Modernising autism spectrum disorder model engineering and treatment via CRISPR-Cas9:A gene reprogramming approach

A neurological abnormality called autism spectrum disorder(ASD)affects how a person perceives and interacts with others,leading to social interaction and communication issues.Limited and recurring behavioural patterns are another feature of the illness.Multiple mutations throughout development are the source of the neurodevelopmental disorder autism.However,a well-established model and perfect treatment for this spectrum disease has not been discovered.The rising era of the clustered regularly interspaced palindromic repeats(CRISPR)-associated protein 9(Cas9)system can streamline the complexity underlying the pathogenesis of ASD.The CRISPR-Cas9 system is a powerful genetic engineering tool used to edit the genome at the targeted site in a precise manner.The major hurdle in studying ASD is the lack of appropriate animal models presenting the complex symptoms of ASD.Therefore,CRISPR-Cas9 is being used worldwide to mimic the ASD-like pathology in various systems like in vitro cell lines,in vitro 3D organoid models and in vivo animal models.Apart from being used in establishing ASD models,CRISPR-Cas9 can also be used to treat the complexities of ASD.The aim of this review was to summarize and critically analyse the CRISPRCas9-mediated discoveries in the field of ASD.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

基于Logistic生长模型的钦蜜9号百香果成熟阶段判别

【目的】探究夏季百香果的生长发育与品质形成规律,并对百香果成熟阶段进行判别。【方法】采用钦蜜9号百香果作为试材,测定其横径、纵径、固酸比、可食率、果皮厚度、硬度等理化指标,利用Logistic生长模型分析理化指标随有效积温增长的变化规律,并应用因子分析法对百香果成熟度进行定量评价,最终划分成熟阶段。【结果】通过观测并记录百香果生长过程,发现其纵径、横径变化趋势符合“慢-快-慢”的生长曲线,分析得出百香果在有效积温达到440℃·d时,基本完成果实膨大。随后以固酸比、可食率、果皮厚度、硬度为品质指标,其中固酸比与可食率指标呈现S型增长趋势,果皮厚度与硬度呈现三次函数下降趋势,并且品质指标与有效积温之间存在显著的相关性。利用因子分析方法构建百香果成熟度评价指标I_(M),采用Logistic生长函数建立百香果成熟度数学模型,模型拟合优度达99.25%,计算得出t1、t2、t3等3个生长分界点。最终确定有效积温为475~736℃·d时,果实处于果肉增重阶段;有效积温为736~997℃·d时,果实处于转色阶段;有效积温为997~1200℃·d时,果实处于成熟阶段。【结论】本研究量化分析了百香果成熟度,能够较好划分果肉增重期、转色期、成熟期三个成熟阶段,为百香果适时机械化采摘与贮藏管理提供依据。

深圳龙岗区2023年“9·7”极端特大暴雨洪涝灾害风险评估与对策

2023年9月7—8日,深圳市出现超历史纪录的极端特大暴雨,打破了深圳市1952年有气象记录以来7项历史极值,其中龙岗区暴雨中心爱联河片区3 h降雨量超100年一遇,导致城市内涝积水。以深圳龙岗区爱联河片区为例,构建城市暴雨洪涝耦合模型,对2023年“9·7”极端特大暴雨洪涝情况进行模拟,分析龙岗中心城区内涝积水情况,为揭示洪涝灾害成因和提出防治对策提供依据。

深圳市2023年“9·7”极端特大暴雨洪涝复盘模拟分析——以深圳龙华区观澜河流域为例

2023年9月7—8日,深圳市出现超历史纪录的特大暴雨,龙岗河、深圳河、观澜河等流域遭受严重洪涝灾害。以龙华区观澜河流域为例,采用洪水分析软件HydroMPM构建城市暴雨洪涝模型,对龙华区观澜河流域2023年“9·7”极端特大暴雨洪涝情况进行了模拟,分析了河道漫溢水淹及城区积水情况,为揭示洪涝灾害成因和提出防治对策提供依据。

