Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents

Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.     

Susceptibility of cells with different stage of malignancy to cytostatic action of resident peritoneal macrophages of Syrian hamsters

Syrian hamster non-activated resident peritoneal cells (PC) and peritoneal macrophages (Mph) was demonstrated. The in vivo selection of highly tumourigenic and highly metastatic variants of this strain correlated with their resistance to CSA PC and Mph in four cell variants out of five examined. The highly tumourigenic Syrian hamster embryo cells in vitro transformed by Rous sarcoma virus were highly resistant to CSA PC without selection in vivo. The resistance of highly malignant cells to CSA PC appeared to be unrelated to their ability to produce immunosuppressing prostaglandins of E type.     

Glaucoma-Induced Optic Disc Morphometric Changes and Glaucoma Diagnostic Ability of Heidelberg Retina Tomograph II in Highly Myopic Eyes

Purpose

This study was performed to first investigate the morphological differences in the optic nerve head between highly myopic non-glaucomatous controls and highly myopic glaucomatous eyes in comparison with the differences between emmetropic non-glaucomatous controls and emmetropic glaucomatous eyes using confocal scanning laser ophthalmoscopy. Further, the ability of the apparatus in glaucoma diagnosis in highly myopic eyes was compared with that in emmetropic eyes.

Methods

Healthy subjects and age-matched patients with early-stage open-angle glaucoma were divided into two groups: emmetropic eyes (−1.0 to +1.0 diopters) and highly myopic eyes (−12.0 to −5.0 diopters).The participants were comprised of 65 emmetropic normal eyes, 59 emmetropic glaucomatous eyes, 62 highly myopic normal eyes, and 68 highly myopic glaucomatous eyes and eyes with pathologic myopia were carefully excluded. Confocal scanning laser tomographic parameters were compared among all subjects after adjustment for age and disc area. The ROC curves and sensitivity and specificity for glaucoma detection using several clinical methods were then compared between the emmetropic and highly myopic eyes.

Results

Rim area, cup/disc area ratio, mean cup depth, and cup shape measure of glaucoma eyes are significantly different from those of normal eyes in both highly myopic eyes and emmetropic eyes. Methodological overestimation of retinal nerve fiber layer cross sectional area due to optic disc tilting was suggested in the highly myopic eyes. The diagnostic performance of glaucoma using several discriminant methods significantly deteriorated in the highly myopic eyes.

Conclusions

In the highly myopic glaucomatous eyes, confocal scanning laser tomographic parameters were significantly different from that of non-glaucomatous highly myopic eyes but diagnostic performance of glaucoma was deteriorated than that in emmetropic eyes. These findings demonstrate the utility and limitations of the apparatus in diagnosing glaucoma in highly myopic patients.     

Morphological classification of pituitary adenomas and its value for clinical diagnosis]

Pituitary adenomas should be classified not only by their tinctorial affinities but also by their degree of differentiation. Then useful correlation to the clinical data can be obtained; On this principle our own collection of 299 tumors was classified in undifferentiated acidophilic, highly differentiated acidophilic GH cell-, highly differentiated acidophilic prolactin cell-adenomas, in undifferentiated mucoid cell-, highly differentiated mucoid ACTH cell-, highly differentiated mucoid TSH cell-adenomas, in chromophobic adenomas of small cell type and of large cell type, and in oncocytic adenomas. 95% of the cases with acromegaly based on undifferentiated acidophilic or highly differentiated GH cell adenomas. All patients with hypothalamic-hypophyseal Cushing's syndrome or Nelson's syndrome had undifferentiated mucoid cell adenomas or highly differentiated ACTH cell adenomas. In cases with hyperprolactinemia prolactin cell adenomas or chromophobic adenomas of large cell type with ultrastructurally demonstrated very highly developed rough endoplasmic reticulum or endocrinologically inactive chromophobic adenomas of small cell type were found. In the latter cases the prolactin is probably produced not by the tumor but by the surrounding tumor-free pituitary tissue.     

