class="MsoNormal" style="text-align: justify;">Metadherin (MTDH), also known as LYRIC or AEG-1, is an oncogene that enhances tumor progression, metastasis, drug resistance, and immune escape in various cancers by modulating multiple oncogenic pathways, including NF-κB, PI3K/AKT, Wnt/β-catenin, MAPK, and AMPK. Due to the unknown of the complete structure of MTDH, the deep mechanisms of MTDH and selective inhibitors targeting MTDH remain to be explored. The Protein-Protein interaction (PPI) with the Staphylococcal nuclease domain containing 1 (SND1) is a crucial mechanism underlying the function of MTDH. Current studies have demonstrated that inhibitors, including antisense oligonucleotides, peptides, and small molecules targeting MTDH or MTDH-SND1 interactions, provide novel strategies to inhibit the oncogenetic effects of MTDH. This review summarizes and discusses the structure, function, and regulation of MTDH in cancers, providing the potential therapeutic perspectives of MTDH or MTDH-SND1 PPI for drug discovery.

class="MsoNormal" style="margin-top: 6pt; text-align: justify;">The dawn of the Artificial Intelligence (AI) era presents a plethora of new possibilities for analyzing regional economic development. The present article provides an in-depth exploration of the methods employed in this field, highlighting the immense opportunities that AI offers while also addressing potential challenges. The role of AI is crucial in complex data handling, enabling efficient analyses of intricate regional economic patterns. This capacity is paramount in shaping economic policies and strategies that are reflective of each region's unique needs and potential. The article firstly explores various AI methods used in economic analysis, including but not limited to machine learning, deep learning, and natural language processing. It delves into the application of these methods in discerning development trends, predicting economic shifts, and identifying strategic economic drivers unique to various regions. Subsequently, the potential of AI to transform regional economic analysis is discussed, encompassing its capability to process large and complex datasets, its power to predict future trends based on past and present data, and its ability to aid in strategic decision-making. However, this new era of AI-driven economic analysis is not without challenges. The latter part of this article thus confronts the issues related to data privacy, ethical use of AI, and the necessity of interdisciplinary skills in AI and economics. This exploration contributes to a broader understanding of how AI is transforming the landscape of regional economic development analysis, illuminating both its present use and future implications. By understanding these dynamics, we can better harness the potential of AI to advance economic prosperity in various regions around the globe.

class="MsoNormal" style="text-align: justify;">Despite the status of the United States as one of the world’s economic superpowers, the country is plagued by child poverty. The issue of child poverty is most prominent in rural, majority-minority communities, where years of limited opportunity, often created by systematic oppression, have created a vicious cycle of economic despair. There are a number of policies that have been explored which could limit the effects of child poverty, most notably the Expanded Child Tax Credit (ECTC), which was introduced as part of the American Rescue Plan Act (ARPA) of 2021. This paper uses a combination of qualitative and quantitative methods to thoroughly examine this policy (ECTC) and its potential to both cut child poverty in the short term and increase educational attainment and economic mobility in the long term for recipients. The ECTC program ended in 2022 and only lasted in a short period. By examining the impacts of a similar and long-standing but less accessible and generous program, the Earned Income Tax Credit (EITC), on educational attainment in specific communities we can theorize and determine the significance the Expanded CTC would have. We use EITC program as a proxy of ECTC and reach inference of the long-term impact of ECTC program on children’s education attainment. The result of this research indicates a number of benefits of the Expanded Child Tax Credit, including its potential to cut child poverty and increase educational attainment, its impact on future economic prosperity in rural, majority-minority communities, and the policy’s ability to decrease economic disparities between non-metro and metropolitan areas.

