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The H1047R mutation of PIK3CAis highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047Rover PI3KαWTis crucial due to the role that PI3KαWTplays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047Rwith high selectivity over PI3KαWT, resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047Rincluding a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo- and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry. Computational investigation supported a cyclic half-chair transition state to rationalize the high selectivity in benzyl systems.

The COVID-19 pandemic has exacerbated mortality rates among immunocompromised patients, accentuating the need for novel, targeted therapies. Transplant recipients, with their inherent immune vulnerabilities, represent a subgroup at significantly heightened risk. Current conventional therapies often demonstrate limited effectiveness in these patients, calling for innovative treatment approaches. In immunocompromised transplant recipients, several viral infections have been successfully treated by adoptive transfer of virus-specific T-cells (VST). This paper details the successful application of SARS-CoV-2-specific memory T-cell therapy, produced by an interferon-γ cytokine capture system (CliniMACS® Prodigy device), in three stem cell transplant recipients diagnosed with COVID-19 (case 1: alpha variant, cases 2 and 3: delta variants). These patients exhibited persistent SARS-CoV-2 PCR positivity accompanied by bilateral pulmonary infiltrates and demonstrated only partial response to standard treatments. Remarkably, all three patients recovered and achieved viral clearance within 3 to 9 weeks post-VST treatment. Laboratory follow-up investigations identified an increase in SARS-CoV-2-specific T-cells in two of the cases. A robust anti-SARS-CoV-2 S (S1/S2) IgG serological response was also recorded, albeit with varying titers. The induction of memory T-cells within the CD4 + compartment was confirmed, and previously elevated interleukin-6 (IL-6) and IL-8 levels normalized post-VST therapy. The treatment was well tolerated with no observed adverse effects. While the need for specialized equipment and costs associated with VST therapy present potential challenges, the limited treatment options currently available for COVID-19 within the allogeneic stem cell transplant population, combined with the risk posed by emerging SARS-CoV-2 mutations, underscore the potential of VST therapy in future clinical practice. This therapeutic approach may be particularly beneficial for elderly patients with multiple comorbidities and weakened immune systems.

This contribution critically examines the implications of the Request submitted by the Court of Justice with a view to amending Protocol No. 3 on the Statute of the Court of Justice of November 2022, which suggested the General Court be given the jurisdiction to hear and decide questions referred for a preliminary ruling under Article 267 TFEU. The key argument is that the structural consequences of the Court´s Request for the judicial architecture of the European Union go well beyond another mere technical (re)arrangement of a head of competence within Article 256TFEU. If implemented – and potentially further expanded in the future by transferring jurisdiction on preliminary rulings in other specific areas to the GC – the structure of the Union judiciary and the preliminary ruling procedure itself is bound to change significantly.

The purpose of this paper is to explore how the travel habits of Ukrainian tourists changed after the beginning of the 2022 war in Ukraine in comparison to the year 2021. The theoretical part of the paper discusses the impacts of war on tourism; in the empirical part, the secondary and the primary research on the Ukrainians’ travel habits before and during the war is performed. The research gives an insight into the frequency of travelling, planned spending on travel, ethnic dilemmas on travelling, and travel destinations. The research is essential in the context of war and post-war periods for understanding the psychological and behavioral effects, assessing economic consequences, addressing destination marketing and recovery efforts, and facilitating reconciliation and social integration. Research limitations include the scope and generalizability of the findings, self-reporting biases, causality and temporal issues, and limited timeframe and context.

The diverse structures and profound biological activities of lignan natural products have enticed significant effort in the exploration of new methodologies for their total synthesis. We have prepared γ-butyrolactone oximes from readily available δ-nitro alcohols via Boc2O mediated cyclization. The mild conditions are compatible with a wide range of functional groups, and this methodology has been applied to the total synthesis of five lignan natural products.

