Transcriptome analysis of collagen VI-related muscular dystrophy muscle biopsies.

Objective: To define the transcriptomic changes responsible for the histologic alterations in skeletal muscle and their progression in collagen VI-related muscular dystrophy (COL6-RD).

Methods: COL6-RD patient muscle biopsies were stratified into three groups based on the overall level of pathologic severity considering degrees of fibrosis, muscle fiber atrophy, and fatty replacement of muscle tissue. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared their transcriptome with age- and sex-matched controls.

Effect of Caregiver Depressive Symptoms on the Concordance Between Caregiver and Youth Assessment of Youth Physical Health.

Objectives: To explore how caregivers' (birth parents, adoptive parents, relative caregivers, and unrelated caregivers) depressive symptoms moderate the concordance between their and their youth's assessment of the youth's physical health symptoms, diseases, and physical health status.

Methods: Participants included 224 youth with mean age of 18.0 years (SD = 1.

Photoredox-mediated hydroalkylation and hydroarylation of functionalized olefins for DNA-encoded library synthesis.

DNA-encoded library (DEL) technology features a time- and cost-effective interrogation format for the discovery of therapeutic candidates in the pharmaceutical industry. To develop DEL platforms, the implementation of water-compatible transformations that facilitate the incorporation of multifunctional building blocks (BBs) with high C(sp) carbon counts is integral for success. In this report, a decarboxylative-based hydro of DNA-conjugated trifluoromethyl-substituted alkenes enabled by single-electron transfer (SET) and subsequent hydrogen atom termination through electron donor-acceptor (EDA) complex activation is detailed.

Solid-Phase Photochemical Decarboxylative Hydroalkylation of Peptides.

The compatibility of photochemistry with solid-phase peptide synthesis is demonstrated via photochemical hydroalkylation to form C(sp)-C(sp) bonds between on-resin Giese acceptors and redox-active esters. Both iridium-based photocatalysts and Hantszch ester led to high yields, with final reaction conditions producing full conversions within 30 min under ambient conditions. The chemistry is compatible with a broad range of peptide side chains, redox-active esters, and resin.

Excited-State Dynamics and Nonlinear Optical Properties of Hyperpolarizable Chromophores Based on Conjugated Bis(terpyridyl)Ru(II) and Palladium and Platinum Porphyrinic Components: Impact of Heavy Metals upon Supermolecular Electro-Optic Properties.

A new series of strongly coupled oscillators based upon (porphinato)Pd, (porphinato)Pt, and bis(terpyridyl)ruthenium(II) building blocks is described. These , , , and chromophores feature bis(terpyridyl)Ru(II) moieties connected to the (porphinato)metal unit via an ethyne linker that bridges the 4'-terpyridyl and porphyrin macrocycle -carbon positions. Pump-probe transient optical data demonstrate sub-picosecond excited singlet-to-triplet-state relaxation.

Elucidation of Thorium Redox-Active Ligand Complexes: Evidence for a Thorium-Tri(radical) Species.

A series of thorium(IV) complexes featuring the redox-active 4,6-di--butyl--(2,6-di-isopropylphenyl)--iminobenzoquinone (iq) ligand family have been synthesized and characterized. The neutral iminoquinone ligand was used to generate Th(iq)Cl(dme) () and Th(iq)Cl (), both of which show dative bonds between the thorium(IV) ion and the ligands. One electron reduction of the ligand forms the unique tris(iminosemiquinone) complex, Th(isq)Cl (), which features a radical in each ligand.

Mindful of personality trait change: Are treatment effects on personality trait change ephemeral and attributable to changes in states?

Objective: Are treatment effects on personality trait change ephemeral and attributable to change in clinical states? Data of an intervention study were used to examine if change in clinical states (e.g., stress or depression) accounts for change in personality traits and to test whether both changes in traits and clinical states were independently associated with substance use.

