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OBJECTIVE: To study the effects of chemotherapy on cognitive function in breast cancer patients, and to investigate the relationship of MemTrax test of memory and related functions to the FACT-Cog functional self-assessment for the evaluation and management of chemobrain. METHODS: In this prospective cohort study, clinical information of pathologically confirmed female breast cancer patients who decided to receive chemotherapy were collected in a questionnaire which was developed for this study and provided as a supplementary file. The FACT-Cog self-assessment and MemTrax test were administered before and after the chemotherapy treatments. Patients with chemobrain were identified using published criteria based on FACT-Cog scores, and MemTrax scores from chemobrain patients were analyzed. RESULTS: Fifty-six patients participated in this study, of which 41 participants completed 4 or more cycles of chemotherapy and were included in the final analyses here. Using the reported high end of minimal clinical differences (10.6 points) of FACT-Cog before and after chemotherapy, 18 patients suffered from chemobrain in this study. In these 18 chemobrain patients, no cognitive impairments were detected by MemTrax, which paradoxically demonstrated an improvement in the normal cognitive range. CONCLUSION: The cognitive impairment induced by chemotherapy in breast cancer patients is detectable by the FACT-Cog in a Chinese cohort but is not detected by the MemTrax memory test. The fact that the more objective MemTrax could not detect the impairment could alleviate patients' concerns which in turn would be beneficial for patients' mental health.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Pruebas Neuropsicológicas/estadística & datos numéricos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Deterioro Cognitivo Relacionado con la Quimioterapia/tratamiento farmacológico , Anciano , Memoria/efectos de los fármacos , Encuestas y Cuestionarios , Estudios de CohortesRESUMEN
INTRODUCTION: A valid, reliable, accessible measurement for the early detection of cognitive decline in patients with Parkinson's disease (PD) is in urgent demand. The objective of the study is to assess the clinical utility of the MemTrax Memory Test in detecting cognitive impairment in patients with PD. METHODS: The MemTrax, a fast on-line cognitive screening tool based on continuous recognition task, and Montreal Cognitive Assessment (MoCA) were administered to 61 healthy controls (HC), 102 PD patients with normal cognition (PD-N), 74 PD patients with mild cognitive impairment (PD-MCI) and 52 PD patients with dementia (PD-D). The total percent correct (MTx- %C), average response time (MTx-RT), composite score (MTx-Cp) of MemTrax and the MoCA scores were comparatively analyzed. RESULTS: The MoCA scores were similar between HC and PD-N, however, MTx- %C and MTx-Cp were lower in PD-N than HC(p < 0.05). MTx- %C, MTx-Cp and the MoCA scores were significantly lower in PD-MCI versus PD-N and in PD-D versus PD-MCI (p ≤ 0.001), while MTx-RT was statistically longer in PD-D versus PD-MCI (p ≤ 0.001). For PD groups, the MemTrax performance correlated with the MoCA scores. To detect PD-MCI, the optimal MTx- %C and MTx-Cp cutoff were 75 % and 50.0, respectively. To detect PD-D, the optimal MTx- %C, MTx-RT and MTx-Cp cutoff were 69 %, 1.341s and 40.6, respectively. CONCLUSION: The MemTrax provides rapid, valid and reliable metrics for assessing cognition in PD patients which could be useful for identifying PD-MCI at early stage and monitoring cognitive function decline during the progression of disease.