The authors investigated the importance of women's economic empowerment and its impact on the rise of female entrepreneurship and human capital in South Africa. The research included a case study analysis with four in-depth expert interviews. Data triangulation ensured the study's validity, and the case was examined through pattern matching. The results demonstrate that female entrepreneurs face challenges such as access to resources and education, socio-cultural norms, a lack of social protection and a large and unprotected informal sector. The government and institutions shall promote women's enablement through a direct labour market intervention, support for the informal sector, a gender-sensitive constitutional, legal and institutional framework, the enforcement and oversight of gender-responsive laws and policies and access to resources and education. Furthermore, women require digital inclusion, entrepreneur networks, social protection and reformed socio-cultural norms. If female entrepreneurs are empowered adequately, they would contribute to nations' human capital, economic growth and development.

AbstractThe global financial crisis that erupted in August 2007 following the collapse of the US subprime mortgage market had a significant impact on the financial markets. Ten years ago, Slovenia was confronted with the outbreak of significant financial and economic turbulence, and only in 2017 did the country’s GDP return to pre-crisis levels. Taking into account the fact that the performance of companies deteriorates to a certain extent during a crisis, this paper examines the influence of selected factors on the price of statutory audits for large companies in Slovenia in the period 2010 to 2014. The final sample consists of 177 large enterprises in Slovenia for each year or a total of 885 units (population). The main factors observed were taken from the financial statements. These are operating revenue, profit (loss), and indebtedness of the enterprise. Three hypotheses were tested by regression analysis, ANOVA, and Independent-Samples Median Test. In the research, we found that statistically significant factors of the price of a statutory audit due to the Slovenian Agency for Public Oversight are only the operating income of the audited enterprise. Over the past 40 years, studies have been conducted worldwide to determine audit fees, with a focus on English-speaking countries. This field of research is still in its infancy in Slovenia, and little research has been done on the determinants of the fees charged by the firms that exist here.

In this paper the authors investigate the importance of women’s economic empowerment and its impact on the rise of female entrepreneurship and human capital in Namibia. The research includes a case study analysis with four in-depth expert interviews. Data triangulation ensure the study’s validity, and the case was examined through pattern matching. The results demonstrate that female entrepreneurs face challenges such as access to resources and education, socio-cultural norms, a lack of social protection, and a large and unprotected informal sector. The government and institutions shall promote women’s empowerment through a direct labour market intervention, support for the informal sector, a gender-sensitive constitutional, legal, and institutional framework, the enforcement and oversight of gender-responsive laws and policies, and access to resources and education. Furthermore, women require digital inclusion, entrepreneur networks, social protection, and reformed socio-cultural norms. If female entrepreneurs are empowered adequately, they will contribute to nations’ human capital, economic growth, and development.

Privatisation, a buzzword of the 20th century, has varied approaches; it could be a broad approach of liberalisation to introduce market forces without any change of ownership, termed as ‘partial privatisation’. In narrow terms, it refers to denationalisation or divestiture and change of ownership by sale to private individuals. Public sector in India has grown over the years and operational autonomy has been granted. Disinvestment of government shareholding, has been an annual budgetary exercise; it includes strategic sale. Of late, various disinvestment approaches that are followed include share buyback, cross shareholding offer for sale, follow-on public offer, block deal exchange trade fund. The realisation of disinvestment has been about 56% of the total, and new options have to be explored.Asset monetisation, an approach to encash assets with an objective to raise resources to finance new projects, is planned with an objective to develop infrastructure by involving private sector by following different forms of the publicÐprivate partnership approach. National Monetisation Policy (NMP) has been announced by the government of India to raise ₹600,000 crore over the period of next four years, that is, from 2022 to 25, to cover up the infrastructure gap. As such, monetisation of assetsÑcore as well as non-coreÑwould be a great step in achieving the objective of Atmanirbhar Bharat[self-reliant India], and India to become $5 trillion economy by 2024. Privatisation, liberalisation and asset monetisation appear to be a simple theoretical exercise; it would require planning for newer approaches to attract private funds and also to have political will.

