Immunogenomics Analysis Reveals that TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer

Although immunotherapy continues to demonstrate efficacy in a variety of refractory cancers, currently, no any immunotherapeutic strategy is clinically used for gastric cancer (GC) except its microsatellite instable subtype. Thus, it is important to identify molecular biomarkers for predicting the responders to GC immunotherapy. TP53 mutations frequently occur in GC and are associated with unfavorable clinical outcomes in GC. We performed a comprehensive characterization of the associations between TP53 mutations and immune activities in GC based on two large-scale GC cancer genomics data. We compared expression and enrichment levels of 787 immune-related genes and 23 immune gene-sets among TP53-mutated GCs, TP53‐wildtype GCs, and normal tissue, and explored the correlations between p53-mediated pathways and immune activities in GC. Strikingly, almost all analyzed immune gene-sets were significantly downregulated in enrichment levels in TP53-mutated GCs compared to TP53‐wildtype GCs. These less active immune pathways and cell types in TP53-mutated GCs included 15 immune cell types and function, tumor-infiltrating lymphocytes, regulatory T cells, immune checkpoint, cytokine and cytokine receptor, human leukocyte antigen, pro‐inflammatory, and parainflammation. Moreover, we identified a number of p53-mediated pathways and proteins that were significantly associated with immune activities in GC. Furthermore, we demonstrated that the TP53 mutation itself could result in the depressed immune activities in GC and other cancer types. We revealed that chromosomal instability was an important mechanism for the depressed tumor immunity in TP53-mutated cancers. Finally, we showed that immune cell infiltration and immune activities were likely positively associated with survival prognosis in GC. Our findings suggest that p53 may play an important role in activating tumor immunity in GC and other cancer types and that the TP53 mutation status could be useful in stratifying cancer patients responsive to a certain immunotherapy.     

嘧肽霉素影响烟草花叶病毒RNA蓄积量的研究

嘧肽霉素是新报道的由土壤中分离筛选出来的不吸水链霉菌辽宁变种(Streptomyces achygroscopicus var.liaoningensis)产生的,其有效成分是胞嘧啶核苷肽类化合物,已获得农药临时登记,该药剂对烟草花叶病毒(Tobacco mosaic virus,TMV)等多种病毒病害具有很好的防治效果。定量竞争PCR(Quantitative competitive PCR,QCPCR)是一种定量检测细胞因子较为精确的方法,其实质是待测核酸(DNA或RNA)与内参模板一起竞争参与PCR反应,并通过电泳将扩增产物在凝胶上明显的分开,从而进一步进行定性或定量分析。     

Lipase of Pseudomonas cepacia for biotechnological purposes: purification,crystallization and characterization

Commercial lipase (triacylglycerol lipase, EC 3.1.1.3) of Pseudomonas cepacia (Amano) has been purified to homogeneity by a single chromatography on phenyl Sepharose. The eluted lipase crystallized spontaneously at 4°C in the eluent, containing 58–69% 2-propanol. The yield of the lipase was 87–100% and the specific activity during the hydrolysis of triolein 5800 U/mg protein. This protein has a molecular weight of 34.1 kDa as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Its purity was determined by SDS-Page and capillary zone electrophoresis to be ≥ 99%. Immobilization on Sepharose increased its stability in organic solvents. This lipase of P. cepacia differs from that of other Pseudomonas strains in respect of substrate specificity and during crystallization. It exhibits a high stability in organic solvents and supercritical carbon dioxide.     

