Artificial Intelligence in Pharmaceutical Sciences

Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of drug research and development(R&D).With the advancement of experimental technology and computer hardware,artificial intelligence(AI)has recently emerged as a leading tool in analyzing abundant and high-dimensional data.Explosive growth in the size of biomedical data provides advantages in applying AI in all stages of drug R&D.Driven by big data in biomedicine,AI has led to a revolution in drug R&D,due to its ability to discover new drugs more efficiently and at lower cost.This review begins with a brief overview of common AI models in the field of drug discovery;then,it summarizes and discusses in depth their specific applications in various stages of drug R&D,such as target discovery,drug discovery and design,preclinical research,automated drug synthesis,and influences in the pharmaceutical market.Finally,the major limitations of AI in drug R&D are fully discussed and possible solutions are proposed.

Regulating single-atom Mn sites by precisely axial pyridinic-nitrogen coordination to stabilize the oxygen reduction

Designing single-atom catalysts for oxygen reduction reaction(ORR)are fashionable but challenging to boost the zinc-air battery performance.Significantly enhanced ORR activity by manganese(Mn)singleatom catalysts can be achieved by accurately regulating the coordination number of isolated Mn atoms.Theoretical calculations indicate that the single Mn-N5sites possess lower free energy barrier and higher oxygen adsorption performance than single Mn-N4sites to accelerate the ORR kinetics.Target to it,here we synthesize an atomically dispersed Mn-N5catalyst by precisely axial coordination of pyridinic-N doped into two-dimensional(2D)porous nanocarbon sheets(~3.56 nm thickness),which reveals outstanding catalytic activity and ultrahigh stability for the ORR in zinc-air battery owing to the inhomogeneous charge distribution of Mn-N5sites compared to the conventional single-site Mn-N4catalyst and Pt/C.This work gives a new strategy for in situ regulating the electronic structure of metal single-atoms and further promoting the overall ORR performance in energy systems.

Discovery and characterization of a new hydrothermal field at 2°N on the slow-spreading Carlsberg Ridge

A new hydrothermal field(Tianshi)was discovered on the rift valley wall through plume anomaly surveys and geological work conducted in 2012 and 2018 between 2°35′N and 2°43′N of the slow-spreading Carlsberg Ridge(CR).Here,the results of two expeditions conducted to detect and characterize the new hydrothermal field are reported.Mineralogical and geochemical data,as well as 14 C ages of a sediment core collected near the field are presented to reveal the hydrothermal history.Results show that the Tianshi field is a basalt-hosted hydrothermal system.Geochemical data of the sediments collected near the field indicate a strong hydrothermal contribution,and hydrothermal Fe and Cu fluxes range from 30 to 155 mg/(cm^(2)·ka)and 0.59 to 11.49 mg/(cm^(2)·ka),respectively.Temporal variations in the fluxes of hydrothermal Fe indicate that there have been at least three amplified hydrothermal venting events(H 1,H 2,and H 3)in the Tianshi field over the last 35.2 ka,in 28.6-35.2 ka BP,22.0-27.6 ka BP,and 1.2-11.4 ka BP,respectively.Hydrothermal event H 2 was driven by an increased magmatic production associated with sea level fall during the Last Glacial Maximum,while event H 3 was promoted by tectonic activity associated with a rapid sea level rise.This study further verified the role of sea level change in modulating hydrothermal activity on mid-ocean ridges.

Mechanism of nanoparticle aggregation in gas-liquid microfluidic mixing

Using gas-liquid segmented micromixers to prepare nanoparticles that have a homogeneous particle size, controllable shape, and monodispersity advantages. Although nanoparticle aggregation within a microfluid has been shown to be affected by the shear effect, the shear effect triggering conditions in gasliquid two-phase flow is unclear and the aggregation behavior of nanoparticles under the shear effect is difficult to predict, resulting in uncontrollable physical and chemical properties of nanoparticle aggregates. In this study, a numerical simulation of nanoparticle aggregation in gas-liquid two-phase flow under the shear effect is performed using the CFD-DEM method. Then, the effects of total flow rate,gas-liquid two-phase flow ratio, and particle volume fraction on particle aggregation were analyzed to achieve control of particle aggregation shape and size. Meanwhile, the triggering mechanism of the shear effect and the mechanism of the shear effect on the aggregation of nanoparticles were clarified. The results show that increasing the total flow rate or decreasing the gas-liquid two-phase flow rate ratio can induce the shear effect, which reduces the particle aggregation size and makes the morphology tend to be spherical. Moreover, increasing the particle volume fraction, and total flow rate or decreasing the gas-liquid two-phase flow rate ratio also increases the number of particle collisions and induce interparticle adhesion. Hence, particle adhesion and the shear effect compete with each other and together affect particle aggregation.

