Comparative transcriptomic analyses of thymocytes using 10x Genomics and Parse scRNA-seq technologies.

Background: Single-cell RNA sequencing experiments commonly use 10x Genomics (10x) kits due to their high-throughput capacity and standardized protocols. Recently, Parse Biosciences (Parse) introduced an alternative technology that uses multiple in-situ barcoding rounds within standard 96-well plates. Parse enables the analysis of more cells from multiple samples in a single run without the need for additional reagents or specialized microfluidics equipment.

Single cell characterization of blood and expanded regulatory T cells in autoimmune polyendocrine syndrome type 1.

Immune tolerance fails in autoimmune polyendocrine syndrome type 1 (APS-1) because of mutations. We have used single cell transcriptomics to characterize regulatory T cells (Tregs) sorted directly from blood and from expanded Tregs in APS-1 patients compared to healthy controls. We revealed only CD52 and LTB (down) and TXNIP (up) as consistently differentially expressed genes in the datasets.

Cytotoxic CD8 Temra cells show loss of chromatin accessibility at genes associated with T cell activation.

As humans age, their memory T cell compartment expands due to the lifelong exposure to antigens. This expansion is characterized by terminally differentiated CD8 T cells (Temra), which possess NK cell-like phenotype and are associated with chronic inflammatory conditions. Temra cells are predominantly driven by the sporadic reactivation of cytomegalovirus (CMV), yet their epigenomic patterns and cellular heterogeneity remain understudied.

Using the gini coefficient to measure the chemical diversity of small-molecule libraries.

Modern databases of small organic molecules contain tens of millions of structures. The size of theoretically available chemistry is even larger. However, despite the large amount of chemical information, the "big data" moment for chemistry has not yet provided the corresponding payoff of cheaper computer-predicted medicine or robust machine-learning models for the determination of efficacy and toxicity.

In pursuit of resolution in time-of-flight mass spectrometry: A historical perspective.

Time-of-flight mass spectrometry is reviewed from its inception in the 1940s to the present day. The review is concerned with fundamentals of time-of-flight analyzers and of ion sources to the extent that sources influence analyzers. The patent literature has been covered, and efforts made to bring to light less well-known papers and studies © 2015 Wiley Periodicals, Inc.

Development and implementation of (Q)SAR modeling within the CHARMMing web-user interface.

Recent availability of large publicly accessible databases of chemical compounds and their biological activities (PubChem, ChEMBL) has inspired us to develop a web-based tool for structure activity relationship and quantitative structure activity relationship modeling to add to the services provided by CHARMMing (www.charmming.org).

Genetic deletion of transglutaminase 2 does not rescue the phenotypic deficits observed in R6/2 and zQ175 mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines.

High-Throughput Automated Phenotyping of Two Genetic Mouse Models of Huntington's Disease.

Phenotyping with traditional behavioral assays constitutes a major bottleneck in the primary screening, characterization, and validation of genetic mouse models of disease, leading to downstream delays in drug discovery efforts. We present a novel and comprehensive one-stop approach to phenotyping, the PhenoCube™. This system simultaneously captures the cognitive performance, motor activity, and circadian patterns of group-housed mice by use of home-cage operant conditioning modules (IntelliCage) and custom-built computer vision software.

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods.

Hepatitis C virus (HCV) is a global health challenge, affecting approximately 200 million people worldwide. In this study we developed SAR models with advanced machine learning classifiers Random Forest and k Nearest Neighbor Simulated Annealing for 679 small molecules with measured inhibition activity for NS5B genotype 1b. The activity was expressed as a binary value (active/inactive), where actives were considered molecules with IC50 ≤0.

Computational tools and resources for metabolism-related property predictions. 2. Application to prediction of half-life time in human liver microsomes.

Background: The most important factor affecting metabolic excretion of compounds from the body is their half-life time. This provides an indication of compound stability of, for example, drug molecules. We report on our efforts to develop QSAR models for metabolic stability of compounds, based on in vitro half-life assay data measured in human liver microsomes.

PDB ligand conformational energies calculated quantum-mechanically.

We present here a greatly updated version of an earlier study on the conformational energies of protein-ligand complexes in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med.

Nuclear inelastic scattering and Mössbauer spectroscopy as local probes for ligand binding modes and electronic properties in proteins: vibrational behavior of a ferriheme center inside a β-barrel protein.

In this work, we present a study of the influence of the protein matrix on its ability to tune the binding of small ligands such as NO, cyanide (CN(-)), and histamine to the ferric heme iron center in the NO-storage and -transport protein Nitrophorin 2 (NP2) from the salivary glands of the blood-sucking insect Rhodnius prolixus. Conventional Mössbauer spectroscopy shows a diamagnetic ground state of the NP2-NO complex and Type I and II electronic ground states of the NP2-CN(-) and NP2-histamine complex, respectively. The change in the vibrational signature of the protein upon ligand binding has been monitored by Nuclear Inelastic Scattering (NIS), also called Nuclear Resonant Vibrational Spectroscopy (NRVS).

