The competitive landscape of the dsRNA world.

The ability to sense and respond to infection is essential for life. Viral infection produces double-stranded RNAs (dsRNAs) that are sensed by proteins that recognize the structure of dsRNA. This structure-based recognition of viral dsRNA allows dsRNA sensors to recognize infection by many viruses, but it comes at a cost-the dsRNA sensors cannot always distinguish between "self" and "nonself" dsRNAs.

ScanFold 2.0: a rapid approach for identifying potential structured RNA targets in genomes and transcriptomes.

A major limiting factor in target discovery for both basic research and therapeutic intervention is the identification of structural and/or functional RNA elements in genomes and transcriptomes. This was the impetus for the original ScanFold algorithm, which provides maps of local RNA structural stability, evidence of sequence-ordered (potentially evolved) structure, and unique model structures comprised of recurring base pairs with the greatest structural bias. A key step in quantifying this propensity for ordered structure is the prediction of secondary structural stability for randomized sequences which, in the original implementation of ScanFold, is explicitly evaluated.

Synthesis and reactivity of donor stabilized thionylium (SO) dications.

Robust mono-, di-, and tridentate base-stabilized thionylium (SO) dications were synthesized from the treatment of SOCl with MeSiOSCF and pyridine-based ligands. Computational and experimental data are consistent with Lewis acidities comparable to BF and PF and these compounds were shown to activate C-F bonds of fluoroalkanes. These dications also react with PhPO and CuO to effect O abstraction in an overall redox-neutral deoxygenation process driven by the evolution of SO.

Analyses of human cancer driver genes uncovers evolutionarily conserved RNA structural elements involved in posttranscriptional control.

Experimental breakthroughs have provided unprecedented insights into the genes involved in cancer. The identification of such cancer driver genes is a major step in gaining a fuller understanding of oncogenesis and provides novel lists of potential therapeutic targets. A key area that requires additional study is the posttranscriptional control mechanisms at work in cancer driver genes.

Prediction and analysis of functional RNA structures within the integrative genomics viewer.

In recent years, interest in RNA secondary structure has exploded due to its implications in almost all biological functions and its newly appreciated capacity as a therapeutic agent/target. This surge of interest has driven the development and adaptation of many computational and biochemical methods to discover novel, functional structures across the genome/transcriptome. To further enhance efforts to study RNA secondary structure, we have integrated the functional secondary structure prediction tool ScanFold, into IGV.

9-BBN and chloride catalyzed reduction of chlorophosphines to phosphines and diphosphines.

The commercially available Lewis acid, 9-BBN and Lewis basic [EtN]Cl are used as catalysts for the reduction of chlorophosphines RPCl in the presence of phenylsilane. Aryl-chlorophosphines afford primarily diphosphines (PR) while secondary phosphines predominate for alkyl-substituted precursors. Use of the combined catalysts leads to reduced reaction time and temperature, providing a rapid, scalable, and facile protocol for the preparation of diphosphines or secondary phosphines.

Multiresponsive Cyclometalated Crown Ether Bearing a Platinum(II) Metal Center.

Multiresponsive materials can adapt to numerous changes in their local environment, which makes them highly valuable for various applications. Although nanostructured and polymeric multiresponsive materials are plentiful, small-molecule analogues are scarce. This work presents a compact cyclometalated platinum(II) complex that bears a crown ether cavity (-Pt); the intimate ring/emitter connectivity is key to unlocking multiresponsiveness.

Bipyridinium and Phenanthrolinium Dications for Metal-Free Hydrodefluorination: Distinctive Carbon-Based Reactivity.

The development of novel Lewis acids derived from bipyridinium and phenanthrolinium dications is reported. Calculations of Hydride Ion Affinity (HIA) values indicate high carbon-based Lewis acidity at the ortho and para positions. This arises in part from extensive LUMO delocalization across the aromatic backbones.

A map of the SARS-CoV-2 RNA structurome.

SARS-CoV-2 has exploded throughout the human population. To facilitate efforts to gain insights into SARS-CoV-2 biology and to target the virus therapeutically, it is essential to have a roadmap of likely functional regions embedded in its RNA genome. In this report, we used a bioinformatics approach, ScanFold, to deduce the RNA structural landscape of the SARS-CoV-2 genome with the highest likelihood of being functional.

Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders.

COVID-19 is a global pandemic, thus requiring multiple strategies to develop modalities against it. Herein, we designed multiple bioactive small molecules that target a functional structure within the SARS-CoV-2's RNA genome, the causative agent of COVID-19. An analysis to characterize the structure of the RNA genome provided a revised model of the SARS-CoV-2 frameshifting element, in particular its attenuator hairpin.

A survey of RNA secondary structural propensity encoded within human herpesvirus genomes: global comparisons and local motifs.

There are nine herpesviruses known to infect humans, of which Epstein-Barr virus (EBV) is the most widely distributed (>90% of adults infected). This ubiquitous virus is implicated in a variety of cancers and autoimmune diseases. Previous analyses of the EBV genome revealed numerous regions with evidence of generating unusually stable and conserved RNA secondary structures and led to the discovery of a novel class of EBV non-coding (nc)RNAs: the stable intronic sequence (sis)RNAs.

Design of small molecules targeting RNA structure from sequence.

The design and discovery of small molecule medicines has largely been focused on a small number of druggable protein families. A new paradigm is emerging, however, in which small molecules exert a biological effect by interacting with RNA, both to study human disease biology and provide lead therapeutic modalities. Due to this potential for expanding target pipelines and treating a larger number of human diseases, robust platforms for the rational design and optimization of small molecules interacting with RNAs (SMIRNAs) are in high demand.

An map of the SARS-CoV-2 RNA Structurome.

