Control Mechanisms Research Articles

INCREASING THE HUMAN RESOURCES POTENTIAL OF STATE AUDIT BODIES AS A BASIS FOR IMPROVING THE EFFICIENCY AUDIT MECHANISM

Recent economic and financial scandals worldwide, the growth of the shadow economy, the increase in funds concealed from the budget, the rise of corruption, and insufficient adherence to financial discipline create very serious problems. The development of an audit system that creates a transparent and comprehensive informational environment for the government and the public, and plays a key role in economic regulation, is aimed at addressing these serious issues and improving the economic and managerial environment. The purpose of the paper is to explore how increasing the human resources potential of state audit bodies serves as a basis for improving the efficiency audit mechanism. The improvement of the functioning of the state audit system and the enhancement of the knowledge and expertise of personnel and specialists working in this field are based on the critical need to assess and refine the existing system. At the current stage of development, improving the mechanisms of state audit and financial control, as well as monitoring the effective use of budget expenditures, has become a priority. In this context, the concept of state budget policy has undergone changes and is now focused on results-based management. To achieve these goals, new approaches to assessing economic efficiency are being developed, with the improvement of the efficiency audit mechanism being the main focus. The development of auditing institutions plays an important role in accelerating the country's socio-economic development. As a result of these institutions' activities, it becomes possible to identify new financial and economic resources necessary for economic growth. Increasing transparency in society and strengthening financial discipline in economic activities are also closely linked to the work of these institutions. The paper examines the issues of enhancing the knowledge and experience of personnel and specialists, who play a key role in the development of the audit institute.

Investigation into the Yaw Control of a Twin-Rotor 10 MW Wind Turbine

Multi-rotor system (MRS) wind turbines can provide a competitive alternative to large-scale wind turbines due to their significant advantages in reducing capital, transportation, and operating costs. The main challenges of MRS wind turbines include the complexity of the supporting structure, mathematical modeling of the aerodynamic interaction between the rotors, and the yaw control mechanism. In this work, MATLAB 2018b/Simulink® software was used to model and simulate a twin-rotor wind turbine (TRWT), and an NREL 5 MW wind turbine was used to verify the model outputs. Different random signals of wind velocities and directions were used as inputs to each rotor to generate different thrust loads, inducing twisting moments on the main tower. A yaw controller system was adapted to ensure that the turbine constantly faced the wind to maximize the power output. A DC motor was used as the mechanism’s actuator. The goal was to achieve a compromise between aligning the rotors with the wind direction and reducing the torque induced on the main tower. A comparison between linear and nonlinear controllers was performed to test the yaw system actuator’s response at different wind speeds and directions. Sliding mode control (SMC) was chosen, as it was suitable for the nonlinearity of the system, and its performance showed a faster response compared with the PID controller, with a settling time of 0.17 sec and a very low overshoot. The controller used the transfer function of the motor to generate a sliding surface. The dynamic responses of the controlled angle are shown and discussed. The controller showed promising results, with a suitable response and low chattering signals.

A ZO-2 scaffolding mechanism regulates the Hippo signalling pathway.

Contact inhibition of proliferation is a critical cell density control mechanism governed by the Hippo signalling pathway. The biochemical signalling underlying cell density-dependent cues regulating Hippo signalling and its downstream effectors, YAP, remains poorly understood. Here, we reveal that the tight junction protein ZO-2 is required for the contact-mediated inhibition of proliferation. We additionally determined that the well-established molecular players of this process, namely Hippo kinase LATS1 and YAP, are regulated by ZO-2 and that the scaffolding function of ZO-2 promotes the interaction with and phosphorylation of YAP by LATS1. Mechanistically, YAP is phosphorylated when ZO-2 brings LATS1 and YAP together via its SH3 and PDZ domains, respectively, subsequently leading to the cytoplasmic retention and inactivation of YAP. In conclusion, we demonstrate that ZO-2 maintains Hippo signalling pathway activation by promoting the stability of LATS1 to inactivate YAP.