A lateral-immobilization zebrafish microfluidic chip-based system for in vivo real-time evaluation of antithrombotic agents

Thrombosis remains a major global health concern mainly characterized by high rates of morbidity and mortality.Animal models serve as an indispensable tool to understand the underlying pathogenesis of thrombosis and assess the efficacy of novel antithrombotic drugs.Currently,zebrafish has emerged as a valuable model organism for thrombosis research.However,the traditional method of studying zebrafish thrombosis requires a laborious and time-consuming procedure,including anesthesia and manual immobilization of zebrafish.In this study,based on hydrodynamic force,a lateral-immobilization zebrafish microfluidic chip(LIZMC)was designed to evaluate the cardiovascular system of multiple larvae within a single microscope field of view.Specifically,coupling with microscope imaging,real-time monitoring of the peripheral blood circulation in the tail of phenylhydrazine(PHZ)-induced zebrafish thrombosis was enabled.Furthermore,the reliability of LIZMC for in vivo evaluation of antithrombotic agents in zebrafish was verified using aspirin.Collectively,this novel LIZMC-based system can be used for in vivo zebrafish thrombosis studies and rapid screening of antithrombotic agents.

Design,synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells

Ursolic acid(UA)is a naturally occurring ursane triterpenoid,which exhibits a wide range of unique biological activities.To clarify its mechanism of action(MOA),a series of fluorescent derivatives of UA(5a-c)were designed and synthesized by conjugation with 7-nitrobenzo-2-oxa-1,3-diazole(NBD)fluorophore.Among them,5c exhibited similar anti-proliferative activity with UA against HCT116 cells(half maximal inhibitory concentration(IC_(50))=9.21±0.50μmol/L).Cell imaging experiment indicated that 5c was rapidly taken up in HCT116 cells in a dose and time-dependent manner.Then,5c was found to localize in endoplasmic reticulum(ER),lysosomes,and mitochondria,but not in nucleus of HCT116 cells by confocal microscopy studies.Preliminary MOA proved that UA induced autophagy with a unique intracellular distribution mechanism involving ER and lysosome.In all,our work provides new clues for revealing the molecular mechanism of UA as an antitumor agent.

Advancements in life-on-a-chip: The impact of “Beyond Limits Manufacturing” technology

This review explores the concept of life-on-a-chip,which involves the creation of miniaturized biological systems,such as organs,tissues,and model organisms,on microscale platforms called microfluidic chips.These chips consist of intricately etched channels,wells,and chambers that enable precise control and observation of fluids,cells,and biochemical reactions,facilitating the simulation of various aspects of human or animal physiology and the study of responses to different stimuli,drugs,or disease conditions.The review highlights the application of a novel technology,“Beyond Limit Manufacturing”(BLM),in the development of sophisticated three-dimensional cell models and model organism microchips.Modelorganism-on-a-chip and organ-on-a-chip(OoC)are among the thriving developments in the field of microfluidics,allowing for the reconstruction of living microenvironments and implementation of multiple stimuli.The review discusses the latest advancements in life-on-a-chip technology using BLM and outlines potential future research directions,emphasizing the significant role of these chips in studying complex biological processes in a controlled and scalable manner.

榄香烯对肿瘤恶病质小鼠细胞因子TNF-ɑ IL-6和骨骼肌UPP信号通路的调节作用

目的:研究通过建立肿瘤恶病质小鼠模型,研究榄香烯对肿瘤恶病质骨骼肌萎缩的缓解作用及其可能的机制。方法:C57BL/6小鼠皮下注射Lewis肺腺癌肿瘤细胞建立肿瘤恶病质模型。随机分为健康组、恶病质模型组、醋酸甲地孕酮组和榄香烯组。榄香烯口服乳等治疗14 d后,测量小鼠每日饮食量、肿瘤重量、去瘤体重、腓肠肌和胫骨前肌重量、肝脏重量,H&E染色检测腓肠肌肌丝横截面积,ELISA法检测血清IL-6和TNF-α水平,Western Blot检测腓肠肌中MAFBx、MURF-1的蛋白表达水平。结果:榄香烯组小鼠饮食量、去瘤体重及腓肠肌加胫骨前肌总重量较恶病质模型组增加,腓肠肌横截面积较恶病质模型组面积增大,IL-6及TNF-α水平较恶病质模型组明显下降,MAFBx、MURF-1的蛋白表达水平明显低于恶病质模型组(P<0.05)。同时,相对于醋酸甲地孕酮组,榄香烯组小鼠腓肠肌横截面积增大,IL-6及TNF-α水平降低,MAFBx、MURF-1的蛋白表达受到抑制(P<0.05)。结论:榄香烯可减轻肿瘤恶病质的骨骼肌萎缩,其机制可能与减少小鼠的能量消耗、降低血清TNF-α和IL-6水平、降低骨骼肌MAFBx、MURF-1的蛋白表达水平、调节UPP信号通路的活性有关。