SARS-CoV-2 is a positive-sense single-stranded RNA virus that has exploded throughout the global human population. This pandemic coronavirus strain has taken scientists and public health researchers by surprise and knowledge of its basic biology (e.g.

translational machinery condones polyadenosine repeats.

is a causative agent of human malaria. Sixty percent of mRNAs from its extremely AT-rich (81%) genome harbor long polyadenosine (polyA) runs within their ORFs, distinguishing the parasite from its hosts and other sequenced organisms. Recent studies indicate polyA runs cause ribosome stalling and frameshifting, triggering mRNA surveillance pathways and attenuating protein synthesis.

Structural Elucidation of Selective Solvatochromism in a Responsive-at-Metal Cyclometalated Platinum(II) Complex.

We report the synthesis, characterization, and spectroscopic investigations of a new responsive-at-metal cyclometalated platinum(II) complex. With mild chemical oxidants and reductants, it was possible to obtain the same complex in three different oxidation states and each of these complexes was structurally characterized by single-crystal X-ray diffraction. We discovered that the platinum(II) complex displays strong solvatochromism in the solid state, which can be attributed to modulation of Pt⋅⋅⋅Pt interactions that results in switching between optical and photoluminescent states.

Isolable Anionic, Neutral and Cationic Radicals from Reactions of N,N'-Dimesityldiamidocarbene and Lewis Acids.

B(C F ) undergoes nucleophilic attack by N,N'-dimesityldiamidocarbene (DAC) with fluoride transfer to the boron center, resulting in a new zwitterion (1). This B-F fluoride can be replaced or abstracted to give the corresponding hydride (2) or triflate (3) derivatives or the corresponding cation (4). These species are reduced with KC or Cp Co to give isolable anionic and neutral radicals (5-8).

Cardiorespiratory Fitness Is Associated With Better Cardiometabolic Health and Lower PTSD Severity in Post-9/11 Veterans.

Introduction: Post-traumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular and metabolic diseases and physical inactivity. Cardiorespiratory fitness (CRF), which is modifiable by physical activity, is a strong independent predictor of cardiometabolic health. However, the relationship between CRF and cardiometabolic health in veterans with PTSD is unknown.

Structure-Specific Cleavage of an RNA Repeat Expansion with a Dimeric Small Molecule Is Advantageous over Sequence-Specific Recognition by an Oligonucleotide.

Myotonic dystrophy type 2 (DM2) is a genetically defined muscular dystrophy that is caused by an expanded repeat of r(CCUG) [r(CCUG)] in intron 1 of a CHC-type zinc finger nucleic acid binding protein () pre-mRNA. Various mechanisms contribute to DM2 pathology including pre-mRNA splicing defects caused by sequestration of the RNA splicing regulator muscleblind-like-1 (MBNL1) by r(CCUG). Herein, we study the biological impacts of the molecular recognition of r(CCUG)'s structure by a designer dimeric small molecule that directly cleaves the RNA in patient-derived cells.

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA.

Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the gene.

Mapping the RNA structural landscape of viral genomes.

Functional RNA structures are prevalent in viral genomes, and have been shown to play roles in almost every aspect of their biology. However, the majority of viral RNA remains structurally uncharacterized. This is likely to remain true as the cost of sequencing decreases much faster than the cost of structural characterizations.

Crowder-Induced Conformational Ensemble Shift in Escherichia coli Prolyl-tRNA Synthetase.

The effect of molecular crowding on the structure and function of Escherichia coli prolyl-transfer RNA synthetase (Ec ProRS), a member of the aminoacyl-transfer RNA synthetase family, has been investigated using a combined experimental and theoretical method. Ec ProRS is a multidomain enzyme; coupled-domain dynamics are essential for efficient catalysis. To gain insight into the mechanistic detail of the crowding effect, kinetic studies were conducted with varying concentrations and sizes of crowders.

RNA structural analysis of the MYC mRNA reveals conserved motifs that affect gene expression.

The MYC gene encodes a human transcription factor and proto-oncogene that is dysregulated in over half of all known cancers. To better understand potential post-transcriptional regulatory features affecting MYC expression, we analyzed secondary structures in the MYC mRNA using a program that is optimized for finding small locally-folded motifs with a high propensity for function. This was accomplished by calculating folding metrics across the MYC sequence using a sliding analysis window and generating unique consensus base pairing models weighted by their lower-than-random predicted folding energy.

Computational approaches for the discovery of splicing regulatory RNA structures.

Global RNA structure and local functional motifs mediate interactions important in determining the rates and patterns of mRNA splicing. In this review, we overview approaches for the computational prediction of RNA secondary structure with a special emphasis on the discovery of motifs important to RNA splicing. The process of identifying and modeling potential splicing regulatory structures is illustrated using a recently-developed approach for RNA structural motif discovery, the ScanFold pipeline, which is applied to the identification of a known splicing regulatory structure in influenza virus.

Carbonyl and olefin hydrosilylation mediated by an air-stable phosphorus(iii) dication under mild conditions.

The readily-accessible, air-stable Lewis acid [(terpy)PPh][B(C6F5)4]21 is shown to mediate the hydrosilylation of aldehydes, ketones, and olefins. The utility and mechanism of these hydrosilylations are considered.

ScanFold: an approach for genome-wide discovery of local RNA structural elements-applications to Zika virus and HIV.

In addition to encoding RNA primary structures, genomes also encode RNA secondary and tertiary structures that play roles in gene regulation and, in the case of RNA viruses, genome replication. Methods for the identification of functional RNA structures in genomes typically rely on scanning analysis windows, where multiple partially-overlapping windows are used to predict RNA structures and folding metrics to deduce regions likely to form functional structure. Separate structural models are produced for each window, where the step size can greatly affect the returned model.