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Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.
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Colecalciferol , Deficiência de Vitamina D , Humanos , Colecalciferol/farmacologia , Suplementos Nutricionais , Método Duplo-Cego , Fatores de Risco , Transcriptoma , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/genéticaRESUMO
The recurrence and metastasis in breast cancer within 3 years after the chemotherapies or surgery leads to poor prognosis with approximately 1-year overall survival. Large-scale scanning research studies have shown that taking lipid-lowering drugs may assist to reduce the risk of death from many cancers, since cholesterol in lipid rafts are essential for maintain integral membrane structure and functional signaling regulation. In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are increased, whereas mesenchymal markers including Snail, Twist and α-smooth muscle actin are attenuated. Furthermore, we found that fenofibrate downregulates ubiquitin-dependent GDF-15 degradation, which leads to enhanced GDF-15 expression that inhibits cell migration. Besides, nuclear translocation of FOXO1 is also upregulated by fenofibrate, which may responsible for GDF-15 expression. In summary, fenofibrate with anti-cancer ability hinders TNBC from migration and invasion, and may be beneficial to repurposing use of fenofibrate.
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Fenofibrato , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Fator 15 de Diferenciação de Crescimento/farmacologia , Fator 15 de Diferenciação de Crescimento/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Transição Epitelial-Mesenquimal , Lipídeos , Proliferação de CélulasRESUMO
BACKGROUND: Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age 60 in randomised controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS. We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon/glatiramer acetate (IFN/GA) in pwMS over the age of 60. METHODS: Using data from MSBase registry, this multicentre cohort study included pwMS above 60 who switched to or started on ocrelizumab or IFN/GA. We analysed relapse and disability outcomes after balancing covariates using an inverse probability treatment weighting (IPTW) method. Propensity scores were obtained based on age, country, disease duration, sex, baseline Expanded Disability Status Scale, prior relapses (all-time, 12 months and 24 months) and prior DMT exposure (overall number and high-efficacy DMTs). After weighting, all covariates were balanced. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI). RESULTS: A total of 248 participants received ocrelizumab, while 427 received IFN/GA. The IPTW-weighted ARR for ocrelizumab was 0.01 and 0.08 for IFN/GA. The IPTW-weighted ARR ratio was 0.15 (95% CI 0.06 to 0.33, p<0.001) for ocrelizumab compared with IFN/GA. On IPTW-weighted Cox regression models, HR for time to first relapse was 0.13 (95% CI 0.05 to 0.26, p<0.001). The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months compared with IFN/GA users. However, the two groups did not differ in CDP or CDI over 3.57 years. CONCLUSION: In older pwMS, ocrelizumab effectively reduced relapses compared with IFN/GA. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. Our study also confirms that there is a treatment benefit in older people with MS, given the existence of a clear differential treatment effect between ocrelizumab and IFN/GA in the over 60 age group.
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Anticorpos Monoclonais Humanizados , Acetato de Glatiramer , Humanos , Acetato de Glatiramer/uso terapêutico , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Pessoa de Meia-Idade , Idoso , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Resultado do Tratamento , Estudos de Coortes , Interferons/uso terapêutico , Interferons/efeitos adversos , Recidiva , Sistema de RegistrosRESUMO
Pulmonary inflammation may lead to neuroinflammation resulting in neurological dysfunction, and it is associated with a variety of acute and chronic lung diseases. Paeonol is a herbal phenolic compound with anti-inflammatory and anti-oxidative properties. The aim of this study is to understand the beneficial effects of paeonol on cognitive impairment, pulmonary inflammation and its underlying mechanisms. Pulmonary inflammation-associated cognitive deficit was observed in TNFα-stimulated mice, and paeonol mitigated the cognitive impairment by reducing the expressions of interleukin (IL)-1ß, IL-6, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) in hippocampus. Moreover, elevated plasma miR-34c-5p in lung-inflamed mice was also reduced by paeonol. Pulmonary inflammation induced by intratracheal instillation of TNFα in mice resulted in immune cells infiltration in bronchoalveolar lavage fluid, pulmonary edema, and acute fibrosis, and these inflammatory responses were alleviated by paeonol orally. In MH-S alveolar macrophages, tumor necrosis factor (TNF) α- and phorbol myristate acetate (PMA)-induced inflammasome activation was ameliorated by paeonol. In addition, the expressions of antioxidants were elevated by paeonol, and reactive oxygen species production was reduced. In this study, paeonol demonstrates protective effects against cognitive deficits and pulmonary inflammation by exerting anti-inflammatory and anti-oxidative properties, suggesting a powerful benefit as a potential therapeutic agent.
