Structure of TAR RNA Complexed with a Tat-TAR Interaction Nanomolar Inhibitor that Was Identified by Computational Screening

AbstractHIV-1 TAR RNA functions critically in viral replication by binding the transactivating regulatory protein Tat. We recently identified several compounds that experimentally inhibit the Tat-TAR interaction completely at a 100 nM concentration. We used computational screening of the 181,000-compound Available Chemicals Directory against the three-dimensional structure of TAR [1]. Here we report the NMR-derived structure of TAR complexed with acetylpromazine. This structure represents a new class of compounds with good bioavailability and low toxicity that bind with high affinity to TAR. NMR data unambiguously show that acetylpromazine binds only to the unique 5′ bulge site to which the Tat protein binds. Specificity and affinity of binding are conferred primarily by a network of base stacking and hydrophobic interactions. Acetylpromazine alters the structure of free TAR less than Tat peptides and neomycin do

High-Performance Multi-Mode Ptychography Reconstruction on Distributed GPUs

Ptychography is an emerging imaging technique that is able to provide wavelength-limited spatial resolution from specimen with extended lateral dimensions. As a scanning microscopy method, a typical two-dimensional image requires a number of data frames. As a diffraction-based imaging technique, the real-space image has to be recovered through iterative reconstruction algorithms. Due to these two inherent aspects, a ptychographic reconstruction is generally a computation-intensive and time-consuming process, which limits the throughput of this method. We report an accelerated version of the multi-mode difference map algorithm for ptychography reconstruction using multiple distributed GPUs. This approach leverages available scientific computing packages in Python, including mpi4py and PyCUDA, with the core computation functions implemented in CUDA C. We find that interestingly even with MPI collective communications, the weak scaling in the number of GPU nodes can still remain nearly constant. Most importantly, for realistic diffraction measurements, we observe a speedup ranging from a factor of $10$ to $10^3$ depending on the data size, which reduces the reconstruction time remarkably from hours to typically about 1 minute and is thus critical for real-time data processing and visualization.Comment: work presented in NYSDS 201

Non-ancient solution of the Ricci flow

For any complete noncompact K$\ddot{a}$hler manifold with nonnegative and bounded holomorphic bisectional curvature,we provide the necessary and sufficient condition for non-ancient solution to the Ricci flow in this paper.Comment: seven pages, latex fil

Integrable dispersionless KdV hierarchy with sources

An integrable dispersionless KdV hierarchy with sources (dKdVHWS) is derived. Lax pair equations and bi-Hamiltonian formulation for dKdVHWS are formulated. Hodograph solution for the dispersionless KdV equation with sources (dKdVWS) is obtained via hodograph transformation. Furthermore, the dispersionless Gelfand-Dickey hierarchy with sources (dGDHWS) is presented.Comment: 15 pages, to be published in J. Phys. A: Math. Ge

Crystal structure of the third KH domain of human poly(C)-binding protein-2 in complex with a C-rich strand of human telomeric DNA at 1.6 Å resolution

KH (hnRNP K homology) domains, consisting of ∼70 amino acid residues, are present in a variety of nucleic-acid-binding proteins. Among these are poly(C)-binding proteins (PCBPs), which are important regulators of mRNA stability and posttranscriptional regulation in general. All PCBPs contain three different KH domains and recognize poly(C)-sequences with high affinity and specificity. To reveal the molecular basis of poly(C)-sequence recognition, we have determined the crystal structure, at 1.6 Å resolution, of PCBP2 KH3 domain in complex with a 7-nt DNA sequence (5′-AACCCTA-3′) corresponding to one repeat of the C-rich strand of human telomeric DNA. The domain assumes a type-I KH fold in a βααββα configuration. The protein–DNA interface could be studied in unprecedented detail and is made up of a series of direct and water-mediated hydrogen bonds between the protein and the DNA, revealing an especially dense network involving several structural water molecules for the last 2 nt in the core recognition sequence. Unlike published KH domain structures, the protein crystallizes without protein–protein contacts, yielding new insights into the dimerization properties of different KH domains. A nucleotide platform, an interesting feature found in some RNA molecules, was identified, evidently for the first time in DNA

