Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand...Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand binding structure,dynamics and affinity.Currently,the four mainstream drug targets are G protein-coupled receptors(GPCRs),kinases,ion channels,and nuclear receptors,accounting for over 70%of effective drug targets,most of which are membrane proteins and enzymes.In recent years,various new drug targets have been continuously discovered,and the research focus has shifted from simple affinity analysis to high-throughput and high-content screening,as well as exploring drug-target interaction modes.These deepen reliance on the analytical techniques to have higher sensitivity,recognition specificity,and applicability to diversified target structures,which promoting the rapid development of novel screening methods.展开更多
Cancer screening is a strategy focused on highrisk populations rather than universal populationwide screening, based on a comprehensive evaluation of epidemiological principles and practical feasibility. The effective...Cancer screening is a strategy focused on highrisk populations rather than universal populationwide screening, based on a comprehensive evaluation of epidemiological principles and practical feasibility. The effectiveness of screening depends on factors such as disease prevalence, as well as the sensitivity and specificity of the screening technology employed.展开更多
This study discusses the impact of the increasing use of colonoscopy on the trends of colorectal cancer(CRC)in Korea.Different views are raised on the research methods and conclusions of Kim et al.It emphasizes the ne...This study discusses the impact of the increasing use of colonoscopy on the trends of colorectal cancer(CRC)in Korea.Different views are raised on the research methods and conclusions of Kim et al.It emphasizes the need to carefully consider the balance between the benefits of early detection and the risks of over-screening.This letter also suggests directions for future research and policy considerations in the field of CRC screening and prevention in Korea.展开更多
Objective:To describe temporal changes associated with deployment of an optical character recognition(OCR)-enabled OneIdentity(One-ID)digital platform for rural cervical cancer screening,focusing on over-screening rat...Objective:To describe temporal changes associated with deployment of an optical character recognition(OCR)-enabled OneIdentity(One-ID)digital platform for rural cervical cancer screening,focusing on over-screening rates,CIN2+detection,colposcopy follow-up,and CIN2+management.Methods:A multi-county pre-post observational study was conducted in six rural counties in Shanxi,Yunnan,and Sichuan Provinces(2021±2024),encompassing 153,978 encounters.The digital platform integrates OCR identity capture,deterministic One-ID linkage,and real-time duplicate alerts.Over-screening proportions before and after digital deployment were compared,changes in CIN2+detection rate were evaluated,and colposcopy follow-up and CIN2+management were assessed.Differences were tested withχ2 or Fisher's exact tests.Results:Among 153,978 encounters,the proportion of over-screening decreased from 12.64%in 2023 to 0.17%in 2024 with an absolute reduction of 12.17%(95%CI:11.94±12.40;P<0.001).The share of women receiving a first screening within the preceding 3 y increased from 78.3%to 88.2%(P<0.001).Colposcopy completion improved from 64.1%to 84.9%.The CIN2+detection rate rose from 0.35%(2021±2023 pooled)to 0.67%in 2024(P<0.001)and CIN2+management completion increased from 56.0%to 76.2%(95%CI:13.3±27.2;P<0.001).These improvements were consistent across age groups,counties,and screening strategies.Conclusions:The OCR-enabled One-ID platform substantially reduced over-screening,increased CIN2+detection rate,and strengthened case follow-up/management,particularly where baseline tracking was weak,supporting scalable digital reinforcement of rural screening programmes.展开更多
Colorectal cancer(CRC)is a prevalent malignancy worldwide,posing a significant public health concern.Mounting evidence has confirmed that timely early screening facilitates the detection of incipient CRC,thereby enhan...Colorectal cancer(CRC)is a prevalent malignancy worldwide,posing a significant public health concern.Mounting evidence has confirmed that timely early screening facilitates the detection of incipient CRC,thereby enhancing patient prognosis.Obviously,non-participation of asymptomatic individuals in screening programs hampers early diagnosis and may adversely affect long-term outcomes for CRC patients.In this letter,we provide a comprehensive overview of the current status of early screening practices,while also thoroughly examine the dilemmas and potential solutions associated with early screening for CRC.In response to these issues,we proffer a set of recommendations directed at governmental authorities and the general public,which focus on augmenting financial investment,establishing standardized screening protocols,advancing technological capabilities,and bolstering public awareness campaigns.The importance of collaborative efforts from various stakeholders cannot be overstated in the quest to enhance early detection rates and alleviate the societal burden of CRC.展开更多
Rapid screening of inorganic arsenic(iAs)in groundwater used for drinking by hundreds of millions of mostly rural residents worldwide is crucial for health protection.Most commercial field test kits are based on the G...Rapid screening of inorganic arsenic(iAs)in groundwater used for drinking by hundreds of millions of mostly rural residents worldwide is crucial for health protection.Most commercial field test kits are based on the Gutzeit reaction that uses mercury-based reagents for color development,an environmental concern that increasingly limits its utilization.This study further improves the Molybdenum Blue(MB)colorimetric method to allow for faster screening with more stable reagents.More importantly,a portable three-channel colorimeter is developed for screening iAs relative to the WHO drinking water guideline value(10μg/L).Adding the reducing reagents in sequence not only prolongs the storage time to>7 days,but also accelerates the color development time to 6 min in conjunction with lowering the H_(2)SO_(4) concentration in chromogenic reagents.The optimal pH ranges from 1.2 to 1.3 and is achieved by acidifying groundwater to 1%(V/V)HCl.With detection limits of 3.7μg/L for inorganic arsenate(iAs(V))and 3.8μg/L for inorganic arsenite(iAs(Ⅲ)),testing groundwater with-10μg/L of As has a precision<20%.The method works well for a range of phosphate concentrations of 48-950μg/L(0.5-10μmol/L).Concentrations of total_iAs(6-300μg/L),iAs(V)(6-230μg/L)and iAs(Ⅲ)(0-170μg/L)for 14 groundwater samples from Yinchuan Plain,Pearl River Delta,and Jianghan Plain,are in excellent agreements(linear regression slope:0.969-1.029)with the benchmark methods.The improved chemistry here lays the foundation for the MB colorimetric method to become a commercially viable screening tool,with further engineering and design improvement of the colorimeter.展开更多
