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Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR

Tourism is one of the fastest-growing and most visible sectors of the global economy, contributing significantly to boosting a nation’s economy. Currently, tourism-led economic growth considering sustainable approaches is becoming increasingly important in public policy. Recent urban and regional studies have begun to focus on the sustainability of tourism from social, economic, environmental, and cultural perspectives. The research aims to identify the most important issues and barriers to sustainable tourism development in Uzbekistan and proposes the most effective culturalization strategies to overcome those barriers. This paper involves the application of Global RPM (Globalization, Rationality, Professionalism, and Morality) analysis in combination with SANEL HERMES (Sightseeing, Admission paying, Night touring, Experiencing, Learning, Healing, Enjoying, Rest and Relaxing, Memento shopping, Eating and Drinking, and Staying) model based on data from a variety of sources, including literature review, participation interview, tourist survey, and expert questionnaire to identify and classify influencing factors that show existing barriers to sustainable tourism in Uzbekistan. Finally, a set of culturalization strategies is proposed, evaluated, and ranked by experts using a Quantitative Strategic Planning Matrix. The results of the survey have shown that tourism activities are currently not sustainable in a satisfactory manner. However, if the policymakers consider the relevant strategies and take this study into account, as well as its findings, then Uzbekistan can be made more attractive in terms of sustainable tourism.

Central Asian (CA) countries (Kazakhstan, Kyrgyzstan, Turkmenistan, Tajikistan, Uzbekistan) are assumed to be one of the most attractive tourist destinations since this particular geographical location holds immense potential in tourism products. Due to the COVID-19 pandemic, the flourishing tourism sector of these countries has been immensely affected. The aim of this study is to examine the impact of Central Asian tourists' risk attitudes toward traveling during the COVID-19 pandemic through consideration of sociodemographic characteristics. The research was conducted during January through April 2021 based on a sample of 966 respondents via an online questionnaire. In the survey, risks are divided into four main categories: health, psychological, financial and travel destination. Nominal regression was used to identify the way in which risk perception affected travel intentions during COVID-19 and the research findings indicate that Central Asian tourists’ risk perception has done so. Hygiene, disinfection and a reliable health system in destinations (21%) will be leading factors in future travel.

Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.

The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

Novel 2,4-diaminopyrimidines bearing N,N-disubstituted aminomethyl residues at the 5-position were designed as dihydrofolate reductase (DHFR) inhibitors. These compounds were obtained by treatment of 1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide with secondary amines in a polar solvent and in the presence of triethylamine at room temperature. The procedure was found to be very efficient and suitable for application in high-throughput synthesis. In addition, we found that high-throughput screening for enzymatic and in vitro antibacterial activity could be performed on crude reaction mixtures, thus avoiding any purification step. Over 1200 proprietary secondary amines were selected for high-throughput synthesis, based on structural and diversity-related criteria, and the resulting products were submitted to high-throughput screening. A greater number of hits, and significantly more active compounds, were obtained through structure-based library design than through diversity-based library design. Different classes of inhibitors of DHFR were identified in this way, including compounds derived from di-, tri-, and tetracyclic amines. In general, these products showed high activity against the enzymes derived from both TMP-sensitive and TMP-resistant Streptococcus pneumoniae. Some compounds possessed appreciable selectivity for the bacterial over the human enzyme, whereas other compounds were not at all selective. In most cases, active enzyme inhibitors also displayed antibacterial activity.