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Recent advances in protein conformation sampling by combining machine learning with molecular simulation

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Chinese Physics B 2024年第3期33卷 80-87页

作者：唐一鸣杨中元姚逸飞周运谈圆王子超潘瞳熊瑞孙俊力韦广红 department of Physics State Key Laboratory of Surface Physicsand Key Laboratory for Computational Physical Sciences (Ministry of Education)Shanghai 200438China

The rapid advancement and broad application of machine learning(ML)have driven a groundbreaking revolution in computational biology.One of the most cutting-edge and important applications of ML is its integration with molecular simulations to improve the sampling efficiency of the vast conformational space of large biomolecules.This review focuses on recent studies that utilize ML-based techniques in the exploration of protein conformational landscape.We first highlight the recent development of ML-aided enhanced sampling methods,including heuristic algorithms and neural networks that are designed to refine the selection of reaction coordinates for the construction of bias potential,or facilitate the exploration of the unsampled region of the energy landscape.Further,we review the development of autoencoder based methods that combine molecular simulations and deep learning to expand the search for protein conformations.Lastly,we discuss the cutting-edge methodologies for the one-shot generation of protein conformations with precise Boltzmann weights.Collectively,this review demonstrates the promising potential of machine learning in revolutionizing our insight into the complex conformational ensembles of proteins.

关键词： machine learning molecular simulation protein conformational space enhanced sampling

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Diagnostic significance of complete blood cell count and hemogramderived markers for neonatal sepsis at Southwest Public Hospitals,Ethiopia

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World Journal of Clinical Pediatrics 2024年第2期13卷 114-126页

作者： Dereje Abebe Regassa Rahel Shumi Nagaash Bisirat Fikadu Habtu Woyesa Beyene Haile department of Medical laboratory sciences Wolkite UniversityWolkite 11330Ethiopia department of Medical laboratory sciences Dire Dawa UniversityDire Dawa 3000Ethiopia

BACKGROUND Neonatal sepsis is defined as an infection-related condition characterized by signs and symptoms of bacteremia within the first month of life.It is the leading cause of mortality and morbidity among newborns.While several studies have been conducted in other parts of world to assess the usefulness of complete blood count parameters and hemogram-derived markers as early screening tools for neonatal sepsis,the associations between sepsis and its complications with these blood parameters are still being investigated in our setting and are not yet part of routine practice.AIM To evaluate the diagnostic significance of complete blood cell count hemogramderived novel markers for neonatal sepsis among neonates attending public hospitals in the southwest region of Oromia,Ethiopia,through a case control study.METHODS A case control study was conducted from October 2021 to October 2023 Sociodemographic,clinical history,and laboratory test results data were collected using structured questionnaires.The collected data were entered into Epi-data 3.1 version and exported to SPSS-25 for analysis.Chi-square,independent sample ttest,and receiver operator characteristics curve of curve were used for analysis.A P-value of less than 0.05 was considered statistically significant.RESULTS In this study,significant increases were observed in the following values in the case group compared to the control group:In white blood cell(WBC)count,neutrophils,monocyte,mean platelet volume(MPV),neutrophils to lymphocyte ratio,monocyte to lymphocyte ratio(MLR),red blood cell width to platelet count ratio(RPR),red blood width coefficient variation,MPV to RPR,and platelet to lymphocyte ratio.Regarding MLR,a cut-off value of≥0.26 was found,with a sensitivity of 68%,a specificity of 95%,a positive predictive value(PPV)of 93.2%,and a negative predictive value(NPV)of 74.8%.The area under the curve(AUC)was 0.828(P<0.001).For WBC,a cutoff value of≥11.42 was identified,with a sensitivity of 55%,a specificity of 89%,a PPV of 83.3%,and a NPV of 66

关键词： Complete blood count Hemogram-derived marker Neonate Sepsis Ethiopia

Brain circuits for retching-like behavior

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National Science Review 2024年第1期11卷 145-160页

作者： Lifang Huo Zhimin Ye Meiling Liu Ziqing He Meizhu Huang Dapeng Li Qian Wu Qian Wang Xiaoqun Wang Peng Cao Ji Dong Congping Shang School of Basic Medical sciences Guangzhou National Laboratory The Fifth Afflliated Hospital Guangzhou Medical University Bioland laboratory (Guangzhou Regenerative Medicine and Health Guangdong laboratory) department of Neurobiology School of Basic Medical Sciences Beijing Key Laboratory of Neural Regeneration and Repair Advanced Innovation Center for Human Brain Protection Capital Medical University State Key laboratory of Cognitive Neuroscience and Learning IDG/McGovern Institute for Brain Research Beijing Normal University Changping Life Science laboratory National Institute of Biological sciences

Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body. The nucleus of the solitary tract(NTS) is important for initiating these responses. However, the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses. Here, we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that may be involved in these defensive responses. Among these, we identified Calbindin1-positive(Calb1+) NTS neurons that are molecularly distinct from Tac1+neurons.These Calb1+neurons are critical for nausea and retching induced by cereulide; an emetic toxin secreted by Bacillus Cereus. Strikingly, we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1+NTS neurons, a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A. Together, our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior. These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.

