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1.
Biomacromolecules ; 25(2): 1310-1318, 2024 Feb 12.
Article in English | MEDLINE | ID: mdl-38265878

ABSTRACT

Although the formation of peptide assemblies catalyzed by alkaline phosphatase (ALP) has received increasing attention in inhibiting cancer cells, the detailed enzyme kinetics of the dephosphorylation of the corresponding phosphopeptide assemblies have yet to be determined. We recently discovered that assemblies from a phosphopentapeptide can form intracellular nanoribbons that kill induced pluripotent stem cells or osteosarcoma cells, but the kinetics of enzymatic dephosphorylation remain unknown. Thus, we chose to examine the enzyme kinetics of the dephosphorylation of the phosphopentapeptide [NBD-LLLLpY (1)] from concentrations below to above its critical micelle concentration (CMC). Our results show that the phosphopeptide exhibits a CMC of 75 µM in phosphate saline buffer, and the apparent Vmax and Km values of alkaline phosphatase catalyzed dephosphorylation are approximately 0.24 µM/s and 5.67 mM, respectively. Despite dephosphorylation remaining incomplete at 60 min in all the concentrations tested, dephosphorylation of the phosphopeptide at concentrations of 200 µM or above mainly results in nanoribbons, dephosphorylation at concentrations of CMC largely produces nanofibers, and dephosphorylation below the CMC largely generates nanoparticles. Moreover, the formation of nanoribbons correlates with the intranuclear accumulation of the pentapeptide. By providing the first examination of the enzymatic kinetics of phosphopeptide assemblies, this work further supports the notion that the assemblies of phosphopentapeptides can act as a new functional entity for controlling cell fates.


Subject(s)
Nanotubes, Carbon , Phosphopeptides , Alkaline Phosphatase/metabolism , Kinetics
2.
Acc Chem Res ; 56(21): 3076-3088, 2023 11 07.
Article in English | MEDLINE | ID: mdl-37883182

ABSTRACT

Higher-order or supramolecular protein assemblies, usually regulated by enzymatic reactions, are ubiquitous and essential for cellular functions. This evolutionary fact has provided a rigorous scientific foundation, as well as an inspiring blueprint, for exploring supramolecular assemblies of man-made molecules that are responsive to biological cues as a novel class of therapeutics for biomedicine. Among the emerging man-made supramolecular structures, peptide assemblies, formed by enzyme reactions or other stimuli, have received most of the research attention and advanced most rapidly.In this Account, we will review works that apply enzyme-instructed self-assembly (EISA) to generate intracellular peptide assemblies for developing a new kind of biomedicine, especially in the field of novel cancer nanomedicines and modulating cell morphogenesis. As a versatile and cell-compatible approach, EISA can generate nondiffusive peptide assemblies locally; thus, it provides a unique approach to target subcellular organelles with exceptional cell selectivity. We have arranged this Account in the following way: after introducing the concept, simplicity, and uniqueness of EISA, we discuss the EISA-formed intracellular peptide assemblies, including artificial filaments, in the cell cytosol. Then, we describe the representative examples targeting subcellular organelles, such as mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, and the nucleus, by enzyme-instructed intracellular peptide assemblies for potential cancer therapeutics. After that, we highlight the recent exploration of the transcytosis of peptide assemblies for controlling cell morphogenesis. Finally, we provide a brief outlook of enzyme-instructed intracellular peptide assemblies. This Account aims to illustrate the promise of EISA-generated intracellular peptide assemblies in understanding diseases, controlling cell behaviors, and developing new therapeutics from a class of less explored molecular entities, which are substrates of enzymes and become building blocks of self-assembly after the enzymatic reactions.


