Salt-Dependent Self-Association of Trinucleotide Repeat RNA Sequences.

Repeat RNA sequences self-associate to form condensates. Simulations of a coarse-grained single-interaction site model for (CAG) ( = 30 and 31) show that the salt-dependent free energy gap, Δ, between the ground (perfect hairpin) and the excited state (slipped hairpin (SH) with one CAG overhang) of the monomer for ( even) is the primary factor that determines the rates and yield of self-assembly. For odd , the free energy () of the ground state, which is an SH, is used to predict the self-association kinetics.

Competition between Stacking and Divalent Cation-Mediated Electrostatic Interactions Determines the Conformations of Short DNA Sequences.

Interplay between divalent cations (Mg and Ca) and single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), as well as stacking interactions, is important in nucleosome stability and phase separation in nucleic acids. Quantitative techniques accounting for ion-DNA interactions are needed to obtain insights into these and related problems. Toward this end, we created a sequence-dependent computational TIS-ION model that explicitly accounts for monovalent and divalent ions.

p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cells.

Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed.

Intraperitoneal Administration of p53-armed Oncolytic Adenovirus Inhibits Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells.

Background/aim: Diffuse-type gastric cancer (GC) frequently exhibits peritoneal metastasis, leading to poor prognosis. However, efforts to develop antitumor strategies for preventing the peritoneal metastasis of GC have been unsuccessful. As diffuse-type GC cells often carry a genetic alteration in the tumor suppressor p53 gene, p53 restoration may be a potent strategy for preventing peritoneal metastasis of GC.

Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time.

Folding of ribozymes into well-defined tertiary structures usually requires divalent cations. How Mg2+ ions direct the folding kinetics has been a long-standing unsolved problem because experiments cannot detect the positions and dynamics of ions. To address this problem, we used molecular simulations to dissect the folding kinetics of the Azoarcus ribozyme by monitoring the path each molecule takes to reach the folded state.

Odd-even disparity in the population of slipped hairpins in RNA repeat sequences with implications for phase separation.

Low-complexity nucleotide repeat sequences, which are implicated in several neurological disorders, undergo liquid-liquid phase separation (LLPS) provided the number of repeat units, , exceeds a critical value. Here, we establish a link between the folding landscapes of the monomers of trinucleotide repeats and their propensity to self-associate. Simulations using a coarse-grained Self-Organized Polymer (SOP) model for (CAG) repeats in monovalent salt solutions reproduce experimentally measured melting temperatures, which are available only for small .

Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study.

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy.

Condensates in RNA repeat sequences are heterogeneously organized and exhibit reptation dynamics.

Although it is known that RNA undergoes liquid-liquid phase separation, the interplay between the molecular driving forces and the emergent features of the condensates, such as their morphologies and dynamic properties, is not well understood. We introduce a coarse-grained model to simulate phase separation of trinucleotide repeat RNAs, which are implicated in neurological disorders. After establishing that the simulations reproduce key experimental findings, we show that once recruited inside the liquid droplets, the monomers transition from hairpin-like structures to extended states.

VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression.

Vestigial-like family member 3 (VGLL3) is a member of the VGLL family that serves as cofactors for TEA-domain transcription factors. Although VGLL3 is involved in the proliferation of cancer cells, the molecular mechanisms underlying VGLL3-mediated cell proliferation remain largely unknown. In this study, we found that stable expression of VGLL3 in human lung cancer A549 cells affects glutamine metabolism and increases their dependency on de novo nucleotide synthesis for proliferation.

Vestigial-like family member 3 stimulates cell motility by inducing high-mobility group AT-hook 2 expression in cancer cells.

Vestigial-like family member 3 (VGLL3) is a cofactor for TEA domain transcription factors (TEADs). Although VGLL3 is known to be highly expressed and stimulate cell proliferation in mesenchymal cancer cells, its involvement in mesenchymal phenotypes is largely unknown. In this study, we found that VGLL3 promotes epithelial-to-mesenchymal transition (EMT)-like phenotypic changes.

VGLL3 activates inflammatory responses by inducing interleukin-1α secretion.

Vestigial-like family member 3 (VGLL3), a member of the vestigial-like family, is a cofactor of the TEA-domain-containing transcription factor (TEAD). Although elevation in VGLL3 expression is associated with inflammatory diseases, such as inflammatory sarcomas and autoimmune diseases, the molecular mechanisms underlying VGLL3-mediated inflammation remain largely unknown. In this study, we analyzed the relationship between elevated VGLL3 expression and the levels of NF-κB, a transcription factor that plays a pivotal role in inflammation.

Investigation of Factors Causing Nonuniformity in Luminescence Lifetime of Fast-Responding Pressure-Sensitive Paints.

Factors that cause nonuniformity in the luminescence lifetime of pressure-sensitive paints (PSPs) were investigated. The lifetime imaging method of PSP does not theoretically require wind-off reference images. Therefore, it can improve measurement accuracy because it can eliminate errors caused by the deformation or movement of the model during the measurement.