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Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Pruebas Neuropsicológicas , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Cognición , Pruebas de Estado Mental y DemenciaRESUMEN
PURPOSES: To establish a normative range of MemTrax (MTx) metrics in the Chinese population. METHODS: The correct response percentage (MTx-%C) and mean response time (MTx-RT) were obtained and the composite scores (MTx-Cp) calculated. Generalized additive models for location, shape and scale (GAMLSS) were applied to create percentile curves and evaluate goodness of fit, and the speed-accuracy trade-off was investigated. RESULTS: 26,633 subjects, including 13,771 (51.71%) men participated in this study. Age- and education-specific percentiles of the metrics were generated. Q tests and worm plots indicated adequate fit for models of MTx-RT and MTx-Cp. Models of MTx-%C for the low and intermediate education fit acceptably, but not well enough for a high level of education. A significant speed-accuracy trade-off was observed for MTx-%C from 72 to 94. CONCLUSIONS: GAMLSS is a reliable method to generate smoothed age- and education-specific percentile curves of MTx metrics, which may be adopted for mass screening and follow-ups addressing Alzheimer's disease or other cognitive diseases. HIGHLIGHTS: GAMLSS was applied to establish nonlinear percentile curves of cognitive decline. Subjects with a high level of education demonstrate a later onset and slower decline of cognition. Speed-accuracy trade-off effects were observed in a subgroup with moderate accuracy. MemTrax can be used as a mass-screen instrument for active cognition health management advice.
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Enfermedad de Alzheimer , Trastornos del Conocimiento , Disfunción Cognitiva , Masculino , Humanos , Femenino , Trastornos del Conocimiento/diagnóstico , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Cognición , EscolaridadRESUMEN
Background: Whereas the Montreal Cognitive Assessment (MoCA) and Addenbrooke's cognitive examination-revised (ACE-R) are commonly used tests for the detection of post-stroke cognitive impairment (PSCI), these instruments take 10-30 min to administer and do not assess processing speed, which is a critical impairment in PSCI. MemTrax (MTx) is a continuous recognition test, which evaluates complex information processing, accuracy, speed, and attention, in 2 min. Aim: To evaluate whether MTx is an effective and practical tool for PSCI assessment. Methods: This study enrolled acute ischemic stroke (AIS) patients who have assessed the cognitive status including MTx, clinical dementia rating (CDR), MoCA, Neuropsychiatric Inventory (NPI), Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA), the National Institute of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), and Barthel Index of activity of daily living (BI) combined with the physical examinations of the neurologic system at the 90-day (D90) after the AIS. The primary endpoint of this study was establishing MTx cut-offs for distinguishing PSCI from AIS. Results: Of the 104 participants, 60 were classified to the PSCI group. The optimized cut-off value of MTx-%C (percent correct) was 78%, with a sensitivity and specificity for detecting PSCI from Non-PSCI of 90.0 and 84.1%, respectively, and an AUC of 0.919. Regarding the MTx-Cp (Composite score = MTx-%C/MTx-RT), using 46.3 as a cut-off value, the sensitivity and specificity for detecting PSCI from Non-PSCI were 80.0 and 93.2%, with an AUC of 0.925. Multivariate linear regression showed that PSCI reduced the MTx-%C (Coef. -14.18, 95% CI -18.41â¼-9.95, p < 0.001) and prolonged the MTx-RT (response time) (Coef. 0.29, 95% CI 0.16â¼0.43, p < 0.001) and reduced the MTx-CP (Coef. -19.11, 95% CI -24.29â¼-13.93, p < 0.001). Conclusion: MemTrax (MTx) is valid and effective for screening for PSCI among target patients and is a potentially valuable and practical tool in the clinical follow-up, monitoring, and case management of PSCI.
