A comparative analysis of gamma and hadron families at the superhigh energies recorded in experiment Pamir

A comparative analysis of hadron and gamma families which have undergone the decascading procedure is made. Results are compared with different models of interactions. In hadron families with energies Summary E sub H sup gamma 20 TeV as well as in gamma families with energies Summary E sub gamma 70 TeV, increasing azimuthal anisotropy is observed

Serendipitous Discovery of Light-Induced \u3cem\u3e(In Situ)\u3c/em\u3e Formation of An Azo-Bridged Dimeric Sulfonated Naphthol as a Potent PTP1B Inhibito

Background Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Results Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. Conclusion We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds

Protein Expression, Characterization and Activity Comparisons of Wild Type and Mutant DUSP5 Proteins

Background The mitogen-activated protein kinases (MAPKs) pathway is critical for cellular signaling, and proteins such as phosphatases that regulate this pathway are important for normal tissue development. Based on our previous work on dual specificity phosphatase-5 (DUSP5), and its role in embryonic vascular development and disease, we hypothesized that mutations in DUSP5 will affect its function. Results In this study, we tested this hypothesis by generating full-length glutathione-S-transferase-tagged DUSP5 and serine 147 proline mutant (S147P) proteins from bacteria. Light scattering analysis, circular dichroism, enzymatic assays and molecular modeling approaches have been performed to extensively characterize the protein form and function. We demonstrate that both proteins are active and, interestingly, the S147P protein is hypoactive as compared to the DUSP5 WT protein in two distinct biochemical substrate assays. Furthermore, due to the novel positioning of the S147P mutation, we utilize computational modeling to reconstruct full-length DUSP5 and S147P to predict a possible mechanism for the reduced activity of S147P. Conclusion Taken together, this is the first evidence of the generation and characterization of an active, full-length, mutant DUSP5 protein which will facilitate future structure-function and drug development-based studies

Comment on “Synthesis, Characterization, and Structures of Persistent Aniline Radical Cation”: It Is a Protonated Aniline and Not an Aniline Radical Cation

The same, but different: The reaction of tri-tert-butylaniline (TBA) with AgSbF6 in CH2Cl2 produces a green-colored intermediate which undergoes decomposition to form a protonated aniline (TBAH+SbF6−). Crystals of the protonated aniline salt (see picture) were analyzed by X-ray diffraction and found to have the same crystal characteristics as the crystals of the supposed cation radical first identified in 2012

Bis(acetyl­acetonato-κ2 O,O′)(2-amino-1-methyl-1H-benzimidazole-κN 3)oxido­vanadium(IV)

The title mixed-ligand oxidovanadium(IV) compound, [VO(C5H7O2)2(C8H9N3)], contains a VIV atom in a distorted octahedral coordination, which is typical for such complexes. The vanadyl group and the N-heterocyclic ligand are cis to each other. The coordination bond is located at the endocyclic N atom of the benzimidazole ligand. Intra­molecular hydrogen bonds between the exo-NH2 group H atoms and acetyl­acetonate O atoms stabilize the crystal structure

Identification of inhibitors that target dual-specificity phosphatase 5 provide new insights into the binding requirements for the two phosphate pockets

Background: Dual-specificity phosphatase-5 (DUSP5) plays a central role in vascular development and disease. We present a p-nitrophenol phosphate (pNPP) based enzymatic assay to screen for inhibitors of the phosphatase domain of DUSP5. Methods: pNPP is a mimic of the phosphorylated tyrosine on the ERK2 substrate (pERK2) and binds the DUSP5 phosphatase domain with a Km of 7.6 ± 0.4 mM. Docking followed by inhibitor verification using the pNPP assay identified a series of polysulfonated aromatic inhibitors that occupy the DUSP5 active site in the region that is likely occupied by the dual-phosphorylated ERK2 substrate tripeptide (pThr-Glu-pTyr). Secondary assays were performed with full length DUSP5 with ERK2 as substrate. Results: The most potent inhibitor has a naphthalene trisulfonate (NTS) core. A search for similar compounds in a drug database identified suramin, a dimerized form of NTS. While suramin appears to be a potent and competitive inhibitor (25 ± 5 μM), binding to the DUSP5 phosphatase domain more tightly than the monomeric ligands of which it is comprised, it also aggregates. Further ligand-based screening, based on a pharmacophore derived from the 7 Å separation of sulfonates on inhibitors and on sulfates present in the DUSP5 crystal structure, identified a disulfonated and phenolic naphthalene inhibitor (CSD3 _2320) with IC50 of 33 μM that is similar to NTS and does not aggregate. Conclusions: The new DUSP5 inhibitors we identify in this study typically have sulfonates 7 Å apart, likely positioning them where the two phosphates of the substrate peptide (pThr-Glu-pTyr) bind, with one inhibitor also positioning a phenolic hydroxyl where the water nucleophile may reside. Polysulfonated aromatic compounds do not commonly appear in drugs and have a tendency to aggregate. One FDA-approved polysulfonated drug, suramin, inhibits DUSP5 and also aggregates. Docking and modeling studies presented herein identify polysulfonated aromatic inhibitors that do not aggregate, and provide insights to guide future design of mimics of the dual-phosphate loops of the ERK substrates for DUSPs. Keywords: DUSP5, Phosphatase, Drug discovery, Docking, Suramin, Vascular anomalie

Роль метилирования генов микроРНК в различных молекулярно-биологических подтипах рака молочной железы

The methylation of CpG islands in the promoter regions of miRNA genes is an epigenetic modification that plays a decisive role in the breast cancer (BC) initiation and progression. The aim of the study was to investigate the frequency of 5 miRNA genes methylation (miRNA-9–1, miRNA-9–3, miRNA-34b/c, miRNA-193A, miRNA-129-2) in mammary epithelial neoplasms. Methylation-specific polymerase chain reaction (MS-PCR) was used to detect methylated genes. 62 patients took part in this study. It was found that the frequency of all 5 miRNAs genes methylation is significantly higher in tumor tissue than in the adjacent histologically unchanged mammary tissue. The authors also performed a correlation analysis and founded a relationship between the methylation rate of certain miRNA genes with some clinical and molecular characteristics of the tumor. This information on epigenetic disorders of BC complements the “molecular portrait” of the tumor and can be used to diagnose and assess the prognosis.Метилирование промоторных CpG-островков генов микроРНК (миРНК) при раке молочной железы (РМЖ) – эпигенетическая модификация, которая играет решающую роль в инициировании и прогрессировании заболевания. В данной статье представлено исследование, цель которого – изучить частоту метилирования пяти генов миРНК (миРНК-9–1, миРНК- 9–3, миРНК-34b/c, миРНК-193a, миРНК-129-2) в эпителиальных опухолях молочной железы. Для выявления метилированных генов использовался метод полимеразной цепной реакции, специфичной к метилированному аллелю (МС-ПЦР). В исследовании приняли участие 62 пациентки. Оказалось, что частота метилирования генов всех пяти миРНК достоверно выше в опухолевой ткани, чем в прилежащей гистологически неизмененной ткани молочных желез. Авторы также провели корреляционный анализ и выявили связь частоты метилирования определенных генов миРНК с некоторыми клиническими и молекулярными характеристиками опухоли. Полученные данные об эпигенетических нарушениях при РМЖ дополняют «молекулярный портрет» опухоли и являются перспективными маркерами для диагностики и оценки прогноза, а также могут стать мишенью для успешной терапии