Subject(s)
Neoplasms , Peptides , Humans , Peptides/chemistry , Proteins
3.
ChemMedChem ; 18(17): e202300258, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37380607

ABSTRACT

Supramolecular assemblies made by the self-assembly of peptides are finding an increasing number of applications in various fields. While the early exploration of peptide assemblies centered on tissue engineering or regenerative medicine, the recent development has shown that peptide assemblies can act as supramolecular medicine for cancer therapy. This review covers the progress of applying peptide assemblies for cancer therapy, with the emphasis on the works appeared over the last five years. We start with the introduction of a few seminal works on peptide assemblies, then discuss the combination of peptide assemblies with anticancer drugs. Next, we highlight the use of enzyme-controlled transformation or shapeshifting of peptide assemblies for inhibiting cancer cells and tumors. After that, we provide the outlook for this exciting field that promises new kind of therapeutics for cancer therapy.


Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Peptides/pharmacology , Peptides/therapeutic use , Peptides/chemistry , Tissue Engineering , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy
4.
BMC Plant Biol ; 23(1): 288, 2023 May 30.
Article in English | MEDLINE | ID: mdl-37254042

ABSTRACT

BACKGROUND: Plants in the genus Artemisia are rich in active ingredients and specialized metabolites. Many of these compounds, especially flavonoids, have potential medicinal and nutritional applications, and are of growing interest to scientists due to their wide range of pharmacological and biological activities. Artemisia cultivars are commonly used as raw materials for medicine, food, and moxibustion in China. However, most of the metabolites produced by Artemisia species have not been identified, and few studies have addressed differences in active compounds between species and cultivars. RESULTS: We here investigated two Artemisia cultivars, 'Nanyangshiyong' (NYSY) and 'Nanyangyaoyong' (NYYY), which are commonly used in foods and moxibustion, respectively. NYSY and NYYY were confirmed to be Artemisia argyi cultivars. Total flavonoids contents and antioxidant activities were higher in NYYY than in NYSY. A total of 882 metabolites were identified in the samples; most of the potentially medicinally active compounds, especially flavonoids (e.g., flavone, flavonol, isoflavone, and anthocyanin), were up-regulated in NYYY compared to NYSY. Furthermore, most of the genes related to flavonoids biosynthesis were up-regulated in NYYY. Correlation analysis was used to identify putative members of transcription factor families that may regulate genes encoding key flavonoids biosynthesis enzymes. CONCLUSIONS: We found that the antioxidant activities and flavonoids contents significantly varied between two Artemisia cultivars of the same species. We also uncovered metabolomic and transcriptomic evidence of the molecular phenomena underlying those differences in flavonoids contents between the two Artemisia cultivars. This study provides a wealth of data for future utilization and improvements of Artemisia cultivars, and highlights a need to study the specific metabolite profiles of plants that are used in foods and medicines.


Subject(s)
Artemisia , Artemisia/genetics , Artemisia/metabolism , Flavonoids/metabolism , Transcriptome , Antioxidants/metabolism , Gene Expression Profiling
5.
Front Neurol ; 13: 866261, 2022.
Article in English | MEDLINE | ID: mdl-35645954

ABSTRACT

Background: The Chinese version of Boston Naming Test (BNT-C) is administered in China widely. However, the neuropsychological parameter of BNT-C in native Chinese-speaking elders in mainland China has not been explored systematically. The aim of this study was to explore cultural influences on BNT-C performance and establish norms among native Chinese-speaking elders in Beijing. Methods: A total of 161 native, Chinese-speaking, cognitively normal elders aged ≥55 years were enrolled from various communities in Beijing. The BNT-C was conducted on all the participants. The internal consistency, participants' familiarity, and naming accuracy were analyzed and compared with data from Chinese areas outside the mainland and from American published previously. The influencing factors and stratified norms for BNT-C were established. Results: The BNT-C showed good internal consistency (α = 0.738). Strong correlation between naming accuracy and object familiarity was found (r = 0.962, P < 0.001). Participants' familiarity and correct naming rate for many items were notably different between the Chinese-speaking elders and English-speaking elders in America. The difference in some items' correct naming rate also existed between Beijing, Taiwan, and Hongkong. Higher education was associated with higher scores, whereas age and gender had no effect on BNT-C performance. The recommended norms of total naming scores for elders with education ≤ 9 and >9 years were 16 and 23, respectively. Conclusion: The participants' familiarity with BNT items differed between different cultures, which further affected the naming accuracy and total scores. The education stratified norms established here are helpful for the better application of BNT-C in mainland China.