关键词： vomiting nausea nucleus of the solitary tract Calbindin1 neural circuits

Decreased LDHB expression in breast tumor cells causes NK cell activation and promotes tumor progression

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Cancer Biology & Medicine 2024年第6期21卷 513-540页

作者： Zhihong Luo Xiaohua Huang Xinyi Xu Kefeng Wei Yi Zheng Ke Gong Wenhua Li Hubei Key laboratory of Cell Homeostasis College of Life Sciences Wuhan University Wuhan University Shenzhen Research Institute Central laboratory University of Chinese Academy of Sciences-Shenzhen Hospital Hubei Province Key laboratory of Allergy and Immunology and department of Immunology School of Basic Medical Sciences Wuhan University

Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a the

关键词： Breast cancer NK cells lactate dehydrogenase B lactic acid tumor immunity

A repertoire of intronic lariat RNAs reveals tissue-specific regulation and target mimicry potential in plants

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Science China Life sciences 2024年第6期67卷 1280-1291页

作者： Yong Zhang Xiaotuo Zhang Qi Tang Lei Li Ting Jiang Yixiao Fang Hong Zhang Jixian Zhai Guodong Ren Binglian Zheng State Key laboratory of Genetic Engineering Institute of Plant Biology School of Life Sciences Fudan University department of Biology School of Life Sciences Southern University of Science and Technology

Lariat RNA is concomitantly produced by excised intron during RNA splicing, which is usually debranched by DBR1, an RNA debranching enzyme. However, increasing evidence showed that some lariat RNA could escape debranching. Little is known about how and why these lariat RNAs could be retained. By comparing the atlas of lariat RNAs between the non-dividing cell(mature pollen) and three actively dividing tissues(young shoot apex, young seeds, and young roots), we identified hundreds to thousands of lariat RNA naturally retained in each tissue, and the incidence of lariat RNA retention is much less in shoot apex while much more in pollen. Many lariat RNAs derived from the same intron or different lariat RNAs from the same pre-m RNA could be retained in one tissue while degraded in the other tissues. By deciphering lariat RNA sequences, we identified an AG-rich(RAAAAVAAAR) motif and a UC-rich(UCUCUYUCUC) motif for pollen-specific and the other three tissues-retained lariat RNAs, respectively. Reconstitution of the pollen-specific AG-rich motif indeed enhanced lariat RNA retention in plants. Biologically, hundreds of lariat RNAs harbored mi RNA binding sites, and dual-luciferase reporter assay showed that these natural lariat RNAs had the potential to protect expression of mi RNA target genes. Collectively, our results uncover that selective retention of lariat RNA is an actively regulatory process, and provide new insights into understanding how lariat RNA metabolism may impact mi RNA activity.

关键词： intron turnover lariat RNA miRNA RNA splicing DBR1

High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione(C3),as a novel EGFR—HER2 dual inhibitor in gastric tumors

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Oncology Research 2024年第2期32卷 251-259页

作者： MESFER AL SHAHRANI REEM GAHTANI MOHAMMAD ABOHASSAN MOHAMMAD ALSHAHRANI YASSER ALRAEY AYED DERA MOHAMMAD RAJEH ASIRI PRASANNA RAJAGOPALAN department of Clinical laboratory sciences College of Applied Medical SciencesKing Khalid UniversityAbhaSaudi Arabia

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.

关键词： Dual inhibitor Drug discovery EGFR/HER2 kinase Gastric cancer High-throughput screening

Advances of graphdiyne-supported metal catalysts in thermocatalytic reactions

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Nano Research 2024年第4期17卷 2223-2233页

作者： Jia Yu Yida Yang Yuliang Li Changyan Cao Weiguo Song Beijing National laboratory for Molecular sciences CAS Research/Education Center for Excellence in Molecular SciencesLaboratory of Molecular Nanostructures and NanotechnologyInstitute of ChemistryChinese Academy of SciencesBeijing 100190China School of Chemical sciences University of Chinese Academy of SciencesBeijing 100049China Beijing National laboratory for Molecular sciences CAS Research/Education Center for Excellence in Molecular SciencesLaboratory of organic solidsInstitute of ChemistryChinese Academy of SciencesBeijing 100190China