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Acetofenonas , Disfunção Cognitiva , Pneumopatias , Pneumopatias/complicações , Acetofenonas/farmacologia , Acetofenonas/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Masculino , Animais , Camundongos , Fator de Necrose Tumoral alfa , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , MicroRNAs/sangue , MicroRNAs/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.
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Proteínas Associadas a CRISPR/administração & dosagem , Edição de Genes/métodos , Genes Dominantes/genética , Terapia Genética/métodos , Perda Auditiva/genética , Estimulação Acústica , Alelos , Animais , Animais Recém-Nascidos , Limiar Auditivo , Sequência de Bases , Proteínas Associadas a CRISPR/metabolismo , Proteínas Associadas a CRISPR/uso terapêutico , Sistemas CRISPR-Cas , Sobrevivência Celular , Cóclea/citologia , Cóclea/metabolismo , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Fibroblastos , Células Ciliadas Auditivas/citologia , Perda Auditiva/fisiopatologia , Perda Auditiva/prevenção & controle , Humanos , Lipossomos , Masculino , Proteínas de Membrana/genética , Camundongos , Reflexo de SobressaltoRESUMO
Pedestrian trajectory prediction is crucial for developing collision avoidance algorithms in autonomous driving systems, aiming to predict the future movement of the detected pedestrians based on their past trajectories. The traditional methods for pedestrian trajectory prediction involve a sequence of tasks, including detection and tracking to gather the historical movement of the observed pedestrians. Consequently, the accuracy of trajectory prediction heavily relies on the accuracy of the detection and tracking models, making it susceptible to their performance. The prior research in trajectory prediction has mainly assessed the model performance using public datasets, which often overlook the errors originating from detection and tracking models. This oversight fails to capture the real-world scenario of inevitable detection and tracking inaccuracies. In this study, we investigate the cumulative effect of errors within integrated detection, tracking, and trajectory prediction pipelines. Through empirical analysis, we examine the errors introduced at each stage of the pipeline and assess their collective impact on the trajectory prediction accuracy. We evaluate these models across various custom datasets collected in Taiwan to provide a comprehensive assessment. Our analysis of the results derived from these integrated pipelines illuminates the significant influence of detection and tracking errors on downstream tasks, such as trajectory prediction and distance estimation.
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OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in patients with Alzheimer's disease (AD), causing burdens on caregivers. Behavioral and psychological symptoms of dementia and subclinical epileptiform discharge (SED) increased with the disease course of AD. However, the interaction between them was still unknown. The present study aimed to evaluate the associations between SED and BPSD. METHODS/DESIGN: Patients with AD from Kaohsiung Municipal Ta-tung Hospital were included in this study. International 10-20 system scalp electroencephalography (EEG) for 13 min was performed to detect SED. Behavioral and psychological symptoms of dementia was assessed by neuropsychiatric inventory (NPI) questionnaires. The occurrence of BPSD subsyndromes was compared between patients with and without SED. RESULTS: Two hundred sixty-three adult patients qualified for the inclusion criteria and were enrolled in this study. The mean age of patients was 80.2 years, and approximately 62% were women. 17.1% of patients showed SED on EEG. Apathy was the most commonly reported BPSD subsyndrome in this cohort. There was no significant difference in the prevalence of BPSD between patients with and without SED. (75.6% vs. 67.4%, p = 0.2806). However, the NPI score of irritability subsyndrome was significantly higher in the SED (+) group (2.6 ± 3.7 vs. 1.2 ± 2.7, p = 0.0028). In addition, subclinical epileptiform discharge in the frontal lobe was associated with a considerably higher occurrence of hyperactivity subsyndrome, including irritability. CONCLUSIONS: SED may not be a direct cause of BPSD, but the presence of SED may affect the manifestation of BPSD.
