Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones.

Venezuelan and eastern equine encephalitis viruses are disease-causing, neuropathic pathogens with no approved treatment options in humans. While expanding the pharmacophoric model of antialphaviral amidines prepared via a quinazolinone rearrangement, we discovered that diamine-treated, 2-dihalomethylquinolinones unexpectedly afforded ring-expanded piperazine-fused benzodiazepinones. Notably, this new chemotype (19 examples) showed potent, submicromolar inhibition of virus-induced cell death, >7-log reduction of viral yield, and tractable structure-activity relationships across both viruses.

Interactive Clustered Heat Map Builder: An easy web-based tool for creating sophisticated clustered heat maps.

Clustered heat maps are the most frequently used graphics for visualization and interpretation of genome-scale molecular profiling data in biology.  Construction of a heat map generally requires the assistance of a biostatistician or bioinformatics analyst capable of working in R or a similar programming language to transform the study data, perform hierarchical clustering, and generate the heat map.  Our web-based Interactive Heat Map Builder can be used by investigators with no bioinformatics experience to generate high-caliber, publication quality maps.

Ruthenium-Catalyzed Asymmetric Allylic Alkylation of Isatins.

A new ruthenium-based catalytic system for branched-selective asymmetric allylic alkylation is disclosed and applied to the synthesis of chiral isatin derivatives. The catalyst, which is generated from commercially available CpRu(MeCN)PF and a BINOL-derived phosphoramidite, is both highly active (TON up to 180) and insensitive to air and moisture. Additionally, the -alkylated isatins accessible using this methodology are versatile building blocks that are readily transformed into chiral analogs of achiral drug molecules.

Mechanistic insights into copper-catalyzed aerobic oxidative coupling of N-N bonds.

Catalytic N-N coupling is a valuable transformation for chemical synthesis and energy conversion. Here, mechanistic studies are presented for two related copper-catalyzed oxidative aerobic N-N coupling reactions, one involving the synthesis of a pharmaceutically relevant triazole and the other relevant to the oxidative conversion of ammonia to hydrazine. Analysis of catalytic and stoichiometric N-N coupling reactions support an "oxidase"-type catalytic mechanism with two redox half-reactions: (1) aerobic oxidation of a Cu catalyst and (2) Cu-promoted N-N coupling.

Copper/TEMPO Redox Redux: Analysis of PCET Oxidation of TEMPOH by Copper(II) and the Reaction of TEMPO with Copper(I).

Copper salts and organic aminoxyls, such as TEMPO (2,2,6,6-tetramethylpiperidine--oxyl), are versatile catalysts for aerobic alcohol oxidation. Previous reports in the literature contain conflicting proposals concerning the redox interactions that take place between copper(I) and copper(II) salts with the aminoxyl and hydroxylamine species, TEMPO and TEMPOH, respectively. Here, we reinvestigate these reactions in an effort to resolve the conflicting claims in the literature.

Efficacy of Care for Blind Painful Eyes.

Purpose: Pain relief for a blind painful eye often follows an escalating paradigm of interventions. This study compares the efficacy of common interventions.

Methods: A retrospective chart review of blind painful eye cases was conducted at a single tertiary institution from April 2012 to December 2016.

Bridging the Chromosome-centric and Biology/Disease-driven Human Proteome Projects: Accessible and Automated Tools for Interpreting the Biological and Pathological Impact of Protein Sequence Variants Detected via Proteogenomics.

The Chromosome-centric Human Proteome Project (C-HPP) seeks to comprehensively characterize all protein products coded by the genome, including those expressed sequence variants confirmed via proteogenomics methods. The closely related Biology/Disease-driven Human Proteome Project (B/D-HPP) seeks to understand the biological and pathological associations of expressed protein products, especially those carrying sequence variants that may be drivers of disease. To achieve these objectives, informatics tools are required that interpret potential functional or disease implications of variant protein sequence detected via proteogenomics.

Cu-Catalyzed Aerobic Oxidative N-N Coupling of Carbazoles and Diarylamines Including Selective Cross-Coupling.

A Cu-catalyzed method has been identified for aerobic oxidative dimerization of carbazoles and diarylamines to the corresponding N-N coupled bicarbazoles and tetraarylhydrazines. The reactions proceed under mild conditions (1 atm O, 60-80 °C) with a catalyst composed of CuBr·dimethylsulfide and N, N-dimethylaminopyridine. Reactions between carbazole and diarylamines show unusually selective cross-coupling, even with a 1:1 ratio of the two substrates.

Radiation-induced alternative transcripts as detected in total and polysome-bound mRNA.

Alternative splicing is a critical event in the posttranscriptional regulation of gene expression. To investigate whether this process influences radiation-induced gene expression we defined the effects of ionizing radiation on the generation of alternative transcripts in total cellular mRNA (the transcriptome) and polysome-bound mRNA (the translatome) of the human glioblastoma stem-like cell line NSC11. For these studies, RNA-Seq profiles from control and irradiated cells were compared using the program SpliceSeq to identify transcripts and splice variations induced by radiation.

CRAVAT 4: Cancer-Related Analysis of Variants Toolkit.

Cancer sequencing studies are increasingly comprehensive and well powered, returning long lists of somatic mutations that can be difficult to sort and interpret. Diligent analysis and quality control can require multiple computational tools of distinct utility and producing disparate output, creating additional challenges for the investigator. The Cancer-Related Analysis of Variants Toolkit (CRAVAT) is an evolving suite of informatics tools for mutation interpretation that includes mutation mapping and quality control, impact prediction and extensive annotation, gene- and mutation-level interpretation, including joint prioritization of all nonsilent mutation consequence types, and structural and mechanistic visualization.

