Probing the Protein Kinases' Cysteinome by Covalent Fragments.

Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines.

Peripheral nerve blocks for through-knee amputation in a patient on extracorporeal membrane oxygenation.

A woman in her 40s with an ischaemic right lower limb, who was on extracorporeal membrane oxygenation (ECMO) following cardiopulmonary failure secondary to bilateral alveolar haemorrhage, was scheduled for through-knee amputation. She was under mechanical ventilation and continuous intravenous medications. Considering her significant comorbidities, peripheral nerve blocks were chosen for anaesthesia.

A patent review of MAPK inhibitors (2018 - present).

Introduction: The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They are involved in a multitude of diseases, including inflammatory, autoimmune, neurodegenerative, and metabolic diseases as well as cancer. In recent years, further developments in the field of MAPK-inhibitors have been reported, including an isoform or downstream target selective inhibition of MAPKs as well as target protein degradation approaches.

Effect of Ultraviolet Radiation on Organic Photovoltaic Materials and Devices.

Organic photovoltaics are a sustainable and cost-effective power-generation technology that may aid the move to zero-emission buildings, carbon neutral cities, and electric vehicles. While state-of-the-art organic photovoltaic devices can be encapsulated to withstand air and moisture, they are currently still susceptible to light-induced degradation, leading to a decline in the long-term efficiency of the devices. In this study, the role of ultraviolet (UV) radiation on a multilayer organic photovoltaic device is systematically uncovered using spectral filtering.

Solar Trees: First Large-Scale Demonstration of Fully Solution Coated, Semitransparent, Flexible Organic Photovoltaic Modules.

with a unique design and semitransparent blue appearance is presented. These modules are implemented in a solar tree installation at the German pavilion in the EXPO2015 in Milan/IT. The modules show power conversion efficiencies of 4.

Role of extracellular GAPDH in Streptococcus pyogenes virulence.

Pathogens generate molecules, or virulence factors, that enable them to colonize host tissues through several mechanisms, including adhesion to host tissues, or superior invasive capability. Some allow the pathogen to evade the host's immune system. Many of these molecules are proteins that are exported to the cell's surface or secreted.

GAPDH in anesthesia.

Thus far, two independent laboratories have shown that inhaled anesthetics directly affect GAPDH structure and function. Additionally, it has been demonstrated that GAPDH normally regulates the function of GABA (type A) receptor. In light of these literature observations and some less direct findings, there is a discussion on the putative role of GAPDH in anesthesia.

Multiple binding partners.

GAPDH interacts with a plethora of diverse cellular proteins. The network of interacting partners, or interactome, is presented for GAPDH with the interacting molecules grouped into specific functional and structural categories. By organizing the binding partners in this way, certain common structural features are beginning to surface, such as acidic dipeptide sequences that are found in several of these binding proteins.

Dynamic oligomeric properties.

This chapter provides a foundation for further research into the relationship between dynamic oligomeric properties and functional diversity. The structural basis that underlies the conformational sub-states of the GAPDH oligomer is discussed. The issue of protein stability is given a thorough analysis, since it is well-established that the primary strategy for protein oligomerization is to stabilize conformation.

Target for diverse chemical modifications.

The chapter begins with an historical perspective of GAPDH isozymes that is juxtaposed to the fact that there is only one somatic functional gene in humans that is virtually identical among the mammalian species. Over the many years of GAPDH research, dozens of labs have reported the existence of multiple forms of GAPDH, which mostly vary as a function of charge with an occasional report of truncated forms. These observations are in part due to GAPDH being a substrate for many enzymatically-controlled post-translational modifications.

GAPDH, as a virulence factor.

Pathogens, such as bacteria, viruses, protozoa and fungi, generate molecules that provide them with a selective advantage, often at the expense of the host. These molecules, or virulence factors, enable pathogens to colonize the host through several mechanisms. Some molecules offer the pathogen an advantage through better adhesion to host tissues, or superior invasive capability.

Functional diversity.

There is increasing evidence to support a gene economy model that is fully based on the principles of evolution in which a limited number of proteins does not necessarily reflect a finite number of biochemical processes. The concept of 'gene sharing' proposes that a single protein can have alternate functions that are typically attributed to other proteins. GAPDH appears to play this role quite well in that it exhibits more than one function.

Compartmentation of GAPDH.

The concept of the cytosol as a space that contains discrete zones of metabolites is discussed relative to the contribution of GAPDH. GAPDH is directed to very specific cell compartments. This chapter describes the utilization of GAPDH's enzymatic function for focal demands (i.

GAPDH and intermediary metabolism.

GAPDH plays a major enzymatic role in the intermediary metabolism of human tissues. In fact, the cells of all organisms require the catalytic capability of GAPDH in order to maintain adequate glycolytic flux. Even the primitive archaea rely on GAPDH in a pivotal step in the Entner-Doudoroff pathway, which is a series of reactions that resembles glycolysis.

