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Abstract There has been a surge of interest in covalent inhibitors for protein kinases in recent years. Despite success in oncology, the off-target reactivity of these molecules is still hampering the use of covalent warhead-based strategies. Herein, we disclose the development of precision-guided warheads to mitigate the off-target challenge. These reversible warheads have a complex and cyclic structure with optional chirality center and tailored steric and electronic properties. To validate our proof-of-concept, we modified acrylamide-based covalent inhibitors of c-Jun N-terminal kinases (JNKs). We show that the cyclic warheads have high resilience against off-target thiols. Additionally, the binding affinity, residence time, and even JNK isoform specificity can be fine-tuned by adjusting the substitution pattern or using divergent and orthogonal synthetic elaboration of the warhead. Taken together, the cyclic warheads presented in this study will be a useful tool for medicinal chemists for the deliberate design of safer and functionally fine-tuned covalent inhibitors.

In this study, a set of spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione derivatives 3a–p were synthesized starting from unsubstituted and N-methyl-substituted diendo- and diexo-2-aminonorbornene carboxamides, as well as various substituted isatins. The typical method involves a condensation reaction of alicyclic aminocarboxamide and isatin in the presence of a catalyst, using a solvent and an acceptable temperature. We developed a cost-effective and ecologically benign high-speed ball milling (HSBM), microwave irradiation (MW), and continuous flow (CF) technique to synthesize spiroquinazolinone molecule 3a. The structures of the synthesized compounds 3a–p were determined using 1D and 2D NMR spectroscopies. Furthermore, docking studies and absorption, distribution, metabolism, and toxicity (ADMET) predictions were used in this work. In agreement with the corresponding features found in the case of both the SARS-CoV-2 main protease (RCSB Protein Data Bank: 6LU7) and human mast cell tryptase (RCSB Protein Data Bank: 2ZA5) based on the estimated total energy and binding affinity, H bonds, and hydrophobicity in silico, compound 3d among our 3a–g, 3i–k, and 3m derivatives was found to be our top-rated compound.

In this paper, we investigate the common narrative in literary history that the inner lives of characters became a central preoccupation of literary modernism – a phenomenon commonly referenced as the “inward turn”. We operationalize this notion via a proxy, tracing the use of verbs relating to inner life across 10 language corpora from the ELTeC collection, which comprises novels from the period between 1840–1920. We expected to find an increase in the use of inner-life verbs corresponding to the traditional periodisation of modernism in each of the languages. However, different experiments conducted with the data do not confirm this hypothesis. We therefore look at the results in a number of more granular ways, but we cannot identify any common trends even when we split the verbs into individual categories, or take canonicity or gender into account. We discuss the obtained results in detail, proposing potential reasons for them and including potential avenues of further research as well as lessons learned.

ObjectivesEmerging results indicate that, in COVID-19, thromboembolic complications contribute to the high mortality and morbidity. Previous research showed that the prevalence of pulmonary embolism (PE) is between 25-50% in COVID-19 patients, however, most of these reports are based on data from patients with severe pneumonia, treated in intensive care units.Materials and methodsWe conducted a retrospective, single-center, observational study to estimate the prevalence of PE in COVID-19 patients who underwent CT angiography and to identify the most important predictors. Adult outpatients with COVID-19, who presented at our COVID Outpatient Clinic between 1st and 31st of March in 2021 and underwent CTA examination were included in this study. Multiple linear regression analysis was used to identify predictors of PE in COVID-19 patients. The predictors were: age, gender, disease duration, CT severity index and log-transformed quantitative D-dimer (logQDDIM) value.Results843 COVID-19 patients were included into the study. 82.56% (693 patients) of the infected patients had a pulmonary CTA examination and D-dimer levels (mean age: 59.82 years ± 15.66). 7.61% (53 patients) of the patients had PE. 2.02% (14 patients) of the patients had main branch or lobar PE. The multiple regression analysis found that only logQDDIM was a significant predictor. A logQDDIM cut-off value of 0.0169 (1.0171 ug/ml serum D-dimer) predicted PE with 99% sensitivity (pConclusionsWe demonstrated in a large cohort of COVID-19 patients that a cut-off value of QDDIM of 1ug/ml can exclude pulmonary embolism in an outpatient setting, implicating that QDDIM might potentially supersede CTA as a screening approach in COVID-19 outpatient clinics.