class="MsoNormal" style="text-align: justify;">This paper provides a thorough review of the shifting landscape of economic analysis, spotlighting recent trends and predicting future paths. While traditional economic models remain key for interpreting economic activity, they are being supplemented by fresh methods and cross-disciplinary viewpoints. The increased attention to inequality studies, using advanced statistical techniques and unique data sources, underscores the growing emphasis on fairness and distribution within economic analysis. The incorporation of behavioral elements into economic models also expands our comprehension of economic decision-making and market results. Notably, the emergence of computational economics-integrating artificial intelligence (AI), big data, and machine learning into economic scrutiny-represents a major development. Often referred to as ’smart economics,’ this field employs technology to formulate, address complex economic dilemmas, and perceive economic activity in unconventional ways. Yet, the application of AI and machine learning in economics introduces new hurdles around data privacy, algorithmic bias, and the transparency of model outcomes. The impact of the digital revolution on economic analysis is significant, as the advent of computational economics and the surge of big data are transforming research techniques and policy implications. Concurrently, the advent of the circular economy indicates a radical shift in our perspective on economic sustainability, carrying considerable implications for environmental policy and business tactics.  In the future, it’s anticipated that these trends will further modify the realm of economic analysis, with AI and machine learning integration, emphasis on sustainability and fairness, and the influence of big data becoming more pronounced. As these changes take place, it’s imperative for researchers, policymakers, and practitioners to remain adaptable and flexible, prepared to capitalize on the opportunities and tackle the challenges these trends present.

class="MsoNormal" style="text-align: justify;">Less-Lethal Weapons, including electric Tasers, velocity-reduction bullet-capture projectiles, rubber bullets, beanbag rounds, and other less-lethal projectiles used in police departments, federal and local law enforcement agencies, and military policing operations, as well as for private use, are topics of significant debate in recent years. These weapons can reduce collateral damage, reputational risk, and legal exposure while preventing wrongful and unnecessary deaths caused by conventional bullet wounds. Yet, opponents have highlighted concerns regarding the safety and effectiveness of these weapons, as well as their potential to cause injury or even death. While the primary duty of law enforcement officials is to preserve order and execute the law while protecting individual rights, they ultimately achieve these goals by exercising their coercive authority. Society expects police officers to rely on their professional training and judgment when using physical force to defend citizens and themselves or to apprehend criminal suspects. Because police officers must occasionally participate in physical acts of coercion, it is unavoidable that some of these interactions may result in bodily injuries to individuals, including the officers themselves. These injuries have real costs, such as medical treatment, lost wages, municipal liability, court claims and settlements, riots, and legal or even criminal exposure, as well as less-tangible collateral costs, such as the erosion of police legitimacy and public trust, which are more difficult to quantify but arguably more influential in shaping long-term public perceptions than personal injuries alone. Less lethal technology eliminates some of the concerns raised by lethal weaponry. This study reviews the advantages and disadvantages of these less-lethal weapon technologies versus traditional firearms for use by the police force, federal agencies, and military police while also performing advanced analytics to model the valuation and return on investment for a law enforcement organization implementing such technologies.

class="MsoNormal" style="margin-top: 10pt; text-align: justify;">This study delves into the intricate interconnections among the financial sector, macroeconomic dynamics, and the advancement of sustainable energy production in South Asia. Utilizing data from 1987 to 2022 in Bangladesh, India, Pakistan, and Sri Lanka, the research employs the Structural Vector Autoregressive (SVAR) method to analyze financial market responses. The findings reveal nuanced insights into the complex relationship between economic and environmental factors, fostering a comprehensive understanding of the region's intricate nexus between financial markets and sustainable energy initiatives. In the Economic Growth model, the negative coefficient for CO2 emissions underscores environmental concerns, indicating an inverse relationship with economic growth. Conversely, positive coefficients for non-fossil energy production, Gross Fixed Capital Formation, stock exchange value, and domestic credit emphasize their positive impact on economic growth. A positive GDP coefficient in the CO2 emission model signifies heightened carbon emissions with economic growth, while a negative coefficient for non-fossil energy production suggests potential environmental benefits. The nearly unitary positive coefficient for Gross Fixed Capital Formation highlights its significant role in driving carbon emissions. The Non-Fossil Energy Production model reveals an inverse relationship between GDP and clean energy, suggesting a potential reliance on fossil fuels during economic growth. Positive coefficients for CO2 emissions, Gross Fixed Capital Formation, stock exchange value, and domestic credit highlight factors influencing non-fossil energy production. Long-run stable coefficients affirm variable significance, while a negative error correction term suggests convergence in developing countries. These models offer nuanced insights into the intricate relationships among economic, environmental, and energy variables, guiding sustainable development policies in South Asia.

