Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells.

Trisomy of human chromosome 21 (T21) gives rise to Down syndrome (DS), the most frequent live-born autosomal aneuploidy. T21 triggers genome-wide transcriptomic alterations that result in multiple atypical phenotypes with highly variable penetrance and expressivity in individuals with DS. Many of these phenotypes, including atypical neurodevelopment, emerge prenatally.

Delays in commitment and treatment court proceedings worsen psychiatric and other medical conditions.

Objective: Adversarial hearings in hospital commitment and de novo treatment proceedings, or court hearings, delay psychiatric treatment in many jurisdictions. In Massachusetts, the "treatment over objection" process requires a court petition. For state hospital patients, the delay to treatment is an initial 34 day waiting period in addition to continuances of court hearings that extend treatment delays.

Diversity upon diversity: linking DNA double-strand break repair to blood cancer health disparities.

Chromosomal translocations arising from aberrant repair of multiple DNA double-strand breaks (DSBs) are a defining characteristic of many cancers. DSBs are an essential part of physiological processes in antibody-producing B cells. The B cell environment is poised to generate genome instability leading to translocations relevant to the pathology of blood cancers.

Strongly Coordinating Ligands To Form Weakly Coordinating Yet Functional Organometallic Anions.

Weakly coordinating anions (WCAs) are generally tailored to act as spectators with little or no function. Here we describe the implementation of strongly coordinating dianionic carboranyl N-heterocyclic carbenes (NHCs) to create organometallic -ate complexes of Au(I) that serve both as WCAs and functional catalysts. These organometallic WCAs can be utilized to form both heterobimetallic (Au(I)/Ag(I); Au(I)/Ir(I)) and organometallic/main group ion pairs (Au(I)/(CPh or SiEt).

Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome.

While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS.

Reversible Silver Electrodeposition from Boron Cluster Ionic Liquid (BCIL) Electrolytes.

Electrochemical systems offer a versatile means for creating adaptive devices. However, the utility of electrochemical deposition is inherently limited by the properties of the electrolyte. The development of ionic liquids enables electrodeposition in high-vacuum environments and presents opportunities for creating electrochemically adaptive and regenerative spacecraft components.

Synthesis of unsymmetrical N-carboranyl NHCs: directing effect of the carborane anion.

The syntheses of unsymmetrical N-heterocyclic carbenes (NHCs) that contain a single N-bound icosahedral carborane anion substituent are reported. Both anionic C-2 and doubly deprotonated dianionic C-2/C-5 NHC lithium complexes are isolated. The latter species is formed selectively, which reveals a surprising directing effect conveyed by icosahedral carborane anion substituents.

Postnatal developmental expression of regulator of G protein signaling 14 (RGS14) in the mouse brain.

Regulator of G protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G protein and mitogen-activated protein kinase (MAPK) signaling pathways. In the adult mouse brain, RGS14 mRNA and protein are found almost exclusively in hippocampal CA2 neurons. We have shown that RGS14 is a natural suppressor of CA2 synaptic plasticity and hippocampal-dependent learning and memory.

Paclitaxel nanosuspensions for targeted chemotherapy - nanosuspension preparation, characterization, and use.

Objective: The purpose of this work was to prepare a stable paclitaxel nanosuspension and test it for potential use as a targeted chemotherapeutic. Different particle coatings were employed to assess their impact on cellular uptake in vitro. In vivo work was then performed to demonstrate efficacy in tumor-bearing mouse models.

RGS14 at the interface of hippocampal signaling and synaptic plasticity.

Learning and memory are encoded within the brain as biochemical and physical changes at synapses that alter synaptic transmission, a process known as synaptic plasticity. Although much is known about factors that positively regulate synaptic plasticity, very little is known about factors that negatively regulate this process. Recently, the signaling protein RGS14 (Regulator of G protein Signaling 14) was identified as a natural suppressor of hippocampal-based learning and memory as well as synaptic plasticity within CA2 hippocampal neurons.

The chemoselective one-step alkylation and isolation of thiophosphorylated cdk2 substrates in the presence of native cysteine.

The elucidation of signalling pathways relies heavily upon the identification of protein kinase substrates. Recent investigations have demonstrated the efficacy of chemical genetics using ATP analogues and modified protein kinases for specific substrate labelling. Here we combine N(6) -(cyclohexyl)ATPγS with an analogue-sensitive cdk2 variant to thiophosphorylate its substrates and demonstrate a pH-dependent, chemoselective, one-step alkylation to facilitate the detection or isolation of thiophosphorylated peptides.