Open Data, Open Source and Open Standards in chemistry: The Blue Obelisk five years on.

Background: The Blue Obelisk movement was established in 2005 as a response to the lack of Open Data, Open Standards and Open Source (ODOSOS) in chemistry. It aims to make it easier to carry out chemistry research by promoting interoperability between chemistry software, encouraging cooperation between Open Source developers, and developing community resources and Open Standards.

Results: This contribution looks back on the work carried out by the Blue Obelisk in the past 5 years and surveys progress and remaining challenges in the areas of Open Data, Open Standards, and Open Source in chemistry.

Rapid, computer vision-enabled murine screening system identifies neuropharmacological potential of two new mechanisms.

The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms.

Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a progressive neurodegenerative disease marked by psychiatric and motor problems. Recently, these findings have been extended to deficits in sleep and circadian function that can be observed in HD patients and in HD mouse models, with abnormal sleep patterns correlating with symptom severity in patients. Here, we studied the behavior of the BAC HD mouse model using an 24/7 automated system; the results indicate significant lengthening of the circadian period in the mutant mice.

Using conformationally locked nucleosides to calibrate the anomeric effect: Implications for glycosyl bond stability.

Steric and electronic parameters such as the anomeric effect (AE) and gauche effect play significant roles in steering the North ⇆ South equilibrium of nucleosides in solution. Two isomeric oxa-bicyclo[3.1.

Optical structure recognition software to recover chemical information: OSRA, an open source solution.

Until recently most scientific and patent documents dealing with chemistry have described molecular structures either with systematic names or with graphical images of Kekulé structures. The latter method poses inherent problems in the automated processing that is needed when the number of documents ranges in the hundreds of thousands or even millions since graphical representations cannot be directly interpreted by a computer. To recover this structural information, which is otherwise all but lost, we have built an optical structure recognition application based on modern advances in image processing implemented in open source tools, OSRA.

What are the consequences of freezing the anomeric effect in nucleosides?

The consequences of freezing the orientation of the oxygen's lone pair orbitals--which determines whether the anomeric effect is operative or not--were studied theoretically and experimentally in two oxobicyclo-[3.1.0]hexane nucleosides (1 and 2).

Dynamics of infraslow potentials in the primary auditory cortex: component analysis and contribution of specific thalamic-cortical and non-specific brainstem-cortical influences.

Several available reports demonstrate the presence of infraslow activity (<0.5 Hz) in structures of the auditory system of the brain. It was reported earlier that specific alterations of this activity in the domain of seconds (0.

Effect of the N-terminus on heme cavity structure, ligand equilibrium, rate constants, and reduction potentials of nitrophorin 2 from Rhodnius prolixus.

The D1A mutant of recombinant NP2 has been prepared and shown to have the expression-initiation methionine-0 cleaved during expression in E. coli, as is the case for recombinant NP4, where Ala is the first amino acid for the recombinant protein as well as for the mature native protein. The heme substituent 1H NMR chemical shifts of NP2-D1A and those of its imidazole, N-methylimidazole, and cyanide complexes are rather different from those of NP2-M0D1.

Sound-induced changes of infraslow brain potential fluctuations in the medial geniculate nucleus and primary auditory cortex in anaesthetized rats.

Recent publications indicate the presence of infraslow activity (<0.5 Hz) in subcortical and cortical sites of the auditory system of the brain. It has been reported that this activity might be sensitive to acoustic stimuli.

Very slow brain potential fluctuations (< 0.5 Hz) in visual thalamus and striate cortex after their successive electrical stimulation in lightly anesthetized rats.

Recently accumulating evidence demonstrates the presence of very slow activity (< 0.5 Hz) in structures of the visual system of the brain. It was found in our laboratory earlier that specific and significant alterations of this activity (mainly in the domain of seconds) occurred in the visual system in response to illumination changes.

Solution NMR studies of an intrinsically unstructured protein within a dilute, 75 kDa eukaryotic protein assembly; probing the practical limits for efficiently assigning polypeptide backbone resonances.

This paper describes an efficient NMR strategy for assigning the backbone resonances of an intrinsically unstructured protein (IUP), p21-KID, bound to its biological target, Cdk2/cyclin A. In order to overcome the challenges associated with the high molecular weight (75 kDa) and low solubility of the ternary complex (0.2 mM), we used perdeuteration, TROSY, and high-sensitivity cryogenic NMR probes at high magnetic-field strengths (i.