6.
Stud Health Technol Inform ; 290: 354-358, 2022 Jun 06.
Article in English | MEDLINE | ID: mdl-35673034

ABSTRACT

At present no adequate annotation guidelines exists for incident report learning. This study aims at utilizing multiple quantitative and qualitative evidence to validate annotation guidelines for incident reporting of medication errors. Through multiple approaches via annotator training, annotation performance evaluation, exit surveys, and user and expert interviews, a mixed methods explanatory sequential design was utilized to collect 2-stage evidence for validation. We recruited two patient safety experts to participate in piloting, three annotators to receive annotation training and provide user feedback, and two incident report system designers to offer expert comments. Regarding the annotation performance evaluation, the overall accuracy reached 97% and 90% for named entity identification and attribute identification respectively. Participants provided invaluable comments and opinions towards improving the annotation methods. The mixed methods approach created a significant evidential basis for the use of annotation guidelines for incident report of medication errors. Further expansion of the guidelines and external validity present options for future research.


Subject(s)
Medication Errors , Risk Management , Humans , Medication Errors/prevention & control , Patient Safety , Surveys and Questionnaires
7.
Methods Mol Biol ; 2530: 159-167, 2022.
Article in English | MEDLINE | ID: mdl-35761048

ABSTRACT

Proteins with a functionalized C-terminus are critical to synthesizing large proteins via expressed protein ligation. To overcome the limitations of currently available C-terminus functionalization strategies, we established an approach based on a small molecule cyanylating reagent that chemically activates a cysteine in a recombinant protein at its N-side amide for undergoing nucleophilic acyl substitution with amines. We demonstrated the versatility of this approach by successfully synthesizing RNAse H with its RNA hydrolyzing activity restored and in vitro nucleosome build with a C-terminal posttranslational modified histone H2A. This technique will expand the landscape of protein chemical synthesis and its application in new research fields significantly.


Subject(s)
Cysteine , Protein Biosynthesis , Histones , Nucleosomes , RNA
8.
J Mol Biol ; 434(8): 167534, 2022 04 30.
Article in English | MEDLINE | ID: mdl-35278475

ABSTRACT

As one of the most valuable tools for genetic code expansion, pyrrolysyl-tRNA synthetase (PylRS) is structurally related to phenylalanyl-tRNA synthetase (PheRS). By introducing mutations that mimic ligand interactions in PheRS into PylRS, we designed a PylRS mutant. This mutant, designated as oClFRS, recognizes a number of o-substituted phenylalanines for their genetic incorporation at amber codon. Its efficiency in catalyzing genetic incorporation of o-chlorophenylalanine (o-ClF) is better than that for Nε-tert-butyloxycarbonyl-lysine catalyzed by PylRS. The crystal structure of oClFRS bound with o-ClF shows that o-ClF binds deeply into a hydrophobic but catalytically inactive pocket in the active site and involves two halogen bonds to achieve strong interactions. The shift of o-ClF to a catalytically active position in the oClFRS active site will be necessary for its activation. This is the first reported aminoacyl-tRNA synthetase that involves two halogen bonds for ligation recognition and might represent an alternative route to develop aminoacyl-tRNA synthetase mutants that are selective for noncanonical amino acids over native amino acids.


Subject(s)
Amino Acyl-tRNA Synthetases , Genetic Code , Lysine/analogs & derivatives , Methanosarcina , Phenylalanine , Amino Acyl-tRNA Synthetases/chemistry , Amino Acyl-tRNA Synthetases/genetics , Halogens/chemistry , Lysine/chemistry , Lysine/genetics , Methanosarcina/enzymology , Mutation , Phenylalanine/chemistry , Phenylalanine/genetics , Protein Binding
9.
ACS Cent Sci ; 8(2): 192-204, 2022 Feb 23.
Article in English | MEDLINE | ID: mdl-35229034

ABSTRACT

As an essential enzyme of SARS-CoV-2, main protease (MPro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an MPro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of MPro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular MPro inhibition information to assess an MPro inhibitor. We used this assay to analyze 30 known MPro inhibitors. Contrary to their strong antiviral effects and up to 10 µM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular MPro inhibition potency implicating their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to its strong antiviral effect with an EC50 value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.