class="MsoNormal" style="text-align: justify;">Tripartite motif-containing (TRIM) proteins consist of over 80 proteins, the majority of which exhibit E3 ubiquitin ligase activity. E3 ligases have a critical role in various cellular processes by specifically recognizing and ubiquitinating substrate proteins to promote their proteasomal degradation or alter their activities. Numerous studies have indicated that TRIMs are involved in carcinogenesis through various mechanisms. However, the regulatory mechanisms delimitating TRIMs’ function as E3 ligases has not yet been specifically addressed in a previous review article. In this review, we focus on recent advancements in understanding how certain TRIMs function solely as E3 ligases during cancer cell proliferation, apoptosis, and metastasis. We comprehensively summarize the target proteins of TRIMs involved in disordered signaling pathways such as Wnt/β-catenin, PI3K/AKT, NF-κB, p53, ERK, and STAT3, as well as those regulating the cell cycle and glycolysis. Following ubiquitination modification by TRIM E3 ligases, these target proteins either undergo proteasome-mediating degradation, maintain steady levels, or get activated/inactivated. This review provides a foundation for the development of E3 ligase-based cancer treatments.

class="MsoNormal" style="text-align: justify;">The manufacturing sector must incorporate digitalization and greening as crucial strategies to attain high level of development in the context of the digital economy, given its significant role in quality of environment. Most of existing studies explore net effect of a single or several factors on the digitalization or greening in the manufacturing industry. Limited investigation has been done to integrate various factors impacting the connection and synchronized advancement of digitalization and greening within the manufacturing. Factors affecting the synergy of digitalization and green change within manufacturing are recognized in this article, and a theoretical framework is established to analyze. FsQCA tool is also put into use to survey configurational cases, which contains synergy degree of green digitalization from 30 provinces’ manufacturing in China. Results show that: (1) Between 2007 and 2020, the development level of digital-green integration in the manufacturing industry shows an upward trend. There are three types of collaborative modes, namely, "industrial robot driven" "market development driven" and "market development driven - industrial robot driven", with each mode consisting of at least one to four equivalent pathways. (2) The marketization level and application of industrial robots are the important external and internal pulling forces that drive the synergy degree of digitalization and green change within manufacturing industry, respectively.(3) The influencing factors of the collaborative mode choice of digital-green development within manufacturing industry are complementary, among which, the degree of marketization is similar to the role of industrial robots in the configuration, which are capable to weaken the negative impact from insufficient government R&D investment support under specific conditions; (4) The non-high collaborative state of digital green in manufacturing industry is mainly due to the low level of marketization, openness, and economic development, as well as the low application rate of industrial robots and software products. This study enriches the theoretical understanding on digitalization and green change of manufacturing industry. Meanwhile, it also provides insights to advance the integrated and synergistic advancement of digital green transformation in manufacturing practice.