Palladium-catalyzed benzylic C(sp)-H carbonylative arylation of azaarylmethyl amines with aryl bromides.

A highly selective palladium-catalyzed carbonylative arylation of weakly acidic benzylic C(sp)-H bonds of azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. This work represents the first examples of use of such weakly acidic pronucleophiles in this class of transformations. In the presence of a NIXANTPHOS-based palladium catalyst, this one-pot cascade process allows a range of azaarylmethylamines containing pyridyl, quinolinyl and pyrimidyl moieties and acyclic and cyclic amines to undergo efficient reactions with aryl bromides and CO to provide α-amino aryl-azaarylmethyl ketones in moderate to high yields with a broad substrate scope and good tolerance of functional groups.

Selectivity in the Elaboration of Bicyclic Borazarenes.

Among aromatic compounds, borazarenes represent a significant class of isosteres in which carbon-carbon bonds have been replaced by B-N bonds. Described herein is a summary of the selective reactions that have been developed for known systems, as well as a summary of computationally-based predictions of selectivities that might be anticipated in reactions of yet unrealized substructures.

Photoinduced 1,2-dicarbofunctionalization of alkenes with organotrifluoroborate nucleophiles radical/polar crossover.

Alkene 1,2-dicarbofunctionalizations are highly sought-after transformations as they enable a rapid increase of molecular complexity in one synthetic step. Traditionally, these conjunctive couplings proceed through the intermediacy of alkylmetal species susceptible to deleterious pathways including β-hydride elimination and protodemetalation. Herein, an intermolecular 1,2-dicarbofunctionalization using alkyl -(acyloxy)phthalimide redox-active esters as radical progenitors and organotrifluoroborates as carbon-centered nucleophiles is reported.

Aryl Fluoride Activation Through Palladium-Magnesium Bimetallic Cooperation: A Mechanistic and Computational Study.

Herein is described a mechanistic study of a palladium-catalyzed cross-coupling of aryl Grignard reagents to fluoroarenes that proceeds via a low-energy heterobimetallic oxidative addition pathway. Traditional oxidative additions of aryl chlorides to Pd complexes are known to be orders of magnitude faster than with aryl fluorides, and many palladium catalysts do not activate aryl fluorides at all. The experimental and computational studies outlined herein, however, support the view that at elevated Grignard : ArX ratios (i.

Phosphorus and Arsenic Atom Transfer to Isocyanides to Form π-Backbonding Cyanophosphide and Cyanoarsenide Titanium Complexes.

Decarbonylation along with E atom transfer from Na(OCE) (E=P, As) to an isocyanide coordinated to the tetrahedral Ti complex [(Tp )TiCl], yielded the [(Tp )Ti(η -ECNAd)] species (Ad=1-adamantyl, Tp =hydrotris(3-tert-butyl-5-methylpyrazol-1-yl)borate). In the case of E=P, the cyanophosphide ligand displays nucleophilic reactivity toward Al(CH ) ; moreover, its bent geometry hints to a reduced Ad-NCP resonance contributor. The analogous and rarer mono-substituted cyanoarsenide ligand, Ad-NCAs , shows the same unprecedented coordination mode but with shortening of the N=C bond.

Synthesis of an elusive, stable 2-azaallyl radical guided by electrochemical and reactivity studies of 2-azaallyl anions.

The super electron donor (SED) ability of 2-azaallyl anions has recently been discovered and applied to diverse reactivity, including transition metal-free cross-coupling and dehydrogenative cross-coupling processes. Surprisingly, the redox properties of 2-azaallyl anions and radicals have been rarely studied. Understanding the chemistry of elusive species is the key to further development.

Using internal electrostatic fields to manipulate the valence manifolds of copper complexes.