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BACKGROUND: Accessible measurements for the early detection of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) are urgently needed to address the increasing prevalence of AD. OBJECTIVE: To determine the benefits of a composite MemTrax Memory Test and AD-related blood biomarker assessment for the early detection of MCI-AD in non-specialty clinics. METHODS: The MemTrax Memory Test and Montreal Cognitive Assessment were administered to 99 healthy seniors with normal cognitive function and 101 patients with MCI-AD; clinical manifestation and peripheral blood samples were collected. We evaluated correlations between the MemTrax Memory Test and blood biomarkers using Spearman's rank correlation analyses and then built discrimination models using various machine learning approaches that combined the MemTrax Memory Test and blood biomarker results. The models' performances were assessed according to the areas under the receiver operating characteristic curve. RESULTS: The MemTrax Memory Test and Montreal Cognitive Assessment areas under the curve for differentiating patients with MCI-AD from the healthy controls were similar. The MemTrax Memory Test strongly correlated with phosphorylated tau 181 and amyloid-ß42/40. The area under the curve for the best composite MemTrax Memory Test and blood biomarker model was 0.975 (95% confidence interval: 0.950-0.999). CONCLUSION: Combining MemTrax Memory Test and blood biomarker results is a promising new technique for the early detection of MCI-AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/psicología , Proteínas tau , Biomarcadores , Diagnóstico Precoz , Péptidos beta-AmiloidesRESUMEN
BACKGROUND: Diabetic retinopathy (DR) is a diabetic complication with complex etiology and severe visual impairment. Dysregulated long noncoding RNAs (lncRNAs) are closely associated with DR. This article focused on the impact of lncRNA transmembrane phosphatase with tensin homology pseudogene 1 (TPTEP1) in DR. METHODS: First, sera were collected from DR patients and healthy control. Human retinal vascular endothelial cells (HRVECs) were exposed to high glucose (HG) to construct a DR model in vitro. A real-time quantitative polymerase chain reaction (RT-qPCR) was carried out to detect TPTEP1. Targeting relationships were predicted using StarBase and TargetScan, and confirmed by the Dual-Luciferase Reporter Assay. Cell Counting Kit 8 (CCK-8) and EdU staining were applied to measure cell viability and proliferation, respectively. Protein expression was determined by a western blotting assay. RESULTS: lncRNA TPTEP1 expression was significantly decreased in the serum of DR patients and HG-stimulated HRVECs. Overexpression of TPTEP1 reduced cell viability and proliferation induced by HG and oxidative stress. In addition, overexpression of miR-489-3p impaired the effects of TPTEP1. Nrf2, which was targeted by miR-489-3p, was down-regulated in HG-treatment HRVECs. Knockdown of Nrf2 enhanced the influence of miR-489-3p and antagonized the effects of TPTEP1. CONCLUSION: This study demonstrated that a TPTEP1/miR-489-3p/NRF2 axis affects the development of DR by regulating oxidative stress.
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Diabetes Mellitus , Retinopatía Diabética , MicroARNs , Factor 2 Relacionado con NF-E2 , ARN Largo no Codificante , Humanos , Apoptosis , Proliferación Celular/genética , Diabetes Mellitus/metabolismo , Retinopatía Diabética/genética , Células Endoteliales/metabolismo , Glucosa/farmacología , Glucosa/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/genética , ARN Largo no Codificante/metabolismoRESUMEN
Liquid metal batteries (LMBs), with the merits of long lifespan and low cost, are deemed as one of the most promising energy storage technologies for large-scale energy storage applications due to the use of liquid metal electrodes and molten salt electrolytes. However, the consequent problem is that the poor wettability between graphite-based collectors and the liquid metal/alloy electrodes leads to large contact resistance, which limits the efficiency and stability of the battery. In this work, a transition layer in situ formed on a graphite-based positive electrode current collector by Ti additive is designed for the first time, which increases the wettability between the positive alloy and the current collector and improves the voltage efficiency of the Li||Sb-Sn cell from 85.6 to 88.4%. These results provide new ideas for the design of high-efficiency LMBs.
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Zn metal with high specific capacity and low redox potential is deemed to be an ideal anode material for aqueous zinc-ion batteries (ZIBs). However, the serious dendrite problems induced by the uneven deposition of zinc shorten the service life and hinder the development of ZIBs. According to the nucleation and growth mechanism, the charge distribution at the anode interface is the critical factor affecting the deposition morphology. Herein, CF4 plasma technology is applied for the first time to in situ modification of the Zn anode, and then, the uniform nanoscale ZnF2 particles are formed. Due to the excellent ionic conductivity and poor electronic conductivity of ZnF2, the ion and electron distribution at the anode interface is orderly regulated, thus guiding uniform and reversible deposition behavior and restraining the dendrite growth. As a result, the Zn@ZnF2-5 anode exhibits low nucleation overpotential (16 mV), long cycle life (2500 h at 1 mA cm-2 and 1 mA h cm-2), and excellent resistance to high current density (20 mA cm-2) and high discharge depth (16%). Meanwhile, the Zn@ZnF2-5|I2@AC full battery shows remarkable cycle stability (1000 cycles) with â¼10% discharge depth of the anode. The novel and practical CF4 plasma in situ modification strategy provides a new idea for the interface modification of zinc anode.
