The incidence of in-hospital cardiac arrest (IHCA) has increased over the past decade,with more than half occurring in intensive care units (ICUs).^([1])ICU cardiac arrest (ICU-CA)presents unique challenges,with worse...The incidence of in-hospital cardiac arrest (IHCA) has increased over the past decade,with more than half occurring in intensive care units (ICUs).^([1])ICU cardiac arrest (ICU-CA)presents unique challenges,with worse outcomes than those in monitored wards,highlighting the need for early detection and intervention.^([2])Up to 80%of patients exhibit signs of deterioration hours before IHCA.^([3])Although early warning scores based on vital signs are useful,their eff ectiveness in ICUs is limited due to abnormal physiological parameters.^([4])Laboratory markers,such as sodium,potassium,and lactate,are predictive of poor outcomes,^([5])but static measurements may not capture the patient’s trajectory.Trends in laboratory indicators,such as variability and extremes,may offer better predictive value.^([6])This study aimed to evaluate ICU-CA predictive factors,with a focus on vital signs and trends of laboratory indicators.展开更多
BACKGROUND:The early diagnosis of acute myocardial infarction(AMI)remains challenging,especially for institutions without the high-sensitive cardiac troponin(hs-c Tn)assay.Herein,we aim to assess the value of creatine...BACKGROUND:The early diagnosis of acute myocardial infarction(AMI)remains challenging,especially for institutions without the high-sensitive cardiac troponin(hs-c Tn)assay.Herein,we aim to assess the value of creatine kinase-myocardial band isoenzyme(CK-MB)combined with different cardiac troponin(c Tn)assays in AMI diagnosis.METHODS:This multicenter,observational study included 3,706 patients with acute chest pain from September 1,2015,to September 30,2017.We classified the participants into three groups according to the c Tn assays:the point-of-care c Tn(POC-c Tn)group,the contemporary c Tn(c-c Tn)group,and hs-c Tn group.The diagnostic value was quantified using sensitivity and the area under the curve(AUC).RESULTS:Compared to the single POC-c Tn/c-c Tn assays,combining CK-MB and POC-c Tn/c-c Tn increased the diagnostic sensitivity of AMI(56.1%vs.63.9%,P<0.001;82.7%vs.84.3%,P=0.025).In contrast,combining CK-MB and hs-c Tn did not change the sensitivity compared with hs-c Tn alone(95.0%vs.95.0%,P>0.999).In the subgroup analysis,the sensitivity of combining CKMB and c-c Tn increased with time from symptom onset<6 h compared with c-c Tn alone(72.8%vs.75.0%,P=0.046),while the sensitivity did not increase with time from symptom onset>6 h(97.5%vs.98.3%,P=0.317).The AUC of the combination of CK-MB and POC-c Tn significantly increased compared to the single POC-c Tn assay(0.776 vs.0.750,P=0.002).The AUC of the combined CKMB and c-c Tn/hs-c Tn assays did not significantly decrease compared with that of the single c-c Tn/hs-c Tn assays within 6 h.CONCLUSIONS:The combination of CK-MB and POC-c Tn or c-c Tn may be valuable for the early diagnosis of AMI,especially when hs-c Tn is not available.展开更多
Influenza A viruses(IAV)are responsible for seasonal flu epidemics,which can lead to high morbidity and mortality each year.Like other viruses,influenza virus can hijack host cellular machinery for its replication.Hos...Influenza A viruses(IAV)are responsible for seasonal flu epidemics,which can lead to high morbidity and mortality each year.Like other viruses,influenza virus can hijack host cellular machinery for its replication.Host cells have evolved diverse cellular defense to resist the invasion of viruses.As the main components of promyelocytic leukemia protein nuclear bodies(PML-NBs),PML can inhibit the replication of many medically important viruses including IAV.However,the mechanism of PML against IAV is unclear.In the present study,we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication,whereas knockdown of endogenous PML expression could enhance IAV replication.Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2,which negatively regulated IAV replication during infection.Moreover,PML stabilized RIG-I to promote the production of typeⅠIFN.Collectively,these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.展开更多
Sm(Co,Cu,Fe,Zr)z magnets have drawn much attention for high-temperature applications due to their high Curie temperature,strong corrosion resistance and thermal stability.The effect of increasing Fe content on the dis...Sm(Co,Cu,Fe,Zr)z magnets have drawn much attention for high-temperature applications due to their high Curie temperature,strong corrosion resistance and thermal stability.The effect of increasing Fe content on the distribution of elements and squareness(Sr)of demagnetization curves were investigated for two kinds of magnets with different nominal compositions of Sm(CobalFe0.15-Cu0.07Zr0.03)7.8 and Sm(CobalFe0.28Cu0.07Zr0.03)6.6 in this work.The magnetic properties of the magnets with higher Fe content fluctuate greatly after different solution treatments,indicating that they are more sensitive to the process temperature.The increase in Fe content can obviously enhance the cellular phase size.Meanwhile,inhomogeneous Cu distribution is observed in the Sm(CobalFe0.28-Cu0.07Zr0.03)6.6 magnet,resulting in the different cellular structures and corresponding magnetic domain patterns in different regions in the inner grains.Furthermore,the lower Cu content regions are responsible for the wider magnetic domain,which have weaker resistance to applied magnetic field.As a result,Sr of demagnetization curve decreases with the increase in Fe content due to the inhomogeneous Cu distribution,which was confirmed by in-situ observation of electron probe micro-analyzer(EPMA)and magneto-optical Kerr optical microscope(MOKE).展开更多