The Performance of Atmospheric Component Model R42L9 of GOALS/LASG

This paper examines the performance of an atmospheric general circulation model (AGCM) developed at the State Key Laboratory of Numerical Modeling for Atmospheric Sciences and Geophysical Fluid Dynamics, Institute of Atmospheric Physics (LASG/IAP). It is a spectral model truncated at R42(2.8125°long×1.66°lat) resolution and with nine vertical levels, and referred to as R42L9/LASG hereafter. It is also the new version of atmospheric component model R15L9 of the global ocean-atmosphere-land system (GOALS/LASG). A 40-year simulation in which the model is forced with the climatological monthly mean sea surface temperature is compared with the 40-year (1958-97) U.S. National Center for Environmental Prediction (NGEP) global reanalysis and the 22-year (1979-2000) Xie-Arkin monthly precipitation climatology. The mean DJF and JJA geographical distributions of precipitation, sea level pressure, 500-hPa geopotential height, 850-hPa and 200-hPa zonal wind, and other fields averaged for the last 30-year integration of the R42L9 model are analyzed. Results show that the model reproduces well the observed basic patterns, particularly precipitation over the East Asian region. Comparing the new model with R15L9/LASG, the old version with coarse resolution (nearly 7.5°long×4.5°lat), shows an obvious improvement in the simulation of regional climate, especially precipitation. The weaknesses in simulation and future improvements of the model are also discussed.

The big bang of genome editing technology: development and application of the CRISPR/Cas9 system in disease animal models

Targeted genome editing technology has been widely used in biomedical studies. The CRISPR- associated RNA-guided endonuclease Cas9 has become a versatile genome editing tool. The CRISPR/Cas9 system is useful for studying gene function through efficient knock-out, knock-in or chromatin modification of the targeted gene loci in various cell types and organisms. It can be applied in a number of fields, such as genetic breeding, disease treatment and gene functional investigation In this review, we introduce the most recent developments and applications, the challenges, and future directions of Cas9 in generating disease animal model. Derived from the CRISPR adaptive immune system of bacteria, the development trend of Cas9 will inevitably fuel the vital applications from basic research to biotechnology and bio- medicine.

Kinetic Model and Simulation Analysis for Toluene Disproportionation and C9-Aromatics Transalkylation

A new kinetic model for commercial unit of toluene disproportionation and C9-armatiocs transalkylation is developed based on the reported reaction scheme.A time based catalyst deactivation function taking weight hourly space velocity(WHSV)into account is incorporated into the model,which reasonably accounts for the loss in activity because of coke deposition on the surface of catalyst during long-term operation.The kinetic parameters are benchmarked with several sets of balanced plant data and estimated by the differential variable metric optimiza- tion method.Sets of plant data at different operating conditions are applied to make sure validation of the model and the results show a good agreement between the model predictions and plant observations.The simulation analysis of key variables such as temperature and WHSV affecting process performance is discussed in detail,giv- ing the guidance to select suitable operating conditions.

IMPROVING 9-INTERSECTION MODEL BY REPLACING THE COMPLEMENT WITH VORONOI REGION

9-intersection model is the most popular framework used for formalizing the spatial relations between two spatial objectsA andB. It transforms the topological relationships between two simple spatial objectsA andB into point-set topology problem in terms of the intersections ofA’s boundary (?A), interior (A 0) and (A ?) withB’s boundary (?B), interior (B 0) and exterior (B ?). It is shown in this paper that there exist some limitations of the original 9-intersection model due to its definition of an object’s exterior as its complement, and it is difficult to distinguish different disjoint relations and relations between complex objects with holes, difficult or even impossible to compute the intersections with the two object’s complements (?A∩B ?,A 0∩?B ?,A ?∩?B,A ?∩B 0 andA ?∩B ?)since the complements are infinitive. The authors suggest to re-define the exterior of spatial object by replacing the complement with its Voronoi region. A new Voronoi-based 9-intersection (VNI) is proposed and used for formalizing topological relations between spatial bojects. By improving the 9-intersection model, it is now possible to distinguish disjoint relations and to deal with objects with holes. Also it is possible to compute the exterior-based intersections and manipulate spatial relations with the VNI.

