Search Results (8,024)

This review examines publications over the past two years devoted to histone deacetylase inhibitors for the treatment of cancer, diseases of the nervous, cardiovascular, digestive, and respiratory systems, and autoimmune diseases. The review covers various classes of histone deacetylase inhibitors depending on the zinc-binding group, in particular hydroxamic acids, benzamides, hydrazides, carboxylic acids, and cyclic peptides. The review pays special attention to the mechanisms of development of pathologies involving various isoforms of histone deacetylases. The review shows that, for the treatment of cancer, nervous, cardiovascular, respiratory systems, and autoimmune diseases, the most promising compounds are hydroxamic acids, and for the treatment of diseases of the digestive system, they are hydrazides and cyclic peptides. Variation in the linker and cap group of hydroxamic acids will allow the creation of an inhibitor selective for a specific histone deacetylase isoform. The review may be useful for molecular biologists, medical workers, and pharmacologists involved in the design of new drugs. Full article

With the rapid growth of user demand for large language models (LLMs) in their work, the application market is driving intense competition among large language model providers (LLMPs). Users have different preferences and psychological perceptions towards the charging models of different LLMPs. LLMPs with different intelligence levels must design pricing strategies based on diverse user characteristics. To investigate the impact of user heterogeneity on the strategic pricing of competing LLMPs, this paper establishes a competitive model with two providers, comprising a highly intelligent initial LLM provider and a follower provider. Both providers can independently decide to adopt either a subscription model or a pay-per-use model, resulting in four pricing mode combinations (dual subscription SS, subscription-pay-per-use SD, pay-per-use-subscription DS, dual pay-per-use DD). The study shows that when the pay-per-use model is adopted, the user’s psychological perception of the “tick-tock effect” reduces the provider’s service price and profit, as the perceived psychological cost lowers the user’s valuation of the product, thereby decreasing demand. Furthermore, we analyze the equilibrium strategies for pricing mode selection by the two providers. The results indicate that the subscription model is not always advantageous for providers. Both providers will only choose to adopt the subscription model when both user usage frequency and perceived psychological cost are high. Conversely, when both user usage frequency and perceived psychological cost are low, the two providers will not simultaneously adopt the subscription model. Interestingly, as the product intelligence levels of the two providers converge, their choices of pricing modes are also more inclined to diverge. These insights guide LLMPs to strategically adjust their pricing models based on user behavioral patterns to maximize profitability in the competitive AI market. Full article

In this article, I argue that the state creates legal advice deserts in immigration and asylum by designing law and policy which drive up legal need, driving down provision through unfavourable conditions for providers, and by placing people in need into areas from which they have no realistic prospect of accessing legal advice and representation. I draw on frameworks of spatial justice and of demand to analyse the impact of the legislative and policy developments in the Special Issue’s focal period of 2022–24 on legal aid in each of the UK’s three legal aid systems: England and Wales, Scotland, and Northern Ireland. The legislative changes included introducing new stages into asylum law, which created new legal needs. Policy changes drove a wholesale geographical shift in demand as all local authorities in the UK (except Scilly) now host people in the asylum process. The changes depended upon the involvement of legal aid lawyers in order to be workable, but the marketised model of legal aid provision in England and Wales, and the low-paid laissez faire model in Northern Ireland, are fundamentally incompatible with that demand. I conclude by arguing that legal aid cannot be an afterthought. Asylum policy should be shaped to reduce failure demand, while legal aid policy should be funded and designed so as to pay for the necessary provision, with interventions to remove the spatial inequalities in access to (legal) justice. Full article

One of the key challenges in the provision of sustainable energy is understanding how younger generations perceive and respond to the relatively higher cost of green energy. This paper examines the attitudes of Generation Z towards paying premium for using products and services made with green power technologies. We surveyed 173 first- and second-year full-time bachelor students from Krakow University of Economics in Poland, combining contingent valuation in daily life scenarios (coffee purchase, apartment rental, travel carbon offset, environmental donation) with measures of connectedness to nature and self-reported tipping behavior. The results show that between 69% and 82% of respondents are willing to pay a premium for green energy. The size of the premium depends on the product that is bought. We find that while respondents are willing to pay a 10.5% premium for coffee prepared in a restaurant that uses only green energy, they are willing to pay just a 3.1% premium for green electricity at home. We also find that respondents are willing to pay three times more for planting a tree than to offset the carbon footprint of a train trip. A stronger emotional and cognitive bond with nature (on a CNS scale) translates into a greater willingness to financially support environmental initiatives. Full article