10.
Comput Intell Neurosci ; 2022: 2709255, 2022.
Article in English | MEDLINE | ID: mdl-35310588

ABSTRACT

As one of the most widely used languages in the world, English plays a vital role in the communication between China and the world. However, grammar learning in English is a difficult and long process for English learners. Especially in English writing, English learners will inevitably make various grammatical writing errors. Therefore, it is extremely important to develop a model for correcting various writing errors in English writing. This can not only be used for automatic inspection and proofreading of English texts but also enable students to achieve the purpose of autonomous practice. This paper constructs an English writing error correction model and applies it to the actual system to realize automatic checking and correction of writing errors in English composition. This paper uses the deep learning model of Seq2Seq_Attention model and transformer model to eliminate deep-level errors. Statistical learning is combined with deep learning and adopted a model integration method. The output of each model is sent to the n-gram language model for scoring, and the highest score is selected as output.


Subject(s)
Language , Writing , Humans , Linguistics , Neural Networks, Computer , Students
12.
ChemMedChem ; 17(1): e202100455, 2022 01 05.
Article in English | MEDLINE | ID: mdl-34423563

ABSTRACT

As the pathogen of COVID-19, SARS-CoV-2 encodes two essential cysteine proteases that process the pathogen's two large polypeptide products pp1a and pp1ab in the human cell host to form 15 functionally important, mature nonstructural proteins. One of the two enzymes is papain-like protease or PLPro . It possesses deubiquitination and deISGylation activities that suppress host innate immune responses toward SARS-CoV-2 infection. To repurpose drugs for PLPro , we experimentally screened libraries of 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PLPro . Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit strong inhibition of PLPro at 200 µM. More comprehensive characterizations revealed seven inhibitors GRL0617, SJB2-043, TCID, DUB-IN-1, DUB-IN-3, PR-619, and S130 with an IC50 value below 40 µM and four inhibitors GRL0617, SJB2-043, TCID, and PR-619 with an IC50 value below 10 µM. Among four inhibitors with an IC50 value below 10 µM, SJB2-043 is the most unique in that it does not fully inhibit PLPro but has a noteworthy IC50 value of 0.56 µM. SJB2-043 likely binds to an allosteric site of PLPro to convene its inhibition effect, which needs to be further investigated. As a pilot study, the current work indicates that COVID-19 drug repurposing by targeting PLPro holds promise, but in-depth analysis of repurposed drugs is necessary to avoid omitting critical allosteric inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Drug Repositioning , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Cysteine Proteinase Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship
13.
ChemMedChem ; 17(1): e202100456, 2022 01 05.
Article in English | MEDLINE | ID: mdl-34242492

ABSTRACT

A number of inhibitors have been developed for the SARS-CoV-2 main protease (MPro ) as potential COVID-19 medications but little is known about their selectivity. Using enzymatic assays, we characterized inhibition of TMPRSS2, furin, and cathepsins B/K/L by more than a dozen of previously developed MPro inhibitors including MPI1-9, GC376, 11a, 10-1, 10-2, and 10-3. MPI1-9, GC376 and 11a all contain an aldehyde for the formation of a reversible covalent hemiacetal adduct with the MPro active site cysteine and 10-1, 10-2 and 10-3 contain a labile ester to exchange with the MPro active site cysteine for the formation of a thioester. Our data revealed that all these inhibitors are inert toward TMPRSS2 and furin. Diaryl esters also showed low inhibition of cathepsins. However, all aldehyde inhibitors displayed high potency in inhibiting three cathepsins. Their determined IC50 values vary from 4.1 to 380 nM for cathepsin B, 0.079 to 2.3 nM for cathepsin L, and 0.35 to 180 nM for cathepsin K. All aldehyde inhibitors showed similar inhibition levels toward cathepsin L. A cellular analysis indicated high potency of MPI5 and MPI8 in inhibiting lysosomal activity, which is probably attributed to their inhibition of cathepsins. Among all aldehyde inhibitors, MPI8 shows the best selectivity toward cathepsin L. With respect to cathepsins B and K, the selective indices are 192 and 150, respectively. MPI8 is the most potent compound among all aldehyde inhibitors in cellular MPro inhibition potency and anti-SARS-CoV-2 activity in Vero E6 cells. Cathepsin L has been demonstrated to play a critical role in the SARS-CoV-2 cell entry. By selectively inhibiting both SARS-CoV-2 MPro and the host cathepsin L, MPI8 potentiates dual inhibition effects to synergize its overall antiviral potency and efficacy. Due to its high selectivity toward cathepsin L that reduces potential toxicity toward host cells and high cellular and antiviral potency, we urge serious consideration of MPI8 for preclinical and clinical investigations for treating COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Cathepsin L/antagonists & inhibitors , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Humans , Molecular Docking Simulation
14.
J Alzheimers Dis ; 84(2): 835-842, 2021.
Article in English | MEDLINE | ID: mdl-34602472