Genome engineering and disease modeling via programmable nucleases for insulin gene therapy;promises of CRISPR/Cas9 technology

Targeted genome editing is a continually evolving technology employing programmable nucleases to specifically change,insert,or remove a genomic sequence of interest.These advanced molecular tools include meganucleases,zinc finger nucleases,transcription activator-like effector nucleases and RNA-guided engineered nucleases(RGENs),which create double-strand breaks at specific target sites in the genome,and repair DNA either by homologous recombination in the presence of donor DNA or via the error-prone non-homologous end-joining mechanism.A recently discovered group of RGENs known as CRISPR/Cas9 gene-editing systems allowed precise genome manipulation revealing a causal association between disease genotype and phenotype,without the need for the reengineering of the specific enzyme when targeting different sequences.CRISPR/Cas9 has been successfully employed as an ex vivo gene-editing tool in embryonic stem cells and patient-derived stem cells to understand pancreatic beta-cell development and function.RNA-guided nucleases also open the way for the generation of novel animal models for diabetes and allow testing the efficiency of various therapeutic approaches in diabetes,as summarized and exemplified in this manuscript.

The 9L^(LUC)/Wistar rat glioma model is not suitable for immunotherapy

The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9L^LUC glioma cells syngenic to Fischer 344 （F344） rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9L^LUC/F344 rats, and tumor regression was found in some 9L^LUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9L^LUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9L^LUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.

The African Climate as Predicted by the IAP Grid-Point Nine-Layer Atmospheric General Circulation Model (IAP-9L-AGCM)

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The origin and accumulation model of crude oils from oil reservoirs Chang 9 and Chang 10 in the Yanchang Formation of the Ordos Basin

In the lower parts of oil reservoirs Chang 9 and Chang 10 of the Yanchang Formation are oil-bearing layers newly found in oil exploration in the Ordos Basin.Based on GC,GC-MS analyses of saturated hydrocarbons from crude oils and source rocks,reservoir fluid inclusions and BasinMod,the origin of crude oils,accumulation period and accumulation models are discussed in combination with other petroleum geology data in this paper.The result shows that(1) there are two different types of crude oils in oil reservoir Chang 9 in the Longdong and Jiyuan regions:crude oils of typeⅠ(Well D86,Well A44,Well A75,Well B227,Well X62 and Well Z150) are mainly de-rived from the Chang 7 source rocks(including mudstones and shales) and distributed in the Jiyuan and Longdong regions;those of typeⅡ(Well Z14 and Well Y427),are distributed in the Longdong region,which are derived from the Chang 9 source rocks.Crude oils from oil reservoir Chang 10 in the Shanbei region are mainly derived from the Chang-9 source rocks;(2) there are two phases of hydrocarbon filling in oil reservoir Chang 9 in the Jiyuan and Longdong regions and oil reservoir Chang 10 in the Shanbei region:The first phase started at the early stage of J2z.The process of hydrocarbon filling was discontinuous in the Late Jurassic,because of the tectonic-thermal event in the Ordos Basin.The second phase was the main accumulation period,and hydrocarbons began to accumulate from the late stage of J2a to the middle-late of K1,mainly at the middle-late stage of K1;(3) there exist two types of accu-mulation models in oil reservoirs Chang 9 and Chang 10 of the Yanchang Formation:source rocks of the reservoirs in oil reservoir Chang 9 in the Jiyuan region and oil reservoir Chang 10 in the Shanbei region,the mixed type of reservoirs on the lateral side of source rocks and source rocks of the reservoirs in oil reservoir Chang 9 in the Long-dong region.

