ALBERT

Description: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little of mutational spectrum in the Chinese population. Thus, here we report the identification of somatic mutations for Chinese PTC using 402 tumor-normal pairs (Discovery: 91 pairs via exome sequencing; validation: 311 pairs via Sanger sequencing). We observed three distinct mutational signatures, evidently different from the two mutational signatures among Caucasian PTCs. Ten significantly mutated genes were identified, most previously uncharacterized. Notably, we found that long non-coding RNA (lncRNA) GAS8-AS1 is the secondary most frequently altered gene and acts as a novel tumor suppressor in PTC. As a mutation hotspot, the c.713A〉G/714T〉C dinucleotide substitution was found among 89.1% patients with GAS8-AS1 mutations and associated with advanced PTC disease ( P = 0.009). Interestingly, the wild-type lncRNA GAS8-AS1 (A 713 T 714 ) showed consistently higher capability to inhibit cancer cell growth compared to the mutated lncRNA (G 713 C 714 ). Further studies also elucidated the oncogene nature of the G protein-coupled receptor LPAR4 and its c.872T〉G (p.Ile291Ser) mutation in PTC malignant transformation. The BRAF c.1799T〉A (p.Val600Glu) substitution was present in 59.0% Chinese PTCs, more frequently observed in patients with lymph node metastasis ( P = 1.6 x 10 –4 ). Together our study defines a exome mutational spectrum of PTC in the Chinese population and highlights lncRNA GAS8-AS1 and LPAR4 as potential diagnostics and therapeutic targets.

Description: Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF below 0.5%) variants. Here, we performed a 3-stage exome-wide association study in Han Chinese men to evaluate the role of low-frequency or rare germline variants in NOA development. The discovery stage included 962 NOA cases and 1348 healthy male controls genotyped by exome chips and was followed by a 2-stage replication with an additional 2168 cases and 5248 controls. We identified three low-frequency variants located at 6p22.2 (rs2298090 in HIST1H1E encoding p.Lys152Arg: OR = 0.30, P = 2.40 x 10 –16 ) and 6p21.33 (rs200847762 in FKBPL encoding p.Pro137Leu: OR = 0.11, P = 3.77 x 10 –16 ; rs11754464 in MSH5 : OR = 1.78, P = 3.71 x 10 –7 ) associated with NOA risk after Bonferroni correction. In summary, we report an instance of newly identified signals for NOA risk in genes previously undetected through GWAS on 6p22.2–6p21.33 in a Chinese population and highlight the role of low-frequency variants with a large effect in the process of spermatogenesis.

Description: P24 antigen is the main structural protein of HIV-1, its detection provide a means to aid the early diagnosis of HIV-1 infection. The aim of this study was to improve the selectivity and sensitivity of the HIV P24 diagnostic assay by developing a cohort of 9E8 affinity-matured antibodies through in vitro phage affinity maturation which was performed by complementarity determining region (CDR)-hot spot mutagenesis strategy. Antibody 9E8-491 had an affinity constant of 5.64 x 10 –11 M, which was 5.7-fold higher than that of the parent antibody (9E8). Furthermore, the affinity, sensitivity and specificity of 9E8-491 were higher than those of 9E8, which indicate that 9E8-491 is a good candidate detection antibody for HIV P24 assay. Structure analysis of matured variants revealed that most hydrogen bonds resided in HCDR3. Among the antibody–antigen predicted binding residues, Tyr 100A/100B was the original conserved residue that was commonly present in HCDR3 of 9E8 and variants. Arg 100 /Asp 100C was the major variant substitution that most likely influenced the binding differences among variants and 9E8 monoclonal antibody. Both efficient library panning and predicted structural data were in agreement that the binding residues were mostly located in HCDR3 and enabled identification of key residues that influence antibody affinity.

