The impact of vibrations due to underground trains on Beijing metro line 15 on sensitive equipment in the Institute of Microelectronics of Tsinghua University was discussed to propose a viable solution to mitigate the...The impact of vibrations due to underground trains on Beijing metro line 15 on sensitive equipment in the Institute of Microelectronics of Tsinghua University was discussed to propose a viable solution to mitigate the vibrations.Using the state-of-the-art three-dimensional coupled periodic finite element-boundary element(FE-BE) method,the dynamic track-tunnel-soil interaction model for metro line 15 was used to predict vibrations in the free field at a train speed of 80 km/h.Three types of tracks(direct fixation fasteners,floating slab track and floating ladder track) on the Beijing metro network were considered in the model. For each track,the acceleration response in the free field was obtained.The numerical results show that the influence of vibrations from underground trains on sensitive equipment depends on the track types.At frequencies above 10 Hz,the floating slab track with a natural frequency of 7 Hz can be effective to attenuate the vibrations.展开更多
In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNI...In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNIBP)by incorporating an aromatic moiety to the left wing of the lead K-5 a2.The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase(RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors(NNRTI)-resistant mutations.Especially,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations(L1001,K103 N,Y181 C,Y188 L and E138 K)with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine(ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also investigated.Furthermore,26 exhibited favorable pharmacokinetics(PK)profiles and with a bioavailability of 33.8%.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.展开更多
A short history of informetric and bibliometric studies is provided and the role of the Belgian information and library scientist Paul Otlet is highlighted.The difference between the terms informetrics,bibliometrics a...A short history of informetric and bibliometric studies is provided and the role of the Belgian information and library scientist Paul Otlet is highlighted.The difference between the terms informetrics,bibliometrics and scientometrics is explained,following Ingwersen and Bjrneborn.A short overview of topics is given and some predictions related to the future of the field are made.It is the author's opinion that besides many practical applications,the field will also develop using axiomatic and algebraic(structural)approaches.The author has no doubt that China will become a leading country in the field.展开更多
With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To ...With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50values ranging from 3.43 to 21.4 nmol/L.Especially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.展开更多
Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a s...Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.展开更多
HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major ...HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)derivatives were prepared via structural modifications of the leads K-5a2 and 25a.Among them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC_(50) Z 1.75 nmol/L),3.0-fold(L100I,EC_(50) Z 2.84 nmol/L),2.4-fold(K103N,EC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,EC50 Z 5.38 nmol/L),2.9-fold(Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold(E138K,EC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,EC_(50) Z 3.76 nmol/L)and 5.3-fold(RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug ETR.Molecular docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 RT.Moreover,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(LD_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.展开更多
This paper introduces a video application-aware cross-layer framework for joint performance-energy optimization,considering the scenario of multiple users upstreaming real-time Motion JPEG2000 video streams to the acc...This paper introduces a video application-aware cross-layer framework for joint performance-energy optimization,considering the scenario of multiple users upstreaming real-time Motion JPEG2000 video streams to the access point of a WiFi wireless local area network and extends the PHY-MAC run-time cross-layer scheduling strategy that we introduced in (Mangharam et al., 2005; Pollin et al., 2005) to also consider congested network situations where video packets have to be dropped. We show that an optimal solution at PHY-MAC level can be highly suboptimal at application level, and then show that making the cross-layer framework application-aware through a prioritized dropping policy capitalizing on the inherent scalability of Motion JPEG2000 video streams leads to drastic average video quality improvements and inter-user quality variation reductions of as much as 10 dB PSNR, without affecting the overall energy consumption requirements.展开更多
Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety pr...Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.展开更多
