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Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

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Acta pharmaceutica Sinica b 2024年第7期14卷 3086-3109页

作者： yihang Hao Haofan Wang xianggen liu Wenrui Gai Shilong Hu Wencheng liu zhuang Miao yu Gan xianghua yu Rongjia Shi yongzhen tan ting Kang Ao Hai yi Zhao yihang fu yaling tang ling ye jin liu xinhua liang bowen Ke State Key laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of StomatologySichuan UniversityChengdu 610041China College of Computer Science Sichuan UniversityChengdu 610065China Department of Anesthesiology Laboratory of Anesthesia and Critical Care MedicineNational-Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic *** primary challenge is to integrate diverse pharmacophores within a single-molecule *** address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local *** integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound *** framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent *** a sequence of local editing to navigate the molecular space,DeepSA successfully identified At-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal *** insights into At-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NlRp3 inflammasome *** findings not only highlight the efficacy of At-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.

关键词： Multifunctional drugs Deep simulated annealing Molecule generation Articaine derivatives AI-enhanced drug discovery

Complete blood and urine paraprotein tests as response assessments in multiple myeloma patients treated with bortezomib,cyclophosphamide,and dexamethasone

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Chronic Diseases and translational Medicine 2024年第1期10卷 62-68页

作者： xialu lan fujing Zhang Chen yang Wei Su jianhua Du Shuangjiao liu Miao Chen bing Han Daobin Zhou junling zhuang Department of Hematology Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina Department of pathology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouChina Department of laboratory Medicine Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina

background: this study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma(MM)during the induction phase of treatment with bortezomib,cyclophosphamide,and dexamethasone(bCD).Methods :We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with bCD as front-line regimen at peking Union Medical College Hospital from january 1,2013 to December 31,***: there were 107 patients with International Staging System(ISS)III and 51 with paraprotein of light *** these,77 completed nine cycles of the bCD *** the number of treatment cycles increased,the proportions of serum and urine immunofixation electrophoresis(IfE)tests elevated from 40.39%to 62.22%and 16.75%to 37.78%,*** than 90%of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle,but that of urinary M protein was less than 60%.the detection rate of urinary M protein in light chain MM was more than 70%per *** with a very good partial response(VGpR)had longer progression-free survival(pfS)than those with uncertain VGpR(32 vs.26 months,p=0.0336).Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation,those who were regularly assessed at every other cycle showed more favorable pfS than those who visited irregularly(27 vs.22 months,p=0.059).Conclusion: Urinary M protein detection rate is significantly lower than that in serum,leading to an overestimation of efficacy,premature reduction of treatment intensity,and shortened *** response assessments are critical to treatment decisions and clinical diagnoses.

关键词： bortezomib light chain subtype multiple myeloma response assessment

Molecular Chain flexibility and Dielectric loss at High-frequency:Impact of Ester bond Arrangement in poly(ester imide)s

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Chinese journal of polymer Science 2024年第8期42卷 1122-1133页

作者： ya-Dong li hong li lu-Kun feng feng bao Ming-liang Wang Cai-Zhen Zhu Zhao-Hui Zheng xiao-bin Ding jian xu Chengdu Institute of Organic Chemistry Chinese Academy of SciencesChengdu 610041China university of Chinese Academy of Sciences Beijing 100081China Institute of low-Dimensional Materials Genome Initiative College of Chemistry and Environmental EngineeringShenzhen UniversityShenzhen 518060China

the evolution of high-frequency communication has accentuated the significance of controlling dielectric properties in polymer ***,it has been theorized that rigid molecular chains lead to lower dielectric ***,the validity of this proposition at high frequencies remains *** scrutinize the correlation between chain flexibility and dielectric properties,we synthesized six poly(ester imide)s(pEIs)with systematically varied molecular chain flexibilities by modifying the ester's substitution on the aromatic *** introduction of ester bonds bestowed all pEI films with a low dielectric dissipation factor(D_(f)),ranging from 0.0021 to 0.0038 at 10 GHz in dry *** dry D_(f)displayed a pattern consistent with volume polarizability(p/V).Unexpectedly,pI-mmm-t,featu ring the most flexible molecular chain,exhibited the lowest dielectric loss under both dry(0.0021@10 GHz)and hygroscopic(0.0029@10 GHz)***,the observed increase in D_(f)after humidity absorption suggests that the high dielectric loss of pEI in applications may be attributed to its hygroscopic *** simulations and characterization of the aggregation structure revealed that the smaller cavities within flexible molecular chains,after close stacking,impede the entry of water *** sacrificing high-temperature resistance,the precursor exhibited enhanced solubility properties and could be processed into high-quality *** research unveils new insights into the relationship between flexibility and highfrequency dielectric loss,offering innovative perspectives on synthesizing aromatic polymers with exceptional dielectric properties.