Physical assessment courses for nurses typically include a didactic education component and a physical skills laboratory for hands-on practice. Skills instruction focuses on a head-to-toe assessment of body systems, including inspection, palpation, percussion, and auscultation. Comparable learning outcomes can be achieved in both online and traditional classrooms. Telehealth education needs to be included in physical assessment instruction as telehealth services expand to provide greater access to health care. This article provides strategies for incorporating education into online physical assessment courses for nurses and suggests online resources for effective telehealth integration into clinical practice.

Clinical preceptors are essential to nurse practitioner education, although supply is an ongoing challenge. Seeking solutions, a unique interprofessional work group was formed comprising faculty, clinical placement personnel, and marketing expertise to evaluate existing preceptor benefits and resources. Using the most recent evidence, new strategies prioritized preceptor communication, engagement, recognition, and rewards. Enhanced benefits included the creation of new continuing education offerings, social media recognition, improved communication, and inclusion of preceptors at university events. As a result, adjunct faculty nearly doubled. An interprofessional work group is an effective model to design and implement strategies to enhance preceptor communication, motivation, and engagement.

One of the goals of Industry 4.0 is the adoption of data-driven models to enhance various aspects of the manufacturing process, such as monitoring equipment conditions, ensuring product quality, detecting failures, and preparing optimal maintenance plans. However, many machine-learning algorithms require a large amount of training data to reach desired performance. In numerous industrial applications, such data is either not available or its acquisition is a costly process. In such cases, simulation frameworks are employed to replicate the behavior of real-world facilities and generate data for further analysis. Simulation frameworks typically provide high-quality data but are often slow which can be problematic when real-time decision-making is required. Control approaches based on simulation-based data commonly face challenges related to inflexibility, particularly in dynamic production environments undergoing frequent reconfiguration and upgrades. This paper introduces a method that seeks to strike a balance between the reliance on simulated data and the limited robustness of simulation-based control methods. This balance is achieved by supplementing available data with additional expert knowledge, enabling the matching of similar data sources and their combination for reuse. Furthermore, we augment the methods with an explainability layer, facilitating collaboration between the human expert and the AI system, leading to informed and actionable decisions. The performance of the proposed solution is demonstrated through a case study on gas production from an underground reservoir resulting in reduced downtime, heightened process reliability, and enhanced overall performance. This paper builds upon our conference paper (Kuk et al., 2023), addressing the same problem with an extended, more generic methodology, and presenting entirely new results. [ABSTRACT FROM AUTHOR]

The emergence of online university degree programs is an opportunity for Chile, struggling with low tertiary education attainment rates and a skills gap in the labor market. However, little attention has been dedicated to whether the employers in Chile perceive online and on-campus university education as equivalent. This study investigated the perceptions of a convenient sample of 38 employers from different industries, using Likert scale questions and a hypothetical hiring scenario. The survey results were then consulted with three experts who provided their interpretations. The findings indicated that the investigated sample generally does not perceive online and on-campus university education as equivalent but would not discard an online degree graduate only due to their academic background. However, when given a choice between a 100% online, 100% on-campus, and a hybrid degree holder, none of them would choose a 100% online degree graduate. Instead, 57% would hire a hybrid degree graduate and 43% a 100% on-campus graduate. There is a significant, positive correlation between the perceived equivalence in rigor, learning experience, and learning content and the willingness to hire an online degree graduate. The university’s reputation is a crucial factor influencing hiring decisions in Chile. The degree’s relevance may be insignificant compared to other factors considered by the hiring managers.

Libra, announced in June of 2019 by Facebook and later rebranded to Diem, has not been released yet. This paper investigates Diem's possible effects on unbanked people and shows the most critical factors for targeting people without bank accounts. The report also elaborates on Diem's market potential. To further investigate the existing research gap, relevant literature is examined, and technical characteristics are given. In addition to that, eight experts from the areas 'cryptocurrencies', 'blockchain', 'fintech', and 'finance and banking' are interviewed on the topic. The paper finds that Diem can achieve broad adoption in emerging markets, increase financial inclusion and facilitate remittances. However, this can only be achieved if the current hurdles of the project are overcome. In particular, important is an agreement with regulators. The paper also estimates how much revenue this project could generate and what problems and risks could arise regarding negative interest rates and data protection.