Description: Data on biological mechanisms of aging are mostly obtained from cross-sectional study designs. An inherent disadvantage of this design is that inter-individual differences can mask small but biologically significant age-dependent changes. A serially sampled design (same individual at different time points) would overcome this problem but is often limited by the relatively small numbers of available paired samples and the statistics being used. To overcome these limitations, we have developed a new vector-based approach, termed three-component analysis, which incorporates temporal distance, signal intensity and variance into one single score for gene ranking and is combined with gene set enrichment analysis. We tested our method on a unique age-based sample set of human skin fibroblasts and combined genome-wide transcription, DNA methylation and histone methylation (H3K4me3 and H3K27me3) data. Importantly, our method can now for the first time demonstrate a clear age-dependent decrease in expression of genes coding for proteins involved in translation and ribosome function. Using analogies with data from lower organisms, we propose a model where age-dependent down-regulation of protein translation-related components contributes to extend human lifespan.

Description: In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs)...

Description: Bellamya aeruginosa is a widely distributed Chinese freshwater snail that is heavily harvested, and its natural habitats are under severe threat due to fragmentation and loss. We were interested whether the large geographic distances between populations and habitat fragmentation have led to population differentiation and reduced genetic diversity in the species. To estimate the genetic diversity and population structure of B. aeruginosa , 277 individuals from 12 populations throughout its distribution range across China were sampled: two populations were sampled from the Yellow River system, eight populations from the Yangtze River system, and two populations from isolated plateau lakes. We used seven microsatellite loci and mitochondrial cytochrome oxidase I sequences to estimate population genetic parameters and test for demographic fluctuations. Our results showed that (1) the genetic diversity of B. aeruginosa was high for both markers in most of the studied populations and effective population sizes appear to be large, (2) only very low and mostly nonsignificant levels of genetic differentiation existed among the 12 populations, gene flow was generally high, and (3) relatively weak geographic structure was detected despite large geographic distances between populations. Further, no isolation by linear or stream distance was found among populations within the Yangtze River system and no signs of population bottlenecks were detected. Gene flow occurred even between far distant populations, possibly as a result of passive dispersal during flooding events, zoochoric dispersal, and/or anthropogenic translocations explaining the lack of stronger differentiation across large geographic distances. The high genetic diversity of B. aeruginosa and the weak population differentiation are likely the results of strong gene flow facilitated by passive dispersal and large population sizes suggesting that the species currently is not of conservation concern. High levels of intra-population genetic diversity and low inter-population differentiation was found in Bellamya aeruginosa in China. Population sizes were intermediate to large and levels of gene flow were high suggesting that both gene flow and population size help to maintain high genetic variation. Gene flow occurred even between far distant populations, likely as a result of passive dispersal during flooding events, zoochoric dispersal and possibly anthropogenic translocations.

Description: The present study was conducted to determine the 24, 48, 72, and 96-h median lethal concentration (LC50) of acephate and investigate the antioxidant response and acetylcholinesterase (AChE) activities in liver, gill, and spleen of Synechogobius hasta exposed to 0 (control), 5, and 10 mg/L acephate, at the fixed interval time of 24, 48, 72, and 96 h, respectively. LC50 value was 60.83 mg/L at 24 h, 51.36 mg/L at 48 h, 47.07 mg/L at 72 h and 40.13 mg/L at 96 h, respectively. Dismutase (SOD), catalase (CAT), AChE activities, and malondialdehyde (MDA) levels in these tissues for the control remained stable over the exposure period. However, for the two tested groups, tissue-, dose-, and time-dependent responses of these parameters were observed in S. hasta . In general, hepatic SOD and CAT activities were significantly inhibited at 24 h, activated, and increased at 48 h, but again inhibited from 48 to 96 h in fish exposed to the two tested concentrations. Hepatic MDA levels of fish for the two tested concentration peaked at 48 h, significantly higher than the control. Hepatic AChE activity was inhibited at 24 h, peaked at 48 h, and then declined at 72 h for the two tested groups. For gills, the highest SOD and CAT activities for the two tested groups were observed at 48 h, higher than the control. AChE activities for the two tested groups were significantly inhibited at 24 h, but activated at 48 h. At 96 h, AChE activities among the treatments showed no significant differences. Gill MDA levels at 48 h for the tested groups were significantly higher than the control, but showed no significant differences at 24 and 72 h among the treatments. In spleen, SOD and CAT activities at 48 h for the two tested groups were significantly higher than those in the control, but at 96 h the vice versa was true. Spleenic AChE activities and MDA levels for the two tested groups were inhibited at 24 h, activated at 48 h, and then were again inhibited at 72 h. Based on these observations earlier, the results obtained in our study will have important toxicological implications for waterborne acephate pollution and, meantime, provide the basis for the effective risk assessment of acephate in water environment and appropriate safety recommendations for fish. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2011.

