DCB-3503, a Tylophorine Analog, Inhibits Protein Synthesis through a Novel Mechanism

BACKGROUND: DCB-3503, a tylophorine analog, inhibits the growth of PANC-1 (human pancreatic ductal cancer cell line) and HepG2 (human hepatocellular cancer cell line) tumor xenografts in nude mice. The inhibition of growth leads to cancer cell differentiation instead of cell death. However, the mechanisms of action of tylophorine analogs is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that DCB-3503 suppresses the expression of pro-oncogenic or pro-survival proteins with short half-lives, including cyclin D1, survivin, beta-catenin, p53, and p21, without decreasing their mRNA levels. Proteasome inhibitor reversed the inhibitory effect of DCB-3503 on expression of these proteins. DCB-3503 inhibited the incorporation of radiolabeled amino acid and thymidine, and to a much lesser degree of uridine, in a panel of cell lines. The mechanism of inhibition of protein synthesis is different from that of cycloheximide (CHX) as assayed in cell culture and HeLa in vitro translation system. Furthermore, in contrast to rapamycin, DCB-3503 does not affect protein synthesis through the mTOR pathway. DCB-3503 treatment shifts the sedimentation profiles of ribosomes and mRNAs towards the polysomal fractions while diminishing monosome abundance, indicative of the inhibition of the elongation step of protein synthesis. Preferential down regulation of several studied proteins under these conditions is likely due to the relative short half-lives of these proteins. CONCLUSION/SIGNIFICANCE: The inhibitory effect of DCB-3503 on translation is apparently distinct from any of the current anticancer compounds targeting protein synthesis. Translation inhibitors with novel mechanism could complement current chemotherapeutic agents for the treatment of human cancers and suppress the occurrence of drug resistance

EXTENSIBLE DATABASE FRAMEWORK FOR MANAGEMENT OF UNSTRUCTURED AND SEMI-STRUCTURED DOCUMENTS

Method and system for querying a collection of Unstructured or semi-structured documents to identify presence of, and provide context and/or content for, keywords and/or keyphrases. The documents are analyzed and assigned a node structure, including an ordered sequence of mutually exclusive node segments or strings. Each node has an associated set of at least four, five or six attributes with node information and can represent a format marker or text, with the last node in any node segment usually being a text node. A keyword (or keyphrase) is specified. and the last node in each node segment is searched for a match with the keyword. When a match is found at a query node, or at a node determined with reference to a query node, the system displays the context andor the content of the query node

Adding Hierarchical Objects to Relational Database General-Purpose XML-Based Information Managements

NETMARK is a flexible, high-throughput software system for managing, storing, and rapid searching of unstructured and semi-structured documents. NETMARK transforms such documents from their original highly complex, constantly changing, heterogeneous data formats into well-structured, common data formats in using Hypertext Markup Language (HTML) and/or Extensible Markup Language (XML). The software implements an object-relational database system that combines the best practices of the relational model utilizing Structured Query Language (SQL) with those of the object-oriented, semantic database model for creating complex data. In particular, NETMARK takes advantage of the Oracle 8i object-relational database model using physical-address data types for very efficient keyword searches of records across both context and content. NETMARK also supports multiple international standards such as WEBDAV for drag-and-drop file management and SOAP for integrated information management using Web services. The document-organization and -searching capabilities afforded by NETMARK are likely to make this software attractive for use in disciplines as diverse as science, auditing, and law enforcement

Comparative analysis of FBS containing media and serum free chemically defined media, CellCor for adipose derived stem cells production

Background: As a result of the aging society, the average OECD life expectancy has grown to about 80 years, yet the average health life still remains at only 65 years, leaving more than 15 years of life in an uncertain health state. Regenerative medicine is a new concept of medicine that combines cells and biomaterials to restore the functions of aged or damaged tissues or organs. It is also a good treatment for chronic diseases and incurable diseases, receiving attention as a new paradigm for treating diseases. Problems: As the market for regenerative medicine grows, mass production of consistent quality cells is required. Media is the most important thing in mass production of consistent quality cells. However, the fetal bovine serum (FBS) containing media that is currently wide used has many problems, such as unidentified viral infection, immunogenicity, lot variations, unstable supply, and ethical issues. To solve these problems and make rapid progress in regenerative medicine, a high-performance serum free chemically defined media (CDM) is needed. Solution: CellCor is a serum free CDM that provides excellent performance, safety, economy and consistency in stem cell production. CellCor allows higher-speed cell production rate than current FBS containing culture media (Figure 1). Compared to the FBS containing media, CellCor is able to maintain stem cell markers, higher population homogeneity, genetic stability, and excellent differentiation potency even at later passage. Please click Additional Files below to see the full abstract

Heterotrophic Flagellates from Freshwater and Soil Habitats in Subtropical China (Wuhan Area, Hubei Province)

