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Chinese hamster ovary (CHO) cell lines are widely used in industry for biological drug production. During cell culture development, considerable effort is invested to understand the factors that greatly impact cell growth, specific productivity and product qualities of the biotherapeutics. While high-throughput omics approaches have been increasingly utilized to reveal cellular mechanisms associated with cell line phenotypes and guide process optimization, comprehensive omics data analysis and management have been a challenge. Here we developed CHOmics, a web-based tool for integrative analysis of CHO cell line omics data that provides an interactive visualization of omics analysis outputs and efficient data management. CHOmics has a built-in comprehensive pipeline for RNA sequencing data processing and multi-layer statistical modules to explore relevant genes or pathways. Moreover, advanced functionalities were provided to enable users to customize their analysis and visualize the output systematically and interactively. The tool was also designed with the flexibility to accommodate other types of omics data and thereby enabling multi-omics comparison and visualization at both gene and pathway levels. Collectively, CHOmics is an integrative platform for data analysis, visualization and management with expectations to promote the broader use of omics in CHO cell research. Author summary: Recombinant proteins have dominated recent blockbuster therapeutic drugs, accounting for 11 of the top 15 drugs by sales. Chinese hamster ovary (CHO) cells are the most widely used expression system for biomanufacturing of many of these biotherapies. Thus, there is increasing interest in leveraging omics technologies for CHO cell line development, bioprocess optimization, and biotherapeutic product quality assessment. However, CHO cells have been largely ignored in the development of publicly available tools to facilitate comprehensive omics data analysis and management, despite being a ubiquitous research tool and biotherapeutic production host. To address the gap, we have recently developed a web-based tool, named "CHOmics", for the integrative and interactive data analysis and visualization specifically designed for CHO. This novel tool provides all-in-one solutions from raw data processing to pathway and gene analysis and offers considerable flexibility to customize analysis and visualization. It further allows for other omics data inputs and thereby enables multi-omics comparison. The open-source tool is freely available at http://www.chomics.org. [ABSTRACT FROM AUTHOR]

This paper presents global research trends involving highly cited articles on ecosystem services from 1981 to 2017 based on a bibliometric analysis of such articles from the SCI-E and SSCI databases of the Web of Science. The analysis revealed that there were 132 highly cited articles, most of which were published between 2005 and 2014. Based on author keywords, the term ecosystem services was strongly linked to biodiversity. The top three journals in terms of total number of highly cited articles published were Ecological Economics, PNAS, and Ecological Indicators. Despite ranking sixth overall, Science ranked first in both impact factor and total citations per article. The US, UK, Netherlands, Spain, and Sweden were the top five most productive and cooperative countries in the world based on total number of highly cited articles and co-authorship network, respectively. The US was highly connected to Canada, the Netherlands, China and the UK. Stockholm University and Stanford University were the most productive institutions in Europe and North America, respectively. Stanford University is associated with many scholars in the field of ecosystem services research because of the InVEST model. Robert Costanza was the most prolific and highly cited author, the latter being largely due to the first valuation of the world’s ecosystem services and natural capital, he and his co-authors published in 1997 in Nature. Terrestrial, urban, and forest ecosystems were the top types of ecosystems assessed. Regulating and provisioning services were the major ecosystem services studied. Quantitative and qualitative assessments were the main research focus. Most of these highly cited studies on ecosystem services are done on areas geographically located in North America and Europe. [ABSTRACT FROM AUTHOR]

The high frequency of prophage insertions in the mlrA gene of clinical serotype O157:H7 isolates renders such strains deficient in csgD-dependent biofilm formation but prophage induction may restore certain mlrA properties. In this study we used transcriptomics to study the effect of high and low sulfamethoxazole–trimethoprim (SMX-TM) concentrations on prophage induction, biofilm regulation, and virulence gene expression in strain PA20 under environmental conditions following 5-hour and 12-hour exposures in broth or on agar. SMX-TM at a sub-lethal concentration induced strong RecA expression resulting in concentration- and time-dependent major transcriptional shifts with emphasis on up-regulation of genes within horizontally-transferred chromosomal regions (HTR). Neither high or low levels of SMX-TM stimulated csgD expression at either time point, but both levels resulted in slight repression. Full expression of Ler-dependent genes paralleled expression of group 1 pch homologues in the presence of high glrA. Finally, stx2 expression, which is strongly dependent on prophage induction, was enhanced at 12 hours but repressed at five hours, in spite of early SOS initiation by the high SMX-TM concentration. Our findings indicate that, similar to host conditions, exposure to environmental conditions increased the expression of virulence genes in a clinical isolate but genes involved in the protective biofilm response were repressed. [ABSTRACT FROM AUTHOR]