The paper analyses the influence of culture and religiosity on corporate social responsibility (CSR) by assessing the three dimensions of the triple-bottom approach - economic, environmental, and social - via creating composite indicators out of the World Value Survey's relevant questions in each field. Austria and Taiwan, two very different countries in terms of economic development, religion, and cultural values, are compared. The analysis is based on the World Value Survey website; therefore, a comparison of the development of these factors over time is possible. Lastly, a correlation analysis regarding the influence of religiosity on each of those dimensions was applied. The correlation analysis resulted in a conclusion that does not follow previous studies. It suggests negative relationships in two out of three dimensions. While a positive correlation between religiosity and the economic dimension is observable in Austria, the correlation between environmental concerns and religiosity in Taiwan appears significant.

AbstractIn multi-panelled higher jurisdictions, a larger, extended formation of judges tends to be established within the court. It bears various names: the grand chamber, the extended chamber, the expanded composition, the reunion of several chambers, a court sitting en banc, an extended section or a division of a court. In larger but not too large jurisdictions, the same role is adopted by the plenary. For ease of reference, I shall refer to all such extended judicial formations with the generic name ‘grand chamber’.To bear the same name does not necessarily mean to perform the same function. As a Czech lawyer, I have always intuitively assumed that the role of such a body within an apex court is to unify the case law. In the Czech Republic, as well as in a number of other supreme continental jurisdictions for that matter, there tends to be only one reason for the presence of a grand chamber within a supreme court: to unify the diverging lines of case law and to set a clear line of precedent. However, that has never really been the job description, least of all the practice, of the Grand Chamber of the Court of Justice of the European Union (‘Court’). This begs the question: what may then be other structural reasons for the existence of such a body within an apex jurisdiction? What is the specific role, function, and ensuing justification for the Grand Chamber of the Court?This article offers some personal reflections on that question. It is structured as follows: it begins with a short comparative overview of some of the grand chambers within European (national) courts, overseas in the common law world, as well as at the European Court of Human Rights, in order to tease out the functional rationale for various types of extended judicial compositions within those systems (Part I). Next, two types of such functional justifications for grand chambers in the form of ideal models are identified (Part II). Finally, those justifications are then considered in light of the legislative design and the current practice of the Grand Chamber of the Court, before concluding with two modest suggestions (Part III).

The e-commerce is becoming increasingly essential and principally relevant in the modern world, especially in the current pandemic. Due to the increased use of the Internet, the growth of e-commerce has escalated. This research focuses on the e-commerce environments of Singaporean and Austrian markets. It contains an outline touching on the theoretical parts and the conduct of an empirical study where the survey results from 206 participants were studied, analysed, and compared. The statistical methods chosen for this research were the t-test analysis and the correlation analysis. The empirical study served as a quantitative discussion on both countries’ e-commerce markets. The analysis of the completed questionnaires provided a better and clear understanding of the buying behaviours and their potential impact on the e-commerce markets in Singapore and Austria. Considering the results from the comparisons, the research has also highlighted some interesting findings and differences in the buying behaviours of Singaporean and Austrian shoppers.

Pandemic is a type of epidemic that spreads over significant geographical areas and affects a large percent of population on a national or global level. Pandemic, as a project, has a lifecycle, a beginning and an end, though uncertain. The objective of the article is to trace various types of pandemics, to discuss their adverse effects of unemployment, distrust and loss of production. It presents various stimuli and remedial measures, a model to work out pandemic cost and its financial impact—estimated as ₹130 lakh crore in India. The article also gives an overview of positive results in the form of appreciations and acknowledgements, change in work culture resulting in work from home (WFH) approach. Financial restructuring resorted to by various business houses and future policy implications are also presented. The article is based on data drawn from government notifications and published reports. The study is exploratory, descriptive and analytical; it is presented in six parts.

