Small Molecule Inhibitors of Topoisomerase I Identified by Machine Learning and In Vitro Assays.

Tuberculosis (TB) caused by is a leading infectious cause of death globally. The treatment of patients becomes much more difficult for the increasingly common multi-drug resistant TB. Topoisomerase I is essential for the viability of and has been validated as a new target for the discovery of novel treatment against TB resistant to the currently available drugs.

Poleward shifts and altered periodicity in boreal bird irruptions over six decades.

Range boundaries are long-term biogeographic features of species distributions and abundance. However, many species demonstrate dynamic range boundaries, reflecting strong seasonal and annual variability in migratory behaviour. As a form of facultative migration, irruptions involve the movement of many individuals outside of their resident range in response to climate variability, resource availability, and demographic processes.

Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer.

The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated.

Improved performance of SPECT-CT In-111 capromab pendetide by correlation with diffusion-weighted magnetic resonance imaging for identifying metastatic pelvic lymphadenopathy in prostate cancer.

Purpose: To preliminarily evaluate the potential for an improvement in diagnostic performance by a combined interpretation of In-111 capromab pendetide single photon emission computed tomography (SPECT) including computed tomography (CT) image fusion with magnetic resonance diffusion-weighted imaging (MR-DWI) for identifying prostate cancer in pelvic lymph nodes thru correlation with histopathology.

Materials And Methods: This institutional approved, retrospective study identified patients with available histopathology of lymph nodes removed at the time of radical prostatectomy and who had undergone staging with In-111 capromab pendetide SPECT-CT and/or pelvic MRI (including DWI). The performance of In-111 capromab pendetide SPECT for identifying malignant lymph nodes was assessed.

The wicked problem of China's disappearing coral reefs.

We examined the development of coral reef science and the policies, institutions, and governance frameworks for management of coral reefs in China in order to highlight the wicked problem of preserving reefs while simultaneously promoting human development and nation building. China and other sovereign states in the region are experiencing unprecedented economic expansion, rapid population growth, mass migration, widespread coastal development, and loss of habitat. We analyzed a large, fragmented literature on the condition of coral reefs in China and the disputed territories of the South China Sea.

Price to be paid for two-metal catalysis: magnesium ions that accelerate chemistry unavoidably limit product release from a protein kinase.

Incorporation of divalent metal ions into an active site is a fundamental catalytic tool used by diverse enzymes. Divalent cations are used by protein kinases to both stabilize ATP binding and accelerate chemistry. Kinetic analysis establishes that Cyclin-dependent kinase 2 (CDK2) requires simultaneous binding of two Mg(2+) ions for catalysis of phosphoryl transfer.

Briefly bound to activate: transient binding of a second catalytic magnesium activates the structure and dynamics of CDK2 kinase for catalysis.

We have determined high-resolution crystal structures of a CDK2/Cyclin A transition state complex bound to ADP, substrate peptide, and MgF(3)(-). Compared to previous structures of active CDK2, the catalytic subunit of the kinase adopts a more closed conformation around the active site and now allows observation of a second Mg(2+) ion in the active site. Coupled with a strong [Mg(2+)] effect on in vitro kinase activity, the structures suggest that the transient binding of the second Mg(2+) ion is necessary to achieve maximum rate enhancement of the chemical reaction, and Mg(2+) concentration could represent an important regulator of CDK2 activity in vivo.

Structure of a thyroid hormone receptor DNA-binding domain homodimer bound to an inverted palindrome DNA response element.

Thyroid hormone receptor (TR), as a member of the nuclear hormone receptor family, can recognize and bind different classes of DNA response element targets as either a monomer, a homooligomer, or a heterooligomer. We report here the first crystal structure of a homodimer TR DNA-binding domain (DBD) in complex with an inverted repeat class of thyroid response element (TRE). The structure shows a nearly symmetric structure of the TR DBD assembled on the F2 TRE where the base recognition contacts in the homodimer DNA complex are conserved relative to the previously published structure of a TR-9-cis-retinoic acid receptor heterodimer DNA complex.

Regulation of luteinizing hormone receptor mRNA expression by mevalonate kinase--role of the catalytic center in mRNA recognition.