We studied the diversity of heterotrophic flagellates from the sandy sediments of the Yangtze River, sandy and silty sediments of Donghu Lake, soil, moss and litter from the Luojiashan and Moshan hills as well as litter from the floodplain near Donghu Lake in April 2010. Sixty-seven heterotrophic flagellate species were identified by means of phase and interference contrast light microscopy and transmission electron microscopy. The majority of the observed flagellates were bacterivorous. Local species richness of river sediment communities was significantly lower than that of lake sediments and terrestrial habitats. The communities from the terrestrial habitats were more heterogeneous than those from freshwater sediments. Common species for the aquatic habitats were Rhynchomonas nasuta, Paraphysomonas sp., Neobodo designis, N. curvifilis, Bodo saltans and Spumella spp. In the soils only Spumella spp. was found in the majority of samples. Most characteristic taxa for the lake sediments were Helkesimastix faecicola, Petalomonas minuta, P. pusilla, Diphylleia rotans, Amastigomonas caudata. Amoeboflagellates such as Cercomonas angustus, C. granulifera, Paracercomonas crassicauda were specific for the terrestrial habitats. There were no specific taxa in the river sediments. The majority of the heterotrophic flagellates identified in this survey have been noted in China earlier. They are common (and usually predominant) for other regions in both freshwater and soil habitats

Papillorenal Syndrome-Causing Missense Mutations in PAX2/Pax2 Result in Hypomorphic Alleles in Mouse and Human

Papillorenal syndrome (PRS, also known as renal-coloboma syndrome) is an autosomal dominant disease characterized by potentially-blinding congenital optic nerve excavation and congenital kidney abnormalities. Many patients with PRS have mutations in the paired box transcription factor gene, PAX2. Although most mutations in PAX2 are predicted to result in complete loss of one allele's function, three missense mutations have been reported, raising the possibility that more subtle alterations in PAX2 function may be disease-causing. To date, the molecular behaviors of these mutations have not been explored. We describe a novel mouse model of PRS due to a missense mutation in a highly-conserved threonine residue in the paired domain of Pax2 (p.T74A) that recapitulates the ocular and kidney findings of patients. This mutation is in the Pax2 paired domain at the same location as two human missense mutations. We show that all three missense mutations disrupt potentially critical hydrogen bonds in atomic models and result in reduced Pax2 transactivation, but do not affect nuclear localization, steady state mRNA levels, or the ability of Pax2 to bind its DNA consensus sequence. Moreover, these mutations show reduced steady-state levels of Pax2 protein in vitro and (for p.T74A) in vivo, likely by reducing protein stability. These results suggest that hypomorphic alleles of PAX2/Pax2 can lead to significant disease in humans and mice

Photothermal responsivity of van der Waals material-based nanomechanical resonators

Nanomechanical resonators made from van der Waals materials (vdW NMRs) provide a new tool for sensing absorbed laser power. The photothermal response of vdW NMRs, quantified from the resonant frequency shifts induced by optical absorption, is enhanced when incorporated in a Fabry-Perot (FP) interferometer. Along with the enhancement comes the dependence of the photothermal response on NMR displacement, which lacks investigation. Here, we address the knowledge gap by studying electromotively driven niobium diselenide drumheads fabricated on highly reflective substrates. We use a FP-mediated absorptive heating model to explain the measured variations of the photothermal response. The model predicts a higher magnitude and tuning range of photothermal responses on few-layer and monolayer NbSe$_{2}$ drumheads, which outperform other clamped vdW drum-type NMRs at a laser wavelength of $532\,$nm. Further analysis of the model shows that both the magnitude and tuning range of NbSe$_{2}$ drumheads scale with thickness, establishing a displacement-based framework for building bolometers using FP-mediated vdW NMRs.Comment: 7 pages, 4 figure

Vitamin D and Exercise Are Major Determinants of Natural Killer Cell Activity, Which Is Age- and Gender-Specific

BackgroundThe coronavirus-19 disease (COVID-19) pandemic reminds us of the importance of immune function, even in immunologically normal individuals. Multiple lifestyle factors are known to influence the immune function.ObjectiveThe aim was to investigate the association between NK cell activity (NKA) and multiple factors including vitamin D, physical exercise, age, and gender.MethodsThis was a cross-sectional association study using health check-up and NKA data of 2,095 subjects collected from 2016 to 2018 in a health check-up center in the Republic of Korea. NKA was measured using the interferon-γ (IFN-γ) stimulation method. The association of NKA with 25-(OH)-vitamin D (25(OH)D) and other factors was investigated by multiple logistic regression analysis.ResultsThe average age of subjects was 48.8 ± 11.6 years (52.9% of subjects were female). Among 2,095 subjects, 1,427 had normal NKA (NKA ≥ 500 pg IFN-γ/mL), while 506 had low NKA (100 ≤ NKA < 500 pg/mL), and 162 subjects had very low NKA (NKA < 100 pg/mL). Compared to men with low 25(OH)D serum level (< 20 ng/mL), vitamin D replete men (30–39.9 ng/mL) had significantly lower risk of very low NKA (OR: 0.358; 95% CI: 0.138, 0.929; P = 0.035). In women, both low exercise (OR: 0.529; 95% CI: 0.299, 0.939; P = 0.030) and medium to high exercise (OR: 0.522; 95% CI: 0.277, 0.981; P = 0.043) decreased the risk compared to lack of physical exercise. Interestingly, in men and women older than 60 years, physical exercise significantly decreased the risk. Older-age was associated with increased risk of very low NKA in men, but not in women.ConclusionPhysical exercise and vitamin D were associated with NKA in a gender- and age-dependent manner. Age was a major risk factor of very low NKA in men but not in women