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Doença de Alzheimer , Apatia , Demência , Humanos , Feminino , Idoso de 80 Anos ou mais , Masculino , Doença de Alzheimer/psicologia , Demência/psicologia , Cuidadores/psicologia , Sintomas Comportamentais/psicologia , Testes NeuropsicológicosRESUMO
(1) Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk factor for predicting cardiovascular diseases. Metabolic syndrome is characterized by a state of chronic inflammation that is related to an increased risk of cardiovascular events and death. In the present study, we aimed to analyze the correlation between cardiometabolic risk factors and Lp-PLA2 levels. (2) We collected the related retrospective medical data of Chinese adults, of which 3983 were men and 2836 were women (aged ≥ 18 years), who underwent health check-ups, and discussed the sex and age-related differences. (3) Data analysis showed that Lp-PLA2 was significantly related to lipoproteins and glutamic pyruvic transaminase (GPT), and that a linear trend was observed with increasing Lp-PLA2 levels for all ages and sexes. However, fasting glucose was significantly related to Lp-PLA2 only in the younger population. The two obesity-related parameters (waist-to-height ratio and waist circumference) also had a greater correlation with Lp-PLA2 levels in the younger groups; however, the correlation weakened in the elderly population. Meanwhile, the correlation between mean arterial pressure and creatinine level and Lp-PLA2 was significant only in younger men. (4) The results show that the expression patterns of Lp-PLA2 differ between sexes and across age groups.
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1-Alquil-2-acetilglicerofosfocolina Esterase , Fatores de Risco Cardiometabólico , Adulto , Masculino , Humanos , Idoso , Feminino , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Estudos Retrospectivos , Fatores de Risco , Lipoproteínas , BiomarcadoresRESUMO
Phosphor-converted white light emitting diodes (pc-WLEDs) are used worldwide for an extensive amount of applications. The device is a complex combination of various components that introduce various technical issues: materials, electrical, chemical, thermal, and so on. All of these combined to obtain a targeted optical characteristic. While most of the pc-WLEDs are sufficient for basic illumination performance, there are still many issues to improve the pc-WLED performance. In this work, we deal with the incorporation of micron size particles of titanium oxide (TiO2) in silicone encapsulant that contains yttrium aluminum garnet (YAG) phosphor in remote phosphor pc-WLED. Based on the light output and the scattering spatial distribution measurements of the phosphor plates, we have found that several essential performance indices, like the color uniformity, the efficiency, and the amount of phosphor for the pc-WLEDs, can be adjusted by tuning the amount of TiO2 particles and thus be optimized. With a comprehensive model using a Monte-Carlo ray tracing process combined with the Mie scattering theory, two TiO2 loading conditions are revealed. The first one is the sparse condition that the TiO2 particles act as the scattering particles such as to increase the output flux to improve the efficiency of YAG. The second one is the dense condition that the TiO2 particles act more as barrier particles such so to decrease the output flux.