Solid-state batteries are widely recognized as the next-generation energy storage devices with high specific energy,high safety,and high environmental adaptability.However,the research and development of solid-state b...Solid-state batteries are widely recognized as the next-generation energy storage devices with high specific energy,high safety,and high environmental adaptability.However,the research and development of solid-state batteries are resource-intensive and time-consuming due to their complex chemical environment,rendering performance prediction arduous and delaying large-scale industrialization.Artificial intelligence serves as an accelerator for solid-state battery development by enabling efficient material screening and performance prediction.This review will systematically examine how the latest progress in using machine learning(ML)algorithms can be used to mine extensive material databases and accelerate the discovery of high-performance cathode,anode,and electrolyte materials suitable for solid-state batteries.Furthermore,the use of ML technology to accurately estimate and predict key performance indicators in the solid-state battery management system will be discussed,among which are state of charge,state of health,remaining useful life,and battery capacity.Finally,we will summarize the main challenges encountered in the current research,such as data quality issues and poor code portability,and propose possible solutions and development paths.These will provide clear guidance for future research and technological reiteration.展开更多
Colorectal cancer(CRC)is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The leading risk factors for CRC include male gender,age over 50,family history,obesity,tobacco ...Colorectal cancer(CRC)is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The leading risk factors for CRC include male gender,age over 50,family history,obesity,tobacco smoking,alco-hol consumption,and unhealthy diet.CRC screening methods vary considerably between countries and depend on incidence,economic resources and healthcare structure.Important aspects of screening include adherence,which can vary signi-ficantly across ethnic and socioeconomic groups.Basic concepts of CRC screening include pre-stratification of patients by identifying risk factors and then using fecal immunochemical test or guaiac-based fecal occult blood test and/or colono-scopy or radiologic imaging techniques.Technological capabilities for CRC scree-ning are rapidly evolving and include stool DNA test,liquid biopsy,virtual colo-nography,and the use of artificial intelligence.A CRC prevention strategy should be comprehensive and include active patient education along with targeted imple-mentation of screening.展开更多
This study investigated environmental distribution and human exposure of polycyclic aromatic hydrocarbons(PAHs)and their derivatives in one Chinese petroleum refinery facility.It was found that,following with high con...This study investigated environmental distribution and human exposure of polycyclic aromatic hydrocarbons(PAHs)and their derivatives in one Chinese petroleum refinery facility.It was found that,following with high concentrations of 16 EPA PAHs(∑Parent-PAHs)in smelting subarea of studied petroleum refinery facility,total derivatives of PAHs[named as XPAHs,including nitro PAHs(NPAHs),chlorinated PAHs(Cl-PAHs),and brominated PAHs(Br-PAHs)]in gas(mean=1.57×10^(4)ng/m^(3)),total suspended particulate(TSP)(mean=4.33×10^(3) ng/m^(3))and soil(mean=4.37×10^(3) ng/g)in this subarea had 1.76-6.19 times higher levels than those from other subareas of this facility,surrounding residential areas and reference areas,indicating that petroleum refining processes would lead apparent derivation of PAHs.Especially,compared with those in residential and reference areas,gas samples in the petrochemical areas had higher∑NPAH/∑PAHs(mean=2.18),but lower∑Cl-PAH/∑PAHs(mean=1.43×10^(-1))and∑Br-PAH/∑PAHs ratios(mean=7.49×10^(-2)),indicating the richer nitrification of PAHs than chlorination during petrochemical process.The occupational exposure to PAHs and XPAHs in this petroleum refinery facility were 24-343 times higher than non-occupational exposure,and the ILCR(1.04×10^(-4))for petrochemical workers was considered to be potential high risk.Furthermore,one expanded high-resolution screening through GC Orbitrap/MS was performed for soils from petrochemical area,and another 35 PAHs were found,including alkyl-PAHs,phenyl-PAHs and other species,indicat-ing that profiles and risks of PAHs analogs in petrochemical areas deserve further expanded investigation.展开更多
Natural antimicrobial peptides(AMPs)are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens.They have found extensive applications in the fields of m...Natural antimicrobial peptides(AMPs)are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens.They have found extensive applications in the fields of medicine,food,and agriculture.However,efficiently screening AMPs from natural sources poses several challenges,including low efficiency and high antibiotic resistance.This review focuses on the action mechanisms of AMPs,both through membrane and non-membrane routes.We thoroughly examine various highly efficient AMP screening methods,including whole-bacterial adsorption binding,cell membrane chromatography(CMC),phospholipid membrane chromatography binding,membranemediated capillary electrophoresis(CE),colorimetric assays,thin layer chromatography(TLC),fluorescence-based screening,genetic sequencing-based analysis,computational mining of AMP databases,and virtual screening methods.Additionally,we discuss potential developmental applications for enhancing the efficiency of AMP discovery.This review provides a comprehensive framework for identifying AMPs within complex natural product systems.展开更多
The high porosity and tunable chemical functionality of metal-organic frameworks(MOFs)make it a promising catalyst design platform.High-throughput screening of catalytic performance is feasible since the large MOF str...The high porosity and tunable chemical functionality of metal-organic frameworks(MOFs)make it a promising catalyst design platform.High-throughput screening of catalytic performance is feasible since the large MOF structure database is available.In this study,we report a machine learning model for high-throughput screening of MOF catalysts for the CO_(2) cycloaddition reaction.The descriptors for model training were judiciously chosen according to the reaction mechanism,which leads to high accuracy up to 97%for the 75%quantile of the training set as the classification criterion.The feature contribution was further evaluated with SHAP and PDP analysis to provide a certain physical understanding.12,415 hypothetical MOF structures and 100 reported MOFs were evaluated under 100℃ and 1 bar within one day using the model,and 239 potentially efficient catalysts were discovered.Among them,MOF-76(Y)achieved the top performance experimentally among reported MOFs,in good agreement with the prediction.展开更多
