Toward an understanding of tourists’ authentic heritage experiences: Evidence from Hong Kong

Authenticity in tourism has been a topic of discussion since the 1960s, but the concept is still to be fully developed. This study focuses on tourists’ perceptions of authenticity, and in particular how they evaluate authentic heritage experiences. The appearance and physical settings of attractions were found to be the initial and most important indicators of authentic or inauthentic experiences. Other criteria for assessing the authenticity of heritage experiences include the presence of local culture and customs, constructed elements, commodification, and atmosphere

Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53

Theresa Klett,1,* Martin Schwer,1,* Larissa N Ernst,1,* Marc U Engelhardt,1 Simon J Jaag,2 Benedikt Masberg,2 Cornelius Knappe,2 Michael Lämmerhofer,2 Matthias Gehringer,3,4 Frank M Boeckler1,5 1Laboratory for Molecular Design & Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 2Pharmaceutical (Bio-) Analysis, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 3Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 4Medicinal Chemistry, Institute for Biomedical Engineering, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 5Interfaculty Institute for Biomedical Informatics (IBMI), Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany*These authors contributed equally to this workCorrespondence: Frank M Boeckler, Laboratory for Molecular Design & Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8 (Haus B), Tübingen, D – 72076, Germany, Tel +49 7071 29 74567, Email [email protected]: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SNAr/SN).Methods: After predicting the theoretical solubility of the fragments by LogP and LogS during the selection process, we determined their experimental solubility using a turbidimetric solubility assay. The reactivities of the different compounds were measured in a high-throughput 5,5’-dithiobis-(2-nitrobenzoic acid) DTNB assay, followed by a (glutathione) GSH stability assay. We employed the CovLib in a (differential scanning fluorimetry) DSF-based screening against different targets: c-Jun N-terminal kinase 3 (JNK3), ubiquitin-specific protease 7 (USP7), and the tumor suppressor p53. Finally, the covalent binding was confirmed by intact protein mass spectrometry (MS).Results: In general, the purchased fragments turned out to be sufficiently soluble. Additionally, they covered a broad spectrum of reactivity. All investigated α-cyanoacrylamides/acrylates and all structurally confirmed epoxides turned out to be less reactive compounds, possibly due to steric hindrance and reversibility (for α-cyanoacrylamides/acrylates). The SNAr and vinyl sulfone fragments are either highly reactive or stable. DSF measurements with the different targets JNK3, USP7, and p53 identified reactive fragment hits causing a shift in the melting temperatures of the proteins. MS confirmed the covalent binding mode of all these fragments to USP7 and p53, while additionally identifying the SNAr-type electrophile SN002 as a mildly reactive covalent hit for p53.Conclusion: The screening and target evaluation of the CovLib revealed first interesting hits. The highly cysteine-reactive fragments VS004, SN001, SN006, and SN007 covalently modify several target proteins and showed distinct shifts in the melting temperatures up to +5.1 °C and − 9.1 °C. Keywords: covalent fragment-based drug discovery, differential scanning fluorimetry, 5,5’-dithiobis-(2-nitrobenzoic acid), intact protein mass spectrometry, glutathion

LARGE-SCALE EXPANSION OF HYPOXIA AT MARINE BENTHAL ZONE IN GEOMORPHOLOGICALLY COMPARABLE BAYS-FJORDS OF CRIMEA PENINSULA UNDER DIFFERENT TECHNOGENIC LOADS

Aim. Comparative analysis of the aeration features of the bottom waters during the different seasons of the year between the Sevastopol and Donuzlav Bays as geomorphological similar in configuration semi-closed sea reservoirs of the Black Sea under different anthropogenic loads. Material and methods. Sevastopol and Donuzlav Bays, located in the Western part of the Crimean Peninsula, were studied. The concentration and total consumption of dissolved oxygen in the water column and the bottom layer were determined in situ using a digital LDO analyzer. The redox potential in bottom sediments was measured using a platinum electrode. Results. Aeration of the water column in the Sevastopol seaside is suitable for normal life of pelagic and epibenthic organisms. At the same time, in the Sevastopol and Donuzlav Bays the large-scale anoxia in the surface layer of bottom sediments was found. Also, the muddy sediments of the Sevastopol Bay’ bed can be an oxygen-deficient extreme biotope for most of the year, the minimum concentration of O2 in the bottom water is not higher than 0.11-0.36 mg/l. The benthal zone here was well aerated only at the end of November. Conclusion. The general patterns of benthic hypoxia were identified for such coast objects as Sevastopol and the Donuzlav Bays, which are similar by their contours and recent seabed structures. Benthal zones of both investigated bays-fjords can be attributed to hypoxic high-gradient habitats, that have a whole generality with oxygen-deficient marine waters habitats – estuarine zones, areas of gas seeps, etc. Strong oxygen deficiency, toxic H2S contamination coupled with organic enrichment a typically benthic environment for such biotopes

Decoding the complex internal chemical structure of garnet porphyroblasts from the Zermatt area, Western Alps

Garnet is a prototypical mineral in metamorphic rocks because it commonly preserves chemical and textural features that can be used for untangling its metamorphic development. Large garnet porphyroblasts may show extremely complex internal structures as a result of a polycyclic growth history, deformation, and modification of growth structures by intra- and intercrystalline diffusion. The complex internal structure of garnet porphyroblasts from garnet–phengite schists (GPS) of the Zermatt area (Western Alps) has been successfully decoded. The centimetre-sized garnet porphyroblasts are composed of granulite facies garnet fragments overgrown by a younger generation of grossular-rich eclogite facies garnet. The early granulite facies garnet (G-Grt) formed from low-P, high-T metamorphism during a pre-Alpine orogenic event. The late garnet (E-Grt) is typical of high-pressure, low-temperature (HPLT) metamorphism and can be related to Alpine subduction of the schists. Thus, the garnet of the GPS are polycyclic (polymetamorphic). G-Grt formation occurred at ~670 MPa and 780°C, E-Grt formed at ~1.7 GPa and 530°C. The G-Grt is relatively rich in Prp and poor in Grs, while E-Grt is rich in Grs and poor in Prp. The Alm content (mol.%) of G-Grt is 68 of E-Grt 55. After formation of E-Grt between and around fragmented G-Grt at 530°C, the GPS have been further subducted and reached a maximum temperature of 580°C before exhumation started. Garnet composition profiles indicate that the initially very sharp contacts between the granulite facies fragments of G-Grt and fracture seals of HPLT garnet (E-Grt) have been modified by cation diffusion. The profiles suggest that Ca did not exchange at the scale of 1 µm, whereas Fe and Mg did efficiently diffuse at the derived maximum temperature of 580°C for the GPS at the scale of 7–8 µm. The Grt–Grt diffusion profiles resulted from spending c. 10 Ma at 530–580°C along the P–T–t path. The measured Grt composition profiles are consistent with diffusivities of log DMgFe = −25.8 m2/s from modelled diffusion profiles. Mg loss by diffusion from G-Grt is compensated by Fe gain by diffusion from E-Grt to maintain charge balance. This leads to a distinctive Fe concentration profile typical of uphill diffusion