagem Assistida por Computador , Imagens de Fantasmas
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