Cytology of ten species in Anemone,one in Anemoclema and six in Clematis (Trib. Anemoneae,Ranunculaceae) from China

The somatic chromosome number and detailed chromosome morphology have been studied in ten species of Anemone, one species of Anemoclema, and six species of Clematis, all from China, namely Anemone davidii Franch. (2n=4x= 32), A. stolonifera Maxim. (2n=2x=16), A. flaccida Fr. Schmidt (2n=2x= 14), A. rivularis Buch.-Ham. (2n=2x= 16), A. begoniifiolia lévl. et Vant. (2n=2x= 16), A. hupehensis Lem. f. alba W. T. Wang (2n =2x = 16), A. tomentosa (Maxim.) Péi (2n=2x= 16), A. rupestris Hook. f. et Thoms. (2n=2x= 14), A. trullifolia var. colestina (Franch.) Finet et Gagnep. (2n = 2x = 14), A. trullifolia var. holophylla Diels (2n=2x= 14), A. demissa Hook. f. et Thoms. (2n=2x= 14), Anemoclema glaucifolium (Franch.) W. T. Wang (2n= 2x= 16), Clematis kockiana Schneid. (2n= 2x=16), C. rehderiana Craib. (2n = 2x = 16), C. ranunculoides Franch. (2n = 2x = 16), C. puberula var. ganpiniana(Lévl. et Vant. ) W. T. Wang (2n = 2x = 16), C. brevicaudata DC. (2n= 2x= 16), C. chrysocoma Franch. (2n = 2x = 16). The species of x = 8 in Anemone, and those in Anemoclema and Clematis have very similar karyotypes which consist of five pairs of large median-centromeric (rarely one pair of which are submedian-centromeric) and three pairs of subterminalor terminal-centromeric chromosomes.     

国产毛茛科银莲花族十七种植物的细胞学研究

研究了国产毛茛科银莲花族Trib．Anemoneae 17种植物的染色体数目和核型。10种银莲花属 Anemone L．植物中,1种(西南银莲花A．davidii)为x=8的四倍体(2n=4x=32),5种(匍枝银莲花A． stolonifera、草玉梅 A．rivularis、卵叶银莲花A ．begoniifolia、水棉花A．hupehensis f. alba、大火草A．tomen- tosa)为x=8的二倍体(2n=2x=16),4种(鹅掌草A．flaccida、湿地银莲花A．rupestris、蓝匙叶银莲花 A．trullifolia var．colestina、拟条叶银莲花A．trullifolia var．holophylla、展毛银莲花A．demissa)为x=7的 二倍体(2n=2x=14)。罂粟莲花Anemoclema glaucifolium 为x=8的二倍体。6种铁线莲属Clematis L.植 物(滇川铁线莲C．kockiana、长花铁线莲C．rehderiana、毛茛铁线莲C．ranunculoides、扬子铁线莲C． puberula var．ganpiniana、短尾铁线莲C．brevicaudata、金毛铁线莲A．chrysocoma)均为x=8的二倍体。银 莲花属中x=7的种类的核型彼此十分相似,均由6对大型具中部着丝点的染色体和1对具端部着丝点 的染色体组成;x=8的二倍体种类的核型与罂粟莲花属和铁线莲属植物的核型十分相似,均由5对大型 具中部着丝点和3对具端部或近端部着丝点的染色体组成。     

Caspase-2 is required for skeletal muscle differentiation and myogenesis

Caspase activation plays a crucial role in skeletal muscle differentiation. We previously found that caspase-2 activity increases during skeletal muscle cell differentiation; however, its direct effect on differentiation has not been fully investigated. Here, we found that caspase-2 activity transiently increased more than two-fold within 24 h following induction of differentiation. Both pharmacological inhibition and shRNA-mediated knockdown of caspase-2 suppressed myogenic differentiation and dramatically impaired myotube formation. Furthermore, shRNA-mediated knockdown prevented induction of p21 and altered cell cycle profiles. Interestingly, caspase-3 activity was also dramatically reduced following caspase-2 inhibition or ablation. Moreover, caspase-2 and p21 were localized to the nucleus during early differentiation. Given the nuclear localization of caspase-2 and p21, as well as the impairment in p21 induction in caspase-2 knockdown cells, we propose that the role of caspase-2 is to regulate p21 induction at the onset of differentiation, which may regulate the myogenic program. Collectively, these results highlight a novel function for caspase-2 in myocyte differentiation and myogenesis.     