Shape changes and cooperativity in the folding of the central domain of the 16S ribosomal RNA.

Both the small and large subunits of the ribosome, the molecular machine that synthesizes proteins, are complexes of ribosomal RNAs (rRNAs) and a number of proteins. In bacteria, the small subunit has a single 16S rRNA whose folding is the first step in its assembly. The central domain of the 16S rRNA folds independently, driven either by Mg ions or by interaction with ribosomal proteins.

Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway.

Vestigial-like 3 (VGLL3) is a member of the VGLL family, whose members serve as cofactors for TEA domain-containing transcription factors (TEADs). TEADs promote tissue and tumor development together with the cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although VGLL3 is involved in tumor cell proliferation, its relationship with TEADs and YAP/TAZ remains largely unknown.

Theory and simulations for RNA folding in mixtures of monovalent and divalent cations.

RNA molecules cannot fold in the absence of counterions. Experiments are typically performed in the presence of monovalent and divalent cations. How to treat the impact of a solution containing a mixture of both ion types on RNA folding has remained a challenging problem for decades.

Ion Condensation onto Ribozyme Is Site Specific and Fold Dependent.

The highly charged RNA molecules, with each phosphate carrying a single negative charge, cannot fold into well-defined architectures with tertiary interactions in the absence of ions. For ribozymes, divalent cations are known to be more efficient than monovalent ions in driving them to a compact state, although Mg ions are needed for catalytic activities. Therefore, how ions interact with RNA is relevant in understanding RNA folding.

Molecular Simulations of Ion Effects on the Thermodynamics of RNA Folding.

How ions affect RNA folding thermodynamics and kinetics is an important but a vexing problem that remains unsolved. Experiments have shown that the free-energy change, Δ G( c), of RNA upon folding varies with the salt concentration ( c) as, Δ G( c) = k  ln  c + const, where the coefficient k is proportional to the difference in the ion preferential coefficient, ΔΓ. We performed simulations of a coarse-grained model, by modeling electrostatic interactions implicitly and with explicit representation of ions, to elucidate the molecular underpinnings of the relationship between Δ G and ΔΓ.

Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover.

We investigated frictional effects on the folding rates of a human telomerase hairpin (hTR HP) and H-type pseudoknot from the Beet Western Yellow Virus (BWYV PK) using simulations of the Three Interaction Site (TIS) model for RNA. The heat capacity from TIS model simulations, calculated using temperature replica exchange simulations, reproduces nearly quantitatively the available experimental data for the hTR HP. The corresponding results for BWYV PK serve as predictions.

Monovalent ions modulate the flux through multiple folding pathways of an RNA pseudoknot.

The functions of RNA pseudoknots (PKs), which are minimal tertiary structural motifs and an integral part of several ribozymes and ribonucleoprotein complexes, are determined by their structure, stability, and dynamics. Therefore, it is important to elucidate the general principles governing their thermodynamics/folding mechanisms. Here, we combine laser temperature-jump experiments and coarse-grained simulations to determine the folding/unfolding pathways of VPK, a variant of the mouse mammary tumor virus (MMTV) PK involved in ribosomal frameshifting.

Sequence-Dependent Three Interaction Site Model for Single- and Double-Stranded DNA.

We develop a robust coarse-grained model for single- and double-stranded DNA by representing each nucleotide by three interaction sites (TIS) located at the centers of mass of sugar, phosphate, and base. The resulting TIS model includes base-stacking, hydrogen bond, and electrostatic interactions as well as bond-stretching and bond angle potentials that account for the polymeric nature of DNA. The choices of force constants for stretching and the bending potentials were guided by a Boltzmann inversion procedure using a large representative set of DNA structures extracted from the Protein Data Bank.

Protein collapse is encoded in the folded state architecture.

Folded states of single domain globular proteins are compact with high packing density. The radius of gyration, R, of both the folded and unfolded states increase as N where N is the number of amino acids in the protein. The values of the Flory exponent ν are, respectively, ≈⅓ and ≈0.

A small intestine volvulus caused by strangulation of a mesenteric lipoma: a case report.

Background: An emergency department encounters a variety of cases, including rare cases of the strangulation of a mesenteric lipoma by the greater omentum band.

Case Presentation: A 67-year-old Japanese man presented with nausea, vomiting, and upper abdominal pain. There were no abnormalities detected by routine blood tests other than a slight rise in his white cell count.

Passive exercise of the lower limbs and trunk alleviates decreased intestinal motility in patients in the intensive care unit after cardiovascular surgery.

[Purpose] The purpose of this study was to clarify the effects of passive exercise of the lower limbs and trunk (PELT) in ICU patients after cardiovascular surgery with decreased bowel motility. [Subjects and Methods] Ten ICU patients with clinically-apparent decreased bowel motility during the period of April to July 2016 were enrolled this study. Bowel sounds (BS) for 5 minutes at rest and 5 minutes after PELT were recorded through an electronic stethoscope.

[Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease].

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.