This study investigates the public acceptance and willingness to pay (WTP) for nuclear energy in Saudi Arabia, a country seeking to diversify its energy portfolio under Vision 2030. Utilizing a cross-sectional survey of 403 residents, the research employs descriptive statistics, regression analysis, and a SWOT analysis to explore the socio-economic and perceptual drivers of public attitudes. The findings reveal that 82.4% of participants support nuclear energy, with a mean WTP of 38.2% of their monthly electricity bill for its development. Key factors positively influencing acceptance include age and knowledge about nuclear energy, while environmental concerns and being married are associated with lower support. Notably, trust in government oversight (64.8%) and the prospect of a new energy source (62.7%) are major reasons for support, whereas health and environmental risks (74.6%) are the primary concerns for opponents. This study provides crucial, evidence-based insights for policymakers, marking the first Saudi-specific research to jointly examine WTP, acceptance determinants through econometric modeling, and strategic implications via SWOT analysis, highlighting the need for targeted public engagement and transparent communication strategies to address public concerns and ensure the successful and sustainable integration of nuclear energy into Saudi Arabia’s energy mix. Full article

Acute pulmonary embolism can range from being completely asymptomatic to causing life-threatening events, which underscores the importance of effective risk stratification. Intermediate-risk patients represent a distinct subgroup characterized by specific clinical, laboratory, and imaging features. Although the majority have favorable outcomes, a significant proportion may still experience adverse events, presenting an ongoing challenge in determining the optimal therapeutic approach. This comprehensive review explores the characteristics of intermediate-risk pulmonary embolism patients, focusing on key diagnostic and prognostic factors, current treatment practices, and the evolving role of novel, specifically catheter-directed interventions. We also provide an overview of current guideline recommendations and discuss recent advancements in the field. Full article

Meta-DETR is a few-shot target detection algorithm that combines meta-learning and transformer architecture to solve the problem of data sample scarcity. This algorithm uses deformable attention to focus feature learning process more accurately on the target and its surroundings. However, the number of sampling points in the deformable attention is fixed, which limits the effective information involved in feature extraction, resulting in insufficient feature extraction of the target and affecting detection performance. To solve this problem, a Meta-DETR few-shot target detection algorithm based on adaptive sampling deformable attention is proposed. Firstly, the cosine similarity between feature points is calculated by query features that are integrated with support features. Secondly, the number of related features of each feature point is counted by the similarity threshold. Thirdly, the final number of sampling points of the feature map are calculated by using the idea of maximum inter-class variance to achieve adaptive sampling. Finally, adaptive sampling deformable attention is integrated into Meta-DETR to achieve few-shot target detection. From the attention activation map, it can be seen that the deformable attention based on adaptive sampling pays more attention to the target itself. Compared with Meta-DETR, the proposed algorithm improves the detection accuracy of novel classes by 0.9%, 0.7%, 1.4%, and 2.1%, respectively, for shots 1, 2, 3, and 10 in partition 1 on the PASCAL VOC dataset; 3.5%, 0.1%, 5.5%, and 5.7%, respectively, for shots 2, 3, 5, and 10 in partition 2; and 1.9%, 1.0%, 2.1%, and 0.1%, respectively, for shots 2, 3, 5, and 10 in partition 3. Compared with MPF-Net, CRK-Net, and FSCE, the proposed algorithm achieves the best performance and can effectively realize detection under few-shot conditions. In addition, experiments on a self-made infrared dataset further validate the effectiveness of the algorithm proposed in this paper. Full article