The article follows the results from the experiments published at the conferences Concrete days 2014 [1] and 2016 [2], in the paper [3], and also in the magazine Beton TKS [4]. The goal of the experiment was the verification of dapped ends with the different configuration of the hanger stirrups. Subsequently, the nonlinear analyses were performed in the scientific program ATENA. In this article, a new comparison with calculations using the CSFM (Compatible Stress Field Method), implemented in software IDEA StatiCa Detail, is performed

This paper shows the importance of European Social Fund’s (ESF) countermeasures for reintegrating long-term unemployed persons aged 50+ in Austria since their number has increased in recent years. Four research questions are defined, which deal with the theoretical background, the ESF’s contribution, the possible causes of long-term unemployment, and their reflection in a country comparison figures. For the qualitative methodology, we conducted expert interviews and case study analysis. Concerning the quantitative method, we evaluated raw data from the AMS Public Employment Service, Austria, and Statistics, Austria. A correlation was established based on the content-related evaluation of the theoretical approaches, the expert analysis, and the presentation of statistics. It is necessary to identify the causes in time and take appropriate measures to prevent them from combating long-term unemployment among this target group.

The shopping center sector has been growing steadily over the last years in Latin America. Many countries such as Chile, Mexico, and Brazil lead the industry in the region, with so many projects still under development and different companies with international expansion perspectives in their portfolio. The purpose of this paper is to identify which are the most recommendable entry mode strategies for Latin American countries and which are the essential resources and capabilities that a shopping center company needs to develop to increase the likelihood of success in the sector. Thus, different factors, such as political, economic, and social factors, which impact the industry operation, are analyzed to create a high-level overview of this industry’s most important subjects. For this purpose, primary and secondary data are used, based on a literature review and an empirical qualitative study, giving information of the Chilean Commercial Real Estate company, and interviewing its top managers. Thereby, the results lead to an entry strategy proposal into the Mexican market, identifying the most important shopping centers in the country, the main actors, and the best opportunities to enter.

Background: We compared serum levels of S100A12, a proinflammatory protein predominantly secreted by neutrophils, in children with newly diagnosed childhood-onset systemic lupus erythematosus (cSLE), systemic juvenile arthritis (sJIA), and systemic undefined recurrent fevers (SURFS) to examine its role as a diagnostic and discriminative marker of inflammation and to indirectly point out the importance of neutrophils and innate immunity in the pathogenesis of these diseases. Materials and methods: In a cross-sectional study, the serum levels of S100A12 protein of 68 children (19 with cSLE, 18 with sJIA, 7 with SURFS, and 24 controls) were determined by enzyme-linked immunosorbent assay and compared between groups and with clinical and laboratory findings. Results: The median serum S100A12 levels were 469 ng/mL in the cSLE group, 6103 ng/mL in the sJIA group, 480 ng/mL in the SURFS group, and 44 ng/mL in the control group. Children with cSLE, sJIA, and SURFS had significantly higher serum S100A12 levels compared to the control group (p< 0.0001). sJIA patients had the highest levels of S100A12 in comparison to other patients (p< 0.0001), while there was no significant difference between children with cSLE and SURFS. Conclusion: Elevated serum SA100A12 levels in children with cSLE, sJIA, and SURFS may indicate intense neutrophil activation, which may play an important role in innate immunity in chronic inflammation in these diseases. Serum S100A12 levels could be used as a diagnostic marker of inflammation and be suitable for distinguishing sJIA and other disorders.