Description: We study the thermal and compositional structure of South China by jointly inverting Rayleigh wave dispersion data, geoid height, topography and surface heat flow with a probabilistic (Bayesian) Monte Carlo method. We find that the lithosphere is thin (85-150 km) beneath the South China Fold system and thickens over the Yangtze Craton to maximum thicknesses of up to 250 km beneath the Sichuan Basin. Our inversion predicts that the lithospheric mantle beneath the South China Fold system and Yangtze Craton is highly fertile (Mg# ~88-90), in agreement with independent geochemical signatures from East China mantle xenoliths. Such fertile compositions, together with the relatively thin lithospheric thickness in the area, point towards a widespread metasomatism/refertilization event. We suggest, as others have, that a flat-subduction episode and subsequent slab removal may have triggered both the delamination of the lowermost part of the subcontinental lithosphere and the generation of asthenospheric melts that metasomatized (refertilized) the remaining lithospheric mantle. Inconsistencies among geophysical observations and anomalously fertile compositions for the Sichuan Basin indicate that this region may be currently affected by small-scale convection or delamination processes. Alternatively, the anomalous observations may be associated with an eastward push of Tibetan lithosphere beneath the Yangtze Craton.

Description: With genome sequence and composition highly analogous to human, rhesus macaque represents a unique reference for evolutionary studies of human biology. Here, we developed a comprehensive genomic framework of rhesus macaque, the RhesusBase2, for evolutionary interrogation of human genes and the associated regulations. A total of 1,667 next-generation sequencing (NGS) data sets were processed, integrated, and evaluated, generating 51.2 million new functional annotation records. With extensive NGS annotations, RhesusBase2 refined the fine-scale structures in 30% of the macaque Ensembl transcripts, reporting an accurate, up-to-date set of macaque gene models. On the basis of these annotations and accurate macaque gene models, we further developed an NGS-oriented Molecular Evolution Gateway to access and visualize macaque annotations in reference to human orthologous genes and associated regulations ( www.rhesusbase.org/molEvo ). We highlighted the application of this well-annotated genomic framework in generating hypothetical link of human-biased regulations to human-specific traits, by using mechanistic characterization of the DIEXF gene as an example that provides novel clues to the understanding of digestive system reduction in human evolution. On a global scale, we also identified a catalog of 9,295 human-biased regulatory events, which may represent novel elements that have a substantial impact on shaping human transcriptome and possibly underpin recent human phenotypic evolution. Taken together, we provide an NGS data-driven, information-rich framework that will broadly benefit genomics research in general and serves as an important resource for in-depth evolutionary studies of human biology.

Description: Author(s): B. F. Miao, L. Sun, Y. W. Wu, X. D. Tao, X. Xiong, Y. Wen, R. X. Cao, P. Wang, D. Wu, Q. F. Zhan, B. You, J. Du, R. W. Li, and H. F. Ding We report the creation of an artificial skyrmion crystal, which is configurable reliably at room temperature. The samples are fabricated by embedding lithography-patterned arrays of micron-sized Co disks onto Co/Pt multilayer films that have perpendicular magnetic anisotropy. Kerr microscopy and mag... [Phys. Rev. B 90, 174411] Published Tue Nov 11, 2014