Aryl fluorosulfates were prepared by a simple method and employed as coupling partners in the Suzuki–Miyaura reaction. The cross-coupling reactions were performed in water under air at room ...temperature without ligands or additives such as surfactants or phase-transfer reagents and proceeded smoothly to give excellent yields. Aryl fluorosulfates could also be used as alternatives to halides or triflates in other coupling reactions.
Chemoenzymatic modification of cell-surface glycan structures has emerged as a complementary approach to metabolic oligosaccharide engineering. Here, we identify Pasteurella multocida ...α2-3-sialyltransferase M144D mutant, Photobacterium damsela α2-6-sialyltransferase, and Helicobacter mustelae α1-2-fucosyltransferase, as efficient tools for live-cell glycan modification. Combining these enzymes with Helicobacter pylori α1-3-fucosyltransferase, we develop a host-cell-based assay to probe glycan-mediated influenza A virus (IAV) infection including wild-type and mutant strains of H1N1 and H3N2 subtypes. At high NeuAcα2-6-Gal levels, the IAV-induced host-cell death is positively correlated with haemagglutinin (HA) binding affinity to NeuAcα2-6-Gal. Remarkably, an increment of host-cell-surface sialyl Lewis X (sLe
) exacerbates the killing by several wild-type IAV strains and a previously engineered mutant HK68-MTA. Structural alignment of HAs from HK68 and HK68-MTA suggests formation of a putative hydrogen bond between Trp222 of HA-HK68-MTA and the C-4 hydroxyl group of the α1-3-linked fucose of sLe
, which may account for the enhanced host cell killing of that mutant.
Most chemical transformations (reactions or conformational changes) that are of interest to researchers have many degrees of freedom, usually too many to visualize without reducing the dimensionality ...of the system to include only the most important atomic motions. In this article, we describe a method of using Principal Component Analysis (PCA) for analyzing a series of molecular geometries (
e.g.
, a reaction pathway or molecular dynamics trajectory) and determining the reduced dimensional space that captures the most structural variance in the fewest dimensions. The software written to carry out this method is called
PathReducer
, which permits (1) visualizing the geometries in a reduced dimensional space, (2) determining the axes that make up the reduced dimensional space, and (3) projecting the series of geometries into the low-dimensional space for visualization. We investigated two options to represent molecular structures within
PathReducer
: aligned Cartesian coordinates and matrices of interatomic distances. We found that interatomic distance matrices better captured non-linear motions in a smaller number of dimensions. To demonstrate the utility of
PathReducer
, we have carried out a number of applications where we have projected molecular dynamics trajectories into a reduced dimensional space defined by an intrinsic reaction coordinate. The visualizations provided by this analysis show that dynamic paths can differ greatly from the minimum energy pathway on a potential energy surface. Viewing intrinsic reaction coordinates and trajectories in this way provides a quick way to gather qualitative information about the pathways trajectories take relative to a minimum energy path. Given that the outputs from PCA are linear combinations of the input molecular structure coordinates (
i.e.
, Cartesian coordinates or interatomic distances), they can be easily transferred to other types of calculations that require the definition of a reduced dimensional space (
e.g.
, biased molecular dynamics simulations).
Principal Component Analysis on a series of molecular geometries (
e.g.
, a reaction coordinate or trajectory) provides maximum structural variance in the fewest dimensions, and so can offer an objective, comprehensible depiction of the transformation.