Background:During the last years,human newborns have been overexposed to biologically reactive aluminum,with possible relevant consequences on their future health and on their susceptibility to a variety of diseases.C...Background:During the last years,human newborns have been overexposed to biologically reactive aluminum,with possible relevant consequences on their future health and on their susceptibility to a variety of diseases.Children,newborns and particularly preterm neonates are at an increased risk of aluminum toxicity because of their relative immaturity.Data sources:Based on recent original publications and classical data of the literatures,we reviewed the aluminum content in mother's food during the intrauterine life as well as in breast milk and infant formula during lactation.We also determined the possible role of aluminum in parenteral nutrition solutions,in adjuvants of vaccines and in pharmaceutical products.A special focus is placed on the relationship between aluminum overexposure and the insurgence of bone diseases.Results:Practical points of management and prevention are suggested.Aluminum sources that infants may receive during the fi rst 6 months of life are presented.In the context of prevention of possible adverse effects of aluminum overload in fetal tissues during development,simple suggestions to pregnant women are described.Finally,practical points of management and prevention are suggested.Conclusions:Pediatricians and neonatologists must be more concerned about aluminum content in all products our newborns are exposed to,starting from monitoring aluminum concentrations in milk-and soybased formulas in which,on the basis of recent studies,there is still too much aluminum.展开更多
Open retropubic radical prostatectomy has been the“gold standard”treatment for locally confined prostate cancer(PCa)but in recent years minimal invasive techniques as laparoscopy and robot-assisted prostatectomy hav...Open retropubic radical prostatectomy has been the“gold standard”treatment for locally confined prostate cancer(PCa)but in recent years minimal invasive techniques as laparoscopy and robot-assisted prostatectomy have become widely available.The trifecta of the surgical treatment of PCa is cancer control,the preservation of continence,and erectile potency.Over the years the complication rates of radical prostatectomy have become very limited with improved cancer control and better functional results.We review the indications and the surgical technique of radical prostatectomy,be it open or laparoscopic,eventually robot-assisted as well as the pre-and postoperative measures and the surgery-related consequences.展开更多
A building integrated photovoltaic system(BIPV)system may produce the same amount of electricity as consumed in the building on a yearly base.The simultaneity of production and consumption however needs to be evaluate...A building integrated photovoltaic system(BIPV)system may produce the same amount of electricity as consumed in the building on a yearly base.The simultaneity of production and consumption however needs to be evaluated:the distribution grid is regarded as virtual storage and is loaded unconventionally or even overloaded.A detailed bottom-up modelling approach of the domestic load,thermal installations and the local generation of BIPV system may give more insight.The present paper aims at quantifying the impact of domestic load profiles on the grid-interaction of BIPV-equipped dwelling in a moderate Belgian climate wherefore the cover factor is defined.For a yearly electricity production that equals the yearly domestic demand,a cover factor of 0.42 is found if a classic heating system is installed,denoting that more than half of the produced electricity will be passed on to the grid and withdrawn on another moment.If a heat pump is used for space heating and domestic hot water,the cover factor decreases to 0.29.展开更多
HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, ...HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.展开更多
Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY)...Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.展开更多
The spirit of now in nowcasting suggests expanding the current to include the near future.Decision theory is then developed by incorporating the consequences of actions into the present.With the future falling into th...The spirit of now in nowcasting suggests expanding the current to include the near future.Decision theory is then developed by incorporating the consequences of actions into the present.With the future falling into the present discounting it is no longer permitted.Value functions are then observed to be determinate only up to scale and shift that are then locked down by fixing values arbitrarily in two selected states,much like declaring water to freeze and boil at zero and a hundred degrees celsius.The locked down value functions associated policy functions are seen to exist in decision contexts in where the only time is now.Examples are studied in univariate and multivariate dimensions for the decision state space and the dimension of shocks delivering state transitions.The policy functions are expanded from realisitic training sets to the full state space using Gaussian Process Regression.They are implemented on real data with reported performances.展开更多
基金Projects(50538010,50848046) supported by the National Natural Science Foundation of ChinaProject(BIL07/07) supported by the Research Council of K.U.Leuven and the National Natural Science Foundation of China
文摘The impact of vibrations due to underground trains on Beijing metro line 15 on sensitive equipment in the Institute of Microelectronics of Tsinghua University was discussed to propose a viable solution to mitigate the vibrations.Using the state-of-the-art three-dimensional coupled periodic finite element-boundary element(FE-BE) method,the dynamic track-tunnel-soil interaction model for metro line 15 was used to predict vibrations in the free field at a train speed of 80 km/h.Three types of tracks(direct fixation fasteners,floating slab track and floating ladder track) on the Beijing metro network were considered in the model. For each track,the acceleration response in the free field was obtained.The numerical results show that the influence of vibrations from underground trains on sensitive equipment depends on the track types.At frequencies above 10 Hz,the floating slab track with a natural frequency of 7 Hz can be effective to attenuate the vibrations.