ABSTRACT

BACKGROUND: Serum levels of inflammatory factors, such as C3, C4, C-reactive protein (CRP), immunoglobulin (Ig) G, IgA, and IgM, in patients with Alzheimer's disease (AD) and their correlation with cognitive function remain unexplored. OBJECTIVE: To investigate the expression of serum inflammatory factors in patients with AD and its correlation with cognitive function. METHODS: Serum levels of C3, C4, CRP, IgG, IgA, and IgM in 200 patients with AD (mild, moderate, and severe) and those in 174 normal controls were assessed. Spearman's rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and activities of daily living (ADL). RESULTS: Among these inflammatory factors, C3 and CRP levels were significantly lower, and IgG and IgA levels were significantly higher in the AD group than in the control group (p < 0.05). There were no significant differences in C4 and IgM levels between the two groups (p > 0.05). In all participants, CRP level was positively correlated with the Mini-Mental State Examination and Montreal Cognitive Assessment scores (p < 0.05). In the AD group, IgA level was negatively associated with ADL scores (p < 0.05). No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). CONCLUSION: Inflammatory factors C3, CRP, IgG, and IgA have the potential to serve as biomarkers for AD. Furthermore, serum IgA was not only correlated with AD but also with ADL. These results support the hypothesis that inflammation is involved in the occurrence and development of AD.


Subject(s)
Alzheimer Disease/blood , Cognition/physiology , Inflammation/blood , Activities of Daily Living , C-Reactive Protein/analysis , Female , Humans , Immunoglobulin G/blood , Male , Mental Status and Dementia Tests/statistics & numerical data , Middle Aged
15.
Molecules ; 26(9)2021 Apr 29.
Article in English | MEDLINE | ID: mdl-33947165

ABSTRACT

Dehydroalanine exists natively in certain proteins and can also be chemically made from the protein cysteine. As a strong Michael acceptor, dehydroalanine in proteins has been explored to undergo reactions with different thiolate reagents for making close analogues of post-translational modifications (PTMs), including a variety of lysine PTMs. The chemical reagent 2-nitro-5-thiocyanatobenzoic acid (NTCB) selectively modifies cysteine to form S-cyano-cysteine, in which the S-Cß bond is highly polarized. We explored the labile nature of this bond for triggering E2 elimination to generate dehydroalanine. Our results indicated that when cysteine is at the flexible C-terminal end of a protein, the dehydroalanine formation is highly effective. We produced ubiquitin and ubiquitin-like proteins with a C-terminal dehydroalanine residue with high yields. When cysteine is located at an internal region of a protein, the efficiency of the reaction varies with mainly hydrolysis products observed. Dehydroalanine in proteins such as ubiquitin and ubiquitin-like proteins can serve as probes for studying pathways involving ubiquitin and ubiquitin-like proteins and it is also a starting point to generate proteins with many PTM analogues; therefore, we believe that this NTCB-triggered dehydroalanine formation method will find broad applications in studying ubiquitin and ubiquitin-like protein pathways and the functional annotation of many PTMs in proteins such as histones.


