Vancomycin is currently used as last-line therapy against many Gram-positive bacterial pathogens. Herein, we report a series of peptidomimetic norbornene-based anion receptors that were designed as ...simple vancomycin mimics New hosts were evaluated for their affinity to both acetate and acetyl D-Ala by
1
H NMR titration. Modest binding to both anions was observed in DMSO-d
6
(Log K
a
1-2 for TBA Acetyl D-Alanine) in the anticipated 1:1 mode of binding.
Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery.
Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale.
Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with >1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors.
SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines.
Abstract Background Three-dimensional contrast-enhanced MR pulmonary angiography (MRPA) is a suitable option for pulmonary embolism (PE) detection. However, there have been few reports on the ...diagnostic accuracy of MRPA for PE detection in a 3-T MR system. The purpose of this study was to evaluate the accuracy of MRPA in a 3-T MR system to detect acute PE with multidetector CT pulmonary angiography (CTPA) as reference standard. Methods Twenty-seven patients (18 males and 9 females, mean age 38.9 ± 14.4 years) underwent both MRPA and CTPA within 3 days (range, 0–3 days) for evaluating PE. Pulmonary emboli in MRPA were independently analyzed on a per-patient and per-lobe basis by two radiologists. CTPA was regarded as reference standard, which was evaluated by another two radiologists in consensus. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for PE detection were calculated. Weighted κ values were calculated to evaluate agreement between readers. Results Twenty-four patients had PE in 55 lung lobes in CTPA, while 3 patients had no PE detected. Readers 1 and 2 correctly detected 47 and 46 lung lobes having clots in 24 and 23 patients, corresponding to sensitivities, specificities, PPV, NPV, and accuracies of 100%, 100%, 100%, 100%, 100%; 100%, 66.7%, 96.0%, 100%, 96.4% on a per-patient basis and 85.5%, 100%, 100%, 90.9%, 94.1%; 83.6%, 93.7%, 90.2%, 89.2%, 89.6% on a per-lobe basis; respectively. Excellent inter-reader agreement (κ values = 1.00 and 0.934; both P < 0.001) were found for detecting PE on a per-patient and per-lobe analysis. Conclusion Three-dimensional contrast-enhanced MRPA with a 3-T MR system is a suitable alternative modality to CTPA to detect PE on a per-patient basis based on this small cohort study.
Fouling of an ultrafiltration membrane by raw lake water, the same water after passage through a layer of heated aluminum oxide particles (HAOPs), and the fractionated natural organic matter (NOM) ...(based on hydrophobicity) of each of those waters was investigated. When each fraction of the raw water was fed to the membrane at the same DOC concentration, the hydrophobic (HPO) fraction was the least well retained by the membrane, but it caused the most fouling, whereas the hydrophilic (HPI) fraction was the most efficiently retained fraction and caused the least fouling. Furthermore, whenever the feed contained mixtures of different fractions, fouling was worse than would be predicted by a simple mixing model, indicating that interactions among the fractions are important factors in the fouling process. Treatment of the raw water by HAOPs substantially removed fulvics from all five feed solutions (raw water, the HPO, TPI transphilic, and HPI fractions, and the reconstituted water) and humics from all except the HPI fraction (which contained very little humic material in the first place). In contrast, HAOPs treatment removed aromatic proteins only from the HPI fraction. HAOPs also selectively removed higher-MW NOM. The treatment significantly mitigated membrane fouling by all the fractions to a greater extent than would be expected based on DOC removal. The fouling of membranes fed either raw water or HAOPs-pretreated water was largely reversed by alkaline cleaning. The NOM that was released by the cleaning step was enriched in aromatic proteins and non-fluorescent fractions, but it contained much less humic and fulvic matter and overall fluorescence than raw water. The results suggest that a non-fluorescent HPO fraction of the NOM accumulated on the membrane and is responsible for substantial fouling, and that interactions among different fractions are important contributors to fouling.
To evaluate the feasibility and value of dual-energy computed tomography myocardial iodine maps in the diagnosis of acute myocardial infarction.
In 6 dogs, arterial-phase myocardial dual-energy ...computed tomography imaging were performed 1 day prior to and 3 hours after the surgical ligation of the left anterior descending artery to generate 100 kVp, 140 kVp, average weighted images, and dual energy myocardial iodine maps. For each of the 17 segments of the left ventricle (LV, 102 total segments), the presence or absence myocardial infarction was determined by histopathology and correlated to blinded reader determination of infarcted and noninfarcted myocardium at computed tomography (CT). Statistical analysis for diagnostic accuracy of aforementioned techniques and inter-reader agreement was performed.
The LV myocardial contrast enhancement at the average weighted images and iodine maps were uniform in all 6 dogs before surgery. Following anterior descending artery ligation, histopathology showed 40 infarcted left ventricular segments and 62 noninfarcted segments. For the postligation CT scans, 100 kVp, 140 kVp, average weighted images, and myocardial iodine maps showed 33, 28, 33, 34 infarcted segments and 53, 56, 56, 52 noninfarcted segments for both readers; corresponding to per-segment sensitivities of 83%, 70%, 80%, 92% and specificities of 85%, 90%, 92%, 80% for detecting myocardial infarction. No statistical difference was found for diagnostic accuracy of 100 kV, 140 kV, weighted average images, and iodine maps to detect myocardial infarct segments (all P > 0.05 for both readers). Good inter-reader agreement was seen for myocardial infarct detection using iodine maps (kappa = 0.80).