A series of tetradentate tris(phosphinimine) ligands (Ptren) was developed and bound to Cu to form the trigonal pyramidal, -symmetric cuprous complexes [Ptren-Cu][BAr ] () (PR = PMe, PMePh, PMePh, PPh, PMe(NEt), BAr = B(CF)). Electrochemical studies on the Cu complexes were undertaken, and the permethylated analog, , was found to display an unprecedentedly cathodic Cu/Cu redox potential (-780 mV Fc/Fc in isobutyronitrile). Elucidation of the electronic structures of density functional theory (DFT) studies revealed atypical valence manifold configurations, resulting from strongly σ-donating phosphinimine moieties in the -plane that destabilize 2 (d /d ) orbital sets and uniquely stabilized (d ) orbitals.

Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates.

We report a 3-component reaction between -benzyl ketimines, [1.1.1]propellane, and pinacol boronates to generate benzylamine bicyclo[1.

Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor-Acceptor Complex Photoactivation.

The use of bicyclo[1.1.1]pentanes (BCPs) as -disubstituted aryl bioisosteres has gained considerable momentum in drug development programs.

Rules for the design of aza-glycine stabilized triple-helical collagen peptides.

The stability of the triple-helical structure of collagen is modulated by a delicate balance of effects including polypeptide backbone geometry, a buried hydrogen bond network, dispersive interfacial interactions, and subtle stereoelectronic effects. Although the different amino acid propensities for the Xaa and Yaa positions of collagen's repeating (Glycine-Xaa-Yaa) primary structure have been described, our understanding of the impact of incorporating aza-glycine (azGly) residues adjacent to varied Xaa and Yaa position residues has been limited to specific sequences. Here, we detail the impact of variation in the Xaa position adjacent to an azGly residue and compare these results to our study on the impact of the Yaa position.

New strategies for fluorescently labeling proteins in the study of amyloids.

Amyloid proteins are widely studied, both for their unusual biophysical properties and their association with disorders such as Alzheimer's and Parkinson's disease. Fluorescence-based methods using site-specifically labeled proteins can provide information on the details of their structural dynamics and their roles in specific biological processes. Here, we describe the application of different labeling methods and novel fluorescent probe strategies to the study of amyloid proteins, both for in vitro biophysical experiments and for in vivo imaging.

Nickel-catalyzed enantioselective vinylation of aryl 2-azaallyl anions.

A unique enantioselective nickel-catalyzed vinylation of 2-azaallyl anions is advanced for the first time. This method affords diverse vinyl aryl methyl amines with high enantioselectivities, which are frequently occurring scaffolds in natural products and medications. This C-H functionalization method can also be extended to the synthesis of enantioenriched 1,3-diamine derivatives by employing suitably elaborated vinyl bromides.

Comparing models of delivery for cancer genetics services among patients receiving primary care who meet criteria for genetic evaluation in two healthcare systems: BRIDGE randomized controlled trial.

Background: Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services.

Photocatalytic C-H activation and the subtle role of chlorine radical complexation in reactivity.

The functionalization of methane, ethane, and other alkanes derived from fossil fuels is a central goal in the chemical enterprise. Recently, a photocatalytic system comprising [CeCl(OR)] [Ce, cerium(IV); OR, -OCH or -OCClCH] was disclosed. The system was reportedly capable of alkane activation by alkoxy radicals (RO•) formed by Ce-OR bond photolysis.

Synthesis and characterization of fluorescent amino acid dimethylaminoacridonylalanine.

Fluorescent amino acids are powerful biophysical tools as they can be used in structural or imaging studies of a given protein without significantly perturbing its native fold or function. Here, we have synthesized and characterized 7-(dimethylamino)acridon-2-ylalanine (Dad), a red-shifted derivative of the genetically-incorporable amino acid, acridon-2-ylalanine. Alkylation increases the quantum yield and fluorescence lifetime of Dad relative to a previously published amino acid, 7-aminoacridon-2-ylalanine (Aad).

Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput screening.

Small molecules that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple molecules with nanomolar affinity for αS fibrils and moderate specificity for αS over Aβ fibrils.