THE SYNTHESIS AND CRYSTAL STRUCTURE OF B-(32) MODEL COMPOUND: 1-C_4H_9Co(salen)(Py)

The title complex i-C_4H_9Co(salen)(Py) (Py=pyridine. salen=dianion of disalicylideneethylenediamine) has been first synthesized. Its crystal structure has been determined by X-ray diffraction method. The crystsis are monoclinic with space group P2_1/ C. The unit cell parametes are presented. The structure has been refined to a final R of 0.038.

Measurement and correlation of solubility of 9-fluorenone in 11 pure organic solvents from T = 283.15 to 323.15 K

In this work, the solubility data of 9-fluorenone in 11 pure solvents(methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, acetonitrile, ethyl formate, ethyl acetate, dimethyl sulfoxide, n-hexane)were measured by the gravimetric method from 278.15 K to 318.15 K under atmospheric pressure. The results showed that the solubility of 9-fluorenone in all tested solvents increased with the raised temperature. The solubility data were correlated by the modified Apelblat equation, λh model and NRTL(nonradom two fluid) model. The average relative deviation(ARD) correlated by three thermodynamic models in different solvents was all below 5%, which indicated that the three thermodynamic models fit the solubility data well. Furthermore, the mixing thermodynamic properties of 9-fluorenone in pure solvent systems were calculated via NRTL model. The results indicated the dissolution process of 9-fluorenone is spontaneous and entropically favorable. The solubility and the mixing thermodynamic properties provided in this paper would play an important role in industrial manufacture and follow-up operation of 9-fluorenone.

能表达带洞区域拓扑关系的扩展9-交集模型

为了表达带洞区域拓扑关系,通过扩展9-交集模型,将9-交集矩阵的元素扩展为二进制编码,提出了一种新的拓扑关系表达方法——D9-交集模型;讨论了D9-交集模型的性质,并比较了该模型与9-交集模型的表达能力。结果表明,D9-交集模型既能表达简单区域拓扑关系,也能表达带洞区域拓扑关系,还能区分9-交集模型不能区分的拓扑关系,表达能力强于9-交集模型,表达结果更符合人们的认知。

心肺转流对大鼠血浆和肺内基质金属蛋白酶-9的影响

目的基质金属蛋白酶(matrix metalloproteinase,MMP)与心肺转流(cardiopulmonary bypass,CPB)急性肺损伤有关。文中探讨MMP-9血浆浓度在大鼠CPB前后的变化及肺内表达的差异。方法健康雄性SD大鼠20只随机分为对照组和心肺转流组,心肺转流组分别于转流结束即刻、结束后2h和6h各时间点取血和肺组织,对照组分别在相应时间点取样。用酶联免疫吸附法(ELISA)测定血浆MMP-9浓度,免疫组化染色观察肺组织MMP-9的表达。结果 CPB后血浆MMP-9浓度较术前及对照组明显升高,差异有统计学意义。免疫组化染色显示CPB后肺内MMP-9表达明显增强。结论 CPB可以引起大鼠肺内MMP-9表达增强,血液中MMP-9释放增加。