European Union (EU) is facing several challenges, including the disparities in the development, the rise in the populist political parties, and the debt crisis from Greece and Italy. China's One Belt and One Road Initiative provides an opportunity for the EU to overcome the challenges and offers a cooperative strategy for Eurasian countries. It will significantly benefit the lagging behind EU countries by orienting them for culture, commerce, technique, exhibition, and logistics centres for Eurasia. The Mediterranean ports (e.g., Trieste in Italy and Piraeus in Greece) should be revitalised. While the dominant exports from the EU to China are still machinery and electrical products and the room to export them are becoming smaller in the future, the most potential in China is vegetables and food products due to the huge consumer market and the concern on a combination of environmental pollution and food safety. The railways and the seaports from the Mediterranean are the key networks under One Belt and One Road to improve the market connectivity and facilitate bilateral trade between the EU and China.

Financial crises are impacting companies and their supply chains in many ways. This paper aims to build upon knowledge about supply chain and inventory management threats and extend the knowledge to which extent they are connected to financial crises. While there are existing works exploring strategies of companies trying to build resilience against supply chain threats in general, literature about their connection to financial crises is still scarce - even more so in an emerging market context. Therefore, the present work is exploring the strategies of Ugandan businesses, operating in an emerging market context, on building resilience against threats arising in times of financial crisis. By building on other authors' works, a list of 18 sub-threats of financial crises has been identified within this research paper. Furthermore, the empirical research brought forward a list of 26 strategies applied by Ugandan businesses to build resilience against those sub-threats.

AbstractThe purpose of the paper is to research fast-growing economies of East Africa regarding conditions and effects of infrastructure investments in various sectors and their influence on socio-economic growth. The paper aims to provide insights, knowledge and a rudimentary blueprint of how Least Developed Countries can take the first step to initiate dynamic economic growth. An important question is which infrastructure project should be financed with the limited available funds of an emerging market. The authors discuss various infrastructure projects, related conflicts, political issues, social impacts and the growing dependence on international influences. The structure of investment in East Africa and its economic playground with different trade agreements, NGOs Aid Programmes and Development Foundations, as well as International Agreements for development aid is often difficult to understand and its outcome is difficult to measure. So, the foundation of this paper will be built on in-depth interviews and statistical research based on the development theories of Emerging Markets. The authors were able to demonstrate an influence of infrastructure investments on economic and human development by a high positive correlation. In addition, 10 out of 13 analysed infrastructure characteristics showed a significantly positive moderate, high or very high correlation with economic growth.

Reinforced corbels are frequently used in industrial halls. A number of existing corbels are prestressed by unbonded tendons or bars in order to increase their load-bearing capacity, decrease the deflections and restrain cracks spreading. The goal of the project was experimental validation of the reinforced concrete corbel strengthened using unbonded tendons via CSFM (Compatible Stress Field Method). The method is based on materially nonlinear calculation considering the tension stiffening effect of rebars and compression softening of concrete. These effects and other assumptions implemented in CSFM capture real behavior of reinforced concrete members. Besides, CSFM is verified using an independent analysis, which is based on similar assumptions as those in Compatible Stress Field Method.

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injurywith the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address.

Chile is, compared to several other South American countries, geographically and demographically rather limited, but despite that it is the second most important trading and investment partner for Austria in this region. The aim of this paper is to gain firsthand insights into the motivations and perceptions of the entry of Austrian firms into the Chilean market by using an exploratory research approach.Interviews with thirteen qualified and experienced persons were conducted and analyzed, using Mayring’s qualitative content analysis. The Chilean market is an attractive opportunity for Austrian firms, as it performs quite well in international business environment rankings. The study results indicate a variety of motivationsfor entering the market, as well as diverse entry mode decisions based on numerous factors, together with a prevailing positive perception of the Chilean business environment. Several results probably cannot be generalized for the entire country, as the capital city is the center of business, and research in other regions of Chile might have different results. Challenges have been identified in the matters of language, distance, time, culture, recruitment, complexity, local partners and the indigenous population. Chile is a highly developed emerging market where doing business faces few obstacles. Therefore, the country represents a very attractive location in South America with great potential for Austrian companies.