Subject(s)
Alanine/analogs & derivatives , Cysteine/chemistry , Proteins/chemistry , Thiocyanates/chemistry , Alanine/chemistry , Chromatography, High Pressure Liquid , Chromatography, Liquid , Models, Molecular , Protein Conformation , Protein Processing, Post-Translational/drug effects , Recombinant Proteins , Spectrometry, Mass, Electrospray Ionization , Thiocyanates/pharmacology
16.
J Alzheimers Dis ; 75(3): 779-787, 2020.
Article in English | MEDLINE | ID: mdl-32333590

ABSTRACT

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is often the prodromal stage of Alzheimer's disease (AD). Although previous studies have suggested that computerized cognitive training is an effective non-pharmacological intervention for aMCI, large-sample, randomized controlled studies are warranted to provide a high level of evidence. OBJECTIVE: To identify the efficacy of computerized cognitive training for aMCI. METHODS: This study will include 260 patients diagnosed with aMCI from 8 centers in China. A computerized multi-domain adaptive training program will be used in this study, and the targeted cognitive domains include memory, attention, language, and executive function. The patients will be randomized into either a cognitive-training group or an active-control group. The intervention is a 12-week internet-based cognitive training performed for 40 minutes per day, 4 days a week. Neuropsychological assessments and structural and functional MRI will be obtained at baseline, at the end of the intervention, and 6 months after randomization. The primary outcome will be the global cognitive function score assessed by Montreal Cognitive Assessment. The secondary outcomes include changes in other neuropsychological assessments and neuroplasticity changes measured by structural and functional MRI. RESULTS: The trial is currently ongoing, and it is anticipated that recruitment will be completed in December 2020. CONCLUSION: This multi-center, large-sample, randomized controlled trial will investigate the short and long-term effects of computerized cognitive training in patients with aMCI. Furthermore, the combination of functional and structural MRI results will also reveal the underlying mechanisms of the effect of intervention.


Subject(s)
Amnesia/therapy , Cognitive Behavioral Therapy , Cognitive Dysfunction/therapy , Amnesia/complications , Cognitive Dysfunction/complications , Humans , Neuropsychological Tests , Research Design , Treatment Outcome
17.
Alzheimers Dement (N Y) ; 6(1): e12005, 2020.
Article in English | MEDLINE | ID: mdl-32313830

ABSTRACT

INTRODUCTION: Recently, transcranial alternating current stimulation (tACS), which can interact with ongoing neuronal activity, has emerged as a potentially effective and promising treatment for Alzheimer's disease (AD), and the 40 Hz gamma frequency was suggested as a suitable stimulation frequency for AD. METHODS: The TRANSFORM-AD study is a double-blind, randomized-controlled trial that will include 40 individuals with mild AD. Eligible patients need to have amyloid ß (Aß) loads examined by Pittsburgh compound B (PiB) positron emission tomography (PET) or decreased Aß level in cerebrospinal fluid. Participants will be randomized into either a 40 Hz tACS group or a sham stimulation group. Both groups will undergo 30 one-hour sessions across 3 weeks (21 days). The outcome measures will be assessed at baseline, at the end of the intervention, and 3 months after the first session. The primary outcome is global cognitive function, assessed by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), and the secondary outcomes include changes in other neuropsychological assessments and in PiB-PET, structural magnetic resonance imaging (MRI), resting electroencephalography (EEG), and simultaneous EEG-functional MRI (EEG-fMRI) results. RESULTS: The trial is currently ongoing, and it is anticipated that recruitment will be completed in June 2021. DISCUSSION: This trial will evaluate the efficacy and safety of 40 Hz tACS in patients with AD, and further explore the potential mechanisms by analyzing amyloid deposits using PiB-PET, brain volume and white matter integrity by structural MRI, and neural activity by EEG and EEG-fMRI.