Despite the improving coverage of preventative vaccines,hepatitis B remains a severe global public health problem,with more than 250 million patients living with hepatitis B virus(HBV)infection.Current available thera...Despite the improving coverage of preventative vaccines,hepatitis B remains a severe global public health problem,with more than 250 million patients living with hepatitis B virus(HBV)infection.Current available therapies,including nucleos(t)ide analogs and peginterferon,can control HBV replication but fail to eliminate covalently closed circular DNA(cccDNA)and achieve a cure.The HBV core protein(Cp)is a well-conserved structural protein,self-assembling to form the viral capsid.It involves in or modulates almost every stage of the HBV lifecycle,which makes it an attractive target for the development of new anti-HBV therapies.HBV core protein allosteric modulators(CpAMs)have become a hotspot in recent years.Herein,we provide a concise report focusing on the various medicinal chemistry strategies involved in the latest research(2018-2022)of HBV CpAMs,including high throughput screening(HTS),virtual screening(VS),drug repositioning,natural products,substitution decorating approach,scaffold hopping,molecular hybridization,prodrug strategy and conformational constraint strategy,to provide guidance for further development of new and effective anti-HBV drugs.展开更多
Stress granules(SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved i...Stress granules(SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B(CVB)infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3(CVB3) could induce SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the elevated formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.展开更多
Covalent organic polymer(COP)thin film-based memristors have generated intensive research interest,but the studies are still in their infancy.Herein,by controlling the content of hydroxyl groups in the aldehyde monome...Covalent organic polymer(COP)thin film-based memristors have generated intensive research interest,but the studies are still in their infancy.Herein,by controlling the content of hydroxyl groups in the aldehyde monomer,Py-COP thin films with different electronic push-pull effects were fabricated bearing distinct memory performances,where the films were prepared by the solid-liquid interface method on the ITO substrates and further fabricated as memory devices with ITO/Py-COPs/Ag architectures.The Py-COP-1-based memory device only exhibited binary memory behavior with an ON/OFF ratio of 1:10^(1.87).In contrast,the device based on Py-COP-2 demonstrated ternary memory behavior with an ON/OFF ratio of 1:10^(0.6):10^(3.1) and a ternary yield of 55%.The ternary memory mechanism of the ITO/Py-COP-2/Ag memory device is most likely due to the combination of the trapping of charge carriers and conductive filaments.Interestingly,the Py-COPs-based devices can successfully emulate the synaptic potentiation/depression behavior,clarifying the programmability of these devices in neuromorphic systems.These results suggest that the electronic properties of COPs can be precisely tuned at the molecular level,which provides a promising route for designing multi-level memory devices.展开更多
To improve the drill pipe fracture failure phenomenon in deflecting drills with ultra-short radius flexible drill pipes,this study establishes a mechanical model of a deflecting drill with an ultra-short radius flexib...To improve the drill pipe fracture failure phenomenon in deflecting drills with ultra-short radius flexible drill pipes,this study establishes a mechanical model of a deflecting drill with an ultra-short radius flexible drill pipe,numerically simulates the mechanical characteristics of the flexible drill pipe under the conventional drilling process using the finite element analysis method,performs mechanical performance tests on the flexible drill pipe,and optimizes and improves its structure.The results show that,with the gradual increase in the bending angle of the flexible drill pipe unit section,the upper drilling pressure of the flexible drill pipe unit section decreases rapidly and its friction increases approximately linearly.The tensile strength of the optimized ultra-short radius flexible drill pipe is increased by 24.7%,and the minimum threshold of its torsional strength is doubled.This effectively improves the overall strength of the ultra-short radius flexible drill pipe and provides a theoretical basis for downhole drilling stability studies of flexible drill pipes.展开更多