Diabetic retinopathy(DR)remains a leading cause of vision impairment and blindness among individuals with diabetes,necessitating innovative approaches to screening and management.This editorial explores the transforma...Diabetic retinopathy(DR)remains a leading cause of vision impairment and blindness among individuals with diabetes,necessitating innovative approaches to screening and management.This editorial explores the transformative potential of artificial intelligence(AI)and machine learning(ML)in revolutionizing DR care.AI and ML technologies have demonstrated remarkable advancements in enhancing the accuracy,efficiency,and accessibility of DR screening,helping to overcome barriers to early detection.These technologies leverage vast datasets to identify patterns and predict disease progression with unprecedented precision,enabling clinicians to make more informed decisions.Furthermore,AI-driven solutions hold promise in personalizing management strategies for DR,incorpo-rating predictive analytics to tailor interventions and optimize treatment path-ways.By automating routine tasks,AI can reduce the burden on healthcare providers,allowing for a more focused allocation of resources towards complex patient care.This review aims to evaluate the current advancements and applic-ations of AI and ML in DR screening,and to discuss the potential of these techno-logies in developing personalized management strategies,ultimately aiming to improve patient outcomes and reduce the global burden of DR.The integration of AI and ML in DR care represents a paradigm shift,offering a glimpse into the future of ophthalmic healthcare.展开更多
BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group ...BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S.CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane re-gulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium.NS is crucial for early diagnosis and management,which ensures a better quality of life.AIM To report a case of the coexistence of sickle cell anemia(SCA)and CF and perform an integrative literature review.METHODS This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case.The authors identified only 5 cases of SCA associated with CF.No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.RESULTS Herein,the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin.The diagnosis of CF was confirmed by the Coulometry Sweat Test.The rarity of the co-occurrence of these two severe genetic pathologies(CF and SCA)is a challenge for medical science.CONCLUSION This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.展开更多
Objective:This randomized controlled trial aimed to assess the impact of a targeted educational intervention on the awareness and practice of genetic screening and counseling among young adults in Calabar Municipality...Objective:This randomized controlled trial aimed to assess the impact of a targeted educational intervention on the awareness and practice of genetic screening and counseling among young adults in Calabar Municipality,Cross River State.Materials and Methods:Participants(aged 18-45)were randomly assigned to either an intervention group receiving structured health education or a control group receiving general health information.Stratified randomization was used between the groups.A sample size of 340 participants was recruited to detect a 20%difference in outcomes with 80%power.Data were collected using prevalidated questionnaires at baseline,immediately after the intervention,and at a 3-month follow-up.The intervention consisted of three weekly 90-min educational sessions covering genetics,the benefits of screening,and practical guidance on accessing genetic services.The primary outcomes were changes in awareness and practices related to genetic screening,with secondary outcomes focusing on attitudes and intentions toward genetic counseling.Results:Findings revealed that awareness of genetic screening was higher in the intervention group,with 65.9%of participants aware of early detection,compared to 59.4%in the control group,although the difference was not statistically significant(P=0.23).In terms of practice,42.9%of the intervention group and 40.0%of the control group engaged in genetic screening programs,with no significant difference(P=0.57).Logistic regression analysis highlighted that age,educational level,and knowledge of teratogens were significant predictors of genetic screening awareness.Participants aged 36 years and above were 1.52 times more likely to be aware(odds ratio[OR]=1.52,P=0.003),and those with tertiary education had nearly double the likelihood of awareness(OR=1.96,P<0.001).Conclusion:The study underscores the importance of targeted education in improving genetic screening awareness.展开更多
In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics.Similarities and variations of components present significant analytical challenges.A two-dimensional(2...In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics.Similarities and variations of components present significant analytical challenges.A two-dimensional(2D)liquid chromatography-mass spectrometry(LC-MS)method was established for screening and comprehensive profiling of compositions of the antibiotic colistimethate sodium(CMS).A high concentration of phosphate buffer mobile phase was used in the first-dimensional LC system to get the components well separated.For efficient and high-accuracy screening of CMS,a targeted method based on a self-constructed high resolution(HR)mass spectrum database of CMS components was established.The database was built based on the commercial MassHunter Personal Compound Database and Library(PCDL)software and its accuracy of the compound matching result was verified with six known components before being applied to genuine sample screening.On this basis,the unknown peaks in the CMS chromatograms were deduced and assigned.The molecular formula,group composition,and origins of a total of 99 compounds,of which the combined area percentage accounted for more than 95%of CMS components,were deduced by this 2D-LC-MS method combined with the MassHunter PCDL.This profiling method was highly efficient and could distinguish hundreds of components within 3 h,providing reliable results for quality control of this kind of complex drugs.展开更多