18.
J Am Chem Soc ; 142(15): 7047-7054, 2020 04 15.
Article in English | MEDLINE | ID: mdl-32212692

ABSTRACT

Proteins with a functionalized C-terminus such as a C-terminal thioester are key to the synthesis of larger proteins via expressed protein ligation. They are usually made by recombinant fusion to intein. Although powerful, the intein fusion approach suffers from premature hydrolysis and low compatibility with denatured conditions. To totally bypass the involvement of an enzyme for expressed protein ligation, here we showed that a cysteine in a recombinant protein was chemically activated by a small molecule cyanylating reagent at its N-side amide for undergoing nucleophilic acyl substitution with amines including a number of l- and d-amino acids and hydrazine. The afforded protein hydrazides could be used further for expressed protein ligation. We demonstrated the versatility of this activated cysteine-directed protein ligation (ACPL) approach with the successful synthesis of ubiquitin conjugates, ubiquitin-like protein conjugates, histone H2A with a C-terminal posttranslational modification, RNase H that actively hydrolyzed RNA, and exenatide that is a commercial therapeutic peptide. The technique, which is exceedingly simple but highly useful, expands to a great extent the synthetic capacity of protein chemistry and will therefore make a large avenue of new research possible.


Subject(s)
Inteins/genetics , Recombinant Proteins/chemistry , Humans
19.
Lancet Neurol ; 19(1): 81-92, 2020 01.
Article in English | MEDLINE | ID: mdl-31494009

ABSTRACT

China has the largest population of patients with dementia in the world, imposing a heavy burden on the public and health care systems. More than 100 epidemiological studies on dementia have been done in China, but the estimates of the prevalence and incidence remain inconsistent because of the use of different sampling methods. Despite improved access to health services, inadequate diagnosis and management for dementia is still common, particularly in rural areas. The Chinese Government issued a new policy to increase care facilities for citizens older than 65 years, but most patients with dementia still receive care at home. Western medicines for dementia symptoms are widely used in China, but many patients choose Chinese medicines even though they have little evidence supporting efficacy. The number of clinical trials of Chinese and western medicines has substantially increased as a result of progress in research on new antidementia drugs but international multicentre studies are few in number. Efforts are needed to establish a national system of dementia care enhance training in dementia for health professionals, and develop global collaborations to prevent and cure this disease.


Subject(s)
Dementia/epidemiology , Dementia/therapy , China/epidemiology , Dementia/diagnosis , Humans
20.
Medicine (Baltimore) ; 97(26): e11263, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29952998

ABSTRACT

We aimed to assess the accuracy of self-assessment for acute stroke patients via mobile phone application-based scales and determine the value and prospect of clinical use.A cross-sectional study was designed and acute stroke patients were enrolled. We pushed the modified Rankin scale (mRS) and activities of daily living (ADL) scale to patients via mobile phone application for self-assessment on the day before they were out of hospital. We compared the results from nurse assessment and self-assessment.Around 50 patients with the average age 51.72 ±â€Š12.40 completed the self-assessment. A total of 27 patients self-assessed the scales, while caregivers of other 23 patients completed the assessment. In comparison with patient assessment and nurse assessment, significant difference was found in ADL score (P = .004), but was not found in mRS score (P > .05). When comparing caregiver assessment with nurse assessment, no significant difference could be found either in ADL score (P > .05) or in mRS score (P > .05). The kappa value for self-assessment and nurse agreement of ADL was 0.720 (P = .000), with sensitivity 96.8% and specificity 82.0%. The kappa value for self-assessment and nurse agreement of mRS was 0.718 (P = .000), with sensitivity 97.6% and specificity 92.4%.In summary, mobile phone application-based scales are generally accurate, economical and convenient for self-assessment of acute stroke patients with acceptable reliability in our small scale study. Caregivers can serve as the proper assessor when patients are out of hospital. Therefore, it is promising but still need to be further confirmed how practical to use this application in extended care and follow-up.


Subject(s)
Disability Evaluation , Mobile Applications , Self Report , Stroke Rehabilitation/methods , Activities of Daily Living , Adult , Aged , Aged, 80 and over , Caregivers , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Nurses , Reproducibility of Results , Stroke
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