高致病性冠状病毒感染导致宿主免疫应答异常

近二十多年，全球范围内先后爆发了由严重急性呼吸综合征冠状病毒（severe acute respiratory syndrome coronavirus，SARS-CoV）、中东呼吸综合征冠状病毒（middle east respiratory syndrome coronavirus，MERS-CoV）和严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）3种高致病性冠状病毒导致的疫情。这3种高致病性冠状病毒感染通常伴随着免疫系统功能失调，临床表现有淋巴细胞减少症、细胞因子风暴、急性呼吸系统窘迫综合征，甚至多器官衰竭而导致死亡。揭示高致病性冠状病毒在免疫应答中的作用机制，对于预防与控制冠状病毒感染具有重要意义。本文总结了SARS-CoV、MRES-CoV和SARS-CoV-2的进入机制和受体特征、固有免疫应答和适应性免疫应答失调方面的研究进展，强调了高致病性冠状病毒与宿主免疫应答之间的复杂相互作用，以期为防治冠状病毒感染提供参考。     

高纯度大豆卵磷脂对中国仓鼠肺细胞染色体畸变作用

目的研究高纯度大豆卵磷脂对中国仓鼠肺细胞（cHL）染色体畸变作用。方法测定高纯度大豆卵磷脂对CHL细胞的半数抑制浓度（IC50）,根据IC50设立不同剂量组,进行正式试验,分别观察高纯度大豆卵磷脂接触CHL6h,24h及加S9后6h染色体的畸变情况,根据标准进行结果判定。结果染毒6h,24h及加S9后染毒6h染色体畸变为阴性。结论高纯度大豆卵磷脂不能引起CHL细胞染色体产生畸变作用。     

Patterns of leg muscle recruitment vary between novice and highly trained cyclists

This study compared patterns of leg muscle recruitment and coactivation, and the relationship between muscle recruitment, coactivation and cadence, in novice and highly trained cyclists. Electromyographic (EMG) activity of tibialis anterior (TA), tibialis posterior (TP), peroneus longus (PL), gastrocnemius lateralis (GL) and soleus (SOL) was recorded using intramuscular fine-wire electrodes. Four experimental conditions of varying cadence were investigated. Differences were evident between novice and highly trained cyclists in the recruitment of all muscles. Novice cyclists were characterized by greater individual variance, greater population variance, more extensive and more variable muscle coactivation, and greater EMG amplitude in periods between primary EMG bursts. Peak EMG amplitude increased linearly with cadence and was not different at individual preferred cadence in either novice or highly trained cyclists. However, EMG amplitude in periods between primary EMG bursts, as well as the duration of primary EMG bursts, increased with increasing cadence in novice cyclists but were not influenced by cadence in highly trained cyclists. Our findings suggest that muscle recruitment is highly skilled in highly trained cyclists and less refined in novice cyclists. More skilled muscle recruitment in highly trained cyclists is likely a result of neuromuscular adaptations due to repeated performance of the cycling movement in training and competition.     

Novel polymorphic microsatellite markers for the common pandora (Pagellus erythrinus)

Details of six highly polymorphic dinucleotide and one highly polymorphic tetranucleotide microsatellite markers are provided for Pagellus erythrinus. These markers are highly polymorphic, with an expected heterozygosity ranging from 0.713 to 0.959 and allele numbers ranging from seven to 36. These microsatellite markers should help determine population genetic structure and fisheries stocks for management purposes.     

Sequence organisation in nuclear DNA from Physarum polycephalum. Arrangement of highly-repeated sequences

Recombinant plasmids containing highly repetitive Physarum DNA segments were identified by colony hybridisation using a radioactively-labelled total Physarum DNA probe. A large number of these clones also hybridised to a foldback DNA probe purified from Physarum nuclear DNA. The foldback DNA probe was characterised by reassociation kinetic analysis. About one-half of this component was shown to consist of highly repeated sequences with a kinetic complexity of 1100 bp and an average repetition frequency of 5200. Direct screening of 67 recombinant plasmids for foldback sequences using the electron microscope revealed that about one-half were located in segments of DNA containing highly repetitive sequences; the remainder were present in clones containing low-copy number repeated elements. Analysis of two DNA clones showed that they contained repetitive elements located in over half of all DNA segments containing highly repetitive DNA and that the foci containing these highly repetitive sequences had different sequence arrangements. The results are consistent with the hypothesis that the most highly repeated DNA sequence families in the Physarum genome are few in number and are clustered together in different arrangements in about one-sixth of the genome. Over one-half of the foldback DNA complement in the Physarum genome is derived from these segments of DNA.     