High hydrostatic pressure has been used to inactivate pathogens in foods for decades. There is a great potential to adapt this technology to inactivate pathogens in plasma and derivatives. To better evaluate the potential of this method, pathogen inoculated plasma samples were pressurized under different pressure application modes and temperatures. The inactivation efficacy of pathogens and activities of plasma proteins were monitored after treatment. The CFUs of E.coli was examined as the indicator of the inactivation efficiency. The factor V and VIII were chosen as the indicator of the plasma function. Preliminary experiments identified optimized treatment conditions: 200-250MPa, with 5×1 minute multi-pulsed high pressure at near 0°C (ice-water bath). Under this conditions, the inactivation efficacy of EMCV was >8.5log. The CFUs of E. coli were reduced by 7.5log, B. cereus were 8log. However, PPV and S. aureus cannot be inactivated efficiently. The activities of factor II, VII, IX, X, XI, XII, fibrinogen, IgG, IgM stayed over 95% compared to untreated. Factor V and VIII activity was maintained at 46–63% and 77–82%, respectively. [ABSTRACT FROM AUTHOR]

Metaplastic breast carcinoma (MBC) is a rare heterogeneous group of primary breast malignancies, with low hormone receptor expression and poor outcomes. To date, no prognostic markers for this tumor have been validated. The current study was undertaken to evaluate the clinicopathologic characteristics, the response to various therapeutic regimens and the prognosis of MBCs in a large cohort of patients from Tianjin Medical University Cancer Hospital in China. Ninety cases of MBCs diagnosed in our hospital between January 2000 and September 2014 were retrieved from the archives. In general, MBCs presented with larger size, a lower rate of lymph node metastasis, and demonstrated more frequent local recurrence/distant metastasis than 1,090 stage-matched cases of invasive carcinoma of no specific type (IDC-NST), independent of the status of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expressions. The five-year disease-free survival (DFS) of MBC was significantly worse than IDC-NST. Using univariate analysis, lymph node metastasis, advanced clinical stage at diagnosis, high tumor proliferation rate assessed by Ki-67 labeling, and epidermal growth factor receptor (EGFR) overexpression/gene amplification were associated significantly with reduced DFS, while decreased OS was associated significantly with lymph node metastasis and EGFR overexpression/gene amplification. With multivariate analysis, lymph node status was an independent predictor for DFS, and lymph node status and EGFR overexpression/gene amplification were independent predictors for OS. Histologic subtyping and molecular subgrouping of MBCs were not significant factors in prognosis. We also found that MBCs were insensitive to neoadjuvant chemotherapy, routine chemotherapy, and radiation therapy. This study indicates that MBC is an aggressive type of breast cancer with poor prognosis, and that identification and optimization of an effective comprehensive therapeutic regimen is needed. [ABSTRACT FROM AUTHOR]

For multicellular organisms, different tissues coordinate to integrate physiological functions, although this systematically and gradually declines in the aging process. Therefore, an association exists between tissue coordination and aging, and investigating the evolution of tissue coordination with age is of interest. In the past decade, both common and heterogeneous aging processes among tissues were extensively investigated. The results on spatial association of gene changes that determine lifespan appear complex and paradoxical. To reconcile observed commonality and heterogeneity of gene changes among tissues and to address evolution feature of tissue coordination with age, we introduced a new analytical strategy to systematically analyze genome-wide spatio-temporal gene expression profiles. We first applied the approach to natural aging process in three species (Rat, Mouse and Drosophila) and then to anti-aging process in Mouse. The results demonstrated that temporal gene expression alteration in different tissues experiences a progressive association evolution from spatial synchrony to asynchrony and stochasticity with age. This implies that tissue coordination gradually declines with age. Male mice showed earlier spatial asynchrony in gene expression than females, suggesting that male animals are more prone to aging than females. The confirmed anti-aging interventions (resveratrol and caloric restriction) enhanced tissue coordination, indicating their underlying anti-aging mechanism on multiple tissue levels. Further, functional analysis suggested asynchronous DNA/protein damage accumulation as well as asynchronous repair, modification and degradation of DNA/protein in tissues possibly contributes to asynchronous and stochastic changes of tissue microenvironment. This increased risk for a variety of age-related diseases such as neurodegeneration and cancer that eventually accelerate organismal aging and death. Our study suggests a novel molecular event occurring in aging process of multicellular species that may represent an intrinsic molecular mechanism of aging. [ABSTRACT FROM AUTHOR]

In Saccharomyces cerevisiae, transcriptionally silent heterochromatin at HML and HMR loci is established by silencers that recruit SIR complex and promote its propagation along chromatin. Silencers consist of various combinations of two or three binding sites for origin recognition complex (ORC), Abf1 and Rap1. A single ORC, Abf1 or Rap1 site cannot promote silencing, but can enhance silencing by a distant silencer, and is called a protosilencer. The mechanism of protosilencer function is not known. We examine the functions of ORC, Abf1 and Rap1 sites as components of the HMR-E silencer, and as protosilencers. We find that the Rap1 site makes a larger and unique contribution to HMR-E function compared to ORC and Abf1 sites. On the other hand, Rap1 site does not act as a protosilencer to assist HML-E silencer in forming heterochromatin, whereas ORC and Abf1 sites do. Therefore, different mechanisms may be involved in the roles of Rap1 site as a component of HMR-E and as a protosilencer. Heterochromatin formed by ORC or Abf1 site in collaboration with HML-E is not as stable as that formed by HMR-E and HML-E, but increasing the copy number of Abf1 site enhances heterochromatin stability. ORC and Abf1 sites acting as protosilencers do not modulate chromatin structure in the absence of SIR complex, which argues against the hypothesis that protosilencers serve to create a chromatin structure favorable for SIR complex propagation. We also investigate the function of ARS1 containing an ORC site and an Abf1 site as a protosilencer. We find that ARS1 inserted at HML enhances heterochromatin stability, and promotes de novo formation of a chromatin structure that partially resembles heterochromatin in an S phase dependent manner. Taken together, our results indicate that protosilencers aid in the formation and maintenance of heterochromatin structure.