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In order to improve the quality of medical student training, the clinical case-based learning (CBL) teaching mode is analyzed in the aspect of the rate of achievement, practical ability, and psychological effect. A total of 86 medical students who came to our hospital from March 2020 to December 2021 are selected and divided into the CBL group and the control group according to the random number table method. The psychological quality of medical students is evaluated by observing their movements and expressions during their internship. In addition, the questionnaire is used to evaluate the scores of a medical student in future planning, occupational health, and teamwork spirit. The compliance evaluation results show that CBL teaching mode can significantly improve the compliance rate of medical students in training and promote the confidence of future role change to a certain extent.
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Estudiantes de Medicina , Humanos , Estudiantes de Medicina/psicología , Encuestas y CuestionariosRESUMEN
Background: In percutaneous coronary intervention (PCI) era, more clinically valuable risk factors are still needed to determine the occurrence of cardiac rupture (CR). Therefore, we aimed to provide evidence for the early identification of CR in ST-segment elevation myocardial infarction (STEMI). Methods: A total of 22,016 consecutive patients with STEMI admitted to Cangzhou Central Hospital and Tianjin Chest Hospital from January 2013 to July 2021 were retrospectively included, among which 195 patients with CR were included as CR group. From the rest 21,820 STEMI patients without CR, 390 patients at a ratio of 1:2 were included as the control group. A total of 66 patients accepted PCI in the CR group, and 132 patients who accepted PCI in the control group at a ratio of 1:2 were included. The status of first medical contact, laboratory examinations, and PCI characteristics were recorded. Multivariate logistic regression analysis was used to investigate the risk factors related to CR. Results: There was a higher proportion of patients with myocardial infarction (MI) in the high lateral wall in the CR group (23.6% vs. 8.2%, P<0.001). The proportion of single lesions was lower in the CR group (24.2% vs. 45.5%, P=0.004). Female (OR =2.318, 95% CI: 1.431-3.754, P=0.001), age (OR =1.066, 95% CI: 1.041-1.093, P<0.001), smoking (OR =1.750, 95% CI: 1.086-2.820, P=0.022), total chest pain time (OR =1.017, 95% CI: 1.000-1.035, P=0.049), recurrent acute chest pain (OR =2.750, 95% CI: 1.535-4.927, P=0.001), acute myocardial infarction (AMI) in the high lateral wall indicated by ECG (OR =5.527, 95% CI: 2.798-10.918, P<0.001), acute heart failure (OR =3.585, 95% CI: 2.074-6.195, P<0.001), and NT-proBNP level (OR =1.000, 95% CI: 1.000-1.000, P=0.023) were risk factors for CR in all patients. In patients who accepted PCI, single lesion (OR =0.421, 95% CI: 0.204-0.867, P=0.019), preoperative thrombolysis in myocardial infarction (TIMI) grade (OR =0.358, 95% CI: 0.169-0.760, P=0.007), and postoperative TIMI grade (OR =0.222, 95% CI: 0.090-0.546, P=0.001) were risk factors for CR. Conclusions: Non-single lesions and preoperative and postoperative TIMI grades were risk factors for CR in patients who accepted PCI. In addition to previously reported indicators, we found that AMI in the high lateral wall maybe helpful in early and accurate identification and prevention of possible CR.