NMR of heparin API: investigation of unidentified signals in the USP-specified range of 2.12-3.00 ppm.

This article addresses the identification and quantification of the chemical species resulting in resonances at 2.17 and 2.25 ppm in the (1)H nuclear magnetic resonance (NMR) spectrum of pharmaceutical-grade heparin sodium.

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory.

Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus.

Synthesis and O-phosphorylation of 3,3,4,4-tetrafluoroaryl-C-nucleoside analogues.

Enantioenriched tetrafluorinated aryl-C-nucleosides were synthesised in four steps from 1-benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol. The presence of the tetrafluorinated ethylene group is compatible with O-phosphorylation of the primary alcohol, as demonstrated by the successful preparation of the tetrafluorinated naphthyl-C-nucleotide.

Exploring the roles of protein kinases using chemical genetics.

The protein kinase superfamily is one of the most important families of enzymes in molecular biology. Protein kinases typically catalyze the transfer of the γ-phosphate from ATP to a protein substrate (a highly ubiquitous cellular reaction), thereby controlling key areas of cell regulation. Deregulation of protein kinases is known to contribute to many human diseases, and selective inhibitors of protein kinases are a major area of interest in medicinal chemistry.

A quantitative comparison of wild-type and gatekeeper mutant cdk2 for chemical genetic studies with ATP analogues.

Chemical genetic studies with enlarged ATP binding sites and unnatural ATP analogues have been applied to protein kinases for characterisation and substrate identification. Although this system is becoming widely used, there are limited data available about the kinetic profile of the modified system. Here we describe a detailed comparison of the wild-type cdk2 and the mutant gatekeeper kinase to assess the relative efficiencies of these kinases with ATP and unnatural ATP analogues.

Synthesis and reactivity of novel gamma-phosphate modified ATP analogues.

We hereby present a simple yet novel chemical synthesis of a family of gamma-modified ATPs bearing functional groups on the gamma-phosphate that are amenable to further derivatization by highly selective chemical manipulations (e.g., click chemistry, Staudinger ligations).

Access to poly-beta-peptides with functionalized side chains and end groups via controlled ring-opening polymerization of beta-lactams.

Poly-beta-peptides are attractive for biomedical applications because the backbone is similar enough to that of proteins for biocompatibility, but the backbone is sufficiently unnatural that these polymers evade proteolytic degradation. Prior investigations of poly-beta-peptides have been hindered by two principal limitations: (1) most known examples are insoluble, and (2) the range of accessible side chain functionality has been quite limited (mostly simple hydrocarbon units). The present study describes innovations in poly-beta-peptide synthesis that enable the preparation of diversely functionalized examples and provide the basis for broad exploration of the properties and applications of these nylon-3 materials.

Accurate whole human genome sequencing using reversible terminator chemistry.

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost.

Dual mechanism of bacterial lethality for a cationic sequence-random copolymer that mimics host-defense antimicrobial peptides.

Flexible sequence-random polymers containing cationic and lipophilic subunits that act as functional mimics of host-defense peptides have recently been reported. We used bacteria and lipid vesicles to study one such polymer, having an average length of 21 residues, that is active against both Gram-positive and Gram-negative bacteria. At low concentrations, this polymer is able to permeabilize model anionic membranes that mimic the lipid composition of Escherichia coli, Staphylococcus aureus, or Bacillus subtilis but is ineffective against model zwitterionic membranes, which explains its low hemolytic activity.

Using chemical genetics and ATP analogues to dissect protein kinase function.

Protein kinases catalyze the transfer of the gamma-phosphate of ATP to a protein substrate and thereby profoundly alter the properties of the phosphorylated protein. The identification of the substrates of protein kinases has proven to be a very difficult task because of the multitude of structurally related protein kinases present in cells, their apparent redundancy of function, and the lack of absolute specificity of small-molecule inhibitors. Here, we review approaches that utilize chemical genetics to determine the functions and substrates of protein kinases, focusing on the design of ATP analogues and protein kinase binding site mutants.

Heterodimers of alpha1B- and alpha1D-adrenergic receptors form a single functional entity.

Heterologous expression of alpha(1D)-adrenergic receptors (alpha(1D)-ARs) in most cell types results in intracellular retention and little or no functionality. We showed previously that heterodimerization with alpha(1B)-ARs promotes surface localization of alpha(1D)-ARs. Here, we report that the alpha(1B)-/alpha(1D)-AR interaction has significant effects on the pharmacology and signaling of the receptors, in addition to the effects on trafficking described previously.