Advanced functional polymer materials for biomedical applications

AbstractPolymer structures are essential in biomedical applications due to their biocompatibility, biodegradability, and ability to form intricate structures on micro‐ to nanometer scales. This review, emphasizing electrospinning and phase inversion techniques, examines the fabrication strategies and chemical design of polymer structures for biomedical use. Electrospinning, particularly needleless electrospinning, produces nanofibres with high porosity and flexibility and is widely applied in tissue engineering and drug delivery. Phase inversion, including thermal, nonsolvent‐, vapor‐ and evaporation‐induced phase separation, allows precise control over polymer properties but faces challenges in terms of cooling rates and solvent characteristics. Chemical design through doping, functionalization, cross‐linking and copolymerization enhances the biocompatibility, biodegradability and mechanical properties of polymers, facilitating advanced applications in drug delivery, tissue scaffolding and biosensors. Advanced functional polymers are revolutionizing biomedical fields, offering innovative solutions for therapeutic medicine delivery, disease detection, diagnostics, and regenerative medicine. Despite remarkable progress, challenges, such as scalability, cost‐effectiveness, and environmental impact, persist. This review underscores the transformative potential of advanced polymer materials in medical treatments and advocates for continuous research and interdisciplinary collaboration to overcome existing challenges and fully exploit the capabilities of these materials in improving patient care and medical outcomes. Future perspectives highlight enhancing precision control mechanisms, integrating phase inversion with other techniques and developing large‐scale production methods to advance the field further.

Involvement of Complement in Alzheimer's Disease: From Genetics Through Pathology to Therapeutic Strategies.

Complement is a critical component of innate immunity, evolved to defend against pathogens and clear toxic debris rangingfrom dead and dying cells to immune complexes. These roles make complement a key player in homeostasis; however, complement has a dark side. When the rigid control mechanisms fail, complement becomes dysregulated, acting as a driver of inflammation and resultant pathology in numerous diseases. Roles of complement in Alzheimer's disease (AD) and other dementias have emerged in recent years, supported by genetic, biomarker and pathological evidence and animal model studies. Numerous questions remain regarding the precise roles of complement in the brain in health and disease, including where and when complement is expressed, how it contributes to immune defence and garbage disposal in the healthy brain, and exactly how complement contributes to pathology in dementias. In this brief review, we will summarise current knowledge on complement roles in brain, present the evidence implicating complement in AD and explore whether complement represents an attractive therapeutic target for AD.

Selective regulation of aspartyl intramembrane protease activity by calnexin

Signal peptide peptidase-like 2c (SPPL2c) is a testis-specific aspartyl intramembrane protease that contributes to male gamete function both by catalytic and non-proteolytic mechanisms. Here, we provide an unbiased characterisation of the in vivo interactome of SPPL2c identifying the ER chaperone calnexin as novel binding partner of this enzyme. Recruitment of calnexin specifically required the N-glycosylation within the N-terminal protease-associated domain of SPPL2c. Importantly, mutation of the single glycosylation site of SPPL2c or loss of calnexin expression completely prevented SPPL2c-mediated intramembrane proteolysis of all tested substrates. By contrast and despite rather promiscuous binding of calnexin to other SPP/SPPL proteases, expression of the chaperone was exclusively required for SPPL2c-mediated proteolysis. Despite some impact on the stability of SPPL2c most presumably due to assistance in folding of the luminal domain of the protease, calnexin appeared to be recruited rather constitutively to the protease thereby boosting its catalytic activity. In summary, we describe a novel, highly specific mode of intramembrane protease regulation, highlighting the need to systematically approach control mechanisms governing the proteolytic activity of other members of the aspartyl intramembrane protease family.

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex uses its rhomboid pseudo-protease subunit, Dsc2, to assess the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex likely interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be extracted by Cdc48 for endosome and Golgi associated proteasomal degradation (EGAD), while others will undergo ESCRT dependent vacuolar degradation. Some substrates are degraded by both, EGAD- or ESCRT pathways. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thereby preserves cellular membrane protein and lipid composition.

Implications for fall efficacy strategies on center of pressure and center of gravity sway distances in adults with chronic low back pain.

Although chronic low back pain (LBP) is a complex condition often associated with altered motor control and compensatory postural adjustments, existing literature provides inconsistent reports on the underlying control mechanisms for maintaining balance. This study aimed to compare differences in sway distances between the center of pressure (COP) and the center of gravity (COG), while considering limb dominance, in adults with and without LBP. There were 26 subjects with LBP and 39 control subjects who performed three repeated unilateral standing tasks on a force platform. Outcome measures included the sway distances between COP and COG in the anteroposterior (AP) and mediolateral (ML) directions, as well as the results of the fall efficacy scale (FES). A significant group interaction was demonstrated on limb dominance and direction for the sway distance (F = 5.46, p = 0.02). Specifically, the third trial in the ML direction while standing on the dominant limb indicated a significant difference in COP-COG sway distance (t = -2.30, p = 0.01). When FES scores were used as a covariate, a significant three-way interaction (dominance x direction x trial) was found (F = 4.06, p = 0.04). Although no significant group interaction was observed for dominance, direction, and trial, the LBP group demonstrated an ability to leverage fall efficacy following repeated trials to reduce ML balance deficits. Clinicians should consider neuromuscular control and limb dominance when developing fall efficacy strategies for postural adaptations in adults with LBP.