Synthesis and bioassay of isoprenoid 3-alkylthio-1,1,1-trifluoro-2-propanones: Potent,selective inhibitors of juvenile hormone esterase

Four 3-alkylthio-1,1,1-trifluoro-2-propanones with juvenile hormone-like side chains were prepared from citronellol and homogeraniol. These substrates were designed as possible transition-state analogs for the juvenile hormone (JH)-specific esterases present in insects. These four isoprenoid trifluoromethyl ketones were assayed in vitro with JH esterase and general esterases from larvae of the cabbage looper, Trichoplusia ni (Lepidoptera, Noctuidae), and with eel acetylcholinesterase and bovine chymotrypsin. JH esterase inhibition I₅₀ values were in the nanomolar range for all four compounds, while the other esterases had I₅₀'S which were 10³ to 10⁵ higher. The high selectivity of these inhibitors is believed to be due to their similarity in size and functionality to natural JH III. Treatment of T. ni larvae in vivo with solutions of the most active analog, 3-[(E)-4,8-dimethyl-3,7-nonadienylthio]-1,1,1-trifluoro-2-propanone (DNTFP) causes a dose-dependent delay in pupation and a concurrent selective inhibition of JH esterase. These data support the hypothesis that the reduction in in vivo JH titer in larval T. ni is due, in part, to hydrolysis of the hormone by selective esterases. DNTFP appears to be competing with JH for the active site of JH esterase.     

Modification of isolated α and β chains of human hemoglobin by the metal tetrasulfonated phthalocyanines. Studies on hybrid phthalocyanine-heme intermediates

α and β chains of hemoglobin have been modified with cobalt(II) tetrasulfonated phthalocyanine in place of heme. They display properties very similar to those of iron(II) phthalocyanine modified α and β chains. Mixed together they form tetrameric cobalt(II) phthalocyanine hemoglobin.Incorporation of Co(II)L into α and β globins results in stabilization of the protein structure, which is shown by a marked increase in its helicity content. Cobalt phthalocyanine substituted α and β chains are able to combine reversibly with oxygen giving more stable oxygenated species than their native analogues. The rate of both processes is lower in the case of the modified α chain. Recombination of the phthalocyanine α and β chains with the alternate heme containing chains give tetrameric hybrid hemoglobins. These comprise two phthalocyanine modified subunits and two heme containing subunits. The helicity content of the tetrameric hybrid hemoglobin calculated for one subunit is lower that the arithmetic mean of helicities for its isolated subunits. This suggests a destabilizing chain-chain interaction within the tetramer. Unlike in the separated subunits, oxygen binding by hybrid hemoglobins is irreversible. Deoxygenation by argon bubbling leads to the formation of inactive species which in oxygen atmosphere undergo irreversible oxidation with destruction of the complex.     

Antileishmanial evaluation of clubbed bis(indolyl)-pyridine derivatives: One-pot synthesis,in vitro biological evaluations and in silico ADME prediction

A new series of bis(indolyl)-pyridine derivatives 6(a–m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC₅₀ = 102.47 μM) and 6f (IC₅₀ = 99.49 μM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC₅₀ = 490.00 μM). All the synthesized compounds (MIC range = 41.35–228.69 μg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range = 100.00–250.00 μg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.     

Advances in the understanding of same-sex and opposite-sex sexual harassment

Sexual harassment has traditionally been studied as men's harassment of women. This has led to a lack of knowledge about same sex harassment, and women harassing peers. This has also downplayed the inherent sexual nature of sexual harassment acts. While keeping in mind that sexual harassment is undesirable and causes distress, one needs to consider that many acts that are perceived as unwanted may not primarily be motivated by a wish to derogate but rather by an interest in soliciting short-term sex. In the current study we examined both perpetrators as well as victims of harassment, and specified both sex of perpetrator and target (a total of eight sex constellations). We reproduced the previously found association between unrestricted sociosexuality and sexual harassment in a representative sample of 1326 high school students (57% women). In all regression models sociosexuality outcompeted traditional measures such as porn exposure, rape stereotypes and hostile sexism. Based on the original work we divided the harassment acts into two groups of tactics: sexual solicitation and competitor derogation. Men were particularly subject to derogatory tactics from other men, while women were particularly subject to solicitation from opposite sex peers. Sexual harassment may be understood better from a human sexual strategies perspective, including competitor derogation and mate solicitation. As such, sociosexual orientation predicts both same sex derogation and opposite sex solicitation. The current results highlight the importance of considering the sex of both perpetrator and target. This advanced understanding of the inherently sexual nature of sexual harassment needs to inform future prevention studies. Unrestricted sociosexuality predicts sexual harassment in all constellations better than traditional social science models.     