Myocardial single- and dual-energy CT imaging shows high per-segment sensitivity and moderate specificity for detecting acute myocardial infarction in a canine model with histopathology as the standard of reference.
Despite having no obvious anatomical modifications to facilitate movement over land, numerous small fishes from divergent teleost lineages make brief, voluntary terrestrial forays to escape poor ...aquatic conditions or to pursue terrestrial prey. Once stranded, these fishes produce a coordinated and effective “tail-flip” jumping behavior, wherein lateral flexion of the axial body into a C-shape, followed by contralateral flexion of the body axis, propels the fish into a ballistic flight-path that covers a distance of multiple body lengths. We ask: how do anatomical structures that evolved in one habitat generate effective movement in a novel habitat? Within this context, we hypothesized that the mechanical properties of the axial skeleton play a critical role in producing effective overland movement, and that tail-flip jumping species demonstrate enhanced elastic energy storage through increased body flexural stiffness or increased body curvature, relative to non-jumping species. To test this hypothesis, we derived a model to predict elastic recoil work from the morphology of the vertebral (neural and hemal) spines. From ground reaction force (GRF) measurements and high-speed video, we calculated elastic recoil work, flexural stiffness, and apparent material stiffness of the body for Micropterus salmoides (a non-jumper) and Kryptolebias marmoratus (adept tail-flip jumper). The model predicted no difference between the two species in work stored by the vertebral spines, and GRF data showed that they produce the same magnitude of mass-specific elastic recoil work. Surprisingly, non-jumper M. salmoides has a stiffer body than tail-flip jumper K. marmoratus. Many tail-flip jumping species possess enlarged, fused hypural bones that support the caudal peduncle, which suggests that the localized structures, rather than the entire axial skeleton, may explain differences in terrestrial performance.
Using microwave irradiation and protic ionic liquids (pIL) as co-solvent and catalyst for the synthesis of several diphenylmethyl ethers was achieved. The desired ethers were isolated simply by ...filtration through a silica plug to remove the pIL and proceeded in high yields (60–98%). These reactions were extremely rapid (10–30min) and occurred under mild conditions (80°C). This protocol was also successfully applied to the synthesis of thioethers.
The properties and structures of viruses are directly related to the three‐dimensional structure of their capsid proteins, which arises from a combination of hydrophobic and supramolecular ...interactions, such as hydrogen bonds. The design of synthetic materials demonstrating similar synergistic interactions still remains a challenge. Herein, we report the synthesis of a polymer/cyclic peptide conjugate that combines the capability to form supramolecular nanotubes via hydrogen bonds with the properties of an amphiphilic block copolymer. The analysis of aqueous solutions by scattering and imaging techniques revealed a barrel‐shaped alignment of single peptide nanotubes into a large tubisome (length: 260 nm (from SANS)) with a hydrophobic core (diameter: 16 nm) and a hydrophilic shell. These systems, which have a structure that is similar to those of viruses, were tested in vitro to elucidate their activity on cells. Remarkably, the rigid tubisomes are able to perforate the lysosomal membrane in cells and release a small molecule into the cytosol.
Peptide und Polymere: Konjugate aus Polymeren und cyclischen Peptiden bilden supramolekulare Strukturen, Tubisome genannt, aus einem hydrophoben Kern und einer hydrophilen Schale. Sie perforieren die lysosomale Membran in Zellen und ermöglichen so die Freisetzung kleiner Moleküle in das Zytosol.
Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there ...remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.
Sulforaphane can induce the transcription factor, Nrf2, promoting antioxidant and anti-inflammatory responses. In this study, hospitalised patients with community-acquired pneumonia (CAP) were ...treated with stabilised synthetic sulforaphane (SFX-01) to evaluate impact on clinical status and inflammation.
Double-blind, randomised, placebo-controlled trial of SFX-01 (300 mg oral capsule, once daily for 14 days) conducted in Dundee, UK, between November 2020 and May 2021. Patients had radiologically confirmed CAP and CURB-65 (confusion, urea >7 mmol·L
, respiratory rate ≥30 breaths·min
, blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) score ≥1. The primary outcome was the seven-point World Health Organization clinical status scale at day 15. Secondary outcomes included time to clinical improvement, length of stay and mortality. Effects on Nrf2 activity and inflammation were evaluated on days 1, 8 and 15 by measurement of 45 serum cytokines and mRNA sequencing of peripheral blood leukocytes.
The trial was terminated prematurely due to futility with 133 patients enrolled. 65 patients were randomised to SFX-01 treatment and 68 patients to placebo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the cause of CAP in 103 (77%) cases. SFX-01 treatment did not improve clinical status at day 15 (adjusted OR 0.87, 95% CI 0.41-1.83; p=0.71), time to clinical improvement (adjusted hazard ratio (aHR) 1.02, 95% CI 0.70-1.49), length of stay (aHR 0.84, 95% CI 0.56-1.26) or 28-day mortality (aHR 1.45, 95% CI 0.67-3.16). The expression of Nrf2 targets and pro-inflammatory genes, including interleukin (IL)-6, IL-1β and tumour necrosis factor-α, was not significantly changed by SFX-01 treatment. At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p<0.05, log
FC >1).
SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.
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