For multicellular organisms, different tissues coordinate to integrate physiological functions, although this systematically and gradually declines in the aging process. Therefore, an association exists between tissue coordination and aging, and investigating the evolution of tissue coordination with age is of interest. In the past decade, both common and heterogeneous aging processes among tissues were extensively investigated. The results on spatial association of gene changes that determine lifespan appear complex and paradoxical. To reconcile observed commonality and heterogeneity of gene changes among tissues and to address evolution feature of tissue coordination with age, we introduced a new analytical strategy to systematically analyze genome-wide spatio-temporal gene expression profiles. We first applied the approach to natural aging process in three species (Rat, Mouse and Drosophila) and then to anti-aging process in Mouse. The results demonstrated that temporal gene expression alteration in different tissues experiences a progressive association evolution from spatial synchrony to asynchrony and stochasticity with age. This implies that tissue coordination gradually declines with age. Male mice showed earlier spatial asynchrony in gene expression than females, suggesting that male animals are more prone to aging than females. The confirmed anti-aging interventions (resveratrol and caloric restriction) enhanced tissue coordination, indicating their underlying anti-aging mechanism on multiple tissue levels. Further, functional analysis suggested asynchronous DNA/protein damage accumulation as well as asynchronous repair, modification and degradation of DNA/protein in tissues possibly contributes to asynchronous and stochastic changes of tissue microenvironment. This increased risk for a variety of age-related diseases such as neurodegeneration and cancer that eventually accelerate organismal aging and death. Our study suggests a novel molecular event occurring in aging process of multicellular species that may represent an intrinsic molecular mechanism of aging.

Over the next few years, the efficient use of next-generation sequencing (NGS) in human genetics research will depend heavily upon the effective mechanisms for the selective enrichment of genomic regions of interest. Recently, comprehensive exome capture arrays have become available for targeting approximately 33 Mb or approximately 180,000 coding exons across the human genome. Selective genomic enrichment of the human exome offers an attractive option for new experimental designs aiming to quickly identify potential disease-associated genetic variants, especially in family-based studies. We have evaluated a 2.1 M feature human exome capture array on eight individuals from a three-generation family pedigree. We were able to cover up to 98% of the targeted bases at a long-read sequence read depth of > or = 3, 86% at a read depth of > or = 10, and over 50% of all targets were covered with > or = 20 reads. We identified up to 14,284 SNPs and small indels per individual exome, with up to 1,679 of these representing putative novel polymorphisms. Applying the conservative genotype calling approach HCDiff, the average rate of detection of a variant allele based on Illumina 1 M BeadChips genotypes was 95.2% at > or = 10x sequence. Further, we propose an advantageous genotype calling strategy for low covered targets that empirically determines cut-off thresholds at a given coverage depth based on existing genotype data. Application of this method was able to detect >99% of SNPs covered > or = 8x. Our results offer guidance for "real-world" applications in human genetics and provide further evidence that microarray-based exome capture is an efficient and reliable method to enrich for chromosomal regions of interest in next-generation sequencing experiments.

In all eukaryotes, histone variants are incorporated into a subset of nucleosomes to create functionally specialized regions of chromatin. One such variant, H2A.Z, replaces histone H2A and is required for development and viability in all animals tested to date. However, the function of H2A.Z in development remains unclear. Here, we use ChIP-chip, genetic mutation, RNAi, and immunofluorescence microscopy to interrogate the function of H2A.Z (HTZ-1) during embryogenesis in Caenorhabditis elegans, a key model of metazoan development. We find that HTZ-1 is expressed in every cell of the developing embryo and is essential for normal development. The sites of HTZ-1 incorporation during embryogenesis reveal a genome wrought by developmental processes. HTZ-1 is incorporated upstream of 23% of C. elegans genes. While these genes tend to be required for development and occupied by RNA polymerase II, HTZ-1 incorporation does not specify a stereotypic transcription program. The data also provide evidence for unexpectedly widespread independent regulation of genes within operons during development; in 37% of operons, HTZ-1 is incorporated upstream of internally encoded genes. Fewer sites of HTZ-1 incorporation occur on the X chromosome relative to autosomes, which our data suggest is due to a paucity of developmentally important genes on X, rather than a direct function for HTZ-1 in dosage compensation. Our experiments indicate that HTZ-1 functions in establishing or maintaining an essential chromatin state at promoters regulated dynamically during C. elegans embryogenesis., Competing Interests: XZ and RDG are employed by NimbleGen Systems, Inc., a microarray company that might profit from the publication of this paper.