Next generation multimodal chromatography resins via an iterative mapping approach: Chemical diversity, high-throughput screening, and chromatographic modelling.

Multimodal chromatography resins are becoming a key tool in the purification of biomolecules. The main objective of this research was the establishment of an iterative framework for the rapid development of new multimodal resins to provide novel selectivity for the future purification challenges. A large chemically diverse virtual library of 100 multimodal Capto™ MMC ligand analogues was created, and a broad array of chemical descriptors were calculated for each ligand in silico.

Postexposure progression of pneumoconiosis among former Appalachian coal miners.

Background: The prevalence of pneumoconiosis among working United States underground coal miners has been increasing for the past two decades, with the highest rates of disease observed among miners in the central Appalachian states of Kentucky, Virginia, and West Virginia. Surveillance for this disease in the United States focuses on working coal miners, who continue to be occupationally exposed to dust. This study examines the radiographic evidence for postexposure progression of pneumoconiosis in a population of former coal miners no longer occupationally exposed to coal mine dust who were seen at a community radiology clinic in eastern Kentucky.

COVID-19 nightmare response and stress: A new Mexico sample based survey.

Studies conducted during the COVID-19 Pandemic have reported increased rates of mental illnesses including depression, anxiety, and post-traumatic stress disorder (PTSD) [1]. A common symptom of mental illness is change in Rapid Eye Movement (REM) sleep, the phase of sleep associated with dreaming and nightmares. The COVID-19 pandemic offers a unique opportunity to evaluate the effects of systemic stress on nightmares.

New AMS C dates track the arrival and spread of broomcorn millet cultivation and agricultural change in prehistoric Europe.

Broomcorn millet (Panicum miliaceum L.) is not one of the founder crops domesticated in Southwest Asia in the early Holocene, but was domesticated in northeast China by 6000 BC. In Europe, millet was reported in Early Neolithic contexts formed by 6000 BC, but recent radiocarbon dating of a dozen 'early' grains cast doubt on these claims.

The National Institute for Occupational Safety and Health B Reader Certification Program-An Update Report (1987 to 2018) and Future Directions.

Objective: The National Institute for Occupational Safety and Health (NIOSH) B Reader Program provides the opportunity for physicians to demonstrate proficiency in the International Labour Office (ILO) system for classifying radiographs of pneumoconioses. We summarize trends in participation and examinee attributes and performance during 1987 to 2018.

Methods: Since 1987, NIOSH has maintained details of examinees and examinations.

Patterns of progressive massive fibrosis on modern coal miner chest radiographs.

Clinical teaching generally asserts that large opacities of progressive massive fibrosis (PMF) on chest radiographs present primarily bilaterally in the upper lung zones, and with an elevated background profusion of small opacities. However, the contemporary basis for these descriptions is limited.Radiographs taken for the Coal Workers' Health Surveillance Program during 2000-2015 and previously determined to have large opacities ("PMF radiographs",  = 204), and a random sample previously deemed free of large opacities ( =22), were independently reevaluated by three National Institute for Occupational Safety and Health (NIOSH) B Readers.

Modulation of TCR-dependent NFAT signaling is impaired in HIV-1 Nef isolates from elite controllers.

HIV-1 Nef modulates the activation state of CD4 T cells by altering signaling events elicited by the T cell receptor (TCR). Primary nef sequences exhibit extensive inter-individual diversity that influences their ability to downregulate CD4 and HLA class I; however, the impact of nef variation on modulation of T cell signaling is poorly characterized. Here, we measured TCR-mediated activation of NFAT transcription factor in the presence of nef alleles isolated from 45 elite controllers (EC) and 46 chronic progressors (CP).

A new strategy to efficiently cleave and form C-H bonds using proton-coupled electron transfer.

Oxidative activation and reductive formation of C-H bonds are crucial in many chemical, industrial, and biological processes. Reported here is a new strategy for these transformations, using a form of proton-coupled electron transfer (PCET): intermolecular electron transfer coupled to intramolecular proton transfer with an appropriately placed cofactor. In a fluorenyl-benzoate, the positioned carboxylate facilitates rapid cleavage of a benzylic C-H bond upon reaction with even weak 1 oxidants, for example, decamethylferrocenium.

Low acclimation capacity of narrow-ranging thermal specialists exposes susceptibility to global climate change.