class="MsoNormal" style="text-align: justify;">Population, as a fundamental element in urban development, often reflects a city's economic development pattern through its spatial distribution and dynamic changes. Studying population spatial distribution is pivotal for bolstering the economic activity capacity in urban agglomerations and guiding regional economic health. Using the Changsha-Zhuzhou-Xiangtan urban agglomeration as a case study, this paper analyzes its overall spatial structure and the spatiotemporal evolution of population at the district and county levels. This analysis utilizes population density, population redistribution index, and population geographic concentration as key indices. Additionally, a spatial econometric model is constructed to assess the impact of economic, social, and environmental factors on population spatial patterns. Findings reveal several key points: (1) Furong District serves as the primary central area, boasting a population geographic concentration of 25.1% in 2021. Tianxin District, Kaifu District, Yuhua District, Shifeng District, Yuelu District, and Hetang District constitute the secondary central areas, while Yutang District, Tianyuan District, Lusong District, Yuhu District, Wangcheng District, and Changsha County form the tertiary level areas. (2) Population density within the Changsha-Zhuzhou-Xiangtan urban agglomeration gradually decreases from Furong District outward. The first central area and sub-central areas experience increasing population density, highlighting a polarization trend in the population distribution. (3) The overall Moran's index for the spatial distribution of population in the Changsha-Zhuzhou-Xiangtan urban agglomeration is significantly positive, indicating a strong spatial autocorrelation and a deepening spatial agglomeration of population distribution. (4) Per capita disposable income, financial expenditure, and education level positively influence the geographical concentration of population in the urban agglomeration, while GDP per capita, road area per capita, and environmental quality exert a negative impact. Notably, the most influential factors shaping population spatial distribution are GDP per capita, disposable income per capita, and air quality.

class="MsoNormal" style="text-align: justify;">Purpose: To realize the benefits a Quality Management System (QMS), an organization needs to effectively implement its principles. This includes embracing these principles within an enabling environment. Hence, organizational structure is a critical success factor for adopting quality management systems. This paper aims at understanding how the organizational structure impacts ISO 9001 QMS implementation and vise versa, besides exploring how quality management initiatives affect organizational resilience through parts. Design/methodology/approach: The research deploys a qualitative methodology, with an outsider-insider approach. 32 semi-structured interviews were conducted, plus one final reflective interview. Interview questions dealt with structural constructs: communication, employee engagement, employee empowerment, process/routine-orientation, multidisciplinarity, cross-functionality, expertise-utilization and change-readiness. The questions also dealt with how the organizational structure impacted ISO 9001 implementation and vice versa. Findings: The results show that ISO 9001 implementation was more successful and fruitful under process-orientation and to some degree under semi-process orientation, while it looked inconsistent under routine-orientation. This indicates a significant role played by the organizational structure when it comes to ISO 9001 implementation. More importantly, the results also demonstrate that ISO 9001 implementation managed to improve organizational resilience by consistently driving the organizational structure toward higher levels of process-orientation for process-oriented units, whereas it failed to realize such impact for routine-oriented units. Originality/value: This study is unique as it is the first - within the reviewed literature - to examine the moderating role of the organizational structure between the ISO 9001 standard and organizational resilience. It draws a roadmap for the successful realization of organizational resilience through quality management systems, considering organizational structure constructs.

class="MsoNormal">Background: Bladder cancer (BLCA), particularly invasive BLCA, has become a medical burden worldwide as it is associated with recurrence and easy metastasis. There are specific differences in the expression of various miRNAs in tumor and normal tissues. Hence, miRNAs can be used as biomarkers for tumor diagnosis and prognostic evaluation. The current study aimed to predict the downstream target genes of BLCA-related miRNAs and explore their association with immune infiltration. Method: Data on BLCA-related mRNA and miRNA expression levels were downloaded from The Cancer Genome Atlas. Correlation analysis and Cox regression analysis were performed to validate the miRNA risk model. The infiltration of various immune cells should be compared to determine the distinct differences between the immunological microenvironment of the two risk groups. Results: A predictive framework of BLCA was established using the expression levels of two miRNAs. Cox regression analysis showed that the low-risk group had a better prognosis. Then, the target genes of miRNA were predicted, and the target genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Moreover, variations in immune cells and functions between the high- and low-risk groups were assessed. Conclusion: The prognostic features composed of two associated miRNAs (MIR-25, MIR-548AN) may help predict the overall survival of BLCA.