Interactions between prostasomes and leukocytes

Prostasomes are membranous vesicles (150–200 nm diameter) present in human semen. They are secreted by the prostate gland and contain large amounts of cholesterol, sphingomyelin and Ca²⁺. In addition, some of their proteins are enzymes. Prostasomes enhance the motility of ejaculated sperm and are involved in a number of biological functions. In a previous work, we found that prostasome can fuse to spermatozoa at slightly acidic pH values, as demonstrated by the transfer of the lipophilic octadecylrhodamine probe. In this paper, we study the interactions of two leukocyte populations (polymorphonuclear and mononuclear) with prostasomes and find a pH-dependent adhesion (revealed by microscopic observation), but no fusion. These phenomena may be relevant for the functions of leukocytes in human reproduction.     

Relationships between floristic gradients in a primary succession

Abstract. Correlations between five floristic gradients at small spatial extents (10 - 20 m) and one successional gradient over a larger spatial extent (1.5 km) are analysed. Floristic data (62 taxa) were sampled on five terminal moraines of known age deposited after the ‘Little Ice Age’ (1750–1930). The floristic gradients on the moraine ridges were sampled by two or three transects on each moraine, and the successional gradient by 114 plots on all moraines. The sequential orders of species were determined by constrained and unconstrained Correspondence Analysis. The similarities between species order on the successional gradient and the exposure gradients at the same age were tested against the null hypothesis of no correlation. The null hypothesis was rejected using both Monte Carlo permutation tests and Spearman's rank correlations, except on the oldest moraine. Here a closed canopy has developed, which eliminates the environmental variability associated with ridge morphology. The similarity between the successional gradient and the moraine-ridge gradients is attributed to variation in environmental severity, mainly caused by glacier wind and related factors such as temperature and moisture. Similarity was highest on the moraines in the middle of the glacier foreland, which have many successional stages present and have a relatively exposed relief. The distribution of growth/life-forms along gradients of small spatial extent are comparable to the successional gradient, but lichens, herbs and graminoids differ in their behaviour. The resemblance between species gradients at a small spatial extent and species gradients on a larger spatial extent is interpreted as an ecological self-similar pattern, where young and old substrate are linked to exposed-xeric and protected-mesic habitats, respectively.     

A new Ruscinian site in Europe: Baza-1 (Baza basin,Andalusia, Spain)

The Guadix–Baza depression (southeastern Spain) preserves one of the best continental Plio-Pleistocene records of the European continent. The new site, Baza-1, is the first Ruscinian locality with fauna of large vertebrates known in the basin. During the summer seasons of 2001, 2002, 2015 and 2016, systematic excavations were undertaken in the site over an area of 25 m², which provided > 400 fossil remains of Ruscinian mammals. The faunal assemblage is diverse, comprising 17 genera. Rodentia are represented by Ruscinomys sp., Apocricetus barrierei, Debruijnimys julii, Apodemus gorafensis, Castillomys gracilis, Occitanomys cf. brailloni, Paraethomys meini, Paraethomys aff. abaigari, Stephanomys cordii, Trilophomys cf. castroi and Eliomys aff. intermedius. Large mammals are represented by two proboscideans, Anancus arvernensis and Mammut borsoni, the rhino Stephanorhinus sp. cf. S. jeanvireti, the equid cf. Hipparion sp., two bovids, a large sized Alephis sp. and a small-to-middle sized Bovidae indet. (cf. Antilope sp.), and a middle sized deer, Cervinae indet. This record is completed by the presence of a chelonid, Testudinae indet. Biostratigraphic data from micro and macromammals suggest an age for the assemblage between 4 and 4.5 Ma.