免疫细胞浸润在非小细胞肺癌诊断与预后中的应用

免疫细胞浸润对癌症的诊断与预后有着重要意义。文中收集TCGA数据库已收录的非小细胞肺癌肿瘤与正常组织基因表达数据,利用CIBERSORT工具得到22种免疫细胞占比来评估免疫细胞浸润情况。以22种免疫细胞占比为特征,用机器学习方法构建了非小细胞肺癌肿瘤与正常组织的分类模型,其中随机森林方法构建的模型分类效果AUC=0.987、敏感性0.98及特异性0.84。并且用随机森林方法构建的肺腺癌和肺鳞癌肿瘤组织分类模型效果AUC=0.827、敏感性0.75及特异性0.77。用LASSO回归筛选22种免疫细胞特征,保留8种强相关特征组成的免疫细胞评分结合临床特征构建了非小细胞肺癌预后模型。经评估及验证,预后模型C-index=0.71并且3年和5年的校准曲线拟合良好,可以对预后风险度进行准确预测。本研究基于免疫细胞浸润所构建的分类模型与预后模型,旨在对非小细胞肺癌的诊断与预后研究提供新的策略。     

“A cleaner break”: Genetic divergence between geographic groups and sympatric phenotypes revealed in ballan wrasse (Labrus bergylta)

Capture and long‐distance translocation of cleaner fish to control lice infestations on marine salmonid farms has the potential to influence wild populations via overexploitation in source regions, and introgression in recipient regions. Knowledge of population genetic structure is therefore required. We studied the genetic structure of ballan wrasse, a phenotypically diverse and extensively used cleaner fish, from 18 locations in Norway and Sweden, and from Galicia, Spain, using 82 SNP markers. We detected two very distinct genetic groups in Scandinavia, northwestern and southeastern. These groups were split by a stretch of sandy beaches in southwest Norway, representing a habitat discontinuity for this rocky shore associated benthic egg‐laying species. Wrasse from Galicia were highly differentiated from all Scandinavian locations, but more similar to northwestern than southeastern locations. Distinct genetic differences were observed between sympatric spotty and plain phenotypes in Galicia, but not in Scandinavia. The mechanisms underlying the geographic patterns between phenotypes are discussed, but not identified. We conclude that extensive aquaculture‐mediated translocation of ballan wrasse from Sweden and southern Norway to western and middle Norway has the potential to mix genetically distinct populations. These results question the sustainability of the current cleaner fish practice.     

Screening of plant extracts for organic management of downy mildew of sorghum

Antipathogenic potential of 38 plants was evaluated in the form of aqueous extracts against Peronoclerospora sorghi, causing downy mildew of sorghum. Conidial suspension and plant extracts were mixed individually and allowed to stand for 5 min and then used to inoculate the host by sprout-dip method. The sprouts thus inoculated were grown in pots, and the disease incidence was observed. Eight plant extracts (Cicer areatinum, Datura metel, Croton sparsiflorus, Parthenium hysterophorus, Nerium oleander, Chromolaena odorata, Duranta repens and Oxalis latifolia) at 20% concentration performed at par with chemical fungicide (Mancozeb 75%) by exhibiting total suppression of disease incidence to 0%, when compared with 64.1% of negative control. Organic management of air-borne inoculum of downy mildew of sorghum is feasible and preferable when compared with chemical control methods, considering human and environmental health concerns. The use of water extract keeps the technology simple so that it can be directly prepared and used by the farmers. Short-listing of eight most effective water extracts would help in self-reliance of farmers, reducing their dependence on commercial products.     

Stream hierarchy defines riverscape genetics of a North American desert fish

Global climate change is apparent within the Arctic and the south‐western deserts of North America, with record drought in the latter reflected within 640 000 km² of the Colorado River Basin. To discern the manner by which natural and anthropogenic drivers have compressed Basin‐wide fish biodiversity, and to establish a baseline for future climate effects, the Stream Hierarchy Model (SHM) was employed to juxtapose fluvial topography against molecular diversities of 1092 Bluehead Sucker (Catostomus discobolus). MtDNA revealed three geomorphically defined evolutionarily significant units (ESUs): Bonneville Basin, upper Little Colorado River and the remaining Colorado River Basin. Microsatellite analyses (16 loci) reinforced distinctiveness of the Bonneville Basin and upper Little Colorado River, but subdivided the Colorado River Basin into seven management units (MUs). One represents a cline of three admixed gene pools comprising the mainstem and its lower‐gradient tributaries. Six others are not only distinct genetically but also demographically (i.e. migrants/generation <9.7%). Two of these (i.e. Grand Canyon and Canyon de Chelly) are defined by geomorphology, two others (i.e. Fremont‐Muddy and San Raphael rivers) are isolated by sharp declivities as they drop precipitously from the west slope into the mainstem Colorado/Green rivers, another represents an isolated impoundment (i.e. Ringdahl Reservoir), while the last corresponds to a recognized subspecies (i.e. Zuni River, NM). Historical legacies of endemic fishes (ESUs) and their evolutionary potential (MUs) are clearly represented in our data, yet their arbiter will be the unrelenting natural and anthropogenic water depletions that will precipitate yet another conservation conflict within this unique but arid region.     