Background and Clinical Significance: Arterial and venous thromboses are typically distinct clinical entities, each governed by unique pathophysiological mechanisms. The concurrent manifestation of both, particularly in the setting of massive pulmonary embolism (PE), is exceptionally rare and poses significant diagnostic and therapeutic challenges. Case Presentation: This report describes a 61-year-old male with well-controlled hypertension and type 2 diabetes who developed extensive thromboses involving deep vein thrombosis (DVT) of the right popliteal vein, arterial thrombosis of the left iliac artery, and massive PE. The patient was initially managed conservatively, in accordance with the European Society of Cardiology (ESC) 2019 Guidelines for Acute PE, using unfractionated heparin (UFH), low-molecular-weight heparin, a direct oral anticoagulant (DOAC), and adjunctive therapy. This approach was chosen due to the absence of hemodynamic instability. However, given failed percutaneous revascularization and persistent arterial occlusion, surgical thromboendarterectomy (TEA) was ultimately required. Post hoc genetic testing was prompted by the complex presentation in the absence of classical provoking factors—such as trauma, surgery, malignancy, or antiphospholipid syndrome—consistent with recommendations for selective thrombophilia testing in atypical or severe cases. The analysis revealed four thrombophilia-associated polymorphisms: heterozygous Factor V Leiden (FVL; R506Q genotype), Plasminogen Activator Inhibitor-1 (PAI-1; 4G/5G genotype), Methylenetetrahydrofolate reductase (MTHFR; c.677C > T genotype), and homozygous Angiotensin-Converting Enzyme Insertion/Deletion (ACE I/D; DD genotype). Conclusions: While each variant has been individually associated with thrombotic risk, their co-occurrence in a single patient with simultaneous arterial and venous thromboses has not, to our knowledge, been previously documented. This case underscores the potential for gene–gene interactions to amplify thrombotic risk, even in the presence of variants traditionally considered to confer only modest to moderate risk. It highlights the need for a multidisciplinary approach and raises questions regarding pharmacogenetics, anticoagulation, and future research into cumulative genetic risk in complex thrombotic phenotypes. Full article

The development of information technology allows firms to access consumer purchase records, enabling them to distinguish between new and old consumers. Firms can then provide these groups with respective product pricing and promised delivery time. This paper develops a two-period dynamic model based on game theory to examine the effects of behavior-based pricing and behavior-based promised delivery time strategies on product price, promised delivery time, firm profits, consumer surplus, and social welfare under conditions where consumers exhibit time-sensitive preferences. We find, first, when firms opt to implement behavior-based pricing and promised delivery time strategies, they should offer lower (higher) prices and longer (shorter) delivery times to new (old) consumers. Second, the implementation of behavior-based pricing and promised delivery time strategies may decrease firm profits while enhancing consumer surplus. Third, when consumers exhibit stronger time-sensitive preferences, behavior-based pricing and promised delivery time strategies can enhance social welfare; conversely, they may have a detrimental impact on social welfare. Finally, we extend the model into three aspects—asymmetric strategy selection, firm logistics service costs, and myopic consumer behavior—to enrich our research and test the robustness of the model. The results of this paper supply managerial implications and theoretical references for firms’ strategic implementation and policy-making by relevant government departments. Full article

This study investigates whether, and to what extent, dividend-paying firms follow pecking order behavior when altering their capital structure. Using a panel of 3173 U.S. firms from 1960 to 2020 (49,424 firm-year observations), we examine four financing activities: equity and debt issuance under a financing deficit, and equity repurchases and debt redemptions under a financing surplus. We find that firms generally follow the pecking order when issuing or redeeming debt but deviate from it when issuing or repurchasing equity. Adherence to the pecking order also varies with issuance and repurchase size. Very large debt issues and redemptions are associated with lower pecking order coefficients, while large equity issues and repurchases are associated with higher pecking order coefficients, although equity coefficients remain below 0.7. Our findings provide novel evidence of how financing choices, along with issuance and repurchase magnitudes, shape pecking order behavior among dividend-paying firms, offering new insights into capital structure literature. Full article

Digital pollution, encompassing energy consumption, e-waste, and the environmental impact of digital technologies, poses a significant and increasingly pressing environmental challenge that has received insufficient research attention. This study explores public perceptions, attitudes, and behaviors related to digital pollution, focusing on both individuals’ willingness to pay for environmentally friendly digital solutions and their actions to reduce digital environmental impact. Through a comprehensive survey of 300 UK participants, we examined the associations between demographic factors, knowledge levels, perceptions, and environmental actions. While traditional demographic factors such as age and income showed no significant correlation with willingness to pay, we found strong positive correlations with the frequency of environmental consideration (r = 0.47), willingness to act (r = 0.42), and perceived importance of digital pollution (r = 0.40). Notably, knowledge of digital pollution was not correlated with willingness to pay, while self-assessed tech-savviness and environmental knowledge had positive correlations with both willingness to pay and actions taken. Based on a robust cluster analysis, we identified four distinct participant groups: ’Engaged Eco-Tech Enthusiasts’ (youngest, most tech-savvy, and with the highest willingness to act), ‘Knowledgeable Traditionalists’ (oldest, highest knowledge scores, and moderate action), ‘Unengaged Pragmatists’ (lowest engagement), and ‘Affluent Moderates’ (wealthiest and with moderate engagement). These findings provide valuable insights for developing targeted interventions and communication strategies to address this emerging environmental challenge. Full article

Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 μg/kg) in C57BL/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage infiltration, and elevated hepatic and serum triglyceride levels after 12 weeks. Despite serum aryl hydrocarbon receptor (AhR) ligand levels normalizing by 12 weeks, the persistent effects suggest TCDD sequestration in fat tissue. TCDD inhibited the expression of mitochondrial proteins (COX1, TOM20, TFAM, H2AX) and reduced mitochondrial oxygen consumption. Liver-specific AhR knockout ameliorated TCDD-induced mitochondrial dysfunction, lipid accumulation, and macrophage infiltration. Mechanistically, TCDD-induced hepatic plasminogen activator inhibitor-1 (PAI-1) promoted adipocyte hypertrophy. In the liver, PAI-1 disrupted the interaction between tissue-type plasminogen activator (tPA) and apolipoprotein B (ApoB), thereby enhancing very-low-density lipoprotein (VLDL) assembly. These findings reveal that hepatocyte-derived circulating PAI-1, upregulated via hepatic AhR activation, contributes to adipocyte hypertrophy and hepatosteatosis through the intracellular modulation of the tPA–PAI-1 axis. Thus, hepatic AhR activation drives mitochondrial dysfunction and obesity, even after a single TCDD exposure. Full article

Hirshleifer’s difference-form contest technology is a useful tool in the study of a class of conflict, especially military combats. We aim to highlight an important feature that the Hirshleifer contest model distinctively has, namely passivity (bidding zero effort) may stand as an effective choice in conflict even when the contest is highly deterministic (i.e., with small noise). For that purpose, we establish two propositions on the contest with $n\ge 2$ risk-neutral contestants under small noise. The first proposition states that every contestant bids arbitrarily close to zero (if not bidding zero with positive probability at all) under sufficiently small noise. The second proposition, more strikingly, states that every contestant either bids arbitrarily close to the second-highest valuation (among all the contestants’ valuations), or simply remains passive with certainty under any sufficiently small noise. We further show that the first proposition holds for the contest between risk-averse individuals endowed with constant absolute risk aversion as well, and illustrate by an example how quickly polarization in bidding among contestants, as is predicted by the propositions, may emerge as the noise of the contest abates. These results help pave the way toward a complete characterization of the difference-form contest. Full article

Oil consumption brings both energy security risks and environmental responsibilities. While traditional studies assign environmental responsibility primarily to oil producers, our research uncovers a geographical displacement of accountability: substantial oil volumes are embedded in traded goods and ultimately consumed in distant regions. Although China’s “dual control” policy regulates fossil energy use, it fails to account for the complexities of embodied oil flows. This oversight leads to imbalanced interregional responsibility allocation and resource exploitation issues. Adopting the “consumer pays” principle, this study makes methodological advances by innovatively combining multi-regional input–output (MRIO) modeling with geographically and temporally weighted regression (GTWR) analysis. The integrated approach provides spatial–temporal resolution in tracking embodied oil flows and their drivers across China’s provinces. Key findings include (1) strong concentration of oil inflows in developed eastern and central provinces, alongside rapid growth in southwestern regions; (2) evolving temporal patterns where economic growth and distance remain persistent drivers, while green technology and urbanization emerge as growing mitigating factors; (3) spatially, northwestern regions rely heavily on external supplies due to economic growth and urbanization, southeastern areas face rising transport costs, while green technologies in coastal regions have yet to significantly curb inflows due to rebound effects. These insights provide a new analytical framework for energy policy, supporting region-specific solutions to balance development and sustainability from a consumption perspective. Full article

Problem-based learning (PBL) is a student-centered instruction approach focused on skills development in problem-solving, interaction, autonomy, and critical thinking to learn and act to co-create new knowledge and solutions. Rarely, but authors sometimes identify the benefits of PBL for educators, for example, by allocating instructional time more flexibly for monitoring student performance and discussing issues. However, in the era where collaboration among universities and industries is emphasized, the authors pay little attention to contextualizing PBL in a broader context, such as bringing benefits for relationship management with the industry and alumni, promoting regional development, corporate and social responsibility, marketing of educational organizations, and talent development to create a mutual benefit-based ecosystem. Academic discussions about PBL planning and implementation also neglect the needs and motivation of industry stakeholders to get involved, thus narrowing not only the possibilities for cooperation between both parties but also negatively affecting student learning outcomes, which also directly depend on industry partners. Full article