Supported metal catalysts are widely used in the modern chemical industry.The electronic interaction between supports and active components is of great significance for heterogeneous catalysis.Graphdiyne(GDY),a new type of carbon allotrope with sp-hybridized carbon atoms,πconjugate structure,and electron transmission capability,is a promising candidate as catalyst support.Recent years have witnessed the rapid progress of GDY-supported metal catalysts for different catalysis reactions.Considering that most processes in the current chemical industry are thermocatalytic reactions,we herein give an overview about the advances and particular characteristics of GDY-supported catalysts in these reactions.The geometric structure and electronic properties of GDY are first introduced.Then,the synthesis methods for GDY-supported metal catalysts and their applications in thermocatalytic reactions are discussed,in which the effect of electronic interaction on catalytic performance is highlighted.Finally,the current challenges and future directions of GDY-supported metal catalysts for thermocatalysis are proposed.It is expected that this review will enrich our understanding of the advances of GDY as a superior support for metal catalysts in thermocatalytic reactions.

关键词： graphdiyne metal catalysts thermocatalytic reactions heterogeneous catalysis

Long-lived lunar volcanism sustained by precession-driven core-mantle friction

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National Science Review 2024年第2期11卷 114-123页

作者： Shuoran Yu Xiao Xiao Shengxia Gong Nicola Tosi Jun Huang Doris Breuer Long Xiao Dongdong Ni State Key laboratory of Lunar and Planetary sciences Macau University of Science and Technology Planetary Science Institute State Key Laboratory of Geological Processes and Mineral Resources School of Earth Sciences China University of Geosciences CAS Key laboratory of Planetary sciences Shanghai Astronomical Observatory Institute of Planetary Research German Aerospace Centre(DLR)

Core-mantle friction induced by the precession of the Moon’s spin axis is a strong heat source in the deep lunar mantle during the early phase of a satellite’s evolution, but its influence on the long-term thermal evolution still remains poorly explored. Using a one-dimensional thermal evolution model, we show that core-mantle friction can sustain global-scale partial melting in the upper lunar mantle until ～3.1 Ga, thus accounting for the intense volcanic activity on the Moon before ～3.0 Ga. Besides, core-mantle friction tends to suppress the secular cooling of the lunar core and is unlikely to be an energy source for the long-lived lunar core dynamo. Our model also favours the transition of the Cassini state before the end of the lunar magma ocean phase(～4.2 Ga), which implies a decreasing lunar obliquity over time after the solidification of the lunar magma ocean. Such a trend of lunar obliquity evolution may allow volcanically released water to be buried in the lunar regolith of the polar regions. As a consequence, local water ice could be more abundant than previously thought when considering only its accumulation caused by solar wind and comet spreading.

关键词： Moon precession orbit volcanism

Rapid Unconscious Acquisition of Conditioned Fear with Low-Spatial-Frequency but Emotionally Neutral Stimuli

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Research 2024年第1期2023卷 753-762页

作者： Yujie Chen Si Chen Zhongju Sun Xilei Zhang Xiangyong Yuan Liang Wang Yi Jiang State Key laboratory of Brain and Cognitive sciences CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of PsychologyChinese Academy of SciencesBeijing 100101China department of Psychology University of Chinese Academy of SciencesBeijing 100049China Chinese Institute for Brain Research Beijing 102206China CAS Key laboratory of Mental Health Institute of PsychologyChinese Academy of SciencesBeijing 100101China

It has long been proposed that emotionally“prepared”(i.e.,fear-related)stimuli are privileged in the unconscious acquisition of conditioned fear.However,as fear processing is suggested to highly depend on the coarse,low-spatial-frequency(LSF)components of the fear-related stimuli,it is plausible that LSF may play a unique role in the unconscious fear conditioning even with emotionally neutral stimuli.Here,we provided empirical evidence that,following classical fear conditioning,an invisible,emotionally neutral conditioned stimulus(CS+)with LSF,but not with high spatial frequency(HSF),can rapidly elicit stronger skin conductance responses(SCRs)and larger pupil diameters than its CS−counterpart.In comparison,consciously perceived emotionally neutral CS+with LSF and HSF elicited comparable SCRs.Taken together,these results support that the unconscious fear conditioning does not necessarily entail emotionally prepared stimuli but prioritizes LSF information processing and highlight the crucial distinctions between the unconscious and the conscious fear learning.These findings not only coincide with the postulation that a rapid,spatial-frequency-dependent subcortical route is engaged in unconscious fear processing but also suggest the existence of multiple routes for conscious fear processing.

关键词： neutral necessarily diameters