IntroductionIn Europe, associations between different types of nonparental care and internalizing and externalizing behaviors in children have not been adequately explored (Gialamas, A et al. J ...Epiemiol Community Health. 2015). Internalizing and externalizing symptoms in childhood can have lifetime repercussions, thus understanding their risk factors and the potentially protective role of family policies is highly relevant.ObjectivesTo explore the associations between different types of nonparental care prior to primary school and internalizing and externalizing behaviors across young adolescence.MethodsSix parent-offspring prospective birth cohort studies across five European countries within the EU Child Cohort Network (EUCCN) were included in the study. A two-stage individual participant data (IPD) meta-analysis on complete cases was performed. Linear regression models (one for each age group: 5-6 years, 7-9 years, 10-13 years) were applied in each cohort separately and then cohort-specific coefficients and standard errors were combined using random-effects (restricted estimate maximum likelihood (REMD) meta-analysis to attain overall effect estimates. Data were then stratified by socioeconomic position and sex.ResultsThere were 74 453 parent-offspring dyads to study children’s internalizing difficulties and 72 462 parent-offspring dyads to study children’s externalizing difficulties. Center-based care attendance was associated with lower levels of internalizing difficulties 5-6 years -1.13 (95%CI:- 2.68, 0.42), p=0.15; 7-9 years -1.38 (95%CI:- 2.85, 0.10), p=0.07; 10-13 years -1.06 (95%CI:- 1.95, -0.17), p=0.02. Children who attended other forms of nonparental care appeared to have higher levels of internalizing difficulties: 5-6 years 0.02 (95%CI:- 1.96, 2.01), p=0.98, 7-9 years 0.91 (95%CI:0.23, 1.58), p=0.009; 10-13 years 0.52 (95%CI:- 0.23, 1.27), p=0.17. Other forms of nonparental care (not including center-based care) had a positive association with externalizing symptoms : 5-6 years 2.45 (95%CI:0.35, 4.55), p=0.02: 7-9 years 2.78 (95%CI: 0.60, 4.95), p=0.01;10-13 years 1.93 (95%CI:-0.45, 4.32), p=0.11. We found some evidence of effect moderation by the child’s sex and socioeconomic position (SEP).ConclusionsThe results suggest that center-based care may protect children from developing internalizing behaviors, but other forms of nonparental care may put children at more risk of developing more internalizing and externalizing behaviors. Also, factors such as sex and SEP may interact with nonparental care in influencing externalizing behaviors.Disclosure of InterestNone Declared
A new class of synthetic cannabinoids has emerged as new psychoactive substances (NPS). Similar in structure to JWH‐022, these substances contain alkene modifications to the tail region of the ...synthetic cannabinoid core structure, and nomenclature denotes these new analogues as pent‐4en or but‐3en species. Internationally, two analogues from this new series recently emerged: MDMB‐4en‐PINACA and MMB‐4en‐PICA. Previously, data regarding activity and potential toxicity were not available. In vitro assessment of cannabinoid receptor 1 (CB1) activation via the β‐arrestin 2 recruitment was studied for three (3) pent‐4en analogues, one (1) but‐3en analogue, and one (1) principal metabolite. MDMB‐4en‐PINACA (2.47 nM, 239%), MDMB‐4en‐PICA (11.5 nM, 302%), and MDMB‐3en‐BINACA (14.3 nM, 286%) were highly potent and efficacious (comparison: JWH‐018, 25.3 nM, 100%), while the potencies of MMB‐4en‐PICA and MDMB‐4en‐PINACA 3,3‐dimethylbutanoic acid were markedly lower. Modifications to core and tail structural features (i.e., indole vs. indazole) led to relatively small differences in potency, while changes among the head region led to larger differences. Sample‐mining and data‐mining conducted on toxicology samples led to the identification of MDMB‐4en‐PINACA in 25 forensic toxicology cases, including postmortem and impaired driving investigations, with case details and limited histories described herein. Moderate geographical distribution of MDMB‐4en‐PINACA was noted in the United States with emergence in the Northeast, Midwest, South, and West regions. Results from toxicology testing paired with case history show the potential for MDMB‐4en‐PINACA to cause or contribute to impairment or death. Forensic scientists, public health and public safety officials, law enforcement, clinicians, medical examiners, and coroners should consider involvement of emergent synthetic cannabinoids in their work and that new analogues containing an alkene tail can retain similar or increased potency and toxicity.
As new psychoactive substance (NPS) markets evolve, so do the chemistries of the drugs detected. Synthetic cannabinoids represents one of the most diverse classes, as new substances emerge rapidly. The latest analogues contain alkene modifications to the tail region and are noted pent‐4en and but‐3en. Herein, we studied their activity as well as their positivity. MDMB‐4en‐PINACA was the most potent and the most commonly encountered analogue, appearing in several forensic investigations (e.g., postmortem and DUID).
The aqueous phase photochemistry of pyruvic acid, an important oxidation product of isoprene, is known to generate larger oligomeric species that may contribute to the formation of secondary organic ...aerosol in the atmosphere. Using high resolution negative mode electrospray ionization mass spectrometry, the aqueous photochemistry of dilute solutions of pyruvic acid (10, 1, and 0.5 mM) under anaerobic conditions was investigated. Even at the lowest concentration, covalently bonded dimers and trimers of pyruvic acid were observed as photochemical products. We calculate that it is energetically possible to photochemically generate parapyruvic acid, a dimer of pyruvic acid that is known to form via dark oligomerization processes. Subsequent photochemical reactions of parapyruvic acid with pyruvic acid form larger oligomeric products, such as 2,4-dihydroxy-2-methyl-5-oxohexanoic acid. A robust and relatively simple photochemical mechanism is discussed that explains both the conditional dependence and wide array of products that are observed.