Objectives:Decades of clinical and fundamental research advancements in oncology have led to significant breakthroughs such as early screening,targeted therapies,and immunotherapy,contributing to reduced mortality rat...Objectives:Decades of clinical and fundamental research advancements in oncology have led to significant breakthroughs such as early screening,targeted therapies,and immunotherapy,contributing to reduced mortality rates in cancer patients.Despite these achievements,cancer continues to be a major public health challenge.This study employs bibliometric techniques to visually analyze the English literature on cancer prevention,screening,diagnosis,treatment,and rehabilitation.Methods:We systematically reviewed publications from 01 March 2014,to 01 March 2024,indexed in the Web of Science core collection.Tools such as VOSviewer Version 1.6.20 is characterized by its core idea of co-occurrence clustering.CiteSpace 6.3.R3 is distinguished by its powerful capabilities in bibliometric analysis,including co-citation analysis,co-occurrence analysis of keywords,author collaboration network analysis,and journal co-citation analysis,providing effective insights into research hotspots and detecting emerging trends.Bibliometrix version 3.0.3 offers rich visualization features,including collaboration network diagrams,citation distribution graphs,and keyword clouds.facilitated the analysis of the literature,helping to map out the current research landscape,identify pressing issues,and discern emerging trends,thus offering insights for future research directions.Results:The analysis revealed that major research hotspots include lung and breast cancer.Attention is predominantly concentrated on cancer treatment,subdivided into targeted therapy,immunotherapy,traditional Chinese medicine,and the development of new anticancer drugs.Significant terms identified in the study include immune checkpoint inhibitors,tumor microenvironment,and cancer stem cells.Conclusion:This bibliometric analysis highlights the evolving directions in oncology research,pinpointing nanotherapy,resistance to targeted therapies,and the integration of artificial intelligence as pivotal future research avenues in the prevention,screening,diagnosis,treatment,and rehabilitation of cancer.展开更多
BACKGROUND Nosocomial fever of unknown origin(nFUO)is a frequent and challenging diagnostic entity,encompassing diverse infectious and non-infectious etiologies.Timely identification is crucial,yet evidence on the dia...BACKGROUND Nosocomial fever of unknown origin(nFUO)is a frequent and challenging diagnostic entity,encompassing diverse infectious and non-infectious etiologies.Timely identification is crucial,yet evidence on the diagnostic accuracy of commonly employed sepsis screening tools and biomarkers remains sparse.We hypothesized that these tools and biomarkers measured at fever onset could distinguish infectious from non-infectious causes of nFUO in critically ill adults.AIM To evaluate the diagnostic utility of sepsis tools and biomarkers in identifying infectious causes of nFUO.METHODS This prospective observational study included patients admitted to the Acute Care Emergency Medicine Unit,Postgraduate Institute of Medical Education and Research,Chandigarh,India(July 2023 to December 2024).nFUO was defined by Durack and Street criteria.Diagnostic performance of sepsis screening tools(systemic inflammatory response syndrome,Sequential Organ Failure Assessment,quick Sequential Organ Failure Assessment,National Early Warning Score,and Modified Early Warning Score)and biomarkers[procalcitonin(PCT),C-reactive protein(CRP)]at fever onset was assessed using receiver operating characteristic curve analysis.RESULTS Of 80 cases(mean age 42.9±16.5 years;80% male),42.5% had infectious causes,38.7% non-infectious,and 18.8% remained undiagnosed.Pneumonia(26.2%)and bloodstream infections(11.2%)were the most common infectious etiologies,while central fever and thrombophlebitis(each 7.5%)were predominant among non-infectious causes.Sepsis tools showed poor diagnostic accuracy,with area under the receiver operating characteristic curve(AUC)values close to 0.5.PCT demonstrated modest performance(AUC=0.61;optimal cut-off:0.85μg/L),while CRP was paradoxically higher in non-infectious cases(AUC=0.45).Overall mortality was 20% and was highest among undiagnosed patients(33.3%).Fever duration and hospitalization length were significantly greater in infectious cases.CONCLUSION Sepsis tools,PCT,and CRP have limited utility in identifying infectious causes of nFUO in critically ill adults and should not solely guide initial decision-making.展开更多
Detection and treatment of colorectal cancer(CRC)at an early stage is vital for long-term survival.Liquid biopsy has emerged as a promising new avenue for non-invasive screening of CRC as well as prognostication and s...Detection and treatment of colorectal cancer(CRC)at an early stage is vital for long-term survival.Liquid biopsy has emerged as a promising new avenue for non-invasive screening of CRC as well as prognostication and surveillance of minimal residual disease.Cell free DNA(cfDNA)is a promising liquid biopsy analyte and has been approved for use in clinical practice.Here,we explore the current challenges of utilizing cfDNA in the screening and prognostication of CRC but also for detecting driver mutations in healthy,presymptomatic patients with normal colonic crypts.CfDNA for the detection of cancerous or premalignant colonic lesions has already been extensively explored,however few have considered utilizing cfDNA in the detection of driver mutations in healthy patients.Theoretically,this would allow us to detect patients who are at a higher risk of tumorigenesis decades in advance of established malignancy and stratify them into higher risk groups for early-intervention screening programs.We also explore the solutions necessary to overcome the challenges that prevent liquid biopsy from entering mainstream clinical use.The potential for liquid biopsy is immense if these challenges are successfully circumvented,and can dramatically reduce CRC rates as well as improve survival in patients.展开更多
Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challengin...Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.展开更多
Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Vir...Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection.Nonetheless,current drug exploitation targeting viral helicases is still in infancy.This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus(TMV)helicase using Food and Drug Administration(FDA)-approved commercially available molecule library.The ranked top 6 hits were further validated by root mean square deviations/fluctuations(RMSD/F),molecular mechanics Poisson Boltzmann surface area(MM-PBSA),density functional theory(DFT)calculations,and bioactivity evaluation.Encouragingly,lumacaftor(ΔE_(total)=-29.0kcal/mol,K_(d)=0.22μmol/L,half maximal inhibitory concentration(IC_(50))=162.5μmol/L)displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin(K_(d)=9.35μmol/L,IC_(50)>200μmol/L).Therefore,lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability.Besides,the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis.Overall,current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.展开更多
文摘Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand binding structure,dynamics and affinity.Currently,the four mainstream drug targets are G protein-coupled receptors(GPCRs),kinases,ion channels,and nuclear receptors,accounting for over 70%of effective drug targets,most of which are membrane proteins and enzymes.In recent years,various new drug targets have been continuously discovered,and the research focus has shifted from simple affinity analysis to high-throughput and high-content screening,as well as exploring drug-target interaction modes.These deepen reliance on the analytical techniques to have higher sensitivity,recognition specificity,and applicability to diversified target structures,which promoting the rapid development of novel screening methods.