class="MsoNormal" style="text-align: justify;">The clean energy revolution is a global concern. Cross-border collaboration is crucial for sharing knowledge, pooling resources, and tackling complex challenges on a global scale. International partnerships can accelerate innovation by drawing on diverse knowledge and experience from different regions. Access to capital is a key driver of innovation and entrepreneurship in clean energy. Institutional investors and financial institutions increasingly recognize the potential for high returns from the clean energy sector. This research aimed to understand whether "dirty" energies, such as the Brent Crude Spot, WTI, FTSE 350 Oil, Gas & Coal, EURO STOXX Oil & Gas, influence the formation of sustainable energy prices, namely Geothermal Index, Solar Energy Index, NASDAQ OMX Bio Clean Fuels Index, Wind Energy Index, WilderHill Clean Energy Index, during the 2020 Covid-19 pandemic and the Russian invasion of Ukraine in 2022. When comparing the two sub-periods, the results show that the level of autocorrelation in price formation has increased, i.e., the mean rhoDCCA went from 32 to 45, the weak correlation coefficients without trend decreased from 30 to 19, and the anti-persistence has also decreased from 8 to 4. The strong rhoDCCA increased from 2 to 4; during the Tranquil period, the FTSE 350 / EURO STOXX Oil index pairs had a rhoDCCA of 0.76. While in the Stress subperiod, the NASDAQ OMX Bio / Solar Energy pairs had a slope of 0.70, and the FTSE 350 / EURO STOXX Oil indices had a rhoDCCA of 0.91. Evidence shows a notable dissociation between fossil energy prices and sustainable energy sources. This dissociation is characterized by various degrees of influence between fossil energy prices and sustainable energy indices, from low to moderate. This dissociation between fossil energy prices and sustainable energy prices suggests that investments in sustainable energy can offer diversification opportunities.

class="MsoNormal" style="text-align: justify;">The rapid growth of renewable solar and wind energy necessitates extensive, long-term energy storage solutions to stabilize the electric grid and address the intermittent nature of these sources. In the absence of cost-effective long-duration, large-scale (LDLS) energy storage, there is a risk of increased disruptive blackouts and brownouts as intermittent energy sources approach 50% of electricity generation. Our analysis underscores volumetric energy density as a pivotal determinant in LDLS energy storage solutions, which is particularly crucial during periods of diminished renewable resource availability, such as the rainy season. Despite emphasis on conventional electric batteries and mechanical storage technologies such as compressed air and pumped hydro for LDLS, their costs pose a significant obstacle to widespread adoption, especially in emerging economies. In this study, we present a groundbreaking approach to LDLS: on-demand electricity generation from carbon-neutral renewable oil, known as "green oil," leveraging Reliance’s innovative catalytic hydrothermal liquefaction (R-CAT-HTL) technology. Our investigation evaluated two distinct sources of green oil production: organic waste streams (e.g., municipal solid waste, agricultural-waste, etc.) and on purpose production of algal biomass. We demonstrate that burning renewable green oil to produce electricity offers a cost-effective solution for large-scale (GWh) long-duration (many days) energy storage, ensuring the stability, reliability, and resiliency of the electric grid. We also demonstrate that minimum 14 days, ideally 30 days energy storage is needed for continuous uninterrupted service, especially critical for manufacturing facilities. Through a meticulous levelized cost of storage (LCOS) analysis comparing green oil with other LDLS technologies reported in literature, we demonstrate the cost effectiveness of green oil. In this model, green oil serves as stored energy, functions akin to a battery and is efficiently converted into electricity through conventional reciprocating engines or next-generation more efficient turbines. Our findings suggest that green oil derived from diverse organic sources is the most economically viable option for GWh-scale storage, particularly when storage requirements extend beyond a single day. This research thus presents a transformative cost-effective solution to the pressing challenge of LDLS energy storage, accelerating a sustainable and resilient energy future.