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BACKGROUND: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. OBJECTIVE: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. METHODS: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). RESULTS: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64, p = 0.006). CONCLUSION: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Anticorpos Monoclonais Humanizados , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , RecidivaRESUMO
BACKGROUND: Myelin Oligodendrocyte Glycoprotein antibody-associated disease (MOGAD) is most classically associated in both children and adults with phenotypes including bilateral and recurrent optic neuritis (ON) and transverse myelitis (TM), with the absence of brain lesions characteristic of multiple sclerosis (MS). ADEM phenotype is the most common presentation of MOGAD in children. However, the presence of clinical phenotypes including unilateral ON and short TM in some patients with MOGAD may lead to their misdiagnosis as MS. Thus, clinically and radiologically, MOGAD can mimic MS and clinical vigilance is required for accurate diagnostic workup. CASE PRESENTATION: We present three cases initially diagnosed as MS and then treated with alemtuzumab. Unexpectedly, all three patients did quite poorly on this medication, with a decline in their clinical status with worsening of expanded disability status scale (EDSS) and an increasing lesion load on magnetic resonance imaging of the brain. Subsequently, all three cases were found to have anti-MOG antibody in their serum. CONCLUSIONS: These cases highlight that if a patient suspected to have MS does not respond to conventional treatments such as alemtuzumab, a search for alternative diagnoses such as MOG antibody disease may be warranted.
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Mielite Transversa , Neurite Óptica , Alemtuzumab/efeitos adversos , Autoanticorpos , Humanos , Glicoproteína Mielina-Oligodendrócito , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/tratamento farmacológicoRESUMO
PURPOSE: To improve the performance of less experienced clinicians in the diagnosis of benign and malignant spinal fracture on MRI, we applied the ResNet50 algorithm to develop a decision support system. METHODS: A total of 190 patients, 50 with malignant and 140 with benign fractures, were studied. The visual diagnosis was made by one senior MSK radiologist, one fourth-year resident, and one first-year resident. The MSK radiologist also gave the binary score for 15 qualitative imaging features. Deep learning was implemented using ResNet50, using one abnormal spinal segment selected from each patient as input. The T1W and T2W images of the lesion slice and its two neighboring slices were considered. The diagnostic performance was evaluated using tenfold cross-validation. RESULTS: The overall reading accuracy was 98, 96, and 66% for the senior MSK radiologist, fourth-year resident, and first-year resident, respectively. Of the 15 imaging features, 10 showed a significant difference between benign and malignant groups with p < = 0.001. The accuracy achieved by using the ResNet50 deep learning model for the identified abnormal vertebral segment was 92%. Compared to the first-year resident's reading, the model improved the sensitivity from 78 to 94% (p < 0.001) and the specificity from 61 to 91% (p < 0.001). CONCLUSION: Our deep learning-based model may provide information to assist less experienced clinicians in the diagnosis of spinal fractures on MRI. Other findings away from the vertebral body need to be considered to improve the model, and further investigation is required to generalize our findings to real-world settings.
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Aprendizado Profundo , Fraturas da Coluna Vertebral , Neoplasias da Coluna Vertebral , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Fraturas da Coluna Vertebral/diagnóstico , Neoplasias da Coluna Vertebral/patologiaRESUMO
Globally, the incidence rate for breast cancer ranks first. Treatment for early-stage breast cancer is highly cost effective. Five-year survival rate for stage 0-2 breast cancer exceeds 90%. Screening mammography has been acknowledged as the most reliable way to diagnose breast cancer at an early stage. Taiwan government has been urging women without any symptoms, aged between 45 and 69, to have a screening mammogram bi-yearly. This brings about a large workload for radiologists. In light of this, this paper presents a deep neural network (DNN)-based model as an efficient and reliable tool to assist radiologists with mammographic interpretation. For the first time in the literature, mammograms are completely classified into BI-RADS categories 0, 1, 2, 3, 4A, 4B, 4C and 5. The proposed model was trained using block-based images segmented from a mammogram dataset of our own. A block-based image was applied to the model as an input, and a BI-RADS category was predicted as an output. At the end of this paper, the outperformance of this work is demonstrated by an overall accuracy of 94.22%, an average sensitivity of 95.31%, an average specificity of 99.15% and an area under curve (AUC) of 0.9723. When applied to breast cancer screening for Asian women who are more likely to have dense breasts, this model is expected to give a higher accuracy than others in the literature, since it was trained using mammograms taken from Taiwanese women.