关键词： 5G communications poly(ester imide)s Molecular chain flexibility Dielectric properties Humidity absorption

two missense StK11 gene variations impaired lKb1/adenosine monophosphate-activated protein kinase signaling in peutz-jeghers syndrome

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World journal of Gastrointestinal Oncology 2024年第4期16卷 1532-1546页

作者： jin liu Si-Cong Zeng An Wang Hai-ying Cheng Qian-jun Zhang Guang-xiu lu Hunan Guangxiu Hospital Hunan Normal UniversityChangsha 410000Hunan ProvinceChina Scientific Research Department Reproductive and Genetic Hospital of Citic-XiangyaChangsha 410000Hunan ProvinceChina

bACKGROUND peutz-jeghers syndrome(pjS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(StK11/lKb1)gene *** genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic *** to identify the pathogenicity of two missense variants and provide clinical *** Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with pjS treated at the Reproductive and Genetic Hospital of *** was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with ***,plasmids were constructed and transfected into Hela cells to observe cell *** differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and *** analysis was performed using one-way analysis of variance.ptatistically *** We identified two missense StK11 gene VUS[c.889A>G(***297Gly)and c.733C>t(***245phe)]in 9 unrelated pjS families who were seeking reproductive *** two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase b1(lKb1)*** vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMpK)at thr172 and lKb1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type *** addition,the two missense StK11 variants promoted the proliferation of Hela *** immunohistochemical analysis showed that phosphorylated-AMpK(thr172)expression was significantly lower in gastric,colonic,and uterine polyps from pjS patients with misse

关键词： Missense StK11 peutz-jeghers syndrome Rare disease Genetic counseling Assisted reproductive technique

Self-adjuvant Astragalus polysaccharide-based nanovaccines for enhanced tumor immunotherapy:a novel delivery system candidate for tumor vaccines

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Science china(life Sciences) 2024年第4期67卷 680-697页

作者： Nan li yun Zhang Miaomiao Han tian liu jinjia Wu yingxia xiong yikai fan fan ye bing jin yinghua Zhang Guibo sun xiaobo sun Zhengqi Dong State Key laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Chinese Academy of Medical Sciences&Peking Union Medical College(CAMS)Institute of Medicinal Plant Development(IMPLAD)Beijing 100193China Key laboratory of bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine(Natural Medicine)and Translational MedicineKey Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription from Chinese Academy of Medical SciencesCAMSIMPLADBeijing 100193China Department of pharmaceutics School of Pharmaceutical SciencesHeilongjiang University of Chinese MedicineHarbin 150036China jilin Academy of Chinese Medicine Sciences Changchun 130012China joint Research Center for Chinese Medicinal Herbs IMPLADABRC&ACCLBeijing 100193China

the study of tumor nanovaccines(NVs)has gained interest because they specifically recognize and eliminate tumor ***,the poor recognition and internalization by dendritic cells(DCs)and insufficient immunogenicity restricted the vaccine ***,we extracted two molecular-weight Astragalus polysaccharides(ApS,12.19 k D;ApSHMw,135.67 k D)from Radix Astragali and made them self-assemble with OVA257–264directly forming OVA/ApS integrated nanocomplexes through the microfluidic *** nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve *** in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor *** optimal ApS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline *** fItC-OVA in ApS-NVs could be effectively taken up by DCs,and ApS-NVs could stimulate the maturation of DCs,improving the antigen cross-presentation efficiency in *** possible mechanism was that ApS can induce DC activation via multiple receptors such as dectin-1 and toll-like receptors 2 and *** accumulation of ApS-NVs both in draining and distal lymph nodes were observed following *** ApS-NVs could easily access the lymph ***,ApS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic t *** addition,ApS-NVs achieve a better antitumor effect in established b16-OVA melanoma tumors compared with the OVA+Alum treatment *** antitumor mechanism correlated with the increase in cytotoxic t cells in the tumor ***,the poor tumor inhibitory effect of ApS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by ***,this study developed a promising ApS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.