文摘Cancer screening is a strategy focused on highrisk populations rather than universal populationwide screening, based on a comprehensive evaluation of epidemiological principles and practical feasibility. The effectiveness of screening depends on factors such as disease prevalence, as well as the sensitivity and specificity of the screening technology employed.
文摘This study discusses the impact of the increasing use of colonoscopy on the trends of colorectal cancer(CRC)in Korea.Different views are raised on the research methods and conclusions of Kim et al.It emphasizes the need to carefully consider the balance between the benefits of early detection and the risks of over-screening.This letter also suggests directions for future research and policy considerations in the field of CRC screening and prevention in Korea.
基金supported by the Chongqing Tencent Sustainable Development Foundation through the project"Comprehensive Prevention and Control Demonstration Project for Eliminating Cervical Cancer and Breast Cancer in Low Health Resource Areas of China"(Project No.SD20240904145730)by the Tencent Sustainable Social Value(SSV)Inclusive Health Lab(Project No.SSVPJ202307060001)。
文摘Objective:To describe temporal changes associated with deployment of an optical character recognition(OCR)-enabled OneIdentity(One-ID)digital platform for rural cervical cancer screening,focusing on over-screening rates,CIN2+detection,colposcopy follow-up,and CIN2+management.Methods:A multi-county pre-post observational study was conducted in six rural counties in Shanxi,Yunnan,and Sichuan Provinces(2021±2024),encompassing 153,978 encounters.The digital platform integrates OCR identity capture,deterministic One-ID linkage,and real-time duplicate alerts.Over-screening proportions before and after digital deployment were compared,changes in CIN2+detection rate were evaluated,and colposcopy follow-up and CIN2+management were assessed.Differences were tested withχ2 or Fisher's exact tests.Results:Among 153,978 encounters,the proportion of over-screening decreased from 12.64%in 2023 to 0.17%in 2024 with an absolute reduction of 12.17%(95%CI:11.94±12.40;P<0.001).The share of women receiving a first screening within the preceding 3 y increased from 78.3%to 88.2%(P<0.001).Colposcopy completion improved from 64.1%to 84.9%.The CIN2+detection rate rose from 0.35%(2021±2023 pooled)to 0.67%in 2024(P<0.001)and CIN2+management completion increased from 56.0%to 76.2%(95%CI:13.3±27.2;P<0.001).These improvements were consistent across age groups,counties,and screening strategies.Conclusions:The OCR-enabled One-ID platform substantially reduced over-screening,increased CIN2+detection rate,and strengthened case follow-up/management,particularly where baseline tracking was weak,supporting scalable digital reinforcement of rural screening programmes.
文摘Colorectal cancer(CRC)is a prevalent malignancy worldwide,posing a significant public health concern.Mounting evidence has confirmed that timely early screening facilitates the detection of incipient CRC,thereby enhancing patient prognosis.Obviously,non-participation of asymptomatic individuals in screening programs hampers early diagnosis and may adversely affect long-term outcomes for CRC patients.In this letter,we provide a comprehensive overview of the current status of early screening practices,while also thoroughly examine the dilemmas and potential solutions associated with early screening for CRC.In response to these issues,we proffer a set of recommendations directed at governmental authorities and the general public,which focus on augmenting financial investment,establishing standardized screening protocols,advancing technological capabilities,and bolstering public awareness campaigns.The importance of collaborative efforts from various stakeholders cannot be overstated in the quest to enhance early detection rates and alleviate the societal burden of CRC.
基金the National Key R&D Program of China(No.2021YFA0715900)the National Natural Science Foundation of China(No.41831279)+2 种基金the Shenzhen Key Laboratory of Precision Measurement and Early Warning Technology for Urban Environmental Health Risks(No.ZDSYS20220606100604008)the Guangdong Province Bureau of Education(No.2020KCXTD006)the Guangdong Provincial Key Laboratory of Soil and Groundwater Pollution Control(No.2023B1212060002).
文摘Rapid screening of inorganic arsenic(iAs)in groundwater used for drinking by hundreds of millions of mostly rural residents worldwide is crucial for health protection.Most commercial field test kits are based on the Gutzeit reaction that uses mercury-based reagents for color development,an environmental concern that increasingly limits its utilization.This study further improves the Molybdenum Blue(MB)colorimetric method to allow for faster screening with more stable reagents.More importantly,a portable three-channel colorimeter is developed for screening iAs relative to the WHO drinking water guideline value(10μg/L).Adding the reducing reagents in sequence not only prolongs the storage time to>7 days,but also accelerates the color development time to 6 min in conjunction with lowering the H_(2)SO_(4) concentration in chromogenic reagents.The optimal pH ranges from 1.2 to 1.3 and is achieved by acidifying groundwater to 1%(V/V)HCl.With detection limits of 3.7μg/L for inorganic arsenate(iAs(V))and 3.8μg/L for inorganic arsenite(iAs(Ⅲ)),testing groundwater with-10μg/L of As has a precision<20%.The method works well for a range of phosphate concentrations of 48-950μg/L(0.5-10μmol/L).Concentrations of total_iAs(6-300μg/L),iAs(V)(6-230μg/L)and iAs(Ⅲ)(0-170μg/L)for 14 groundwater samples from Yinchuan Plain,Pearl River Delta,and Jianghan Plain,are in excellent agreements(linear regression slope:0.969-1.029)with the benchmark methods.The improved chemistry here lays the foundation for the MB colorimetric method to become a commercially viable screening tool,with further engineering and design improvement of the colorimeter.