We have shown that hormone-induced downregulation of luteinizing hormone receptor (LHR) in the ovary is post-transcriptionally regulated by an mRNA binding protein. This protein, later identified as mevalonate kinase (MVK), binds to the coding region of LHR mRNA, suppresses its translation, and the resulting ribonucleoprotein complex is targeted for degradation. Mutagenesis and crystallographic studies of rat MVK have established Ser146, Glu193, Asp204 and Lys13 as being crucial for its catalytic function.

Surface-enhanced hyper-Raman scattering (SEHRS) on Ag film over Nanosphere (FON) electrodes: surface symmetry of centrosymmetric adsorbates.

Electrochemical surface-enhanced hyper-Raman scattering (SEHRS) and surface-enhanced Raman scattering (SERS) of centrosymmetric molecules on Ag film over nanosphere (AgFON) electrodes are presented. The SEHR spectra of trans-1,2-bis(4-pyridyl)ethylene (BPE) at different potentials (vs Ag/AgCl) are presented for the first time, and a reversible potential tuning of the SEHR spectra of BPE is demonstrated. The SEHRS and SERS techniques were used to determine to what extent either site symmetry reduction or field gradient effects dictate the origin of the observed vibrational spectra.

Wavelength-scanned surface-enhanced Raman excitation spectroscopy.

A detailed wavelength-scanned surface-enhanced Raman excitation spectroscopy (WS SERES) study of benzenethiol adsorbed on Ag nanoparticle arrays, fabricated by nanosphere lithography (NSL), is presented. These NSL-derived Ag nanoparticle array surfaces are both structurally well-characterized and extremely uniform in size. The WS SERES spectra are correlated, both spatially and spectrally, with the corresponding localized surface plasmon resonance (LSPR) spectra of the nanoparticle arrays.

Surface enhanced Raman spectroscopy: new materials, concepts, characterization tools, and applications.

Surface-enhanced Raman spectroscopy (SERS) is currently experiencing a renaissance in its development driven by the remarkable discovery of single molecule SERS (SMSERS) and the explosion of interest in nanophotonics and plasmonics. Because excitation of the localized surface plasmon resonance (LSPR) of a nanostructured surface or nanoparticle lies at the heart of SERS, it is important to control all of the factors influencing the LSPR in order to maximize signal strength and ensure reproducibility. These factors include material, size, shape, interparticle spacing, and dielectric environment.

A Src-like inactive conformation in the abl tyrosine kinase domain.

The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src.

Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.

We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl.

Rapid detection of an anthrax biomarker by surface-enhanced Raman spectroscopy.

A rapid detection protocol suitable for use by first-responders to detect anthrax spores using a low-cost, battery-powered, portable Raman spectrometer has been developed. Bacillus subtilis spores, harmless simulants for Bacillus anthracis, were studied using surface-enhanced Raman spectroscopy (SERS) on silver film over nanosphere (AgFON) substrates. Calcium dipicolinate (CaDPA), a biomarker for bacillus spores, was efficiently extracted by sonication in nitric acid and rapidly detected by SERS.

Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. I. Research design and results on d(CpG) steps.

We describe herein a computationally intensive project aimed at carrying out molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base sequences. This initiative was undertaken by an international collaborative effort involving nine research groups, the "Ascona B-DNA Consortium" (ABC). Calculations were carried out on the 136 cases imbedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs.

Structural basis for the autoinhibition of c-Abl tyrosine kinase.

c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks a phosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it.

Assessment of the molecular dynamics structure of DNA in solution based on calculated and observed NMR NOESY volumes and dihedral angles from scalar coupling constants.

To assess the accuracy of the molecular dynamics (MD) models of nucleic acids, a detailed comparison between MD-calculated and NMR-observed indices of the dynamical structure of DNA in solution has been carried out. The specific focus of our comparison is the oligonucleotide duplex, d(CGCGAATTCGCG)(2), for which considerable structural data have been obtained from crystallography and NMR spectroscopy. An MD model for the structure of d(CGCGAATTCGCG)(2) in solution, based on the AMBER force field, has been extended with a 14 ns trajectory.

Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases.

The early stage of chronic myelogenous leukemia (CML) is caused by the tyrosine kinase Bcr-Abl. Imatinib mesylate (also known as STI-571 and Gleevec), a tyrosine kinase inhibitor, has shown encouraging results in CML clinical trials and has become a paradigm for targeted cancer therapeutics. Recent reports of resistance to imatinib argue for further development of therapies for CML.