关键词： Astragalus polysaccharides nanovaccines OVA immunotherapy self-adjuvant

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transient stimulated Raman scattering spectroscopy and imaging

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light(Science & Applications) 2024年第4期13卷 654-663页

作者： Qiaozhi yu Zhengjian yao jiaqi Zhou Wenhao yu Chenjie zhuang yafeng Qi Hanqing xiong National biomedical Imaging Center College of Future TechnologyPeking UniversityBeijing 100871China biomedical Engineering Department College of Future TechnologyPeking UniversityBeijing 100871China

Stimulated Raman scattering(SRS)has been developed as an essential quantitative contrast for chemical imaging in recent ***,while spectral lines near the natural linewidth limit can be routinely achieved by state-of-the-art spontaneous Raman microscopes,spectral broadening is inevitable for current mainstream SRS imaging *** is because those SRS signals are all measured in the frequency *** is a compromise between sensitivity and spectral resolution:as the nonlinear process benefits from pulsed excitations,the fundamental time-energy uncertainty limits the spectral ***,the spectral range and acquisition speed are mutually *** we report transient stimulated Raman scattering(t-SRS),an alternative time-domain strategy that bypasses all these fundamental conjugations.t-SRS is achieved by quantum coherence manipulation:we encode the vibrational oscillations in the stimulated Raman loss(SRl)signal by femtosecond pulse-pair sequence excited vibrational wave packet *** Raman spectrum was then achieved by fourier transform of the time-domain SRl *** all Raman modes are impulsively and simultaneously excited,t-SRS features the natural-linewidth-limit spectral line shapes,laser-bandwidth-determined spectral range,and improved ***~150-fs laser pulses,we boost the sensitivity of typical Raman modes to the sub-mM *** all-plane-mirror high-speed time-delay scanning,we further demonstrated hyperspectral SRS imaging of live-cell metabolism and high-density multiplexed imaging with the natural-linewidth-limit spectral resolution.t-SRS shall find valuable applications for advanced Raman imaging.

关键词： scattering excited mutually

A particle-resolved heat-particle-fluid coupling model by DEM-IMb-lbM

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journal of Rock Mechanics and Geotechnical Engineering 2024年第6期16卷 2267-2281页

作者： Ming xia jinlong fu y.t.feng fengqiang Gong jin yu Hunan Key laboratory of Geomechanics and Engineering Safety Xiangtan UniversityXiangtan411105China Zienkiewicz Institute for Modelling Data and AISwansea UniversitySwanseaSA18EPUK School of Civil Engineering Southeast UniversityNanjing211189China fujian Research Center for tunneling and Urban Underground Space Engineering Huaqiao UniversityXiamen361021China

Multifield coupling is frequently encountered and also an active area of research in geotechnical *** this work,a particle-resolved direct numerical simulation(pR-DNS)technique is extended to simulate particle-fluid interaction problems involving heat transfer at the grain *** this extended technique,an immersed moving boundary(IMb)scheme is used to couple the discrete element method(DEM)and lattice boltzmann method(lbM),while a recently proposed Dirichlet-type thermal boundary condition is also adapted to account for heat transfer between fluid phase and solid *** resulting DEM-IbM-lbM model is robust to simulate moving curved boundaries with constant temperature in thermal *** facilitate the understanding and implementation of this coupled model for non-isothermal problems,a complete list is given for the conversion of relevant physical variables to lattice ***,benchmark tests,including a single-particle sedimentation and a two-particle drafting-kissing-tumbling(DKt)simulation with heat transfer,are carried out to validate the accuracy of our coupled *** further investigate the role of heat transfer in particle-laden flows,two multiple-particle problems with heat transfer are *** examples demonstrate that the proposed coupling model is a promising high-resolution approach for simulating the heat-particle-fluid coupling at the grain level.

