Coverage profile correction of shallow-depth circulating cell-free DNA sequencing via multidistance learning.

Shallow-depth whole-genome sequencing (WGS) of circulating cell-free DNA (ccfDNA) is a popular approach for non-invasive genomic screening assays, including liquid biopsy for early detection of invasive tumors as well as non-invasive prenatal screening (NIPS) for common fetal trisomies. In contrast to nuclear DNA WGS, ccfDNA WGS exhibits extensive inter- and intra- sample coverage variability that is not fully explained by typical sources of variation in WGS, such as GC content. This variability may inflate false positive and false negative screening rates of copy-number alterations and aneuploidy, particularly if these features are present at a relatively low proportion of total sequenced content.

A comparison of adult rhabdomyosarcoma and high-grade neuroendocrine carcinoma of the urinary bladder reveals novel PPP1R12A fusions in rhabdomyosarcoma.

Some rhabdomyosarcomas and sarcomatoid carcinomas with heterologous rhabdomyosarcomatous elements resemble high-grade neuroendocrine carcinoma, creating a diagnostic difficulty. The purpose of this study was to characterize the overlap of adult genitourinary rhabdomyosarcomas, excluding those occurring at paratesticular sites, with high-grade neuroendocrine carcinoma and identify features helpful in their separation. Seventeen cases of rhabdomyosarcoma (11 from the urinary bladder and 3 each from kidney and prostate) were compared to 10 cases of high-grade neuroendocrine carcinoma from the urinary bladder.

ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation.

The interplay between transcription factors and epigenetic writers like the DNA methyltransferases (DNMTs), and the role of this interplay in gene expression, is being increasingly appreciated. ZBTB24, a poorly characterized zinc-finger protein, or the de novo methyltransferase DNMT3B, when mutated, cause Immunodeficiency, Centromere Instability, and Facial anomalies (ICF) syndrome, suggesting an underlying mechanistic link. Chromatin immunoprecipitation coupled with loss-of-function approaches in model systems revealed common loci bound by ZBTB24 and DNMT3B, where they function to regulate gene body methylation.

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma.

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance.

Human Analysts at Superhuman Scales: What Has Friendly Software To Do?

As analysts are expected to process a greater amount of information in a shorter amount of time, creators of big data software are challenged with the need for improved efficiency. Ray, our group's usable, scalable genome assembler, addresses big data problems by using optimal resources and producing one, correct and conservative, timely solution. Only by abstracting the size of the data from both the computers and the humans can the real scientific question, often complex in itself, eventually be solved.

Multilevel X-Pol: a fragment-based method with mixed quantum mechanical representations of different fragments.

The explicit polarization (X-Pol) method is a fragment-based quantum mechanical model, in which a macromolecular system or other large or complex system in solution is partitioned into monomeric fragments. The present study extends the original X-Pol method, where all fragments are treated using the same electronic structure theory, to multilevel representations, called multilevel X-Pol, in which different electronic structure methods are used to describe different fragments. The multilevel X-Pol method has been implemented into a locally modified version of Gaussian 09.

Quercetin-3-methyl ether suppresses proliferation of mouse epidermal JB6 P+ cells by targeting ERKs.

Chemoprevention has been acknowledged as an important and practical strategy for the management of skin cancer. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer-promoting activity. We identified this compound by in silico virtual screening of the Traditional Chinese Medicine Database using extracellular signal-regulated kinase 2 (ERK2) as the target protein.

Norathyriol suppresses skin cancers induced by solar ultraviolet radiation by targeting ERK kinases.

Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, prompting great interest in chemopreventive agents for this disease. In this study, we report the discovery of norathyriol, a plant-derived chemopreventive compound identified through an in silico virtual screening of the Chinese Medicine Library. Norathyriol is a metabolite of mangiferin found in mango, Hypericum elegans, and Tripterospermum lanceolatum and is known to have anticancer activity.

Parallelization of Nullspace Algorithm for the computation of metabolic pathways.

Elementary mode analysis is a useful metabolic pathway analysis tool in understanding and analyzing cellular metabolism, since elementary modes can represent metabolic pathways with unique and minimal sets of enzyme-catalyzed reactions of a metabolic network under steady state conditions. However, computation of the elementary modes of a genome- scale metabolic network with 100-1000 reactions is very expensive and sometimes not feasible with the commonly used serial Nullspace Algorithm. In this work, we develop a distributed memory parallelization of the Nullspace Algorithm to handle efficiently the computation of the elementary modes of a large metabolic network.

Multilevel Parallelization of AutoDock 4.2.

Background: Virtual (computational) screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program.

Identification of dynamical hinge points of the L1 ligase molecular switch.

The L1 ligase is an in vitro selected ribozyme that uses a noncanonically base-paired ligation site to catalyze regioselectively and regiospecifically the 5' to 3' phosphodiester bond ligation, a reaction relevant to origin of life hypotheses that invoke an RNA world scenario. The L1 ligase crystal structure revealed two different conformational states that were proposed to represent the active and inactive forms. It remains an open question as to what degree these two conformers persist as stable conformational intermediates in solution, and along what pathway are they able to interconvert.

Threshold occupancy and specific cation binding modes in the hammerhead ribozyme active site are required for active conformation.

The relationship between formation of active in-line attack conformations and monovalent (Na(+)) and divalent (Mg(2+)) metal ion binding in hammerhead ribozyme (HHR) has been explored with molecular dynamics simulations. To stabilize repulsions between negatively charged groups, different requirements of the threshold occupancy of metal ions were observed in the reactant and activated precursor states both in the presence and in the absence of a Mg(2+) in the active site. Specific bridging coordination patterns of the ions are correlated with the formation of active in-line attack conformations and can be accommodated in both cases.

Computational classification of classically secreted proteins.

The ability to identify classically secreted proteins is an important component of targeted therapeutic studies and the discovery of circulating biomarkers. Here, we review some of the most recent programs available for the in silico prediction of secretory proteins, the performance of which is benchmarked with an independent set of annotated human proteins. The description of these programs and the results of this benchmarking provide insights into the most recently developed prediction programs, which will enable investigators to make more informed decisions about which program best addresses their research needs.

Ab initio conformational space study of model compounds of O-glycosides of serine diamide.

Relative stabilities of rotamers of the N-acetyl-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyl)-L-seryl-N'-methyl amide (1) and eleven analogous molecules containing beta-galactose, alpha- and beta-mannose, alpha- and beta-glucose, and L-threonine were calculated to learn whether they could explain the natural preference for 1 in linkages between the carbohydrate and protein in glycoproteins. The lowest energy rotamers of four O-glycoside models of serine diamide were identified with a Monte Carlo search coupled with molecular mechanics (MM2*). These rotamers were further optimized with an ab initio level of theory (HF/6-31G(d)).