Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Categorical observers for metamerism

A method is proposed to generate categorical colour observer functions (individual colour matching functions) for any field size based on the CIE 2006 system of physiological observer functions. The method combines proposed categorical observer techniques of Sarkar et al with a physiologically-based individual observer model of Asano et al and a clustering technique to produce the optimal set of categorical observers. The number of required categorical observers varies depending on an application with as many as 50 required to predict individual observers' matches when a laser projector is viewed. However, 10 categorical observers are sufficient to represent colour-normal populations for personalized colour imaging. The proposed and recommended categorical observers represent a robust and inclusive technique to examine and quantify observer metamerism in any application of colorimetry.     

Current Status on Stem Cells and Cancers of the Gastric Epithelium

Gastric cancer is still a leading cause of cancer-related mortality worldwide in spite of declining incidence. Gastric cancers are, essentially, adenocarcinomas and one of the strongest risk factors is still infection with Helicobacter pylori. Within the last years, it became clear that gastric self-renewal and carcinogenesis are intimately linked, particularly during chronic inflammatory conditions. Generally, gastric cancer is now regarded as a disease resulting from dysregulated differentiation of stem and progenitor cells, mainly due to an inflammatory environment. However, the situation in the stomach is rather complex, consisting of two types of gastric units which show bidirectional self-renewal from an unexpectedly large variety of progenitor/stem cell populations. As in many other tumors, cancer stem cells have also been characterized for gastric cancer. This review focuses on the various gastric epithelial stem cells, how they contribute to self-renewal and which routes are known to gastric adenocarcinomas, including their stem cells.     

Cerebral microbleeds and cognitive decline in a hemodialysis patient: Case report and review of literature

Cerebral microbleeds (CMBs) are small hemosiderin deposits indicative of prior cerebral microscopic hemorrhage and previously thought to be clinically silent. Recent population‐based cross‐sectional studies and prospective longitudinal cohort studies have revealed association between CMB and cognitive dysfunction. In the general population, CMBs are associated with age, hypertension, and cerebral amyloid angiopathy. In the chronic kidney disease (CKD) population, diminished estimated glomerular filtration rate has been found to be an independent risk factor for CMB, raising the possibility that a uremic milieu may predispose to microbleeds. In the end‐stage renal disease (ESRD) population on hemodialysis, the incidence of microbleeds is significantly higher compared with a control group without history of CKD or stroke. We present an ESRD patient on chronic hemodialysis with a history of gradual cognitive decline and progressive CMBs. Through this case and literature review, we illustrate the need to develop detection and prediction models to treat this frequent development in ESRD patients.     

Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.     

Lignin from Annual Plants as Raw Material Source for Flavors and Basic Chemicals

The enzymatic conversion of lignins, possibly in combination with electrochemical oxidation, makes aromatics such as syringol, guaiacol, vanillin and catechol available in the qualities required by the fragrance industry. The lignins were obtained by soda digestion from wheat straw and Miscanthus, characterized and then converted with laccases. The overall yield amounted up to 9 wt % with a product spectrum confined to four substances. Catechol was the major product, with a fraction of ≈75 %. It can easily be isolated by extraction with acetone.     

Site-Specific PEGylation of Therapeutic Proteins

The use of proteins as therapeutics has a long history and is becoming ever more common in modern medicine. While the number of protein-based drugs is growing every year, significant problems still remain with their use. Among these problems are rapid degradation and excretion from patients, thus requiring frequent dosing, which in turn increases the chances for an immunological response as well as increasing the cost of therapy. One of the main strategies to alleviate these problems is to link a polyethylene glycol (PEG) group to the protein of interest. This process, called PEGylation, has grown dramatically in recent years resulting in several approved drugs. Installing a single PEG chain at a defined site in a protein is challenging. Recently, there is has been considerable research into various methods for the site-specific PEGylation of proteins. This review seeks to summarize that work and provide background and context for how site-specific PEGylation is performed. After introducing the topic of site-specific PEGylation, recent developments using chemical methods are described. That is followed by a more extensive discussion of bioorthogonal reactions and enzymatic labeling.