In this paper, we investigate the common narrative in literary history that the inner lives of characters became a central preoccupation of literary modernism. We operationalise this notion via a proxy, tracing the use of verbs relating to inner life across 10 language corpora from the ELTeC collection, which comprises novels from the period between 1840–1920. We expected to find an increase in the use of inner-life verbs corresponding to the traditional periodisation of modernism in each of the languages. However, different experiments conducted with the data do not confirm this hypothesis. We therefore look at the results in a number of more granular ways, but we cannot identify any common trends even when we split the verbs into individual categories, or take canonicity or gender into account. We discuss the obtained results in detail, proposing potential reasons for them and including potential avenues of further research as well as lessons learned.

In this study, a set of spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione derivatives 3a–p were synthesized starting from unsubstituted and N-methyl-substituted diendo- and diexo-2-aminonorbornene carboxamides, as well as various substituted isatins. The typical method involves a condensation reaction of alicyclic aminocarboxamide and isatin in the presence of a catalyst, using a solvent and an acceptable temperature. We developed a cost-effective and ecologically benign high-speed ball milling (HSBM), microwave irradiation (MW), and continuous flow (CF) technique to synthesize spiroquinazolinone molecule 3a. The structures of the synthesized compounds 3a–p were determined using 1D and 2D NMR spectroscopies. Furthermore, docking studies and absorption, distribution, metabolism, and toxicity (ADMET) predictions were used in this work. In agreement with the corresponding features found in the case of both the SARS-CoV-2 main protease (RCSB Protein Data Bank: 6LU7) and human mast cell tryptase (RCSB Protein Data Bank: 2ZA5) based on the estimated total energy and binding affinity, H bonds, and hydrophobicity in silico, compound 3d among our 3a–g, 3i–k, and 3m derivatives was found to be our top-rated compound. [ABSTRACT FROM AUTHOR]

AimTo assess the state of radiology education across Europe by means of a survey study.MethodsA comprehensive 23-item radiology survey was distributed via email to the International Society of Radiology members, national radiological societies, radiologists and medical physicists. Reminders to complete the survey were sent and the results were analyzed over a period of 4 mo (January-April 2016). Survey questions include length of medical school and residency training; availability of fellowship and subspecialty training; number of residency programs in each country; accreditation pathways; research training; and medical physics education. Descriptive statistics were used to analyze and summarize data.ResultsRadiology residency training ranges from 2-6 years with a median of 5 years, and follows 1 year of internship training in 55% (12 out of 22) European countries. Subspecialty fellowship training is offered in 55% (12 out of 22) European countries. Availability for specialization training by national societies is limited to eight countries. For nearly all respondents, less than fifty percent of radiologists travel abroad for specialization. Nine of 22 (41%) European countries have research requirements during residency. The types of certifying exam show variation where 64% (14 out of 22) European countries require both written and oral boards, 23% (5 out of 22) require oral examinations only, and 5% (1 out of 22) require written examinations only. A degree in medical physics is offered in 59% (13 out of 22) European countries and is predominantly taught by medical physicists. Nearly all respondents report that formal examinations in medical physics are required.ConclusionComparative learning experiences across the continent will help guide the development of comprehensive yet pragmatic infrastructures for radiology education and collaborations in radiology education worldwide.

New 2-thioxopyrimidin-4-ones capable of participating in regioselective reactions with functionally diverse hydrazonoyl chlorides towards angular regioisomers, rather than linear ones, were designed and synthesized to form stereoisomeric cis- and trans-hexahydro [1,2,4]triazolo[4,3-a]quinazolin-9-ones to be tested as antitumor candidates. The angular regiochemistry of the products was verified through crystallographic experiments and NMR studies. In addition, the regioselectivity of the reaction was found to be independent of the stereochemistry of the used 2-thioxopyrimidin-4-one. Only compound 4c demonstrated satisfactory growth inhibition against all the cancer cells used among all the produced drugs.