Dietary Folate and Cofactors Accelerate Age-dependent p16 Epimutation to Promote Intestinal Tumorigenesis.

Unlabelled: The extent to which non-genetic environmental factors, such as diet, contribute to carcinogenesis has been long debated. One potential mechanism for the effects of environmental factors is through epigenetic modifications that affect gene expression without changing the underlying DNA sequence. However, the functional cooperation between dietary factors and cancer-causing epigenetic regulation is largely unknown.

Evolution and expression of the duck TRIM gene repertoire.

Tripartite motif (TRIM) proteins are involved in development, innate immunity, and viral restriction. TRIM gene repertoires vary between species, likely due to diversification caused by selective pressures from pathogens; however, this has not been explored in birds. We mined a assembled transcriptome for the TRIM gene repertoire of the domestic mallard duck (), a reservoir host of influenza A viruses.

A roadmap to robust discriminant analysis of principal components.

Identification of population structure is a common goal for a variety of applications, including conservation, wildlife management, and medical genetics. The outcome of these analyses can have far reaching implications; therefore, it is important to ensure an understanding of the strengths and weaknesses of the methodologies used. Increasing in popularity, the discriminant analysis of principal components (DAPC) method incorporates combinations of genetic variables (alleles) into a model that differentiates individuals into genetic clusters.

A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells.

Survivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature.

Evidence of Coevolution Between Lineages and Their Corresponding Hosts, Lodgepole Pine and Jack Pine.

Variation in rate of infection and susceptibility of spp. to the fungus (syn. ), the causative agent of western gall rust, has been well documented.

Ancient hybridization patterns between bighorn and thinhorn sheep.

Whole-genome sequencing has advanced the study of species evolution, including the detection of genealogical discordant events such as ancient hybridization and incomplete lineage sorting (ILS). The evolutionary history of bighorn (Ovis canadensis) and thinhorn (Ovis dalli) sheep present an ideal system to investigate evolutionary discordance due to their recent and rapid radiation and putative secondary contact between bighorn and thinhorn sheep subspecies, specifically the dark pelage Stone sheep (O. dalli stonei) and predominately white Dall sheep (O.

Epigenome - A mediator for host-microbiome crosstalk.

The interaction between the gut and its eventual trillions of microbe inhabitants during microbial colonization, represents a critical time period for establishing the overall health and wellbeing of an individual. The gut microbiome represents a diverse community of microbes that are critical for many physiological roles of the host including host metabolism. These processes are controlled by a fine-tuned chemical cross talk between the host and microbiota.

The influence of a priori grouping on inference of genetic clusters: simulation study and literature review of the DAPC method.

Inference of genetic clusters is a key aim of population genetics, sparking development of numerous analytical methods. Within these, there is a conceptual divide between finding de novo structure versus assessment of a priori groups. Recently developed, Discriminant Analysis of Principal Components (DAPC), combines discriminant analysis (DA) with principal component (PC) analysis.

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation.

Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its "undruggable" nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization.

Confidently identifying the correct K value using the ΔK method: When does K = 2?

Populations delineated based on genetic data are commonly used for wildlife conservation and management. Many studies use the program structure combined with the ΔK method to identify the most probable number of populations (K). We recently found K = 2 was identified more often when studies used ΔK compared to studies that did not.

Predicting the spread-risk potential of chronic wasting disease to sympatric ungulate species.

Wildlife disease incidence is increasing, resulting in negative impacts on the economy, biodiversity, and potentially human health. Chronic wasting disease (CWD) is a fatal, transmissible spongiform encephalopathy of cervids (wild and captive) which continues to spread geographically resulting in exposure to potential new host species. The disease agent (PrP) is a misfolded conformer of the cellular prion protein (PrP).

Linking genotype to phenotype to identify genetic variation relating to host susceptibility in the mountain pine beetle system.

Identifying genetic variants responsible for phenotypic variation under selective pressure has the potential to enable productive gains in natural resource conservation and management. Despite this potential, identifying adaptive candidate loci is not trivial, and linking genotype to phenotype is a major challenge in contemporary genetics. Many of the population genetic approaches commonly used to identify adaptive candidates will simultaneously detect false positives, particularly in nonmodel species, where experimental evidence is seldom provided for putative roles of the adaptive candidates identified by outlier approaches.

Fully automated sequence alignment methods are comparable to, and much faster than, traditional methods in large data sets: an example with hepatitis B virus.

Aligning sequences for phylogenetic analysis (multiple sequence alignment; MSA) is an important, but increasingly computationally expensive step with the recent surge in DNA sequence data. Much of this sequence data is publicly available, but can be extremely fragmentary (i.e.

Generation of High Expressing Chinese Hamster Ovary Cell Pools Using the Leap-In Transposon System.

Clonally derived cell lines (CDCL) from Chinese Hamster Ovary (CHO) host cell lines, remain the most popular method to manufacture therapeutic proteins. However, CHO cell pools are increasingly being used as an alternate method to produce therapeutic proteins for preclinical drug development in an effort to shorten the time required for new drug development. It is essential that these CHO pools exhibit the desired attributes of CHO CDCLs such as high protein titers and consistent product quality attributes (PQAs).

Targeting survivin for therapeutic discovery: past, present, and future promises.

Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery.

Bioreactor scale up and protein product quality characterization of piggyBac transposon derived CHO pools.

Chinese hamster ovary (CHO) cells remain the most popular host for the production of biopharmaceutical drugs, particularly monoclonal antibodies (mAbs), bispecific antibodies, and Fc-fusion proteins. Creating and characterizing the stable CHO clonally-derived cell lines (CDCLs) needed to manufacture these therapeutic proteins is a lengthy and laborious process. Therefore, CHO pools have increasingly been used to rapidly produce protein to support and enable preclinical drug development.

Transient and stable CHO expression, purification and characterization of novel hetero-dimeric bispecific IgG antibodies.

IgG bispecific antibodies (BsAbs) represent one of the preferred formats for bispecific antibody therapeutics due to their native-like IgG properties and their monovalent binding to each target. Most reported studies utilized transient expression in HEK293 cells to produce BsAbs. However, the expression of biotherapeutic molecules using stable CHO cell lines is commonly used for biopharmaceutical manufacturing.

Generation of stable Chinese hamster ovary pools yielding antibody titers of up to 7.6 g/L using the piggyBac transposon system.

Chinese hamster ovary (CHO) cells remain the default production host for many biopharmaceutical drugs, particularly monoclonal antibodies (mAb). Production of gram and kilogram quantities of protein typically requires the generation of stable CHO clones. Unfortunately, this process takes several months, significantly slowing down the drug discovery and development process.

Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors.

Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation.

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting.

Genome of the long-living sacred lotus (Nelumbo nucifera Gaertn.).

Background: Sacred lotus is a basal eudicot with agricultural, medicinal, cultural and religious importance. It was domesticated in Asia about 7,000 years ago, and cultivated for its rhizomes and seeds as a food crop. It is particularly noted for its 1,300-year seed longevity and exceptional water repellency, known as the lotus effect.

Open innovation for phenotypic drug discovery: The PD2 assay panel.

Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy.

Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases.

Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G.