Effects of freeze–thaw cycles on soil N_2O concentration and flux in the permafrost regions of the Qinghai–Tibetan Plateau

Nitrous oxide(N_2 O) is one of the most important greenhouse gases in the atmosphere; freeze–thaw cycles(FTCs) might strongly influence the emission of soil N_2 O on the Qinghai–Tibetan Plateau(QTP). However, there is a lack of in situ research on the characteristics of soil N_2 O concentration and flux in response to variations in soil properties caused by FTCs.Here, we report the effect of FTC-induced changes in soil properties on the soil N_2 O concentration and flux in the permafrost region of the higher reaches of the Shule River Basin on the northeastern margin of the QTP. We measured chemical properties of the topsoil, activities of soil microorganisms, and air temperature(AT), as well as soil N_2 O concentration and flux, over an annual cycle from July 31, 2011, to July 30, 2012. The results showed that soil N_2 O concentration was significantly affected by soil temperature(ST), soil moisture(SM), soil salinity(SS), soil polyphenol oxidase(SPO), soil alkaline phosphatase(SAP), and soil culturable actinomycetes(SCA), ranked as SM>SS>ST>SPO>SAP>SCA, whereas ST significantly increased soil N_2 O flux, compared with SS. Overall, our study indicated that the soil N_2 O concentration and flux in permafrost zone FTCs were strongly affected by soil properties, especially soil moisture, soil salinity, and soil temperature.

Multi-valent mRNA vaccines against monkeypox enveloped or mature viron surface antigens demonstrate robust immune response and neutralizing activity

Monkeypox was declared a global health emergency by the World Health Organization,and as of March 2023,86,000 confirmed cases and 111 deaths across 110 countries have been reported.Its causal agent,monkeypox virus(MPV)belongs to a large family of double-stranded DNA viruses,Orthopoxviridae,that also includes vaccinia virus(VACV)and others.MPV produces two distinct forms of viral particles during its replication cycles:the enveloped viron(EV)that is released via exocytosis,and the mature viron(MV)that is discharged through lysis of host cells.This study was designed to develop multi-valent m RNA vaccines against monkeypox EV and MV surface proteins,and examine their efficacy and mechanism of action.Four m RNA vaccines were produced with different combinations of surface proteins from EV(A35R and B6R),MV(A29L,E8L,H3L and M1R),or EV and MV,and were administered in Balb/c mice to assess their immunogenicity potentials.A dynamic immune response was observed as soon as seven days after initial immunization,while a strong Ig G response to all immunogens was detected with ELISA after two vaccinations.The higher number of immunogens contributed to a more robust total Ig G response and correlating neutralizing activity against VACV,indicating the additive potential of each immunogen in generating immune response and nullifying VACV infection.Further,the m RNA vaccines elicited an antigen-specific CD4^(+)T cell response that is biased towards Th1.The m RNA vaccines with different combinations of EVand MV surface antigens protected a mouse model from a lethal dose VACV challenge,with the EV and MV antigens-combined vaccine offering the strongest protection.These findings provide insight into the protective mechanism of multi-valent m RNAvaccines against MPV,and also the foundation for further development of effective and safe m RNA vaccines for enhanced protection against monkeypox virus outbreak.

