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Nitric oxide plays a critical role in regulating vascular tone, but excessive nitric oxide release during septic shock results in hypotension due to excessive vasodilation and the formation of toxic free radicals. VBI-S is a phospholipid nanoparticle based fluid composed of lipid bilayers formed primarily by phosphatidylcholine and micelles of soybean oil encapsulated by a monolayer of phosphatidylcholine. These nanoparticles offer a novel solution by absorbing and redistributing nitric oxide and nitrite, potentially mitigating the harmful effects of excessive nitric oxide in sepsis. This paper proposes a mechanism in which VBI-S not only redistributes nitric oxide but also reduces ischemia-reperfusion injury by limiting the production and availability of reactive species. VBI-S captures nitric oxide and nitrite in areas of high concentration and redistributes them in low-nitric oxide environments, primarily within oxygen-deprived tissues. Nitrite then contributes to nitric oxide regeneration in hypoxic microvasculature via various reduction pathways, thereby improving tissue perfusion and minimizing oxidative stress. Preliminary studies suggest that nitrite may also decrease reactive species production, primarily superoxide, through the inhibition of mitochondrial complex I. Additionally, the lipid composition of VBI-S is rich in poly and monounsaturated fatty acids which allows VBI-S to act as a substrate for peroxidation via peroxynitrite. Therefore, VBI-S acts as a decoy target thereby protecting cellular membranes from oxidative damage caused by reactive species. These findings position VBI-S as a promising therapeutic agent, offering both nitric oxide regulation and protection against hypotension and toxic free radicals in septic shock patients. Further research is necessary to fully elucidate the molecular pathways and optimize its clinical application., Competing Interests: Competing interests a. CS is a shareholder and officer of Vivacelle Bio, Inc. Vivacelle Bio is seeking to bring phospholipid nanoparticle formulations to market for the treatment of various medical conditions. b. NC is an employee of Vivacelle Bio, Inc. c. The other authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Clinical practice guidelines (CPGs) are an important tool for the management of children with sepsis. The quality, consistency and concordance of Australian and New Zealand (ANZ) childhood sepsis CPGs with the Australian Commission on Safety and Quality in Healthcare (ACSQHC) sepsis clinical care standards and international sepsis guidelines is unclear., Methods: We accessed childhood sepsis CPGs for all ANZ states and territories through Paediatric Research in Emergency Departments International Collaborative members. The guidelines were assessed for quality using the AGREE-II instrument. Consistency between CPG treatment recommendations was assessed, as was concordance with the ACSQHC sepsis clinical care standards and international sepsis guidelines., Results: Overall, eight CPGs were identified and assessed. CPGs used a narrative and pathway format, with those using both having the highest quality overall. CPG quality was highest for description of scope and clarity of presentation, and lowest for editorial independence. Consistency between guidelines for initial treatment recommendations was poor, with substantial variation in the choice and urgency of empiric antimicrobial administration; the choice, volume and urgency of fluid resuscitation; and the choice of first-line vasoactive agent. Most CPGs were concordant with time-critical components of the ACSQHC sepsis clinical care standard, although few addressed post-acute care. Concordance with international sepsis guidelines was poor., Conclusion: Childhood sepsis CPGs in current use in ANZ are of variable quality and lack consistency with key treatment recommendations. CPGs are concordant with the ACSQHC care standard, but not with international sepsis guidelines. A bi-national sepsis CPG may reduce unnecessary variation in care., (© 2024 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Allosteric pathways in proteins describe networks comprising amino acid residues which may facilitate the propagation of signals between distant sites. Through inter-residue interactions, dynamic and conformational changes can be transmitted from the site of perturbation to an allosteric site. While sophisticated computational methods have been developed to characterize such allosteric pathways linking specific sites on proteins, few attempts have been made to apply these approaches toward identifying new allosteric sites. Here, we use molecular dynamics simulations and suboptimal path analysis to discover new allosteric networks in steroid receptors with a focus on evolutionarily conserved pathways. Using modern receptors and a reconstructed ancestral receptor, we identify networks connecting several sites to the activation function surface 2 (AF-2), the site of coregulator recruitment. One of these networks is conserved across the entire family, connecting a predicted allosteric site located between helices 9 and 10 of the ligand-binding domain. We investigate the basis of this conserved network as well as the importance of this site, discovering that the site lies in a region of the ligand-binding domain characterized by conserved inter-residue contacts. This study suggests an evolutionarily importance of the helix 9-helix 10 site in steroid receptors and identifies an approach that may be applied to discover previously unknown allosteric sites in proteins.

The biophysical and biochemical properties of live tissues are important in the context of development and disease. Methods for evaluating these properties typically involve destroying the tissue or require specialized technology and complicated analyses. Here, we present a novel, noninvasive methodology for determining the spatial distribution of tissue features within embryos, making use of nondirectionally migrating cells and software we termed "Landscape," which performs automatized high-throughput three-dimensional image registration. Using the live migrating cells as bioprobes, we identified structures within the zebrafish embryo that affect the distribution of the cells and studied one such structure constituting a physical barrier, which, in turn, influences amoeboid cell polarity. Overall, this work provides a unique approach for detecting tissue properties without interfering with animal's development. In addition, Landscape allows for integrating data from multiple samples, providing detailed and reliable quantitative evaluation of variable biological phenotypes in different organisms., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

In recent years, hundreds of novel RNA-binding proteins (RBPs) have been identified, leading to the discovery of novel RNA-binding domains. Furthermore, unstructured or disordered low-complexity regions of RBPs have been identified to play an important role in interactions with nucleic acids. However, these advances in understanding RBPs are limited mainly to eukaryotic species and we only have limited tools to faithfully predict RNA-binders in bacteria. Here, we describe a support vector machine-based method, called TriPepSVM, for the prediction of RNA-binding proteins. TriPepSVM applies string kernels to directly handle protein sequences using tri-peptide frequencies. Testing the method in human and bacteria, we find that several RBP-enriched tri-peptides occur more often in structurally disordered regions of RBPs. TriPepSVM outperforms existing applications, which consider classical structural features of RNA-binding or homology, in the task of RBP prediction in both human and bacteria. Finally, we predict 66 novel RBPs in Salmonella Typhimurium and validate the bacterial proteins ClpX, DnaJ and UbiG to associate with RNA in vivo., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The identification of novel, potent, non-steroidal/small molecule functional GR antagonist GSK1564023A selective over PR is described. Associated structure-activity relationships and the process of optimisation of an initial HTS hit are also described., (2010 Elsevier Ltd. All rights reserved.)

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse., (Copyright (c) 2009. Published by Elsevier Ltd.)

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.