关键词： particle-fluid interaction Heat transfer Discrete element method(DEM) lattice boltzmann method(lbM) Dirichlet-type thermal boundary Direct numerical simulation

Verifiable quantum secret sharing scheme based on orthogonal product states

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Chinese physics b 2024年第7期33卷 178-187页

作者：白晨明刘璐张素娟 Department of Mathematics and physics Shijiazhuang Tiedao UniversityShijiazhuang 050043China

In the domain of quantum cryptography,the implementation of quantum secret sharing stands as a pivotal *** this paper,we propose a novel verifiable quantum secret sharing protocol using the d-dimensional product state and lagrange interpolation *** protocol is initiated by the dealer Alice,who initially prepares a quantum product state,selected from a predefined set of orthogonal product states within the C~d■C~d ***,the participants execute unitary operations on this product state to recover the underlying ***,we subject the protocol to a rigorous security analysis,considering both eavesdropping attacks and potential dishonesty from the ***,we conduct a comparative analysis of our protocol against existing *** scheme exhibits economies of scale by exclusively employing quantum product states,thereby realizing significant cost-efficiency *** terms of access structure,we adopt a(t, n)-threshold architecture,a strategic choice that augments the protocol's practicality and suitability for diverse ***,our protocol includes a rigorous integrity verification mechanism to ensure the honesty and reliability of the participants throughout the execution of the protocol.

关键词： quantum secret sharing quantum product state threshold scheme unitary operations

Efficacy of Sailuotong(塞络通)on neurovascular unit in amyloid precursor protein/presenilin-1 transgenic mice with Alzheimer's disease

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journal of traditional Chinese Medicine 2024年第2期44卷 289-302页

作者： sun linjuan lI Chengfu liu jiangang lI Nannan HAN fuhua QIAO Dandan tAO zhuang ZHAN Min CHEN Wenjie ZHANG xiaohui tONG Chenguang CHEN Dong Qi jiangxia liu yang lIANG xiao ZHENG xiaoying ZHANG yunling Department of Neurology Xiyuan HospitalChina Academy of Chinese Medical SciencesBeijing 100091China china population and Development Research Center Beijing 100081China Department of Institute of population Research Peking UniversityBeijing 100087China Graduate School of china Academy of Chinese Medical Sciences Beijing 100700China Graduate School of beijing university of Chinese Medicine Beijing 100029China

ObjECtIVE:to discuss the influence of Sailuotong(塞络通,Slt)on the Neurovascular Unit(NVUs)of amyloid precursor protein(App)/presenilin-1(pS1)mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer's disease(AD).MEtHODS:the mice were allocated into the following nine groups:(a)the C57 black(C57bl)sham-operated group(control group),(b)ischaemic treatment in C57bl mice(the C57 ischaemic group),(c)the App/pS1 sham surgery group(App/pS1 model group),(d)ischaemic treatment in App/pS1 mice(App/pS1 ischaemic group),(e)C57bl mice treated with aspirin following ischaemic treatment(C57bl ischaemic+aspirin group),(f)C57bl mice treated with Slt following ischaemic treatment(C57bl ischaemic+Slt group),(g)App/pS1 mice treated with Slt(App/pS1+Slt group),(h)App/pS1 mice treated with donepezil hydrochloride following ischaemic treatment(App/pS1 ischaemic+donepezil hydrochloride group)and(i)App/pS1 mice treated with Slt following ischaemic treatment(App/pS1 ischaemic+Slt group).the ischaemic model was established by operating on the bilateral common carotid arteries and creating a *** Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of *** hippocampus of each mouse was observed by haematoxylin and eosin(HE)and Congo red *** ultrastructure of NVUs in each group was observed by electron microscopy,and various biochemical indicators were detected by enzymelinked immunosorbent assay(ElISA).the protein expression level was detected by Western *** mRNA expression was detected by quantitative real-time polymerase chain reaction(qRt-pCR).RESUltS:the results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice,which were restored by *** results of HE staining showed that Slt restored the pathological changes of the *** Congo red staining results revealed that Slt also improved the scattered

关键词： Alzheimer disease amyloid beta-protein precursor presenilin-1 mice transgenic replenishing Qi and activating blood neurovascular unit Sailuotong