Creating an International Forage and Grasslands Curriculum

Grasslands cover nearly 2/3 of the land masses of the world and make up 1/4 of the earth\u27s surface. Although various regions of the world have different names for their grasslands, common management principles govern maintaining and improving these lands for the food production and environmental services they provide. There is much talk today about “finding the balance between environmental protection and economic development” but there is little evidence of knowledge about grassland ecosystems being translated into effectively implemented policies designed to restore degraded grasslands. In contrast, there are many examples of the tragic consequences of economic development rather than biological capacity driving decision-making. Historically, people were connected with the land and understood the soil, plant, animal, human “circle of life.” This understanding led to appropriate management. Today, the vast majority of the developed world has little understanding of these natural processes and increasing percentages of the developing world live in cities and are disconnected from the natural ecosystems that service them. Even those few studying agricultural sciences have little appreciation for the scope and diversity of grasslands present in the world. Far fewer have an understanding of the importance of grasslands management principles and needed supporting policies. Thus, there is a need for teaching materials that can be used worldwide to convey the importance and proper management of grasslands and forage-livestock systems

Editorial: Epigenetic Regulation in Cardiovascular Diseases

Cardiovascular disease (CVD) is the leading cause of death globally. Progress in the diagnosis, prevention, and treatment of CVD is contingent on the advancement of our knowledge to explain the complex pathophysiology underlying CVD in which gene expression re-programming plays a fundamental role. Emerging evidence highlights the impact of epigenetic regulation on the transition of gene expression patterns from physiological to pathological states. Epigenetics, originally defined as stably heritable phenotypes resulting from changes in a chromosome without alterations in the DNA sequence, is now more broadly understood to encompass any modification to DNA structure or function that influences phenotypes related to development or disease other than an actual change to the sequence. The epigenetic environment of a gene is mostly determined by DNA methylation, histone modifications, and chromatin remodeling. Various writers, readers, and erasers for different epigenetic marks have been discovered, and their dysfunction tightly correlates with the development of CVD. Research elucidating epigenetic regulations in this field have, in turn, promoted novel drug discoveries to treat CVD. The identification of novel epigenetic players in CVD and how they act to fine-tune molecular processes would help expand our understanding of the complexity of cardiovascular pathophysiology. In the current Research Topic, we have collected 16 high-quality studies that cover promising, recent, and novel research trends in the epigenetic regulation of CVD

Tumor exome sequencing and copy number alterations reveal potential predictors of intrinsic resistance to multi-targeted tyrosine kinase inhibitors

Multi-targeted tyrosine kinase inhibitors (TKIs) have broad efficacy and similar FDA-approved indications, suggesting shared molecular drug targets across cancer types. Irrespective of tumor type, 20-30% of patients treated with multi-targeted TKIs demonstrate intrinsic resistance, with progressive disease as a best response. We conducted a retrospective cohort study to identify tumor (somatic) point mutations, insertion/deletions, and copy number alterations (CNA) associated with intrinsic resistance to multi-targeted TKIs. Using a candidate gene approach (n=243), tumor next-generation sequencing and CNA data was associated with resistant and non-resistant outcomes. Resistant individuals (n=11) more commonly harbored somatic point mutations in NTRK1, KDR, TGFBR2, and PTPN11 and CNA in CDK4, CDKN2B, and ERBB2 compared to non-resistant (n=26, p<0.01). Using a random forest classification model for variable reduction and a decision tree classification model, we were able to differentiate intrinsically resistant from non-resistant patients. CNA in CDK4 and CDKN2B were the most important analytical features, implicating the cyclin D pathway as a potentially important factor in resistance to multi-targeted TKIs. Replication of these results in a larger, independent patient cohort has potential to inform personalized prescribing of these widely utilized agents