基金the National Key Research Program of China under granted No.92164201National Natural Science Foundation of China for Distinguished Young Scholars No.62325403+2 种基金Natural Science Foundation of Jiangsu Province(BK20230498)Jiangsu Funding Program for Excellent Postdoctoral Talent(2024ZB427)the National Natural Science Foundation of China(62304147).
文摘Solid-state batteries are widely recognized as the next-generation energy storage devices with high specific energy,high safety,and high environmental adaptability.However,the research and development of solid-state batteries are resource-intensive and time-consuming due to their complex chemical environment,rendering performance prediction arduous and delaying large-scale industrialization.Artificial intelligence serves as an accelerator for solid-state battery development by enabling efficient material screening and performance prediction.This review will systematically examine how the latest progress in using machine learning(ML)algorithms can be used to mine extensive material databases and accelerate the discovery of high-performance cathode,anode,and electrolyte materials suitable for solid-state batteries.Furthermore,the use of ML technology to accurately estimate and predict key performance indicators in the solid-state battery management system will be discussed,among which are state of charge,state of health,remaining useful life,and battery capacity.Finally,we will summarize the main challenges encountered in the current research,such as data quality issues and poor code portability,and propose possible solutions and development paths.These will provide clear guidance for future research and technological reiteration.
文摘Colorectal cancer(CRC)is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The leading risk factors for CRC include male gender,age over 50,family history,obesity,tobacco smoking,alco-hol consumption,and unhealthy diet.CRC screening methods vary considerably between countries and depend on incidence,economic resources and healthcare structure.Important aspects of screening include adherence,which can vary signi-ficantly across ethnic and socioeconomic groups.Basic concepts of CRC screening include pre-stratification of patients by identifying risk factors and then using fecal immunochemical test or guaiac-based fecal occult blood test and/or colono-scopy or radiologic imaging techniques.Technological capabilities for CRC scree-ning are rapidly evolving and include stool DNA test,liquid biopsy,virtual colo-nography,and the use of artificial intelligence.A CRC prevention strategy should be comprehensive and include active patient education along with targeted imple-mentation of screening.
基金supported by the National Key Research and Development Program of China(No.2019YFC1804501)the National Natural Science Foundation of China(Nos.22036007 and 22122611)+1 种基金the Natural Science Foundation of Shandong Province(No.ZR2020ME228)the Introduction and Cultivation Plan for Young Innovative Talents of Colleges and Universities.
文摘This study investigated environmental distribution and human exposure of polycyclic aromatic hydrocarbons(PAHs)and their derivatives in one Chinese petroleum refinery facility.It was found that,following with high concentrations of 16 EPA PAHs(∑Parent-PAHs)in smelting subarea of studied petroleum refinery facility,total derivatives of PAHs[named as XPAHs,including nitro PAHs(NPAHs),chlorinated PAHs(Cl-PAHs),and brominated PAHs(Br-PAHs)]in gas(mean=1.57×10^(4)ng/m^(3)),total suspended particulate(TSP)(mean=4.33×10^(3) ng/m^(3))and soil(mean=4.37×10^(3) ng/g)in this subarea had 1.76-6.19 times higher levels than those from other subareas of this facility,surrounding residential areas and reference areas,indicating that petroleum refining processes would lead apparent derivation of PAHs.Especially,compared with those in residential and reference areas,gas samples in the petrochemical areas had higher∑NPAH/∑PAHs(mean=2.18),but lower∑Cl-PAH/∑PAHs(mean=1.43×10^(-1))and∑Br-PAH/∑PAHs ratios(mean=7.49×10^(-2)),indicating the richer nitrification of PAHs than chlorination during petrochemical process.The occupational exposure to PAHs and XPAHs in this petroleum refinery facility were 24-343 times higher than non-occupational exposure,and the ILCR(1.04×10^(-4))for petrochemical workers was considered to be potential high risk.Furthermore,one expanded high-resolution screening through GC Orbitrap/MS was performed for soils from petrochemical area,and another 35 PAHs were found,including alkyl-PAHs,phenyl-PAHs and other species,indicat-ing that profiles and risks of PAHs analogs in petrochemical areas deserve further expanded investigation.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82373835,82304437,and 82173781)Regional Joint Fund Project of Guangdong Basic and Applied Basic Research Fund,China(Grant Nos.:2023A1515110417 and 2023A1515140131)+2 种基金Regional Joint Fund-Key Project of Guangdong Basic and Applied Basic Research Fund,China(Grant No.:2020B1515120033)the Key Field Projects of General Universities in Guangdong Province,China(Grant Nos.:2020ZDZX2057 and 2022ZDZX2056)Medical Scientific Research Foundation of Guangdong Province of China(Grant No.:A2022061).
文摘Natural antimicrobial peptides(AMPs)are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens.They have found extensive applications in the fields of medicine,food,and agriculture.However,efficiently screening AMPs from natural sources poses several challenges,including low efficiency and high antibiotic resistance.This review focuses on the action mechanisms of AMPs,both through membrane and non-membrane routes.We thoroughly examine various highly efficient AMP screening methods,including whole-bacterial adsorption binding,cell membrane chromatography(CMC),phospholipid membrane chromatography binding,membranemediated capillary electrophoresis(CE),colorimetric assays,thin layer chromatography(TLC),fluorescence-based screening,genetic sequencing-based analysis,computational mining of AMP databases,and virtual screening methods.Additionally,we discuss potential developmental applications for enhancing the efficiency of AMP discovery.This review provides a comprehensive framework for identifying AMPs within complex natural product systems.
基金financial support from the National Key Research and Development Program of China(2021YFB 3501501)the National Natural Science Foundation of China(No.22225803,22038001,22108007 and 22278011)+1 种基金Beijing Natural Science Foundation(No.Z230023)Beijing Science and Technology Commission(No.Z211100004321001).