Basic biology of GAPDH.

The GAPDH gene is highly conserved with a promoter that contains several types of regulatory elements, perhaps even in a distal intron. Curiously, the transcription start site shows some ambiguity and there are codon-sharing exons at alternate exon junctions. While there is only one functional gene for GAPDH in humans, the genome is littered with pseudogenes, representing a trove of researchable content.

Protection against protein aggregation by alpha-crystallin as a mechanism of preconditioning.

Anesthetic preconditioning occurs when cells previously exposed to inhaled anesthetics are protected against subsequent injury. We hypothesize that inhaled anesthetics may cause slight protein misfolding that involves site-specific dehydration, stimulating cytoprotective mechanisms. Human neuroblastoma cells were exposed to ethanol (as the dehydration agent) followed by quantitative analysis of the expression of five heat shock genes: DNAJC5G, CRYAA, HSPB2, HSF4 and HSF2.

Isoflurane's Effect on Protein Conformation as a Proposed Mechanism for Preconditioning.

Persistent alteration of protein conformation due to interaction with isoflurane may be a novel molecular aspect of preconditioning. We preincubated human serum albumin with isoflurane, dialyzed to release agent, and assessed protein conformation. Susceptibility to chemical modification by methylglyoxal and nitrophenylacetate was also examined.

Isoflurane preconditioning involves upregulation of molecular chaperone genes.

Isoflurane preconditioning is a phenomenon in which cells previously exposed to isoflurane exhibit protection against subsequent noxious stimuli. We hypothesize that isoflurane may cause subtle protein misfolding that persists at a sublethal level, stimulating cytoprotective mechanisms. Human neuroblastoma cells (SH-SY5Y) were exposed to isoflurane followed by quantitative analysis of the expression of several families of heat shock genes (84 total transcripts).

Inhaled Anesthetics Promote Albumin Dimerization through Reciprocal Exchange of Subdomains.

Inhaled anesthetics affect protein-protein interaction, but the mechanisms underlying these effects are still poorly understood. We examined the impact of sevoflurane and isoflurane on the dimerization of human serum albumin (HSA), a protein with anesthetic binding sites that are well characterized. Intrinsic fluorescence emission was analyzed for spectral shifting and self-quenching, and control first derivatives (spectral responses to changes in HSA concentration) were compared against those obtained from samples treated with sevoflurane or isoflurane.

Carnosine protects against the neurotoxic effects of a serotonin-derived melanoid.

Anesthesia-related postoperative cognitive dysfunction (POCD) leads to morbidity in the elderly. Lipid peroxidative byproducts (i.e.

Isoflurane's effect on interfacial dynamics in GAPDH influences methylglyoxal reactivity.

Diabetic surgical patients are at risk for peri- and post-operative complications, which can be prevented by maintaining tight glycemic control during anesthesia. Control of blood sugar would decrease unwanted chemical reactions, such as protein glycation, minimizing tissue dysfunction. Methylglyoxal (MG) is a major contributor to protein modification and tissue dysfunction seen in diabetic patients.

Redox mechanism of neurotoxicity by a serotonin-acrolein polymeric melanoid.

Postoperative cognitive dysfunction may be associated with the toxic products of lipid peroxidation, such as the α,β-unsaturated aldehyde acrolein, which accumulates in aging. We previously identified an acrolein-mediated, serotonin-derived melanoid product, or SDM. This study further characterizes this putative novel neuromelanin, which is not made from catecholamines.

Toxicity of a serotonin-derived neuromelanin.

Postoperative Cognitive Dysfunction (POCD) is associated with increased mortality in the elderly and may occur from lipid peroxidation in aging. We previously showed that sevoflurane sequesters acrolein, which promotes the formation of a novel species of a putative neuromelanin. The current study examined the properties of this serotonin-derived melanoid (SDM).

White organic light-emitting diodes with fluorescent tube efficiency.

The development of white organic light-emitting diodes (OLEDs) holds great promise for the production of highly efficient large-area light sources. High internal quantum efficiencies for the conversion of electrical energy to light have been realized. Nevertheless, the overall device power efficiencies are still considerably below the 60-70 lumens per watt of fluorescent tubes, which is the current benchmark for novel light sources.

Interfacial effects on the conformation of amyloid-beta peptide.

We examined the effects of air-water and water-sevoflurane interfaces on conformational properties of amyloid-beta peptide (ABP). Fractions were extracted from sub-interfacial (air-water) and supra-interfacial (water-sevoflurane) layers and compared with aqueous bulk layers using fluorescence properties of ABP provided by a single tyrosine. The observations suggest that interfacial ABP may be more disordered than bulk ABP.