class="MDPI17abstract" style="margin-left: 0cm; text-align: justify;">In the context of digital economy, Hebei Province, as an important province in central China, has a huge manufacturing base and potential, and the development of digital economy has driven the transformation and upgrading of manufacturing industry to a certain extent. In order to better play the driving role of digital economy in the transformation and upgrading of manufacturing industry, this paper establishes an intermediary effect model based on three intermediary variables: enterprise resource allocation ability, enterprise cost and enterprise innovation ability, and conducts an empirical study on the panel data of 11 prefecture-level cities in Hebei Province from 2017 to 2022. The mechanism of digital economy driving manufacturing upgrading in Hebei Province was discussed. The results show that: (1) there is a significant positive correlation between the development of digital economy and the transformation and upgrading of manufacturing industry, which indicates that the development of digital economy has a direct driving effect on the transformation and upgrading of manufacturing industry; (2) There is also a positive correlation between the development of digital economy and the resource allocation ability and innovation ability of enterprises, indicating that the development of digital economy can improve the resource allocation ability and innovation ability of enterprises, and is conducive to the stable development of enterprises in the future; (3) Enterprise resource allocation ability and enterprise innovation ability play a significant intermediary role in the relationship between digital economy development and the transformation and upgrading of manufacturing industry, indicating that digital economy can indirectly accelerate the transformation of manufacturing enterprises' R & D achievements by improving enterprises' resource allocation ability and innovation ability, thus improving enterprises' market competitiveness and increasing enterprises' earnings. Drive the transformation and upgrading of the manufacturing industry. Based on this research conclusion, the government should give full play to the role of guidance and support, and introduce relevant policies to help the digital economy drive the transformation and upgrading of manufacturing enterprises. Manufacturing enterprises should seize the tide of the development of the digital economy, use digital technology to improve their resource allocation ability and innovation ability, enhance core competitiveness, and accelerate the transformation and upgrading of enterprises.

class="MsoNormal" style="text-align: justify;">Objective: The DSS was utilized to construct colitis model of mouse. The colitis mice were colonized with gut microbiota. The effects of gut microbial metabolites on colitis were studied. The mechanisms of gut microbial metabolites to improve intestinal immunity were also further explored. Methods: The male BALB/c mice were selected to construct colitis mouse model with DSS and colonized with gut microbiota. The content of short-chain fatty acids in intestinal metabolites of mice during modeling were detected with GC-MS. After the mice were sacrificed, the colon tissue was stained to observe the colitis in different groups of mice. The contents of IL-22 and IL-17 in colon tissue was determined with ELISA method. To study the mechanism of relieving colitis, qRT-PCR and western blotting were used to study the horizontal of Ffar2 gene and pSTAT3 and pAKT in colon tissue, respectively. The congenital lymphocytes were isolated and purified, and the migration ability of the congenital lymphocytes was examined by cell scratch plane migration test. Results: The colonization of the gut microbiota had significant effects on the contents of short-chain fatty acids in the intestinal metabolites of colitis mice, of which the effect on the content of acetic acid and butyric acid was more significant. The colonization of gut microbiota could effectively relieve colitis in mice and effectively promote the secretion of IL-22 in colon tissue. Studying the remission mechanism indicated that colonization of gut microbiota with colitis could effectively promote the expression of Ffar2 gene in colon tissue and increase the expression of pSTAT3 and pAKT protein. The migration ability of the lymphocyte was significantly upregulated in the model group compared with the other groups, demonstrating that DSS can effectively activate the lymphocyte; The migration of congenital lymphocyte in the experimental group was significantly alleviated than that in the model group, but it was up-regulated than that in the positive control group, and the colonic tissue of the positive control group was similar to that of the normal group. Conclusion: The short-chain fatty acids in the intestinal flora metabolites can promote the gene expression of the metabolite-sensitive receptor Ffar2. The effective combination of short-chain fatty acids and Ffar2 receptors can promote the phosphorylation of STAT3 and AKT proteins, effectively promote the secretion of IL-22 in intestinal ILC3 cells, alleviate colitis in mice, and thereby improve their intestinal immune function.