刺猬高重复顺序DNA的分子克隆及核苷酸顺序分析

为了分析比较食虫目高重复顺序的结构特征,我们将食虫目动物刺猬的高重复顺序DNA进行了分离、纯化、分子克隆,并测出了1186bp的核苷酸顺序。经分析发现在碱基组成上它与食虫目另一动物臭鼩有许多相似之处,如:G-C碱基对与A-T碱基对在整个片段中分布很不均衡;片段内部含有许多连续多次重复的短片段等,很可能为食虫目动物所特有。     

Localization of breaks induced by vinyl chloride in the human chromosomes of lymphocytes

A group of 67 workers occupationally exposed to VCM was examined for the presence and distribution of breaks along the chromosomal length. Breaks induced by VCM are not randomly distributed as had been expected in a normal population. According to our results there exist highly sensitive and highly resistant locations along the chromosomes to the actions of VCM. The link between the highly sensitive segments of chromosomes, fragile sites and the activation of oncogenes is discussed.     

Immunogenicity of isocomponents of the alpha-toxoid of Cl. oedematiens for mice of opposite reacting genotypes]

There was revealed molecular heterogeneity of the highly purified Cl. oedematiens alpha-toxoid. By the method of isoelectrical focussing alpha-toxoid was divided into isocomponents with the isoelectrical points of 5.33 +/- 0.02 and 4.91 +/- 0.08 with an equal specific activity and serological specificity. In studying the immunogenicity of alpha-toxoid and its isocomponents in experiments on mice of oppositely reacting genotypes it was shown that for mice of the low reacting strain (DBA/2) the the alpha-toxoid isocomponents possessed a much greater immunogenicity than the highly purified alpha-toxoid; under the same conditions the immunogenicity of the alpha-toxoid isocomponents for mice of the highly reacting strain (CBA) failed to differ from the immunogenicity of the highly purified alpha-toxoid.     

Disorderness in Escherichia coli proteome: perception of folding fidelity and protein–protein interactions

Traditionally biased usage of synonymous codons renders selective advantage to proteins expressed at high levels with a few exceptions like in Escherichia coli. Proteome-wide characteristics indicative of trends in highly expressed proteins of E. coli is analyzed in this communication. Implications for the nature of interactions performed by these two groups of highly expressed proteins are discussed here. The group of highly expressed proteins having optimized codon usage through employment of most abundant tRNAs is already shielded from misfolding by their improved error-prone translational machinery. Our data also provide evidence for mechanism by which a significant proportion of highly expressed proteins with high intrinsic disorder evade degradation and successfully carry out their function.     

Hypersensitive response, cell death and histochemical localisation of hydrogen peroxide in host and non-host seedlings infected with the downy mildew pathogen Sclerospora graminicola