Analysis of mitochondrial COI sequences of the Diachasmimorpha longicaudata (Hymenoptera: Braconidae) species complex in Thailand

Diachasmimorpha longicaudata is an Opiinae parasitoid used to control tephritid fruit flies, which cause tremendous economic losses of fruits worldwide. In Thailand, D. longicaudata is classified as three sibling species, DLA, DLB and DLBB, based on the morphological and biological species concepts but their genetic variation has not been studied. Therefore, we investigated the genetic differentiation of the mitochondrial COI gene to clarify the ambiguous taxonomy of this species complex. The 603‐bp COI region was sequenced from laboratory‐bred colonies and field‐collected specimens from seven locations representing five geographical regions in Thailand. DLA was associated with the host Bactrocera correcta while DLB and DLBB were associated with Bactrocera dorsalis. The interspecific nucleotide differences of COI sequences among the three groups ranged from 6.70% to 7.62% (Kimura 2‐parameter distance), which adequately separates species complexes within the order Hymenoptera and supports the current sibling species classification. The neighbor joining, maximum likelihood and consensus Bayesian phylogenetic trees constructed from COI sequences revealed that the three sibling species of laboratory and field‐collected D. longicaudata are monophyletic with 100% support. The high genetic variation and molecular phylogeny of the COI sequences were shown to discriminate between the D. longicaudata species examined in this study.     

Significance of new records of Tridacna squamosa Lamarck, 1819, in the Tuamotu and Gambier Archipelagos (French Polynesia)

The giant clam subfamily Tridacninae (family Cardiidae) is an important group of bivalve molluscs found throughout the Red Sea and Indo-Pacific, from East Africa to the Eastern Pacific biogeographic region. The Tridacna genus is currently revised with numerous cryptic species identified with molecular markers. New Tridacna records from the fringe of the known distribution areas are extremely useful to identify genetically unique species, geographic ranges, and to examine processes associated with species differentiation. While Tridacna maxima is abundant in French Polynesia (Central South Pacific Ocean) the larger fluted giant clam Tridacna squamosa was formerly reported only in the Austral Islands in the south. Following a recent survey that spanned 23 islands and atolls of the Society, Tuamotu and Gambier Archipelagos, the presence of T. squamosa between the Cook Islands and Pitcairn Islands is confirmed using both morphological and molecular information, suggesting a relic distribution across the Central Pacific Ocean. Tridacna squamosa is rare, but present throughout Tuamotu and Gambier. However, it remained undetected from the Society Islands, probably due to historical over-fishing. This species is valued by local inhabitants, and is sought after mainly as gifts and also for a limited local shell trade. The rarity of T. squamosa may call for conservation measures in the near future.     

Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques

Abstract

The drug design and discovery of lipid modulators is very demanding as no new molecule has entered into the market in the last 35 years. Cholesteryl ester transfer protein (CETP) is a promising target as lipid modulators. Inhibition of the CETP enzyme reduces the risk of cardiovascular events. The first CETP inhibitor torcetrapib and related drug candidates failed in the clinical trial due to the off-target effects leading to high toxicity. Thus, newer CETP inhibitors have now paramount importance to accelerate the drug discovery efforts in the field of cardiovascular disease (CVD). In the present study, 140 benzoxazole compounds were studied by using different chemometric techniques, for example, pharmacophore mapping, molecular docking, three-dimensional quantitative structure–activity relationship comparative molecular field analysis (3D-QSAR CoMFA), topomer CoMFA and Bayesian classification, in order to generate complete and reliable information regarding the structural requirements for the CETP inhibition. The best pharmacophore hypothesis was statistically significant (regression coefficient of 0.957 and a lower root mean square of 0.890). Molecular docking study revealed that cyano-substituted compounds form hydrogen bond with targeted macromolecule. The 3D-QSAR CoMFA model also produced a leave-one-out (LOO) cross-validated Q² of 0.527, an R² of 0.853 and an R²_Pred of 0.603. Similarly, two topomer CoMFA models were also statistically significant and reliable in terms of their Q², R² and R²_Pred values. The Bayesian classification study also provided the excellent ROC values of 0.919 and 0.939 for training and test sets, respectively. Overall, this study may help in the rational design of newer benzoxazole type compounds with higher CETP inhibition.

Communicated by Ramaswamy H. Sarma