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Neoplasias da Mama , Mamografia , Idoso , Área Sob a Curva , Neoplasias da Mama/diagnóstico por imagem , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Redes Neurais de ComputaçãoRESUMO
This paper proposed an effective multi-objective design procedure, called light field management, for a single multi-segment reflector that can simultaneously project low beams and high beams for bicycle and e-bike applications. Furthermore, two different regulations can be met, including the K-mark and the ECE Class B regulations. Through light field management, the etendue and flux density of each segment can be effectively managed, so that the design successfully meets the multiple regulations. In the experimental verification, two mockup samples including a plastic reflector with aluminum coating and an aluminum reflector were fabricated to verify the validity of the design. The experiment showed that the contrast across the cutoff line reached 100 and above, where the brightest point for low beams reached 200 lux and the whole pattern reached 250 lux. The supreme behavior of the head lamp shows that the proposed design procedure is valuable and helpful to an optical designer.
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Synovial sarcoma is a rare but aggressive soft-tissue sarcoma associated with translocation t(X;18). Metastasis occurs in approximately 50% of all patients, and curative outcomes are difficult to achieve in this group. Since the efficacies of current therapeutic approaches for metastatic synovial sarcoma remain limited, new therapeutic agents are urgently needed. Tilapia piscidin 4 (TP4), a marine antimicrobial peptide, is known to exhibit multiple biological functions, including anti-bacterial, wound-healing, immunomodulatory, and anticancer activities. In the present study, we assessed the anticancer activity of TP4 in human synovial sarcoma cells and determined the underlying mechanisms. We first demonstrated that TP4 can induce necrotic cell death in human synovial sarcoma AsKa-SS and SW982 cells lines. In addition, we saw that TP4 initiates reactive oxygen species (ROS) production and downregulates antioxidant proteins, such as uncoupling protein-2, superoxide dismutase (SOD)-1, and SOD-2. Moreover, TP4-induced mitochondrial hyperpolarization is followed by elevation of mitochondrial ROS. Calcium overload is also triggered by TP4, and cell death can be attenuated by a necrosis inhibitor, ROS scavenger or calcium chelator. In our experiments, TP4 displayed strong anticancer activity in human synovial sarcoma cells by disrupting oxidative status, promoting mitochondrial hyperpolarization and causing calcium overload.
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Antineoplásicos/farmacologia , Cálcio/metabolismo , Proteínas de Peixes/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sarcoma Sinovial/tratamento farmacológico , Tilápia/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Mitocôndrias/fisiologia , Sarcoma Sinovial/metabolismoRESUMO
In this paper, we present a study of observation of phase error of a volume holographic storage disc during the reading process when the disc is rotated or displaced in the theoretical calculation and the corresponding experiment. This additional phase error will dramatically decrease the bit error rate of a phase-only signal, even applying double-frequency shearing interferometry to retrieve the stored phase signal. Then we propose a novel approach to solve the problem. The stored signal is pre-processed by phase integral along the shearing direction so that applying the integral process to decode the phase signal is not necessary in the readout process. The proposed approach effectively reduces the error in phase retrieval and will be useful when applying double-frequency shearing interferometry in the readout process for volume holographic storage.
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We perform molecular dynamics simulations to investigate the effect of a glass preparation on its yielding transition under oscillatory shear. We use swap Monte Carlo to investigate a broad range of glass stabilities from poorly annealed to highly stable systems. We observe a qualitative change in the nature of yielding, which evolves from ductile to brittle as glass stability increases. Our results disentangle the relative role of mechanical and thermal annealing on the mechanical properties of amorphous solids, which is relevant for various experimental situations from the rheology of soft materials to fatigue failure in metallic glasses.
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Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy.