文摘The high porosity and tunable chemical functionality of metal-organic frameworks(MOFs)make it a promising catalyst design platform.High-throughput screening of catalytic performance is feasible since the large MOF structure database is available.In this study,we report a machine learning model for high-throughput screening of MOF catalysts for the CO_(2) cycloaddition reaction.The descriptors for model training were judiciously chosen according to the reaction mechanism,which leads to high accuracy up to 97%for the 75%quantile of the training set as the classification criterion.The feature contribution was further evaluated with SHAP and PDP analysis to provide a certain physical understanding.12,415 hypothetical MOF structures and 100 reported MOFs were evaluated under 100℃ and 1 bar within one day using the model,and 239 potentially efficient catalysts were discovered.Among them,MOF-76(Y)achieved the top performance experimentally among reported MOFs,in good agreement with the prediction.
文摘Diabetic retinopathy(DR)remains a leading cause of vision impairment and blindness among individuals with diabetes,necessitating innovative approaches to screening and management.This editorial explores the transformative potential of artificial intelligence(AI)and machine learning(ML)in revolutionizing DR care.AI and ML technologies have demonstrated remarkable advancements in enhancing the accuracy,efficiency,and accessibility of DR screening,helping to overcome barriers to early detection.These technologies leverage vast datasets to identify patterns and predict disease progression with unprecedented precision,enabling clinicians to make more informed decisions.Furthermore,AI-driven solutions hold promise in personalizing management strategies for DR,incorpo-rating predictive analytics to tailor interventions and optimize treatment path-ways.By automating routine tasks,AI can reduce the burden on healthcare providers,allowing for a more focused allocation of resources towards complex patient care.This review aims to evaluate the current advancements and applic-ations of AI and ML in DR screening,and to discuss the potential of these techno-logies in developing personalized management strategies,ultimately aiming to improve patient outcomes and reduce the global burden of DR.The integration of AI and ML in DR care represents a paradigm shift,offering a glimpse into the future of ophthalmic healthcare.
文摘BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S.CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane re-gulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium.NS is crucial for early diagnosis and management,which ensures a better quality of life.AIM To report a case of the coexistence of sickle cell anemia(SCA)and CF and perform an integrative literature review.METHODS This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case.The authors identified only 5 cases of SCA associated with CF.No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.RESULTS Herein,the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin.The diagnosis of CF was confirmed by the Coulometry Sweat Test.The rarity of the co-occurrence of these two severe genetic pathologies(CF and SCA)is a challenge for medical science.CONCLUSION This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.
文摘Objective:This randomized controlled trial aimed to assess the impact of a targeted educational intervention on the awareness and practice of genetic screening and counseling among young adults in Calabar Municipality,Cross River State.Materials and Methods:Participants(aged 18-45)were randomly assigned to either an intervention group receiving structured health education or a control group receiving general health information.Stratified randomization was used between the groups.A sample size of 340 participants was recruited to detect a 20%difference in outcomes with 80%power.Data were collected using prevalidated questionnaires at baseline,immediately after the intervention,and at a 3-month follow-up.The intervention consisted of three weekly 90-min educational sessions covering genetics,the benefits of screening,and practical guidance on accessing genetic services.The primary outcomes were changes in awareness and practices related to genetic screening,with secondary outcomes focusing on attitudes and intentions toward genetic counseling.Results:Findings revealed that awareness of genetic screening was higher in the intervention group,with 65.9%of participants aware of early detection,compared to 59.4%in the control group,although the difference was not statistically significant(P=0.23).In terms of practice,42.9%of the intervention group and 40.0%of the control group engaged in genetic screening programs,with no significant difference(P=0.57).Logistic regression analysis highlighted that age,educational level,and knowledge of teratogens were significant predictors of genetic screening awareness.Participants aged 36 years and above were 1.52 times more likely to be aware(odds ratio[OR]=1.52,P=0.003),and those with tertiary education had nearly double the likelihood of awareness(OR=1.96,P<0.001).Conclusion:The study underscores the importance of targeted education in improving genetic screening awareness.
基金support from the Science Research Program Project for Drug Regulation,Jiangsu Medical Products Administration,China(Grant No.:202207)the National Drug Standards Revision Project,China(Grant No.:2023Y41)+1 种基金the National Natural Science Foundation of China(Grant No.:22276080)the Foreign Expert Project,China(Grant No.:G2022014096L).
文摘In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics.Similarities and variations of components present significant analytical challenges.A two-dimensional(2D)liquid chromatography-mass spectrometry(LC-MS)method was established for screening and comprehensive profiling of compositions of the antibiotic colistimethate sodium(CMS).A high concentration of phosphate buffer mobile phase was used in the first-dimensional LC system to get the components well separated.For efficient and high-accuracy screening of CMS,a targeted method based on a self-constructed high resolution(HR)mass spectrum database of CMS components was established.The database was built based on the commercial MassHunter Personal Compound Database and Library(PCDL)software and its accuracy of the compound matching result was verified with six known components before being applied to genuine sample screening.On this basis,the unknown peaks in the CMS chromatograms were deduced and assigned.The molecular formula,group composition,and origins of a total of 99 compounds,of which the combined area percentage accounted for more than 95%of CMS components,were deduced by this 2D-LC-MS method combined with the MassHunter PCDL.This profiling method was highly efficient and could distinguish hundreds of components within 3 h,providing reliable results for quality control of this kind of complex drugs.
基金supported by the grants from the Scientific and Technological Innovation Project of Information Traditional Chinese Medicine,China Academy of Chinese Medical Sciences(No.CI2021 B002).