A Fluid-Structure Interaction Simulation of Coal and Gas Outbursts Based on the Interaction between the Gas Pressure and Deformation of a Coal-Rock Mass

Based on the theories of the gas seepage in coal seams and the deformation of the coal-rock medium,the gas seepage field in coal-rock mass is coupled with the deformation field of the coal-rock mass to establish a fluidstructure interaction model for the interaction between coal gas and coal-rock masses.The outburst process in coal-rock masses under the joint action of gas pressure and crustal stress is simulated using the material point method.The simulation results show the changes in gas pressure,velocity distribution,maximum principal stress distribution,and damage distribution during the process of the coal and gas outburst,as well as themovement and accumulation of coal-rock masses after the occurrence of the outburst.It was found that the gas pressure gradient was greatest at theworking face after the occurrence of the outburst,the gas pressures and pressure gradients at each location within the coal seamgradually decreased with time,and the damage distribution was essentially the same as the minimum principal stress distribution.The simulation further revealed that the outburst first occurred in themiddle of the tunnel excavation face and that the speed at which particles of coal mass were ejected was highest at the center and decreased toward the upper and lower sides.The study provides a scientific basis for enhancing our understanding of the mechanism behind coal and gas outbursts,as well as their prevention and control.

Selective Separation and Analysis of Pb(II) Using a New Surface Imprinted Multi-Walled Carbon Nanotubes Combined with AAS

A new surface ion-imprinted Multi-walled carbon nanotubes (MCNTs), which was 6,6'-((1E,1'E)-(pyridine-2,6-diyl- bis(azanylyl))bis(methanylylidene))bis(2-allyl-phenol) and Pb(II) complex as functional monomer and template ion was presented for extracting and enrichment traces of Pb(II) ion. Parameters affecting the recovery of Pb(II) have been investigated in detail. The novel IMCNTs display high affinity, specificity, and selectivity for Pb(II) with a maximum uptake capacity of 115.5 mg·g–1 at pH 4.0. Meanwhile, only 11 mins was enough for extracting 98.5% Pb(II) for the IMCNTs. No significant loss in adsorption capacity is observed when the IMCNTs are reused for eleven times. Separation and preconcentration with IMCNTs particles results in a limit of detection of 0.47 μg·L–1 (3σ) and RSD (n = 8) of 1.16% by using atomic absorption spectrophotometer (AAS)

Microfluidic separation of particles by synergistic effect of geometry-induced hydrodynamics and magnetic field

Microfluidic combined with magnetic field have been demonstrated to be the promising solutions for fast and low-damage particles separation.However,the difficulties in the precise layout of magnets and accurate prediction of particle trajectories lead to under and over separation of target particles.A novel particle separation lab-on-chip(LOC)prototype integrated with microstructures and micropolar arrays is designed and characterized.Meanwhile,a numerical model for the separation of magnetic particles by the synergistic effect of geometry-induced hydrodynamics and magnetic field is constructed.The effect of geometry and magnetic field layout on particle deflection is systematically analyzed to implement accurate prediction of particle trajectories.It is found that the separation efficiency of magnetic particles increased from 50.2%to 91.7%and decreased from 88.6%to 85.7%in the range of depth factors from 15µm to 27µm and width factors from 30µm to 60µm,respectively.In particular,the combined effect of the offset distance of permanent magnets and the distance from the main flow channel exhibits a significant difference from the conventional perception.Finally,the developed LOC prototype was generalized for extension to arbitrary systems.This work provides a new insight and robust method for the microfluidic separation of magnetic particles.

A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial

We recently reported that inhibitors against human dihydroorotate dehydrogenase(DHODH)have broad-spectrum antiviral activities including their inhibitory efficacies on SARS-CoV-2 replication in infected cells.However,there are limited data from clinical studies to prove the application of DHODH inhibitors in Coronavirus disease 2019(COVID-19)patients.In the present study,we evaluated Leflunomide,an approved DHODH inhibitor widely used as a modest immune regulator to treat autoimmune diseases,in treating COVID-19 disease with a small-scale of patients.Cases of 10 laboratory-confirmed COVID-19 patients of moderate type with obvious opacity in the lung were included.Five of the patients were treated with Leflunomide,and another five were treated as blank controls without a placebo.All the patients accepted standard supportive treatment for COVID-19.The patients given Leflunomide had a shorter viral shedding time(median of5 days)than the controls(median of 11 days,P=0.046).The patients given Leflunomide also showed a significant reduction in C-reactive protein levels,indicating that immunopathological inflammation was well controlled.No obvious adverse effects were observed in Leflunomide-treated patients,and they all discharged from the hospital faster than controls.This preliminary study on a small-scale compassionate use of Leflunomide provides clues for further understanding of Leflunomide as a potential antiviral drug against COVID-19.