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Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer's disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/psicología , Cognición , Disfunción Cognitiva/psicología , Humanos , Tamizaje Masivo , Pruebas de Estado Mental y Demencia , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: A valid, reliable, accessible, engaging, and affordable digital cognitive screen instrument for clinical use is in urgent demand. OBJECTIVE: To assess the clinical utility of the MemTrax memory test for early detection of cognitive impairment in a Chinese cohort. METHODS: The 2.5-minute MemTrax and the Montreal Cognitive Assessment (MoCA) were performed by 50 clinically diagnosed cognitively normal (CON), 50 mild cognitive impairment due to AD (MCI-AD), and 50 Alzheimer's disease (AD) volunteer participants. The percentage of correct responses (MTx-% C), the mean response time (MTx-RT), and the composite scores (MTx-Cp) of MemTrax and the MoCA scores were comparatively analyzed and receiver operating characteristic (ROC) curves generated. RESULTS: Multivariate linear regression analyses indicated MTx-% C, MTx-Cp, and the MoCA score were significantly lower in MCI-AD versus CON and in AD versus MCI-AD groups (all with p≤0.001). For the differentiation of MCI-AD from CON, an optimized MTx-% C cutoff of 81% had 72% sensitivity and 84% specificity with an area under the curve (AUC) of 0.839, whereas the MoCA score of 23 had 54% sensitivity and 86% specificity with an AUC of 0.740. For the differentiation of AD from MCI-AD, MTx-Cp of 43.0 had 70% sensitivity and 82% specificity with an AUC of 0.799, whereas the MoCA score of 20 had 84% sensitivity and 62% specificity with an AUC of 0.767. CONCLUSION: MemTrax can effectively detect both clinically diagnosed MCI and AD with better accuracy as compared to the MoCA based on AUCs in a Chinese cohort.
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Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Diagnóstico Precoz , Pruebas de Estado Mental y Demencia , Anciano , Enfermedad de Alzheimer/complicaciones , Pueblo Asiatico , Disfunción Cognitiva/etiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Sensibilidad y EspecificidadRESUMEN
Diabetic retinopathy (DR) is a primary complication of diabetes mellitus. DR can cause severe vision loss for patients. miR-122 is elevated in DR patients, while its role in DR is unclear. Hence, the purpose of this study was to analyze the effect of miR-122 on the function of high glucose-induced REC cells and the underlying molecular mechanisms. In this study, our results revealed that miR-122 was up-regulated in high glucose-induced human retinal pigment epithelial cells (ARPE-19). High glucose decreased the cell viability of ARPE-19 cells, which was then restored by miR-122 knockdown. In addition, miR-122 knockdown suppressed apoptosis of high glucose-induced ARPE-19 cells. High glucose also inhibited B-cell lymphoma-2 (Bcl-2) level and increased cleaved caspase-3 level in ARPE-19 cells, which were reversed by miR-122 knockdown. Tissue inhibitor of metalloproteinases-3 (TIMP3) was a direct target of miR-122. TIMP3 was decreased in high glucose-induced ARPE-19 cells, and the decrease was abrogated by miR-122 knockdown. In addition, the effects of miR-122 overexpression in cell viability and apoptosis of high glucose-induced ARPE-19 were abolished by overexpression of TIMP3. In conclusion, the effect and mechanism of miR-122 on high glucose-induced ARPE-19 cells were demonstrated for the first time. miR-122 promoted diabetic retinopathy through targeting TIMP3, making miR-122 a promising target for diabetic retinopathy therapy.