基金financial support from the Key Project of NSFC for International Cooperation(No.81420108027,China)the National Natural Science Foundation of China(NSFC Nos.81273354,81573347,81903453)+6 种基金Young Scholars Program of Shandong University(YSPSDU No.2016WLJH32,China)Shandong Provincial Natural Science Foundation(ZR2019BH011,China)China Postdoctoral Science Foundation(2018M640641,2019T120596)Key research and development project of Shandong Province(No.2017CXGC1401,China)KU Leuven(GOA 10/014,Belgium)the Spanish Government(MINECO Project SAF2017-881074-R,AEI/FEDER,UE)Generalitat de Catalunya(2017SGR1746,Spain)for the financial support
文摘In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNIBP)by incorporating an aromatic moiety to the left wing of the lead K-5 a2.The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase(RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors(NNRTI)-resistant mutations.Especially,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations(L1001,K103 N,Y181 C,Y188 L and E138 K)with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine(ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also investigated.Furthermore,26 exhibited favorable pharmacokinetics(PK)profiles and with a bioavailability of 33.8%.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.
文摘A short history of informetric and bibliometric studies is provided and the role of the Belgian information and library scientist Paul Otlet is highlighted.The difference between the terms informetrics,bibliometrics and scientometrics is explained,following Ingwersen and Bjrneborn.A short overview of topics is given and some predictions related to the future of the field are made.It is the author's opinion that besides many practical applications,the field will also develop using axiomatic and algebraic(structural)approaches.The author has no doubt that China will become a leading country in the field.
基金financial support from the National Natural Science Foundation of China(NSFC nos.81973181 and 81903453)Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)+6 种基金Science Foundation for Excellent Young Scholars of Shandong Province(ZR2020YQ61,China)Foreign Cultural and Educational Experts Project(GXL20200015001,China)China Postdoctoral Science Foundation(2022M721948)Shandong Province Natural Science Foundation for Youths(ZR2023QH217,China)Natural Science Foundation of Jiangsu Province(BK20230252,China)Qilu Young Scholars Program of Shandong UniversityTaishan Scholar Program at Shandong Province。
文摘With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50values ranging from 3.43 to 21.4 nmol/L.Especially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.81973181,82273773)Shandong Provincial Natural Science Foundation(Nos.ZR2020YQ61,ZR2020JQ31)Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province。
文摘Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.
基金financial support from the National Natural Science Foundation of China(NSFC Nos.81973181,82273773)Shandong Provincial Natural Science Foundation(ZR2020YQ61,ZR2020JQ31,China)Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province.
文摘HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)derivatives were prepared via structural modifications of the leads K-5a2 and 25a.Among them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC_(50) Z 1.75 nmol/L),3.0-fold(L100I,EC_(50) Z 2.84 nmol/L),2.4-fold(K103N,EC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,EC50 Z 5.38 nmol/L),2.9-fold(Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold(E138K,EC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,EC_(50) Z 3.76 nmol/L)and 5.3-fold(RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug ETR.Molecular docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 RT.Moreover,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(LD_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.
文摘This paper introduces a video application-aware cross-layer framework for joint performance-energy optimization,considering the scenario of multiple users upstreaming real-time Motion JPEG2000 video streams to the access point of a WiFi wireless local area network and extends the PHY-MAC run-time cross-layer scheduling strategy that we introduced in (Mangharam et al., 2005; Pollin et al., 2005) to also consider congested network situations where video packets have to be dropped. We show that an optimal solution at PHY-MAC level can be highly suboptimal at application level, and then show that making the cross-layer framework application-aware through a prioritized dropping policy capitalizing on the inherent scalability of Motion JPEG2000 video streams leads to drastic average video quality improvements and inter-user quality variation reductions of as much as 10 dB PSNR, without affecting the overall energy consumption requirements.
基金financial support from Natural Science Foundation of China (81974507)Guangdong Basic and Applied Basic Research Foundation (2021A1515110740, China)+5 种基金China Postdoctoral Science Foundation (2021M702003)Shandong Province Natural Science Foundation for Youths (ZR2022QH036, China)the Foundation for Innovative Research Groups of State Key Laboratory of Microbial Technology (WZCX2021-03, China)Foreign cultural and educational experts Project (GXL20200015001, China)Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31, China)the Shandong Provincial Key research and development project (2019JZZY021011, China)。
文摘Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.