class="MsoNormal" style="text-align: justify;">Many of Keynes´s ideas and concepts are proven correct in this paper. The demand side, mainly business investments, drives the economy. Business firms steer the business cycle via profit expectations and animal spirits. Injections to and withdrawals from the circular flow of income are multiplied throughout the economy in accordance with Keynes´s multiplier. A sudden and sharp rise in households´ saving rates has a detrimental effect on aggregate demand, in line with Keynes´s paradox of thrift. Finance, not saving in the S=I sense, is the necessary condition for business investments and economic growth to be realized. Keynes´s finance motive thus makes money endogenous, contradicting the textbook result that exogenous money steers aggregate demand, contradicting the mainstream loanable funds theory and putting into question the Keynesian theory of sticky prices as a condition for real growth. However, a crucial omission in Keynes´s productive writings is the lack of an accelerator tying income to investment. Some of his followers such as Paul Samuelson tried to remedy that by developing multiplier-accelerator models. The problem with them is that the accelerator lacks micro foundations, in specific disregarding business confidence. Linking macro accounting identities with empirical national accounts data for five major economies produces the finding that business firms explain more than all aggregate expenditure growth during a 25-year period. Thus, it is concluded that business confidence is the root of the business cycle. Making the accelerator account for business confidence casts new light on the perhaps most well-known Keynesian “truth”: active fiscal policy as a main force stabilizing the business cycle. With business confidence being the endogenous and ubiquitous variable driving the business cycle, it turns out that any exogenous factor has the possibility to affect it. Policy needs to be viewed as a competing factor to the factor(s) driving the cycle in the other, destabilizing direction. The more powerful those factors are (e.g., a deadly virus), the tougher it gets for policy to “win” the competition, turning business confidence around. This leads up to the paper´s main conclusion: the worse the economy, the stronger is the case for active fiscal policy, but the lesser is the chance for it to succeed.

class="MsoNormal" style="text-align: justify;">Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.

class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph; punctuation-wrap: simple; mso-line-break-override: restrictions; margin: 0cm 5.3pt .0001pt 5.9pt;">Cloud computing is one of the fastest growing domains of the IT industry, however, the growth rates for each of the models on a global and local (Russian) scale have not been generalized, despite the obvious value of such analysis. Modern business and industry in Russia is going through another period of instability and at the same time is forced to follow the trend of digitalization. That is why a balanced scientific analysis and forecast of the development of cloud technologies is needed, as the main factor in improving business efficiency. The purpose of the study: is to review the main models of cloud services for modern business and industry, describing their capabilities separately and the prospects for the market as a whole. The materials for the study were analytical reports of leading consulting companies and materials from specialized web-sites. Result: The article considers cloud technologies as the main global technological trend, describes popular models of cloud services, their opportunities for business and industry. Russian and global leaders in the provision of cloud services are also described, the growth rates of these markets for each of the models are indicated. The most popular and promising cloud service models in 2022 are: UCaaS, CaaS, SaaS, IaaS, RPAaaS, PaaS. The cloud technology market will show strong growth until 2030, generating both hybrid and absolutely new service models. The private business, industrial and public sectors will increasingly move to cloud services. The main trends in the development of cloud technologies until 2030 are: hybrid cloud, artificial intelligence (AI) and cloud computing, deployment of cloud services in the planetary orbit. The results obtained are very valuable for analysts and industry experts. The above trend analysis provides valuable predictive data to research economists, investors, business and industry leaders and other stakeholders on how the cloud services market will grow in the next 5-7 years. The results of the study also have a general theoretical nature, substantiating the importance of further forecasting the development of this market (especially using mathematical methods).