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BACKGROUND: The widespread incidence and prevalence of Alzheimer's disease and mild cognitive impairment (MCI) has prompted an urgent call for research to validate early detection cognitive screening and assessment. OBJECTIVE: Our primary research aim was to determine if selected MemTrax performance metrics and relevant demographics and health profile characteristics can be effectively utilized in predictive models developed with machine learning to classify cognitive health (normal versus MCI), as would be indicated by the Montreal Cognitive Assessment (MoCA). METHODS: We conducted a cross-sectional study on 259 neurology, memory clinic, and internal medicine adult patients recruited from two hospitals in China. Each patient was given the Chinese-language MoCA and self-administered the continuous recognition MemTrax online episodic memory test on the same day. Predictive classification models were built using machine learning with 10-fold cross validation, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC). Models were built using two MemTrax performance metrics (percent correct, response time), along with the eight common demographic and personal history features. RESULTS: Comparing the learners across selected combinations of MoCA scores and thresholds, Naïve Bayes was generally the top-performing learner with an overall classification performance of 0.9093. Further, among the top three learners, MemTrax-based classification performance overall was superior using just the top-ranked four features (0.9119) compared to using all 10 common features (0.8999). CONCLUSION: MemTrax performance can be effectively utilized in a machine learning classification predictive model screening application for detecting early stage cognitive impairment.
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Disfunción Cognitiva/clasificación , Disfunción Cognitiva/psicología , Aprendizaje Automático/clasificación , Pruebas de Estado Mental y Demencia , Modelos Psicológicos , Anciano , Disfunción Cognitiva/diagnóstico , Estudios Transversales , Femenino , Humanos , Aprendizaje Automático/normas , Masculino , Pruebas de Estado Mental y Demencia/normas , Persona de Mediana Edad , Pruebas Neuropsicológicas/normasRESUMEN
The authors apologize that in our published paper entitled "Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia" Cell and Tissue Research (Published online: 22 October 2019).
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Preeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been elucidated. It has been reported that thioredoxin-interacting protein (TXNIP), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, is a key point in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1ß (IL-1ß) production in the placenta of patients with PE. The objective of the current study was to explore if TXNIP plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesized that ER stress would induce TXNIP production, which would bind with NLRP3 inflammasomes to activate IL-1ß production. These cells showed a higher protein level of NLRP3 and IL-1ß, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with TXNIP siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. Outgrowth of the explant with TXNIP lentivirus in H/R or tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that TXNIP could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.
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Recycling of the spent LIBs to extract Li and Co not only offers raw materials for batteries but also lays a sustainable way for battery development. Herein, we adopt a route combining hydrometallurgical and pyro-electrochemical routes to extract Li2CO3 and Co powder from the spent LIBs of cell phones. The LiCoO2-based cathode materials were firstly dissolved in H2SO4 solution containing H2O2 as the reductant, and the optimal conditions for attaining a high extraction rate of 99% were studied. After that, the precipitated Co(OH)2 was calcinated in air under 500 °C to generate Co3O4 which was thereafter electrochemically converted into Co powder and oxygen in molten Na2CO3-K2CO3. Overall, the hybrid method employing both hydro- and pyro-route provides an effective pathway to recover both Li2CO3 and Co powder from spent LIBs.
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At its fundamental basis, Alzheimer's disease (AD) is a pathological process that affects neuroplasticity, leading to a specific disruption of episodic memory. This review will provide a rationale for calls to screen for the early detection of AD, appraise the currently available cognitive instruments for AD detection, and focus on the development of the MemTrax test, which provides a new approach to detect the early manifestations and progression of the dementia associated with AD. MemTrax assesses metrics that reflect the effects of neuroplastic processes on learning, memory, and cognition, which are affected by age and AD, particularly episodic memory functions, which cannot presently be measured with enough precision for meaningful use. Further development of MemTrax would be of great value to the early detection of AD and would provide support for the testing of early interventions.
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Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 µM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.
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Ácidos Carboxílicos/administración & dosificación , Ácidos Carboxílicos/química , Cognición/efectos de los fármacos , Memoria/efectos de los fármacos , Monoaminooxidasa/metabolismo , Nootrópicos/administración & dosificación , Nootrópicos/química , Amidas/administración & dosificación , Amidas/química , Animales , Cognición/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Memoria/fisiología , Ratones Endogámicos C57BL , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/química , Ratas , Resultado del TratamientoRESUMEN
A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.