Hypersensitive response, cell death and release of hydrogen peroxide as measures of host and non‐host defense mechanisms upon inoculation with the downy mildew pathogen Sclerospora graminicola were studied histochemically at the light microscopy level. The materials consisted of coleoptile tissues of the highly susceptible (cv. HB3), highly resistant (cv. IP18293) and induced resistant pearl millet host seedlings and non‐host sorghum (cv. SGMN10/8) and cotyledon of french bean (cv. S9). Resistance up to 80% protection against the downy mildew pathogen was induced in the highly susceptible HB3 cultivar of pearl millet by treating the seeds with 2% aqueous leaf extract of Datura metel for 3 h. Time course study with the pathogen inoculated highly resistant pearl millet cultivar revealed the appearance of hypersensitive response in 20% of seedlings as necrotic spots as early as 2 h after inoculation. In contrast, a similar reaction was observed in the highly susceptible pearl millet cultivar only 8 h after inoculation with the pathogen. In induced resistant seedlings, appearance of hypersensitive response was recorded 4 h after inoculation. Delayed hypersensitive response was observed in both the non‐host species at 10 h after inoculation. Hypersensitive response in the seedlings of the highly resistant pearl millet cultivar 24 h after inoculation showed 100% hypersensitive response, which was not observed in susceptible and non‐host species, although the induced resistant seedlings showed 90% hypersensitive response after that period of time. Cell death in the tissues of the test seedlings was also observed to change with time. Statistical analysis revealed that the tissues of highly resistant pearl millet seedlings required 2.9 h to attain 50% cell death. Tissues of induced resistant and highly susceptible pearl millet seedlings required 4.65 and 6.50 h respectively. In non‐hosts, 50% cell death was not recorded. Quantification of hydrogen peroxide in the tissue periplasmic spaces of the test seedlings revealed 2.94 h as the time required for 50% hydrogen peroxide accumulation in the tissues of highly resistant pearl millet seedlings. Tissues of induced resistant and highly susceptible pearl millet seedlings needed 3.76 and 5.5 h respectively. Fifty percent hydrogen peroxide localisation in non‐hosts could not be recorded. These results suggested the involvement of hydrogen peroxide, cell death and hypersensitive response in pearl millet host defense against S. graminicola.     

Sequence organisation in nuclear DNA from Physarum polycephalum: Arrangement of highly-repeated sequences

Recombinant plasmids containing highly repetitive Physarum DNA segments were identified by colony hybridisation using a radioactively-labelled total Physarum DNA probe. A large number of these clones also hybridised to a foldback DNA probe purified from Physarum nuclear DNA. The foldback DNA probe was characterised by reassociation kinetic analysis. About one-half of this component was shown to consist of highly repeated sequences with a kinetic complexity of 1100 bp and an average repetition frequency of 5200. Direct screening of 67 recombinant plasmids for foldback sequences using the electron microscope revealed that about one-half were located in segments of DNA containing highly repetitive sequences; the remainder were present in clones containing low-copy number repeated elements. Analysis of two DNA clones showed that they contained repetitive elements located in over half of all DNA segments containing highly repetitive DNA and that the foci containing these highly repetitive sequences had different sequence arrangements. The results are consistent with the hypothesis that the most highly repeated DNA sequence families in the Physarum genome are few in number and are clustered together in different arrangements in about one-sixth of the genome. Over one-half of the foldback DNA complement in the Physarum genome is derived from these segments of DNA.     

Expression of l-phosphinothricin synthesis enzymes in Pichia pastoris for synthesis of l-phosphinothricin

Biotechnology Letters - With the ban of highly toxic herbicides, such as paraquat and glyphosate, phosphinothricin (PPT) is becoming the most popular broad-spectrum and highly effective herbicide....     

Self peptides bound by HLA class I molecules are derived from highly conserved regions of a set of evolutionarily conserved proteins

An evolutionary analysis of self peptides reported to be bound by HLA class I molecules showed that these peptides are largely derived from proteins that have been highly conserved in the history of mammals. These proteins also often have universal tissue expression and have a higher than average frequency of highly hydrophilic residues. The peptides themselves are generally still more highly conserved than the source proteins and have a higher frequency of highly hydrophobic residues, evidently often derived from conserved hydrophobic cores of the source proteins. These results suggest that the mechanism by which peptides are derived for MHC presentation may preferentially select peptides from conserved protein regions. In the case of parasite-derived peptides, such a mechanism would be adaptive in that it would reduce the likelihood of escape mutants.     

Newly evolved highly repeated DNA sequences ofTupaia glis (Tupaiidae,Scandentia)

We have studied highly repeated DNA sequences ofTupaia glis (Tupaiidae, Scandentia) with restriction endonucleases and Southern blotting techniques. Five highly repeated DNA fragments have been isolated fromT. glis and hybridized with genomic DNAs (cleaved by different restriction enzymes) of several non-human primate species and one insectivore (E. europaeus), in order to highlight eventual differences or similarities of their highly repeated DNA sequences. Our first preliminary findings suggest that the newly isolated highly repeated DNA fragments ofT. glis are distinct from both non-human primates and insectivore, the two taxonomic groups considered most similar to the Tupaiidae.