鼻渊合剂对急性鼻窦炎模型大鼠鼻窦黏膜p38MAPK信号通路及IL-9/IL-10的影响

目的观察鼻渊合剂治疗急性鼻窦炎的临床疗效,并探讨其对大鼠急性鼻窦炎模型鼻窦黏膜p38MAPK信号通路及IL?9、IL-10的影响。方法建造大鼠急性鼻窦炎模型,设中、西药组、生理盐水组,分别使用鼻渊合剂、克拉霉素分散片及桉柠蒎肠溶软胶囊、生理盐水灌胃,观察症状积分,并设空白组,测定造模后0、7、14、21d鼻窦黏膜IL-9、IL-10及p-p38水平,进行统计学分析。结果通过大鼠症状积分比较,表明中、西药都有治疗作用。造模后大鼠IL-9及p-p38水平明显增高;用药后中药、西药组大鼠鼻窦黏膜IL-9及p-p38水平随治疗周期明显下降,与生理盐水组比较有显著性差异(P<0.05),中药组IL-9及p-p38水平下降与西药组无显著性差异。用药后中药组、西药组及生理盐水组鼻窦黏膜IL-10水平随治疗周期逐步升高,中药组、西药组与生理盐水组比较均存在显著性差异(P<0.05),中药组与西药组比较无显著性差异。结论鼻渊合剂治疗急性鼻窦炎有确切疗效,IL-9、IL-10参与了急性鼻窦炎发病的免疫过程,与p38MAPK通路存在一定关系,鼻渊合剂有促进IL-10、抑制p-p38活化阻断p38MAPK通路抑制IL-9产生的作用。

榄香烯乳联合化疗对小鼠Lewis肺癌组织S100A4及MMP-9蛋白表达的影响

【目的】观察榄香烯乳联合化疗对Lewis肺癌的抑瘤作用及其对S100A4及MMP-9表达的影响,探讨其作用机制。【方法】将24只接种Lewis肺癌瘤株的C57BL/6小鼠随机分为肺癌模型组、化疗组、榄香烯乳组、榄香烯乳联合化疗组,每组6只。接种后第11天开始给药治疗,化疗组给予小鼠腹腔注射足叶乙甙(3 mg·kg^(-1)·d^(-1))、顺铂(3 mg·kg^(-1)·d^(-1)),榄香烯乳组给予小鼠腹腔注射榄香烯乳(100 mg·kg^(-1)·d^(-1)),榄香烯乳联合化疗组小鼠腹腔注给予射榄香烯乳(100 mg·kg^(-1)·d^(-1))、足叶乙甙(3 mg·kg^(-1)·d^(-1))、顺铂(3 mg·kg^(-1)·d^(-1))。连续给药7 d后,观察各组小鼠瘤体质量,脾脏、胸腺指数变化,计算抑瘤率及抑制转移率,采用酶联免疫吸附(ELISA)法检测瘤组织中S100A4蛋白和基质金属蛋白酶-9(MMP-9)含量,采用免疫组化法检测瘤组织中S100A4和MMP-9蛋白表达。【结果】与化疗组比较,榄香烯乳联合化疗组抑瘤率及抑制转移率均明显升高,肺癌小鼠脾脏指数、胸腺指数显著增加,瘤组织中S100A4和MMP-9含量明显降低,S100A4和MMP-9蛋白阳性表达率降低明显(P<0.05或P<0.01)。【结论】榄香烯乳联合化疗可抑制小鼠Lewis肺癌的生长转移,其机制可能与降低癌组织中S100A4、MMP-9蛋白的表达有关。

美洲大蠊Per a 9的抗原表位特征及三维结构建模

Per a 9是美洲大蠊主要过敏原蛋白之一。通过生物信息学方法了解美洲大蠊过敏原蛋白Per a 9的结构特征,为蟑螂变态反应性疾病的诊断和治疗提供线索。BLAST得到Per a 9相似序列,构建同源进化树,结果显示美洲大蠊Per a 9与德国小蠊精氨酸激酶在进化上具有较近的亲缘关系。Per a 9主要为α+β结构的亲水性蛋白,其主要抗原表位集中于33—46、55—74、89—117、123—135、199—217、235—243、251—266、286—354区域。Motif预测其具有1个鸟嘌呤磷酸转移酶活性位点,6个蛋白激酶C磷酸化位点,7个酪氨酸激酶II磷酸化位点和2个N豆蔻酰化位点。其预测的三维结构基本能反应Per a 9真实的空间构象,这将为今后进一步了解和掌握Per a 9结构和功能的关系打下理论基础。