文摘Background:During the last years,human newborns have been overexposed to biologically reactive aluminum,with possible relevant consequences on their future health and on their susceptibility to a variety of diseases.Children,newborns and particularly preterm neonates are at an increased risk of aluminum toxicity because of their relative immaturity.Data sources:Based on recent original publications and classical data of the literatures,we reviewed the aluminum content in mother's food during the intrauterine life as well as in breast milk and infant formula during lactation.We also determined the possible role of aluminum in parenteral nutrition solutions,in adjuvants of vaccines and in pharmaceutical products.A special focus is placed on the relationship between aluminum overexposure and the insurgence of bone diseases.Results:Practical points of management and prevention are suggested.Aluminum sources that infants may receive during the fi rst 6 months of life are presented.In the context of prevention of possible adverse effects of aluminum overload in fetal tissues during development,simple suggestions to pregnant women are described.Finally,practical points of management and prevention are suggested.Conclusions:Pediatricians and neonatologists must be more concerned about aluminum content in all products our newborns are exposed to,starting from monitoring aluminum concentrations in milk-and soybased formulas in which,on the basis of recent studies,there is still too much aluminum.
文摘Open retropubic radical prostatectomy has been the“gold standard”treatment for locally confined prostate cancer(PCa)but in recent years minimal invasive techniques as laparoscopy and robot-assisted prostatectomy have become widely available.The trifecta of the surgical treatment of PCa is cancer control,the preservation of continence,and erectile potency.Over the years the complication rates of radical prostatectomy have become very limited with improved cancer control and better functional results.We review the indications and the surgical technique of radical prostatectomy,be it open or laparoscopic,eventually robot-assisted as well as the pre-and postoperative measures and the surgery-related consequences.
文摘A building integrated photovoltaic system(BIPV)system may produce the same amount of electricity as consumed in the building on a yearly base.The simultaneity of production and consumption however needs to be evaluated:the distribution grid is regarded as virtual storage and is loaded unconventionally or even overloaded.A detailed bottom-up modelling approach of the domestic load,thermal installations and the local generation of BIPV system may give more insight.The present paper aims at quantifying the impact of domestic load profiles on the grid-interaction of BIPV-equipped dwelling in a moderate Belgian climate wherefore the cover factor is defined.For a yearly electricity production that equals the yearly domestic demand,a cover factor of 0.42 is found if a classic heating system is installed,denoting that more than half of the produced electricity will be passed on to the grid and withdrawn on another moment.If a heat pump is used for space heating and domestic hot water,the cover factor decreases to 0.29.
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.82173677,81773574)the Key Project of NSFC for International Cooperation(No.81420108027)+2 种基金the Shandong Provincial Key Research and Development Project(No.2019JZZY021011)the Science Foundation for Outstanding Young Scholars of Shandong Province(No.ZR2020JQ31)NIH/NIAID grant(No.R01AI150491,Cocklin,PI,Salvino,Co-I)。
文摘HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.
基金financial support from the National Natural Science Foundation of China (Nos. 81973181, 81903453)Shandong Provincial Natural Science Foundation (No. ZR2019BH011)+7 种基金Natural Science Foundation of Jiangsu Province (No. BK2019041035)China Postdoctoral Science Foundation (Nos. 2019T120596, 2018M640641)Science Foundation for Outstanding Young Scholars of Shandong Province (No. ZR2020JQ31)Science Foundation for Excellent Young Scholars of Shandong Province (No. ZR2020YQ61)National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2019ZX09301126)Shandong Provincial Key Research and Development Project (Nos. 2017CXGC1401, 2019JZZY021011)Foreign cultural and educational experts Project (No. GXL20200015001)the Taishan Scholar Program at Shandong Province and KU Leuven (No. GOA 10/014)。
文摘Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.
文摘The spirit of now in nowcasting suggests expanding the current to include the near future.Decision theory is then developed by incorporating the consequences of actions into the present.With the future falling into the present discounting it is no longer permitted.Value functions are then observed to be determinate only up to scale and shift that are then locked down by fixing values arbitrarily in two selected states,much like declaring water to freeze and boil at zero and a hundred degrees celsius.The locked down value functions associated policy functions are seen to exist in decision contexts in where the only time is now.Examples are studied in univariate and multivariate dimensions for the decision state space and the dimension of shocks delivering state transitions.The policy functions are expanded from realisitic training sets to the full state space using Gaussian Process Regression.They are implemented on real data with reported performances.
