Peptide-Based 2-Aminophenylamide Probes for Targeting Endogenous Class I Histone Deacetylase Complexes

Lysine deacetylases or histone deacetylases (HDACs) remove acetylation markers from numerous cellular proteins, thereby regulating their function and activity. Recently established peptide probes containing the HDAC-trapping amino acid α-aminosuberic acid ω-hydroxamate (AsuHd) have been used to investigate the compositions of HDAC complexes in a site-specific manner. Here we report the new HDAC-trapping amino acid 2-amino-8-[(2-aminophenyl)amino]-8-oxooctanoic acid (AsuApa) and the utility of AsuApa-containing probes for HDAC complex profiling on a proteome-wide scale. Unlike AsuHd-containing probes, AsuApa enriched only HDACs 1, 2, and 3 efficiently and was the most potent probe tested for capturing the last of these. These findings indicate that the inherent specificity of reported small-molecule pimelic diphenylamide HDAC inhibitors is preserved in AsuApa and that this HDAC-trapping amino acid represents a potent tool for investigating class I HDAC complexes.     

Overcoming psychological resistance toward using recycled water in California

We use data from a representative sample of adult Californians (N = 1500) to examine the relation between information and sociodemographic factors to the willingness to adopt recycled water in 10 different applications. We find that direct consumption or skin contact with recycled water stirs the strongest resistance. We conducted a randomized experiment to test how respondents would react to learning that there is large, existing, indirect potable use program in Orange County. While both messages boost support for almost all uses of recycled water, respondents still resist drinking, bathing and cooking with it. Contrary to some previous findings, the response to both information cues generally does not appear to depend upon level of education.     

Sequence-Selective Covalent CaaX-Box Receptors Prevent Farnesylation of Oncogenic Ras Proteins and Impact MAPK/PI3 K Signaling

Oncogenic Ras proteins are implicated in the most common life-threatening cancers. Despite intense research over the past two decades, the progress towards small-molecule inhibitors has been limited. One reason for this failure is that Ras proteins interact with their effectors only via protein-protein interactions, which are notoriously difficult to address with small organic molecules. Herein we describe an alternative strategy, which prevents farnesylation and subsequent membrane insertion, a prerequisite for the activation of Ras proteins. Our approach is based on sequence-selective supramolecular receptors which bind to the C-terminal farnesyl transferase recognition unit of Ras and Rheb proteins and covalently modify the essential cysteine in the so-called CaaX-box.     

Concise Synthesis of 1,4-Benzoquinone-Based Natural Products as Mitochondrial Complex I Substrates and Substrate-Based Inhibitors

A short, efficient one-step synthesis of 2-methyl-5-(3-methyl-2-butenyl)-1,4-benzoquinone, a natural product from Pyrola media is described. The synthesis is based on a direct late C−H functionalization of the quinone scaffold. The formation of the natural product was confirmed by means of 2D-NMR spectroscopy. Additional derivatives were synthesized and tested alongside the natural product as potential substrate and substrate-based inhibitors of mitochondrial complex I (MCI). The structure-activity relationship study led to the discovery of 3-methylbuteneoxide-1,4-anthraquinone ( 1 i ), an inhibitor with an IC₅₀ of 5 μM against MCI. The identified molecule showed high selectivity for MCI when tested against other quinone-converting enzymes, including succinate dehydrogenase, and the Na (+)-translocating NADH:quinone oxidoreductase. Moreover, the identified inhibitor was also active in cell-based proliferation assays. Therefore, 1 i can be considered as a novel chemical probe for MCI.     

Impacts of EU funded R&D networks on the generation of key enabling technologies: Empirical evidence from a regional perspective

Cross-regional R&D networks are essential for regional innovativeness. Yet, we lack insights into technology field-specific effects of a region's network connectivity. This study investigates key enabling technologies (KETs) to compare knowledge creation effects of EU funded R&D networks for different technological fields. By applying spatially filtered regression models together with marginal effect interpretations for non-linear models we quantify and compare network effects across KET fields. Results show that the generally positive network effects differ depending on region-internal endowments and the nature of the underlying technologies. Policy implications arise for the interrelations between EU research, industrial and regional policy.     

Depicting communities of Romani studies: on the who,when and where of Roma related scientific publications

Scientometrics - Contemporary research on Roma from diverse disciplines has grown strongly during the last years. This is the first bibliometric study on the field of Romani studies considering the...     

The Impact of Hanseniaspora vineae Fermentation and Ageing on Lees on the Terpenic Aromatic Profile of White Wines of the Albillo Variety

Hanseniaspora vineae is a non-Saccharomyces yeast that has a powerful impact on the sensory profile of wines. Its effect on the aromatic profile of non-aromatic grape varieties, such as Albillo Mayor (Vitis vinifera, L), during vinification is a useful biotechnology to improve sensory complexity. Fermentation in steel barrels using Hanseniaspora vineae and sequential inoculation with Saccharomyces cerevisiae have been used to study the formation of terpenes and cell lysis in the production of Albillo white wines. The GC-MS analysis profile shows a significant effect of H. vineae fermentation on the contents of terpenes (≈×3), mainly in linalool (>×3), β-citronellol (>×4), geraniol (>×2) and α-terpineol (≈×2). The contents of several polyoxygenated terpenes and some volatile phenols with a spicy aroma were increased during fermentation. In summary, Hanseniaspora vineae releases a large number of cell wall polysaccharides during fermentation that affect wine palatability and structure. Hanseniaspora vineae is a powerful bio-tool to enhance the fruitiness, floral notes and freshness in non-aromatic white varieties.     

Lynch Syndrome: Its Impact on Urothelial Carcinoma

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.