Interfering hepatitis B virus(HBV)capsid assembly holds promise as a therapeutic approach for chronic hepatitis B(CHB).Novel anti-HBV agents are urgently needed to overcome drug resistance challenges,with targeted pro...Interfering hepatitis B virus(HBV)capsid assembly holds promise as a therapeutic approach for chronic hepatitis B(CHB).Novel anti-HBV agents are urgently needed to overcome drug resistance challenges,with targeted protein degradation(TPD)emerging as a hopeful strategy.Herein,we report the first degradation of HBV core protein(HBC),a multifunctional structural protein,using small-molecule degraders developed by hydrophobic tagging(HyT)technology.Structureeactivity relationship(SAR)analysis identified compound HyT-S7,featuring an adamantyl group,exhibiting potent inhibitory activity(EC_(50)= 0.46 mmol/L,HepAD38 cells)and degradation ability(DC_(50) = 3.020.54 mmol/L)in a doseand time-dependent manner.Mechanistic studies demonstrated that the autophagyelysosome pathway was a potential driver of HyT-S7-induced HBC degradation.Remarkably,HyT-S7 effectively degraded 11 drug-resistant mutants,including highly resistant strains P25G and T33N,to Phase III drug GLS4.Furthermore,cellular thermal shift assay,surface plasmon resonance assay,and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation.This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.展开更多
Hypertrophic scar(HS)is a plaque fibrous and indurated dermal lesion that may cause physical,psychological,and cosmetic challenges for patients.Intralesional injection of triamcinolone acetonide(TA)is commonly used in...Hypertrophic scar(HS)is a plaque fibrous and indurated dermal lesion that may cause physical,psychological,and cosmetic challenges for patients.Intralesional injection of triamcinolone acetonide(TA)is commonly used in clinical practice,which cause unbearable pain and uneven drug delivery within HS tissue.Herein,we developed a paper battery powered iontophoresis-driven microneedles patch(PBIMNP)for self-management of HS.The high integration of PBIMNP was achieved by incorporating a paper battery as the power source for iontophoresis.The transdermal drug delivery strategy of PBIMNP combined microneedles and iontophoresis techniques,involving“pressing and poking,phase transformation,and diffusion and iontophoresis”,which can actively deliver 90.19%drug into the HS tissue with excellent in vitro drug permeation performance.PBIMNP administration effectively reduced the mRNA and protein levels,leading to a decrease in the expression of TGF-β1 and Col I associated with HS formation,demonstrating its efficacy in HS treatment.The microneedles and wearable design endow the PBIMNP as a highly promising platform for self-administration on HS treatment.展开更多
AIM:To explore the factors influencing the treatment duration and visual prognosis of cytomegalovirus(CMV)retinitis(CMVR)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).METHODS:All participants rec...AIM:To explore the factors influencing the treatment duration and visual prognosis of cytomegalovirus(CMV)retinitis(CMVR)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).METHODS:All participants received ganciclovir intravenous infusion or oral and intravitreal injection of ganciclovir(IVG)3 mg twice a week for 4 consecutive times(induction phase).The affected eyes were divided into stop treatment group(Group A),continue treatment group(Group B),and relapse after treatment group(Group C)according to whether local therapy could be terminated at the end of the induction phase and whether CMVR recurred within 3mo after the termination of local therapy.RESULTS:The study included 31 participants(48 eyes)diagnosed with CMVR including 11 males and 20 females.The mean age was(28±8.2)y.There were 17 cases of binocular disease(34 eyes)and 14 cases of monocular disease(14 eyes).Visual acuity improved in 26 eyes(54.1%),remained unchanged in 9 eyes(18.8%),and decreased in 13 eyes(27.1%).The peak value of blood CMV in Group B was significantly higher than that in Group A(P=0.013).The number of eyes with anterior chamber inflammation in Group C was significantly lower than that in Groups A and B(P=0.015,P=0.016).The average number of interval days was higher in Group A than in Group B.For Group A,there was a strong positive correlation between the number of eyes with CMV positive blood(r=0.712,P=0.031)and visual acuity changes.For Group B,there was a moderately strong positive correlation between the days of blood CMV after transplantation(r=0.371,P=0.043)and the times of injections.For Group C,there was a strong positive correlation between the peak value of blood CMV(r=0.719,P=0.029)and the times of injection.CONCLUSION:Systemic use of antivirals combined with intravitreal injection of antivirals is effective for patients with CMVR after allo-HSCT surgery.Patients with shorter interval days,higher peak or more days of blood CMV need more injections.Patients with positive blood CMV at initial diagnosis have worse visual prognosis.展开更多
COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infection...COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections.We report herein that a macrolide antibiotic,carrimycin,potently inhibited the cytopathic effects(CPE)and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229 E,OC43,and SARS-CoV-2.Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection.In support of this notion,metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA.Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.展开更多
Simulation of straw grinding process based on discrete element method(DEM)was proposed.According to the force analysis and kinematics analysis,the differential equation of straw particle motion on hammers was deduced,...Simulation of straw grinding process based on discrete element method(DEM)was proposed.According to the force analysis and kinematics analysis,the differential equation of straw particle motion on hammers was deduced,and the formation mechanism of the material circulation layer was obtained.Geometric model of grinder,particle model and contact model were established by EDEM software.The influence of hammer number,hammer thickness and gap of the hammer-sieve on particle grinding number and power consumption were obtained by single factor simulation test.The grinding process is divided into three stages.The hammer smashing plays a dominant role in 0-0.25 s.While the hammer smashing particle number increases slowly and then decreases to the lowest level in 0.25-0.60 s,the tooth plate smashing particle number increases rapidly and dominates,and then forming a material circulation layer.The hammer and tooth plate smashing particle number is basically stable in 0.60-2.00 s,and the tooth plate smashing occupies the dominant position.With the increase of the number and thickness of hammers,the power consumption of crusher tends to increase,and with the increase of the gap between hammers and sieves,the power consumption of crusher decreases first and then increases.The results can provide guidance for the development of high-efficiency and energy-saving grinding equipment for cucumber straw.展开更多
Background:Reduced application of percutaneous coronary intervention(PCI)is associated with higher mortality rates after STsegment elevation myocardial infarction(STEMI).We aimed to evaluate potential factors contribu...Background:Reduced application of percutaneous coronary intervention(PCI)is associated with higher mortality rates after STsegment elevation myocardial infarction(STEMI).We aimed to evaluate potential factors contributing to the refusal of PCI in STEMI patients in China.Methods:We studied 957 patients diagnosed with STEMI in the emergency departments(EDs)of six public hospitals in China.The differences in baseline characteristics and 30-day outcome were investigated between patients who refused PCI and those who underwent PCI.Multivariable logistic regression was used to evaluate the potential factors associated with refusing PCI.Results:The potential factors contributing to refusing PCI were older than 65 years(odds ratio[OR]2.66,95%confidence interval[Cl]1.56-4.52,P<0.001),low body mass index(BMI)(OR 0.91,95%Cl 0.84-0.98,P=0.013),not being married(OR 0.29,95%Cl 0.17-0.49,P<0.001),history of myocardial infarction(MI)(OR 2.59,95%Cl 1.33-5.04,P=0.005),higher heart rate(HR)(OR 1.02,95%Cl 1.01-1.03,P=0.002),cardiac shock in the ED(OR 5.03,95%Cl 1.48-17.08,P=0.010),pre-hospital delay(>12 h)(OR 3.31,95%Cl 1.83-6.02,P<0.001)and not being hospitalized in a tertiary hospital(OR 0.45,95%Cl 0.27-0.75,P=0.002).Compared to men,women were older,were less often married,had a lower BMI and were less often hospitalized in tertiary hospitals.Conclusions:Patients who were older,had lower economic or social status,and had poorer health status were more likely to refuse PCI after STEMI.There was a sex difference in the potential predictors of refusing PCI.Targeted efforts should be made to improve the acceptance of PCI among patients with STEMI in China.展开更多
基金supported by grants from the Key R&D Program of Shandong Province (2021ZLGX02)the National Science Foundation of China (81901934, 82325031)+1 种基金the National Key R&D Program of China (2020YFC1512700, 2020YFC1512705, 2020YFC1512703)the Clinical Research Center of Shandong University (2020SDUCRCC025)。
文摘The incidence of in-hospital cardiac arrest (IHCA) has increased over the past decade,with more than half occurring in intensive care units (ICUs).^([1])ICU cardiac arrest (ICU-CA)presents unique challenges,with worse outcomes than those in monitored wards,highlighting the need for early detection and intervention.^([2])Up to 80%of patients exhibit signs of deterioration hours before IHCA.^([3])Although early warning scores based on vital signs are useful,their eff ectiveness in ICUs is limited due to abnormal physiological parameters.^([4])Laboratory markers,such as sodium,potassium,and lactate,are predictive of poor outcomes,^([5])but static measurements may not capture the patient’s trajectory.Trends in laboratory indicators,such as variability and extremes,may offer better predictive value.^([6])This study aimed to evaluate ICU-CA predictive factors,with a focus on vital signs and trends of laboratory indicators.