Thermal acclimation is hypothesized to offer a selective advantage in seasonal habitats and may underlie disparities in geographic range size among closely-related species with similar ecologies. Understanding this relationship is also critical for identifying species that are more sensitive to warming climates. Here, we study North American plethodontid salamanders to investigate whether acclimation ability is associated with species' latitudinal extents and the thermal range of the environments they inhabit.

Inhibition of NF-κB-dependent HIV-1 replication by the marine natural product bengamide A.

HIV-1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi-cycle HIV-1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z, bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV-1 with 50% effective concentrations (ECs) of 3.8 μM or less.

Internet Gaming Disorder in Children and Adolescents.

The American Psychiatric Association recently included Internet gaming disorder (IGD) as a potential diagnosis, recommending that further study be conducted to help illuminate it more clearly. This paper is a summary of the review undertaken by the IGD Working Group as part of the 2015 National Academy of Sciences Sackler Colloquium on Digital Media and Developing Minds. By using measures based on or similar to the IGD definition, we found that prevalence rates range between ∼1% and 9%, depending on age, country, and other sample characteristics.

Reactivity of the copper(iii)-hydroxide unit with phenols.

Kinetic studies of the reactions of two previously characterized copper(iii)-hydroxide complexes (LCuOH and LCuOH, where L = ,'-bis(2,6-diisopropylphenyl)-2,6-pyridine-dicarboxamide and L = ,'-bis(2,6-diisopropyl-4-nitrophenyl)pyridine-2,6-dicarboxamide) with a series of substituted phenols (ArOH where X = NMe, OMe, Me, H, Cl, NO, or CF) were performed using low temperature stopped-flow UV-vis spectroscopy. Second-order rate constants () were determined from pseudo first-order and stoichiometric experiments, and follow the trends CF < NO < Cl < H < Me < OMe < NMe and LCuOH < LCuOH. The data support a concerted proton-electron transfer (CPET) mechanism for all but the most acidic phenols (X = NO and CF), for which a more complicated mechanism is proposed.

Isolating the Effects of the Proton Tunneling Distance on Proton-Coupled Electron Transfer in a Series of Homologous Tyrosine-Base Model Compounds.

The distance dependence of concerted proton-coupled electron transfer (PCET) reactions was probed in a series of three new compounds, where a phenol is covalently bridged by a 5, 6, or 7 membered carbocycle to the quinoline. The carbocycle bridge enforces the change in distance between the phenol oxygen (proton donor) and quinoline nitrogen (proton acceptor), d, giving rise to values ranging from 2.567 to 2.

In vitro functional assessment of natural HIV-1 group M Vpu sequences using a universal priming approach.

The HIV-1 accessory protein Vpu exhibits high inter- and intra- subtype genetic diversity that may influence Vpu function and possibly contribute to HIV-1 pathogenesis. However, scalable methods to evaluate genotype/phenotype relationships in natural Vpu sequences are limited, particularly those expressing the protein in CD4+ T-cells, the natural target of HIV-1 infection. A major impediment to assay scalability is the extensive genetic diversity within, and immediately upstream of, Vpu's initial 5' coding region, which has necessitated the design of oligonucleotide primers specific for each individual HIV-1 isolate (or subtype).

Proton-Coupled Electron Transfer in a Series of Ruthenium-Linked Tyrosines with Internal Bases: Evaluation of a Tunneling Model for Experimental Temperature-Dependent Kinetics.

Photoinitiated proton-coupled electron transfer (PCET) kinetics has been investigated in a series of four modified tyrosines linked to a ruthenium photosensitizer in acetonitrile, with each tyrosine bearing an internal hydrogen bond to a covalently linked pyridine or benzimidazole base. After correcting for differences in driving force, it is found that the intrinsic PCET rate constant still varies by 2 orders of magnitude. The differences in rates, as well as the magnitude of the kinetic isotope effect (KIE = kH/kD), both generally correlate with DFT calculated proton donor-acceptor distances.

Nef Proteins from HIV-1 Elite Controllers Are Inefficient at Preventing Antibody-Dependent Cellular Cytotoxicity.