Palladium-Catalyzed Cyclization Reaction of o-Haloanilines, CO2 and Isocyanides： Access to Quinazoline-2,4（1H,3H）-diones

Quinazoline-2,4（1H,3H）-diones are core structural subunits frequently found in many biologically important compounds. The reaction of 2- aminobenzonitrile and CO2, which was frequently studied, only provided N3-unsubstituted quinazoline-2,4（1H,3H）-dione compounds. Herein we report palladium-catalyzed cyclization reactions of o-haloanilines, CO2 and isocyanides to prepare N3-substituted quinazoline-2,4（1H,3H）-diones. Electron-rich o-bromoanilines participated in the cyclization reaction using Cs2CO3 at high temperature, and electron-deficient o-bromoaniline or o-iodoaniline sub- strates conducted the reaction using CsF as base to deliver corresponding quinazoline-2,4（1H,3H）-dione products in good yields.

Design, Synthesis and Biological Evaluation of Potent and Selective S1PR1 Agonists for the Treatment of Ulcerative Colitis

The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel disease.In this study,a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug design.Among them,compound 9i was identified as a potent and selective S1PR1 agonist with activities onβ-arrestin recruitment(EC50=0.36 nmol/L)and receptor internalization(EC50=8.09 nmol/L).Meanwhile,compound 9i displayed an oral bioavailability up to 93.6%.Based on its excellent activity to S1PR1 and pharmacokinetic properties,compound 9i effectively alleviated dextran sulfate sodium(DSS)-induced ulcerative colitis in mice at a dose of 0.1 mg/kg.

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

Human dihydroorotate dehydrogenase(DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis(RA), psoriasis and multiple sclerosis(MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structureeactivity relationship(SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range.Further structure optimization revealed that an acrylamide with small hydrophobic groups(Me, Cl or Br)at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53-55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic(PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

Numerical simulation of broken pin effects on the flow field and cooling performance of a double-wall cooling configuration

In this paper, the flow characteristics of the double wall structure are presented and the effect of the broken pin size on the cooling performance and flow field of the double wall configuration is investigated. A periodic plate model with seven units is adopted, and there are an impingement hole and a film hole in each unit. Under five blowing ratios, six different sizes of the broken pin are compared, and the double wall configuration without broken pins is taken as the baseline.The results show that if the broken pins height is too small, the cooling effectiveness usually cannot be improved. With the presence of broken pins with a height of more than 0.4, the effectiveness is improved due to the enhancement of reattachment and recirculation of coolant. With the increase of the broken pin height, the cooling effectiveness increases. However, the increase of the diameter does not always improve the cooling performance, since the limiting effect of the wall jet. In this study, Case 6 with the largest broken pin always has the best cooling performance, but also the largest flow resistance. In Case 6 temperature is reduced by almost 15 K compared to the baseline, and more areas have relatively higher cooling effectiveness.

Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network

Backgrounds Arachidonic acid (AA) metabolic network is activated in the most inflammatory related diseases, and small-molecular drugs targeting AA network are increasingly available. However, side effects of above mentioned drugs have always been the biggest obstacle.什)-2-( 1 -hydroxy 1-4-oxocycIohexyl) ethyl caffeate (HOEC), a natural product acted as an inhibitor of 5-Iipoxygenase (5-LOX) and 15-LOX in vitro^ exhibited weaker therapeutic effect in high dose than that in low dose to collagen induced arthritis (CIA) rats. In this study, we tried to elucidate the potential regulatory mechanism by using quantitative pharmacology. Methods: First, we generated an experimental data set by monitoring the dynamics of AA metabolites, concentration in A23187 stimulated and different doses of HOEC co-incubated RAW264.7. Then we constructed a dynamic model of A23187-stimulated AA metabolic model to evaluate how a model-based simulation of AA metabolic data assists to find the most suitable treatment dose by predicting the pharmacodynamics of HOEC? Results: Compared to the experimental data, the model could simulate the inhibitory effect of HOEC on 5-LOX and 15-LOX, and reproduced the increase of the metabolic flux in the cyclooxygenase (COX) pathway. However, a concomitant, early-stage of stimulation-related decrease of prostaglandins (PGs) production in HOEC incubated RAW264.7 cells was not simulated in the model. Conclusion-. Using the model, we predict that higher dose of HOEC disrupts the flux balance in COX and LOX of the AA network, and increased COX flux can interfere the curative effects of LOX inhibitor on resolution of inflammation which is crucial for the efficient and safe drug design.

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors.Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological,genetic,and environmental factors.Nevertheless,the increasing understanding of G protein-coupled receptor(GPCR)opens a new possibility in drug discovery.Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs.This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases.Besides,we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.