文摘Objectives:Decades of clinical and fundamental research advancements in oncology have led to significant breakthroughs such as early screening,targeted therapies,and immunotherapy,contributing to reduced mortality rates in cancer patients.Despite these achievements,cancer continues to be a major public health challenge.This study employs bibliometric techniques to visually analyze the English literature on cancer prevention,screening,diagnosis,treatment,and rehabilitation.Methods:We systematically reviewed publications from 01 March 2014,to 01 March 2024,indexed in the Web of Science core collection.Tools such as VOSviewer Version 1.6.20 is characterized by its core idea of co-occurrence clustering.CiteSpace 6.3.R3 is distinguished by its powerful capabilities in bibliometric analysis,including co-citation analysis,co-occurrence analysis of keywords,author collaboration network analysis,and journal co-citation analysis,providing effective insights into research hotspots and detecting emerging trends.Bibliometrix version 3.0.3 offers rich visualization features,including collaboration network diagrams,citation distribution graphs,and keyword clouds.facilitated the analysis of the literature,helping to map out the current research landscape,identify pressing issues,and discern emerging trends,thus offering insights for future research directions.Results:The analysis revealed that major research hotspots include lung and breast cancer.Attention is predominantly concentrated on cancer treatment,subdivided into targeted therapy,immunotherapy,traditional Chinese medicine,and the development of new anticancer drugs.Significant terms identified in the study include immune checkpoint inhibitors,tumor microenvironment,and cancer stem cells.Conclusion:This bibliometric analysis highlights the evolving directions in oncology research,pinpointing nanotherapy,resistance to targeted therapies,and the integration of artificial intelligence as pivotal future research avenues in the prevention,screening,diagnosis,treatment,and rehabilitation of cancer.
文摘BACKGROUND Nosocomial fever of unknown origin(nFUO)is a frequent and challenging diagnostic entity,encompassing diverse infectious and non-infectious etiologies.Timely identification is crucial,yet evidence on the diagnostic accuracy of commonly employed sepsis screening tools and biomarkers remains sparse.We hypothesized that these tools and biomarkers measured at fever onset could distinguish infectious from non-infectious causes of nFUO in critically ill adults.AIM To evaluate the diagnostic utility of sepsis tools and biomarkers in identifying infectious causes of nFUO.METHODS This prospective observational study included patients admitted to the Acute Care Emergency Medicine Unit,Postgraduate Institute of Medical Education and Research,Chandigarh,India(July 2023 to December 2024).nFUO was defined by Durack and Street criteria.Diagnostic performance of sepsis screening tools(systemic inflammatory response syndrome,Sequential Organ Failure Assessment,quick Sequential Organ Failure Assessment,National Early Warning Score,and Modified Early Warning Score)and biomarkers[procalcitonin(PCT),C-reactive protein(CRP)]at fever onset was assessed using receiver operating characteristic curve analysis.RESULTS Of 80 cases(mean age 42.9±16.5 years;80% male),42.5% had infectious causes,38.7% non-infectious,and 18.8% remained undiagnosed.Pneumonia(26.2%)and bloodstream infections(11.2%)were the most common infectious etiologies,while central fever and thrombophlebitis(each 7.5%)were predominant among non-infectious causes.Sepsis tools showed poor diagnostic accuracy,with area under the receiver operating characteristic curve(AUC)values close to 0.5.PCT demonstrated modest performance(AUC=0.61;optimal cut-off:0.85μg/L),while CRP was paradoxically higher in non-infectious cases(AUC=0.45).Overall mortality was 20% and was highest among undiagnosed patients(33.3%).Fever duration and hospitalization length were significantly greater in infectious cases.CONCLUSION Sepsis tools,PCT,and CRP have limited utility in identifying infectious causes of nFUO in critically ill adults and should not solely guide initial decision-making.
文摘Detection and treatment of colorectal cancer(CRC)at an early stage is vital for long-term survival.Liquid biopsy has emerged as a promising new avenue for non-invasive screening of CRC as well as prognostication and surveillance of minimal residual disease.Cell free DNA(cfDNA)is a promising liquid biopsy analyte and has been approved for use in clinical practice.Here,we explore the current challenges of utilizing cfDNA in the screening and prognostication of CRC but also for detecting driver mutations in healthy,presymptomatic patients with normal colonic crypts.CfDNA for the detection of cancerous or premalignant colonic lesions has already been extensively explored,however few have considered utilizing cfDNA in the detection of driver mutations in healthy patients.Theoretically,this would allow us to detect patients who are at a higher risk of tumorigenesis decades in advance of established malignancy and stratify them into higher risk groups for early-intervention screening programs.We also explore the solutions necessary to overcome the challenges that prevent liquid biopsy from entering mainstream clinical use.The potential for liquid biopsy is immense if these challenges are successfully circumvented,and can dramatically reduce CRC rates as well as improve survival in patients.
基金supported by the Science and Technology Development Fund,Macao SAR,China(Grant Nos.:FDCT 0001/2020/AKP and 006/2023/SKL)Guangxi Science and Technology Major Program,China(Program No.:Guike AA22096022).
文摘Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
基金financially supported by National Natural Science Foundation of China(Nos.32372610,U23A20201,32160661,32202359)National Key Research and Development Program of China(No.2022YFD1700300)the Central Government Guides Local Science and Technology Development Fund Projects(Nos.[Qiankehezhongyindi(2023)001]and[Qiankehezhongyindi[2024]007])。
文摘Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection.Nonetheless,current drug exploitation targeting viral helicases is still in infancy.This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus(TMV)helicase using Food and Drug Administration(FDA)-approved commercially available molecule library.The ranked top 6 hits were further validated by root mean square deviations/fluctuations(RMSD/F),molecular mechanics Poisson Boltzmann surface area(MM-PBSA),density functional theory(DFT)calculations,and bioactivity evaluation.Encouragingly,lumacaftor(ΔE_(total)=-29.0kcal/mol,K_(d)=0.22μmol/L,half maximal inhibitory concentration(IC_(50))=162.5μmol/L)displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin(K_(d)=9.35μmol/L,IC_(50)>200μmol/L).Therefore,lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability.Besides,the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis.Overall,current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.