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Polineuropatias/fisiopatologia , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Polineuropatias/diagnóstico , Polineuropatias/terapia , UltrassonografiaRESUMO
Folate-mediated one-carbon (1C) metabolism is a major target of many therapies in human diseases. Studies have focused on the metabolism of serine 3-carbon as it serves as a major source for 1C units. The serine 3-carbon enters the mitochondria transferred by folate cofactors and eventually converted to formate and serves as a major building block for cytosolic 1C metabolism. Abnormal glycine metabolism has been reported in many human pathological conditions. The mitochondrial glycine cleavage system (GCS) catalyzes glycine degradation to CO2 and ammonium, while tetrahydrofolate (THF) is converted into 5,10-methylene-THF. GCS accounts for a substantial proportion of whole-body glycine flux in humans, yet the particular metabolic route of glycine 2-carbon recycled from GCS during mitochondria glycine decarboxylation in hepatic or bone marrow 1C metabolism is not fully investigated, due to the limited accessibility of human tissues. Labeled glycine at 2-carbon was given to humans and primary cells in previous studies for investigating its incorporations into purines, its interconversion with serine, or the CO2 production in the mitochondria. Less is known on the metabolic fate of the glycine 2-carbon recycled from the GCS; hence, a model system tracing its metabolic fate would help in this regard. We took the direct approach of isotopic labeling to further explore the in vitro and in vivo metabolic fate of the 2-carbon from [2-13C]glycine and [2-13C]serine. As the 2-carbon of glycine and serine is decarboxylated and catabolized via the GCS, the original 13C-labeled 2-carbon is transferred to THF and yield methyleneTHF in the mitochondria. In human hepatoma cell-lines, 2-carbon from glycine was found to be incorporated into deoxythymidine (dTMP, dT + 1), M + 3 species of purines (deoxyadenine, dA and deoxyguanine, dG), and methionine (Met + 1). In healthy mice, incorporation of GCS-derived formate from glycine 2-carbon was found in serine (Ser + 2 via cytosolic serine hydroxy methyl transferase), methionine, dTMP, and methylcytosine (mC + 1) in bone marrow DNA. In these experiments, labeled glycine 2-carbon directly incorporates into Ser + 1, A + 2, and G + 2 (at C2 and C8 of purine) in the cytosol. It is noteworthy that since the serine 3-carbon is unlabeled in these experiments, the isotopic enrichments in dT + 1, Ser + 2, dA + 3, dG + 3, and Met + 1 solely come from the 2-carbon of glycine/serine recycled from GCS, re-enters the cytosolic 1C metabolism as formate, and then being used for cytosolic syntheses of serine, dTMP, purine (M + 3) and methionine. Taken together, we established model systems and successfully traced the metabolic fate of mitochondrial GCS-derived formate from glycine 2-carbon in vitro and in vivo. Nutritional supply significantly alters formate generation from GCS. More GCS-derived formate was used in hepatic serine and methionine syntheses, whereas more GCS-derived formate was used in dTMP synthesis in the bone marrow, indicating that the utilization and partitioning of GCS-derived 1C unit are tissue-specific. These approaches enable better understanding concerning the utilization of 1C moiety generated from mitochondrial GCS that can help to further elucidate the role of GCS in human disease development and progression in future applications. More studies on GCS using these approaches are underway.
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Aminoácido Oxirredutases/metabolismo , Formiatos/metabolismo , Glicina/metabolismo , Mitocôndrias/metabolismo , Complexos Multienzimáticos/metabolismo , Serina/metabolismo , Transferases/metabolismo , Animais , Linhagem Celular , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
A novel optical sensor is proposed and demonstrated with the use of spherical-wave Bragg degeneracy of a volume holographic optical element. Bragg degeneracy can be performed perfectly for a volume hologram written by two plane waves or spherical waves. But only spherical reference light is useful to perform severe shifting selectivity in one direction and Bragg degeneracy in another direction. The experiment corresponding to theoretical simulation was demonstrated in a volume holographic optical element, which was an optical servo for a collinear volume holographic disc. Through clever design, the displacement response of the tracking beam was observed for a magnification magnitude of 980% to the displacement of the probe beam so that the resolution requirement of the photosensor can be reduced. Besides, a high linearity of the displacement response was observed. To discover the design freedom, a theoretical study of the displacement response was done for the servo by two spherical waves. The linearity, the magnification magnitude, and the diffraction efficiency were examined and the property of the Bragg degeneracy was figured out.