256色鼠标事件管理程序的编制

介绍２５６色图形方式下鼠标事件管理程序编制的基本思想，并给出了主要函数的源程序。     

The Primary Role of Apurinic Sites in Tumor Initiation

The profiles of DNA adducts determined for benzo[a]pyrene (BP), 7,12-dimethylbenz[a]anthracene (DMBA) and dibenzo[a,l]pyrene (DB[a,l]P) reveal that a majority of adducts are released from DNA by depurination. Papillomas were induced in mouse skin by several PAH, and mutations in the c-Harvey-ras oncogene were determined to investigate the relationship between DNA adducts and ras oncogene mutations. The pattern of mutations induced by each PAH correlated with the profile of depurinating adducts. DB[a,l]P and DMBA formed predominantly depurinating adenine adducts (78% and 79%, respectively) and consistently induced a CAA → CTA transversion in codon 61 of ras. In contrast, BP produced both guanine (46%) and adenine (25%) depurinating adducts and induced a GGC → GTC mutation in codon 13 of c-H-ras in 54% of tumors and a CAA → CTA mutation in codon 61 in 15% of tumors. These results support the hypothesis that mis-replication of unrepaired apurinic sites generated by loss of PAH-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.     

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.     

Interaction of Cucurbit[7]uril with Oxime K027, Atropine,and Paraoxon: Risky or Advantageous Delivery System?

Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood–brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC—pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.     

Advances in Transgenic Mouse Models to Study Infections by Human Pathogenic Viruses

Medical research is changing into direction of precision therapy, thus, sophisticated preclinical models are urgently needed. In human pathogenic virus research, the major technical hurdle is not only to translate discoveries from animals to treatments of humans, but also to overcome the problem of interspecies differences with regard to productive infections and comparable disease development. Transgenic mice provide a basis for research of disease pathogenesis after infection with human-specific viruses. Today, humanized mice can be found at the very heart of this forefront of medical research allowing for recapitulation of disease pathogenesis and drug mechanisms in humans. This review discusses progress in the development and use of transgenic mice for the study of virus-induced human diseases towards identification of new drug innovations to treat and control human pathogenic infectious diseases.     

二氢杨梅素防治磨损颗粒诱导的小鼠颅骨骨溶解的实验研究

目的: 探讨二氢杨梅素（DMY）对磨损颗粒诱导的小鼠颅骨骨溶解的作用。方法: 选用30只8周龄雄性C57BL/J6小鼠,随机分成3组,每组10只。分别为假手术组（Sham）、阳性对照组（Control）和二氢杨梅素组（DMY）。假手术组手术不加钛颗粒,阳性对照组和DMY组手术时颅骨部位注入30 mg钛颗粒构建小鼠颅骨骨溶解模型。术后DMY组每天连续予500 mg/kg DMY灌胃;假手术组和阳性对照组给予相应体积的生理盐水灌胃。14 d后取眼眶静脉血,随后处死所有实验动物并收集颅骨标本。所有标本行Micro-CT扫描、采集计算机3D重建图像并进行定量分析,随后标本脱钙后以石蜡包埋,进行病理学分析。 结果: Micro-CT扫描3D重建图像显示DMY组小鼠颅骨表面骨溶解严重程度显著低于阳性对照组;Micro-CT扫描显示DMY组小鼠颅骨骨密度明显高于阳性对照组（P<0.05）。HE染色及TRAP染色分析显示,与阳性对照组相比,DMY组小鼠颅骨骨溶解区域破骨细胞数明显减少。DMY组小鼠血清IL-1β、TNF-α、NF-κB受体激活剂配体（RANKL）水平显著低于阳性对照组（P<0.05）;骨保护素（OPG）水平显著高于阳性对照组（P<0.05）。体外细胞培养实验显示,DMY可在体外显著抑制RANKL诱导的破骨细胞分化。结论: DMY可有效抑制磨损颗粒诱导的小鼠颅骨骨溶解。     

固定化转小鼠金属硫蛋白-Ⅰ基因聚球藻去除重金属的研究

利用海藻酸钠/CaCl2凝胶包埋法固定转小鼠金属硫蛋白-Ⅰ(mMT-Ⅰ)基因聚球藻7002及其野生宿主藻,就固定化藻的生长、对重金属的耐受性及其去除重金属的性能进行了初步研究。结果表明,固定化藻细胞比游离藻细胞生长较慢,培养周期较长,且最大细胞浓度偏低,但固定化可有效提高藻细胞对重金属的耐受性。固定化转mMT-Ⅰ聚球藻对Pb,Cd和Hg的耐受系数(以每单位的细胞吸光值OD750计)分别为6.077,0.610,1.093 mmol/L,而固定化野生聚球藻对于Pb,Cd和Hg的耐受系数分别为1.981,0.170,0.091 mmol/L;固定化转mMT-I聚球藻对重金属的去除效能明显优于游离藻:经3 d的处理,固定化转MT藻对Pb,Cd,Hg的去除率分别为88.09%,81.23%,91.45%,而固定化野生藻在相同的条件下则分别为77.3%,73.47%,85.44%。     

Patterns of deposition of urine containing chemosignals that affect puberty and reproduction by wild stock male and female house mice (Mus domesticus)

House mice release chemosignals in their urine that influence the timing of puberty and reproductive condition in conspecific females. These experiments tested the possibility that mice depositing urine containing chemosignals that affect puberty and reproduction do so differentially with respect to urine cues from conspecifics. Mice were tested in cages containing samples of urine or water on cotton in wire mesh capsules protruding from the cage floor. Their urine deposition patterns were recorded on squares of filter paper positioned below the cages. Males deposited more urine than females housed in groups, estrous females, diestrous females, or prepubertal females. All groups of mice deposited urine in a nonrandom fashion with regard to urine cues from conspecifics. Male mice deposited more urine near locations previously soiled by females than near water or other males. Grouped females deposited more urine near male urine cues and avoided depositing urine near urine from other group-housed females. Both estrous and diestrous female mice deposited more urine near males than near other urine cues or water, possibly to attract mates. Prepubertal females avoided depositing their urine near male urine and urinated more near urine from grouped females than near other urine types or water. Young females may be avoiding possible male mates until they have attained puberty. This avoidance behavior may enhance the long-term reproductive success of the females that otherwise might mature and mate at too young an age.     

乙型肝炎表面抗原联合rmIL-12诱导的小鼠细胞免疫应答

目的探讨乙型肝炎表面抗原(HBsAg)联合重组鼠白介素-12(rmIL-12)对免疫小鼠诱导细胞免疫应答的影响。方法以不同给药方式、不同剂量的HBsAg联合rmIL-12免疫C57BL/6J小鼠,ELISA法检测小鼠血清及脾淋巴细胞中IFNγ及IL-4的水平。结果HBsAg+rmIL-12高剂量组免疫的C57BL/6J小鼠,其脾淋巴细胞IFNγ水平明显高于BALB/c小鼠;3种不同给药方式均可诱导C57BL/6J小鼠血清和脾细胞IFNγ水平明显升高,三者之间差异无统计学意义;HBsAg+rmIL-12高、中、低剂量组免疫C57BL/6J小鼠血清可诱导IFNγ水平明显升高,且呈剂量依赖性,脾细胞IFNγ水平在中、低剂量组均未产生效应,高剂量组明显升高,而对IL-4无明显影响。结论rmIL-12可显著增强HBsAg诱导的细胞免疫应答,并使免疫应答转向Th1型,对于发展治疗性乙肝疫苗具有潜在的应用价值。     

Human CD22-Transgenic,Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments

Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a myc-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22⁺ lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22⁺ lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22⁺ lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.