In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously employed in terrorism, the alkylpyridinium aldoximes ...have received primary attention since their early development by I. B. Wilson in the 1950s. Yet these agents, by virtue of their quaternary structure, are limited in rates of crossing the blood-brain barrier, and they require administration parenterally to achieve full distribution in the body. Oximes lacking cationic charges or presenting a tertiary amine have been considered as alternatives. Herein, we examine the pharmacokinetic properties of a lead ionizable, zwitterionic hydroxyiminoacetamido alkylamine in mice to develop a framework for studying these agents in vivo and generate sufficient data for their consideration as appropriate antidotes for humans. Consequently, in vitro and in vivo efficacies of immediate structural congeners were explored as leads or backups for animal studies. We compared oral and parenteral dosing, and we developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote were achieved with sequential administrations out to 10 hours, with brain levels exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime showed substantial protection after gavage, whereas the classic methylpyridinium aldoxime (2-pyridinealdoxime methiodide) was without evident protection. Although further studies in other animal species are necessary, ionizing zwitterionic aldoximes present viable alternatives to existing antidotes for prophylaxis and treatment of large numbers of individuals in terrorist-led events with nerve agent organophosphates, such as sarin, and in organophosphate pesticide exposure.
4‐Substituted 1‐(N‐sulfonyl)‐1,2,3‐triazoles are selectively obtained by using the Cu‐catalyzed azide–alkyne cycloaddition reaction with sulfonyl azides. Performing the reaction at 0 °C in chloroform ...in the presence of 2,6‐lutidine and CuI as the catalyst effectively prevents the ketenimine pathway and provides convenient access to N‐sulfonyltriazoles in good to excellent yields.
Objective: Nowadays, methods for ECG quality assessment are mostly designed to binary distinguish between good/bad quality of the whole signal. Such classification is not suitable to long-term data ...collected by wearable devices. In this paper, a novel approach to estimate long-term ECG signal quality is proposed. Methods: The real-time quality estimation is performed in a local time window by calculation of continuous signal-to-noise ratio (SNR) curve. The layout of the data quality segments is determined by analysis of SNR waveform. It is distinguished between three levels of ECG signal quality: signal suitable for full wave ECG analysis, signal suitable only for QRS detection, and signal unsuitable for further processing. Results: The SNR limits for reliable QRS detection and full ECG waveform analysis are 5 and 18 dB respectively. The method was developed and tested using synthetic data and validated on real data from wearable device. Conclusion: The proposed solution is a robust, accurate and computationally efficient algorithm for annotation of ECG signal quality that will facilitate the subsequent tailored analysis of ECG signals recorded in free-living conditions. Significance: The field of long-term ECG signals self-monitoring by wearable devices is swiftly developing. The analysis of massive amount of collected data is time consuming. It is advantageous to characterize data quality in advance and thereby limit consequent analysis to useable signals.
Drug candidates are generally discovered using biochemical screens employing an isolated target protein or by utilizing cell-based phenotypic assays. Both noncovalent and covalent hits emerge from ...such endeavors. Herein, we exemplify an “Inverse Drug Discovery” strategy in which organic compounds of intermediate complexity harboring weak, but activatable, electrophiles are matched with the protein(s) they react with in cells or cell lysate. An alkyne substructure in each candidate small molecule enables affinity chromatography–mass spectrometry, which produces a list of proteins that each distinct compound reacts with. A notable feature of this approach is that it is agnostic with respect to the cellular proteins targeted. To illustrate this strategy, we employed aryl fluorosulfates, an underexplored class of sulfur(VI) halides, that are generally unreactive unless activated by protein binding. Reversible aryl fluorosulfate binding, correct juxtaposition of protein side chain functional groups, and transition-state stabilization of the S(VI) exchange reaction all seem to be critical for conjugate formation. The aryl fluorosulfates studied thus far exhibit chemoselective reactivity toward Lys and, particularly, Tyr side chains, and can be used to target nonenzymes (e.g., a hormone carrier or a small-molecule carrier protein) as well as enzymes. The “Inverse Drug Discovery” strategy should be particularly attractive as a means to explore latent electrophiles not typically used in medicinal chemistry efforts, until one reacts with a protein target of exceptional interest. Structure–activity data can then be used to enhance the selectivity of conjugate formation or the covalent probe can be used as a competitor to develop noncovalent drug candidates. Here we use the “Inverse Drug Discovery” platform to identify and validate covalent ligands for 11 different human proteins. In the case of one of these proteins, we have identified and validated a small-molecule probe for the first time.
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