基金This study was supported by grants from the National Key R&D Program of China (2017YFC0908700, 2017YFC0908703)National S&T Fundamental Resources Investigation Project (2018FY100600, 2018FY100602)+2 种基金Taishan Pandeng Scholar Program of Shandong Province (tspd20181220)Taishan Young Scholar Program of Shandong Province (tsqn20161065, tsqn201812129)Key R&D Program of Shandong Province (2020SFXGFY03, 2019GSF108073)
文摘BACKGROUND:The early diagnosis of acute myocardial infarction(AMI)remains challenging,especially for institutions without the high-sensitive cardiac troponin(hs-c Tn)assay.Herein,we aim to assess the value of creatine kinase-myocardial band isoenzyme(CK-MB)combined with different cardiac troponin(c Tn)assays in AMI diagnosis.METHODS:This multicenter,observational study included 3,706 patients with acute chest pain from September 1,2015,to September 30,2017.We classified the participants into three groups according to the c Tn assays:the point-of-care c Tn(POC-c Tn)group,the contemporary c Tn(c-c Tn)group,and hs-c Tn group.The diagnostic value was quantified using sensitivity and the area under the curve(AUC).RESULTS:Compared to the single POC-c Tn/c-c Tn assays,combining CK-MB and POC-c Tn/c-c Tn increased the diagnostic sensitivity of AMI(56.1%vs.63.9%,P<0.001;82.7%vs.84.3%,P=0.025).In contrast,combining CK-MB and hs-c Tn did not change the sensitivity compared with hs-c Tn alone(95.0%vs.95.0%,P>0.999).In the subgroup analysis,the sensitivity of combining CKMB and c-c Tn increased with time from symptom onset<6 h compared with c-c Tn alone(72.8%vs.75.0%,P=0.046),while the sensitivity did not increase with time from symptom onset>6 h(97.5%vs.98.3%,P=0.317).The AUC of the combination of CK-MB and POC-c Tn significantly increased compared to the single POC-c Tn assay(0.776 vs.0.750,P=0.002).The AUC of the combined CKMB and c-c Tn/hs-c Tn assays did not significantly decrease compared with that of the single c-c Tn/hs-c Tn assays within 6 h.CONCLUSIONS:The combination of CK-MB and POC-c Tn or c-c Tn may be valuable for the early diagnosis of AMI,especially when hs-c Tn is not available.
基金financially supported by National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(2018ZX09711003)CAMS Initiative for Innovative Medicine(CAMS-I2M-1-010)National Natural Science Foundation of China(81630089)。
文摘Influenza A viruses(IAV)are responsible for seasonal flu epidemics,which can lead to high morbidity and mortality each year.Like other viruses,influenza virus can hijack host cellular machinery for its replication.Host cells have evolved diverse cellular defense to resist the invasion of viruses.As the main components of promyelocytic leukemia protein nuclear bodies(PML-NBs),PML can inhibit the replication of many medically important viruses including IAV.However,the mechanism of PML against IAV is unclear.In the present study,we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication,whereas knockdown of endogenous PML expression could enhance IAV replication.Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2,which negatively regulated IAV replication during infection.Moreover,PML stabilized RIG-I to promote the production of typeⅠIFN.Collectively,these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.
基金financially supported by the National Natural Science Foundation of China(Nos.51331003 and 51871005)the International S&T Cooperation Program of China(No.2015DFG52020).
文摘Sm(Co,Cu,Fe,Zr)z magnets have drawn much attention for high-temperature applications due to their high Curie temperature,strong corrosion resistance and thermal stability.The effect of increasing Fe content on the distribution of elements and squareness(Sr)of demagnetization curves were investigated for two kinds of magnets with different nominal compositions of Sm(CobalFe0.15-Cu0.07Zr0.03)7.8 and Sm(CobalFe0.28Cu0.07Zr0.03)6.6 in this work.The magnetic properties of the magnets with higher Fe content fluctuate greatly after different solution treatments,indicating that they are more sensitive to the process temperature.The increase in Fe content can obviously enhance the cellular phase size.Meanwhile,inhomogeneous Cu distribution is observed in the Sm(CobalFe0.28-Cu0.07Zr0.03)6.6 magnet,resulting in the different cellular structures and corresponding magnetic domain patterns in different regions in the inner grains.Furthermore,the lower Cu content regions are responsible for the wider magnetic domain,which have weaker resistance to applied magnetic field.As a result,Sr of demagnetization curve decreases with the increase in Fe content due to the inhomogeneous Cu distribution,which was confirmed by in-situ observation of electron probe micro-analyzer(EPMA)and magneto-optical Kerr optical microscope(MOKE).