Unlabelled: Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment (elite controllers [EC]). Elimination of HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) requires the presence of envelope glycoproteins (Env) in the CD4-bound conformation, raising the possibility that accumulating CD4 at the surface of virus-infected cells in EC could interact with Env and thereby sensitize these cells to ADCC. We observed a significant increase in the exposure of Env epitopes targeted by ADCC-mediating antibodies at the surface of cells expressing Nef isolates from EC; this correlated with enhanced susceptibility to ADCC.

A robust and scalable TCR-based reporter cell assay to measure HIV-1 Nef-mediated T cell immune evasion.

HIV-1 evades cytotoxic T cell responses through Nef-mediated downregulation of HLA class I molecules from the infected cell surface. Methods to quantify the impact of Nef on T cell recognition typically employ patient-derived T cell clones; however, these assays are limited by the cost and effort required to isolate and maintain primary cell lines. The variable activity of different T cell clones and the limited number of cells generated by re-stimulation can also hinder assay reproducibility and scalability.

Control over excited state intramolecular proton transfer and photoinduced tautomerization: influence of the hydrogen-bond geometry.

The influence of H-bond geometry on the dynamics of excited state intramolecular proton transfer (ESIPT) and photoinduced tautomerization in a series of phenol-quinoline compounds is investigated. Control over the proton donor-acceptor distance (dDA ) and dihedral angle between the proton donor-acceptor subunits is achieved by introducing methylene backbone straps of increasing lengths to link the phenol and quinoline. We demonstrate that a long dDA correlates with a higher barrier for ESIPT, while a large dihedral angle opens highly efficient deactivation channels after ESIPT, preventing the formation of the fully relaxed tautomer photoproduct.

Impaired Nef function is associated with early control of HIV-1 viremia.

Unlabelled: Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors).

Genotypic and functional impact of HIV-1 adaptation to its host population during the North American epidemic.

HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences.

HIV-1 Nef and T-cell activation: a history of contradictions.

HIV-1 Nef is a multifunctional viral protein that contributes to higher plasma viremia and more rapid disease progression. Nef appears to accomplish this, in part, through modulation of T-cell activation; however, the results of these studies over the past 25 years have been inconsistent. Here, the history of contradictory observations related to HIV-1 Nef and its ability to modulate T-cell activation is reviewed, and recent reports that may help to explain Net's apparent ability to both inhibit and activate T cells are highlighted.

Dynamic range of Nef functions in chronic HIV-1 infection.

HIV-1 Nef is required for efficient viral replication and pathogenesis. However, the extent to which Nef's functions are maintained in natural sequences during chronic infection, and their clinical relevance, remains incompletely characterized. Relative to a control Nef from HIV-1 strain SF2, HLA class I and CD4 down-regulation activities of 46 plasma RNA Nef sequences derived from unique chronic infected individuals were generally high and displayed narrow dynamic ranges, whereas Nef-mediated virion infectivity, PBMC replication and CD74 up-regulation exhibited broader dynamic ranges.

Attenuation of multiple Nef functions in HIV-1 elite controllers.

Background: Impaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; however, activity of the accessory protein Nef remains incompletely characterized. We examined the ability of 91 Nef clones, isolated from plasma of 45 EC and 46 chronic progressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariant chain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC.

Results: In general, EC Nef clones were functional; however, all five activities were significantly lower in EC compared to CP.

Brockman, M.A., et al., Human Leukocyte Antigen (HLA) Class I Down-Regulation by Human Immunodeficiency Virus Type 1 Negative Factor (HIV-1 Nef): What Might We Learn From Natural Sequence Variants? Viruses 2012, 4, 1711-1730.

In the original manuscript, the text in figure 1 is illegible. Furthermore, there is an unnecessary carriage return (page 1716, ~line 18) "crystallographic ..

Effect of basic site substituents on concerted proton-electron transfer in hydrogen-bonded pyridyl-phenols.

Separated concerted proton-electron transfer (sCPET) reactions of two series of phenols with pendent substituted pyridyl moieties are described. The pyridine is either attached directly to the phenol (HOAr-pyX) or connected through a methylene linker (HOArCH(2)pyX) (X = 4-NO(2), 5-CF(3), 4-CH(3), and 4-NMe(2)). Electron-donating and -withdrawing substituents have a substantial effect on the chemical environment of the transferring proton, as indicated by IR and (1)H NMR spectra, X-ray structures, and computational studies.