A Galaxy Implementation of Next-Generation Clustered Heatmaps for Interactive Exploration of Molecular Profiling Data.

Clustered heatmaps are the most frequently used graphics for visualization of molecular profiling data in biology. However, they are generally rendered as static, or only modestly interactive, images. We have now used recent advances in web technologies to produce interactive "next-generation" clustered heatmaps (NG-CHM) that enable extreme zooming and navigation without loss of resolution.

Assessment of a Tele-education System to Enhance Retinopathy of Prematurity Training by International Ophthalmologists-in-Training in Mexico.

Purpose: To evaluate a tele-education system developed to improve diagnostic competency in retinopathy of prematurity (ROP) by ophthalmologists-in-training in Mexico.

Design: Prospective, randomized cohort study.

Participants: Fifty-eight ophthalmology residents and fellows from a training program in Mexico consented to participate.

Indenylmetal Catalysis in Organic Synthesis.

Synthetic organic chemists have a long-standing appreciation for transition metal cyclopentadienyl complexes, of which many have been used as catalysts for organic transformations. Much less well known are the contributions of the benzo-fused relative of the cyclopentadienyl ligand, the indenyl ligand, whose unique properties have in many cases imparted differential reactivity in catalytic processes toward the synthesis of small molecules. In this Review, we present examples of indenylmetal complexes in catalysis and compare their reactivity to their cyclopentadienyl analogues, wherever possible.

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization.

A full account of our efforts toward an asymmetric redox bicycloisomerization reaction is presented in this article. Cyclopentadienylruthenium (CpRu) complexes containing tethered chiral sulfoxides were synthesized via an oxidative [3 + 2] cycloaddition reaction between an alkyne and an allylruthenium complex. Sulfoxide complex 1 containing a p-anisole moiety on its sulfoxide proved to be the most efficient and selective catalyst for the asymmetric redox bicycloisomerization of 1,6- and 1,7-enynes.

Development of a Coordinatively Unsaturated Chiral Indenylruthenium Catalyst.

An unprecedented coordinatively unsaturated chiral indenylruthenium complex 12 was designed and synthesized to provide additional coordination sites for Ru-catalyzed asymmetric transformations. In an attempt to catalyze an asymmetric enyne cycloisomerization reaction of 1,6-enyne, significant amounts of hydroxycyclization were observed. Up to 84:16 er of the hydroxycyclization product was obtained in 2-MeTHF.

Diagnostic Discrepancies in Retinopathy of Prematurity Classification.

Purpose: To identify the most common areas for discrepancy in retinopathy of prematurity (ROP) classification between experts.

Design: Prospective cohort study.

Participants: A total of 281 infants were identified as part of a multicenter, prospective, ROP cohort study from 7 participating centers.

Distinct epigenetic features of differentiation-regulated replication origins.

Background: Eukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status.

Results: To identify chromatin states and histone modifications that locally mark replication origins, we profiled origin distributions in eight human cell lines representing embryonic and differentiated cell types.

A Ruthenium/Phosphoramidite-Catalyzed Asymmetric Interrupted Metallo-ene Reaction.

Allylic chlorides prepared from commercially available trans-1,4-dichloro-2-butene were converted to trans-disubstituted 5- and 6-membered ring systems with perfect diastereoselectivity and high enantioselectivity under chiral ruthenium catalysis. These products contain stereodefined secondary and tertiary alcohols that originate from the trapping of an alkylruthenium intermediate with adventitious water. Key to the success of this transformation was the development of a new BINOL-based phosphoramidite ligand containing bulky substitution at its 3- and 3'-positions.

The Global Education Network for Retinopathy of Prematurity (Gen-Rop): Development, Implementation, and Evaluation of A Novel Tele-Education System (An American Ophthalmological Society Thesis).

Purpose: To describe the design, implementation, and evaluation of a tele-education system developed to improve diagnostic competency in retinopathy of prematurity (ROP) by ophthalmology residents.

Methods: A secure Web-based tele-education system was developed utilizing a repository of over 2,500 unique image sets of ROP. For each image set used in the system, a reference standard ROP diagnosis was established.

Influence of Fluorescein Angiography on the Diagnosis and Management of Retinopathy of Prematurity.

Purpose: To examine the influence of fluorescein angiography (FA) on the diagnosis and management of retinopathy of prematurity (ROP).

Design: Prospective cohort study.

Participants: Nine recognized ROP experts (3 pediatric ophthalmologists and 6 retina specialists) interpreted 32 sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images from infants with ROP.

Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation.

ColoWeb: a resource for analysis of colocalization of genomic features.

Background: Next-generation sequencing techniques such as ChIP-seq allow researchers to investigate the genomic position of nuclear components and events. These experiments provide researchers with thousands of regions of interest to probe in order to identify biological relevance. As the cost of sequencing decreases and its robustness increases, more and more researchers turn to genome-wide studies to better understand the genomic elements they are studying.

Color fundus photography versus fluorescein angiography in identification of the macular center and zone in retinopathy of prematurity.

Purpose: To examine the usefulness of fluorescein angiography (FA) in identifying the macular center and diagnosis of zone in patients with retinopathy of prematurity (ROP).

Design: Validity and reliability analysis of diagnostic tools.

Methods: Thirty-two sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images obtained from 16 eyes of 8 infants with ROP were compiled on a secure web site.