基金financial support from the National Natural Science Foundation of China(NSFC Nos.82173677,82211530493)the Science Foundation for Outstanding Young Scholars of Shandong Province(No.ZR2020JQ31).
文摘Despite the improving coverage of preventative vaccines,hepatitis B remains a severe global public health problem,with more than 250 million patients living with hepatitis B virus(HBV)infection.Current available therapies,including nucleos(t)ide analogs and peginterferon,can control HBV replication but fail to eliminate covalently closed circular DNA(cccDNA)and achieve a cure.The HBV core protein(Cp)is a well-conserved structural protein,self-assembling to form the viral capsid.It involves in or modulates almost every stage of the HBV lifecycle,which makes it an attractive target for the development of new anti-HBV therapies.HBV core protein allosteric modulators(CpAMs)have become a hotspot in recent years.Herein,we provide a concise report focusing on the various medicinal chemistry strategies involved in the latest research(2018-2022)of HBV CpAMs,including high throughput screening(HTS),virtual screening(VS),drug repositioning,natural products,substitution decorating approach,scaffold hopping,molecular hybridization,prodrug strategy and conformational constraint strategy,to provide guidance for further development of new and effective anti-HBV drugs.
基金supported by the Natural Science Foundation of China(Grant 81571999 to Z Zhong81672007 to W Zhao+1 种基金81772188 to Y Wang,31300144 to T Wang)support from Heilongjiang Provincial Key Laboratory of Pathogens and Immunity and Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity of Harbin Medical University
文摘Stress granules(SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B(CVB)infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3(CVB3) could induce SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the elevated formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.
基金financially supported by the National Natural Science Foundation of China(Nos.21972021 and 22111530111)the support of China Scholarship Council(No.202206650013).
文摘Covalent organic polymer(COP)thin film-based memristors have generated intensive research interest,but the studies are still in their infancy.Herein,by controlling the content of hydroxyl groups in the aldehyde monomer,Py-COP thin films with different electronic push-pull effects were fabricated bearing distinct memory performances,where the films were prepared by the solid-liquid interface method on the ITO substrates and further fabricated as memory devices with ITO/Py-COPs/Ag architectures.The Py-COP-1-based memory device only exhibited binary memory behavior with an ON/OFF ratio of 1:10^(1.87).In contrast,the device based on Py-COP-2 demonstrated ternary memory behavior with an ON/OFF ratio of 1:10^(0.6):10^(3.1) and a ternary yield of 55%.The ternary memory mechanism of the ITO/Py-COP-2/Ag memory device is most likely due to the combination of the trapping of charge carriers and conductive filaments.Interestingly,the Py-COPs-based devices can successfully emulate the synaptic potentiation/depression behavior,clarifying the programmability of these devices in neuromorphic systems.These results suggest that the electronic properties of COPs can be precisely tuned at the molecular level,which provides a promising route for designing multi-level memory devices.
基金supported by Open Fund of Technology Innovation Center for Directional Drilling Engineering,Ministry of Natural Resources./Innovation Base for Directional Drilling Engineering,Geological Society of China(-No.KF202302)the Geological Survey projects of China Geological Survey(No.DD20221681)+1 种基金Open Found Projects of Sinopec Key Laboratory of Geothermal Resources Exploitation and Utilizatio(No.36650000-23-ZC0607-0054)Open Research Fund Program of Key Laboratory of Metallogenic Prediction of Nonferrous Metals and Geological Environment Monitoring(Ministry of Education),Central South University(2023YSJS06).
文摘To improve the drill pipe fracture failure phenomenon in deflecting drills with ultra-short radius flexible drill pipes,this study establishes a mechanical model of a deflecting drill with an ultra-short radius flexible drill pipe,numerically simulates the mechanical characteristics of the flexible drill pipe under the conventional drilling process using the finite element analysis method,performs mechanical performance tests on the flexible drill pipe,and optimizes and improves its structure.The results show that,with the gradual increase in the bending angle of the flexible drill pipe unit section,the upper drilling pressure of the flexible drill pipe unit section decreases rapidly and its friction increases approximately linearly.The tensile strength of the optimized ultra-short radius flexible drill pipe is increased by 24.7%,and the minimum threshold of its torsional strength is doubled.This effectively improves the overall strength of the ultra-short radius flexible drill pipe and provides a theoretical basis for downhole drilling stability studies of flexible drill pipes.
基金the Key Research and Development Program,Ministry of Science and Technology of the People’s Republic of China(2023YFC2606500)Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)+2 种基金Drug Innovation Major Project(2018ZX09101003-003-003,China)CAMS Innovation Fund for Medical Sciences(CAMS-2021-I2M-1-030,China)National Natural Science Foundation of China(81803592)and Shandong Laboratory Program(SYS202205,China).
文摘Interfering hepatitis B virus(HBV)capsid assembly holds promise as a therapeutic approach for chronic hepatitis B(CHB).Novel anti-HBV agents are urgently needed to overcome drug resistance challenges,with targeted protein degradation(TPD)emerging as a hopeful strategy.Herein,we report the first degradation of HBV core protein(HBC),a multifunctional structural protein,using small-molecule degraders developed by hydrophobic tagging(HyT)technology.Structureeactivity relationship(SAR)analysis identified compound HyT-S7,featuring an adamantyl group,exhibiting potent inhibitory activity(EC_(50)= 0.46 mmol/L,HepAD38 cells)and degradation ability(DC_(50) = 3.020.54 mmol/L)in a doseand time-dependent manner.Mechanistic studies demonstrated that the autophagyelysosome pathway was a potential driver of HyT-S7-induced HBC degradation.Remarkably,HyT-S7 effectively degraded 11 drug-resistant mutants,including highly resistant strains P25G and T33N,to Phase III drug GLS4.Furthermore,cellular thermal shift assay,surface plasmon resonance assay,and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation.This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.
基金financially supported by the Shenzhen Science and Technology Program(Project No.JCYJ20220818102201003)the National Natural Science Foundation of China(Project No.51975597,52175446,and T2225010)+2 种基金the Natural Science Foundation of Guangdong Province(Project No.2022B1515020011)the Shenzhen Medical Research Fund(Project No.A2302034)the Foundation of Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument(Project No.2020B1212060077).
文摘Hypertrophic scar(HS)is a plaque fibrous and indurated dermal lesion that may cause physical,psychological,and cosmetic challenges for patients.Intralesional injection of triamcinolone acetonide(TA)is commonly used in clinical practice,which cause unbearable pain and uneven drug delivery within HS tissue.Herein,we developed a paper battery powered iontophoresis-driven microneedles patch(PBIMNP)for self-management of HS.The high integration of PBIMNP was achieved by incorporating a paper battery as the power source for iontophoresis.The transdermal drug delivery strategy of PBIMNP combined microneedles and iontophoresis techniques,involving“pressing and poking,phase transformation,and diffusion and iontophoresis”,which can actively deliver 90.19%drug into the HS tissue with excellent in vitro drug permeation performance.PBIMNP administration effectively reduced the mRNA and protein levels,leading to a decrease in the expression of TGF-β1 and Col I associated with HS formation,demonstrating its efficacy in HS treatment.The microneedles and wearable design endow the PBIMNP as a highly promising platform for self-administration on HS treatment.
文摘AIM:To explore the factors influencing the treatment duration and visual prognosis of cytomegalovirus(CMV)retinitis(CMVR)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).METHODS:All participants received ganciclovir intravenous infusion or oral and intravitreal injection of ganciclovir(IVG)3 mg twice a week for 4 consecutive times(induction phase).The affected eyes were divided into stop treatment group(Group A),continue treatment group(Group B),and relapse after treatment group(Group C)according to whether local therapy could be terminated at the end of the induction phase and whether CMVR recurred within 3mo after the termination of local therapy.RESULTS:The study included 31 participants(48 eyes)diagnosed with CMVR including 11 males and 20 females.The mean age was(28±8.2)y.There were 17 cases of binocular disease(34 eyes)and 14 cases of monocular disease(14 eyes).Visual acuity improved in 26 eyes(54.1%),remained unchanged in 9 eyes(18.8%),and decreased in 13 eyes(27.1%).The peak value of blood CMV in Group B was significantly higher than that in Group A(P=0.013).The number of eyes with anterior chamber inflammation in Group C was significantly lower than that in Groups A and B(P=0.015,P=0.016).The average number of interval days was higher in Group A than in Group B.For Group A,there was a strong positive correlation between the number of eyes with CMV positive blood(r=0.712,P=0.031)and visual acuity changes.For Group B,there was a moderately strong positive correlation between the days of blood CMV after transplantation(r=0.371,P=0.043)and the times of injections.For Group C,there was a strong positive correlation between the peak value of blood CMV(r=0.719,P=0.029)and the times of injection.CONCLUSION:Systemic use of antivirals combined with intravitreal injection of antivirals is effective for patients with CMVR after allo-HSCT surgery.Patients with shorter interval days,higher peak or more days of blood CMV need more injections.Patients with positive blood CMV at initial diagnosis have worse visual prognosis.
基金financially supported by CAMS Initiative for Innovative Medicine(2020-I2M-Co V19-008,China)the National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(2018ZX09711003,China)+1 种基金the National Key Research and Development Program of China(2020YFC0844900,China)Fundamental Research Funds for CAMS of China(2020HY320001,China)
文摘COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections.We report herein that a macrolide antibiotic,carrimycin,potently inhibited the cytopathic effects(CPE)and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229 E,OC43,and SARS-CoV-2.Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection.In support of this notion,metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA.Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.
基金This work was supported by the National Key Technologies R&D Program of China(No.2014BAD08B04)and the National Natural Science Fund of China(No.51175230,No.51475212)and the Funding for Key R&D Programs in Jiangsu Province(BE2018321).
文摘Simulation of straw grinding process based on discrete element method(DEM)was proposed.According to the force analysis and kinematics analysis,the differential equation of straw particle motion on hammers was deduced,and the formation mechanism of the material circulation layer was obtained.Geometric model of grinder,particle model and contact model were established by EDEM software.The influence of hammer number,hammer thickness and gap of the hammer-sieve on particle grinding number and power consumption were obtained by single factor simulation test.The grinding process is divided into three stages.The hammer smashing plays a dominant role in 0-0.25 s.While the hammer smashing particle number increases slowly and then decreases to the lowest level in 0.25-0.60 s,the tooth plate smashing particle number increases rapidly and dominates,and then forming a material circulation layer.The hammer and tooth plate smashing particle number is basically stable in 0.60-2.00 s,and the tooth plate smashing occupies the dominant position.With the increase of the number and thickness of hammers,the power consumption of crusher tends to increase,and with the increase of the gap between hammers and sieves,the power consumption of crusher decreases first and then increases.The results can provide guidance for the development of high-efficiency and energy-saving grinding equipment for cucumber straw.
基金This study was supprted by grants from the National Key R&D Program of China(Nos.2017YFC0908700,2017Y FC0908703)National S&cT Fundamental Resour-ces Investigation Project(Nos.2018FY 100600,2018FY 100602)+2 种基金Taishan Pandeng Scholar Program of Shandong Province(No.tspd20181220)Taishan Young Scholar Program of Shandong Province(Nos.tsqn20161065,tsqn201812129)Key R&D Program of Shandong Province(Nos.2016ZDJS07A14,2018GSF118003)。
文摘Background:Reduced application of percutaneous coronary intervention(PCI)is associated with higher mortality rates after STsegment elevation myocardial infarction(STEMI).We aimed to evaluate potential factors contributing to the refusal of PCI in STEMI patients in China.Methods:We studied 957 patients diagnosed with STEMI in the emergency departments(EDs)of six public hospitals in China.The differences in baseline characteristics and 30-day outcome were investigated between patients who refused PCI and those who underwent PCI.Multivariable logistic regression was used to evaluate the potential factors associated with refusing PCI.Results:The potential factors contributing to refusing PCI were older than 65 years(odds ratio[OR]2.66,95%confidence interval[Cl]1.56-4.52,P<0.001),low body mass index(BMI)(OR 0.91,95%Cl 0.84-0.98,P=0.013),not being married(OR 0.29,95%Cl 0.17-0.49,P<0.001),history of myocardial infarction(MI)(OR 2.59,95%Cl 1.33-5.04,P=0.005),higher heart rate(HR)(OR 1.02,95%Cl 1.01-1.03,P=0.002),cardiac shock in the ED(OR 5.03,95%Cl 1.48-17.08,P=0.010),pre-hospital delay(>12 h)(OR 3.31,95%Cl 1.83-6.02,P<0.001)and not being hospitalized in a tertiary hospital(OR 0.45,95%Cl 0.27-0.75,P=0.002).Compared to men,women were older,were less often married,had a lower BMI and were less often hospitalized in tertiary hospitals.Conclusions:Patients who were older,had lower economic or social status,and had poorer health status were more likely to refuse PCI after STEMI.There was a sex difference in the potential predictors of refusing PCI.Targeted efforts should be made to improve the acceptance of PCI among patients with STEMI in China.