Toward a Generic Framework for Mission Planning and Execution with a Heterogeneous Multi-Robot System.

This paper presents a comprehensive framework for mission planning and execution with a heterogeneous multi-robot system, specifically designed to coordinate unmanned ground vehicles (UGVs) and unmanned aerial vehicles (UAVs) in dynamic and unstructured environments. The proposed architecture evaluates the mission requirements, allocates tasks, and optimizes resource usage based on the capabilities of the available robots. It then executes the mission utilizing a decentralized control strategy that enables the robots to adapt to environmental changes and maintain formation stability in both 2D and 3D spaces. The framework's architecture supports loose coupling between its components, enhancing system scalability and maintainability. Key features include a robust task allocation algorithm, and a dynamic formation control mechanism, using a ROS 2 communication protocol that ensures reliable information exchange among robots. The effectiveness of this framework is demonstrated through a case study involving coordinated exploration and data collection tasks, showcasing its ability to manage missions while optimizing robot collaboration. This work advances the field of heterogeneous robotic systems by providing a scalable and adaptable solution for multi-robot coordination in challenging environments.

Investigating the Phytochemistry and Underlying Glycemic Control Mechanisms of Litchi chinensis Sonn. (Litchi) Peel Ethyl Acetate Extract in a Fructose/Streptozotocin Diabetic Model of Rats.

The glycemic control potential and flavonoid profile of litchi have been documented for its hydroalcoholic extracts, while there is scarce information regarding its ethyl acetate extract. This study investigated the flavonoid profile, as well as the ameliorative potential and possible underlying mechanisms of litchi peel ethyl acetate extract on type 2 diabetes-related pathologies in a fructose/streptozotocin (STZ) model of diabetic rats. Sprague Dawley rats were induced with diabetes by administering 10% fructose for 2 weeks and a single i.p. injection of low-dose (40 mg/kg bw) STZ. Thereafter, the animals were orally administered with a low-dose (150 mg/kg bw) and high-dose (300 mg/kg bw) of the peel extract (LDPE and HDPE, respectively) and metformin (200 mg/kg bw). Compared to untreated diabetic rats (AUC = 1004 mg.h/dL), the HDPE significantly (p < 0.05) improved glucose tolerance (AUC = 847 mg.h/dL), which was statistically comparable (p ˃ 0.05) to the effect of metformin (AUC = 903 mg.h/dL). Serum insulin and pancreatic histology data showed that the STZ-induced pancreatic damage and insulin depletion was improved by the HDPE, which could be linked to the observed ameliorative effect of the extract on pancreatic lipid peroxidation and SOD and catalase activity. The extract further improved liver and muscle glycogen storage, as well as muscle hexokinase activity and Akt phosphorylation, suggesting that the extract exerts glycemic control by enhancing glycogen storage and modulating insulin-mediated signaling of glucose uptake and utilization. LC-MS data and documented reports suggest that flavonoids, such as epicatechin, cinnamtannin B2, procyanidin B5, and proanthocyanidin A2, are the possible influencing compounds. The ethyl acetate extract of litchi peel could be a source of bioactive flavonoids that can potentiate glycemic control in diabetes and mitigate oxidative stress-related pathologies.

Integral resonant negative derivative feedback suppression control strategy for nonlinear dynamic vibration behavior model

One of the major problems in robotics research has been developing an actuator system for extremely dynamic-legged robots. High torque density and the capacity to control dynamic physical interactions are two design requirements for high-speed locomotion that are challenging for conventional actuators used in manufacturing applications to meet. To address this system and apply the desired control to reach the best stability position, the robot's foot was simulated with the Van der Pol equations, applied the required control, and studied that application. This work describes the actions of a new novel control mechanism known as the Integral Resonant Negative Derivative Feedback (IRNDF) controller, which reduces the vibration response of a double Van der Pol oscillator subjected to external excitations. This unique controller combines integral resonant control (IRC) and negative derivative feedback (NDF) controllers to provide a new controller effect for double Van der Pol oscillators. The multiple scale perturbation technique (MSPT) has been applied to solve the controlled system analytically. The MATLAB and MAPLE programs have been used to complete and clarify all of the numerical talks. The frequency response curves have been used to study the impact that altering the parameter values had on the amplitude. The controlled system vibration amplitude is governed by frequency-response equations (FREs), which have been constructed. In the vibration system, the IRC, NDF, and IRNDF controllers were compared to see which one was the best. Numerical results show that the unique IRNDF controller is the best at reducing oscillations and decreasing amplitude values. The effects of the effective parameters on the controlled system have been identified. The frequency-response equation that was derived has been used to plot the various response curves for the framework that show the stable and unstable zones when the controller is off and on. Lastly, excellent agreement between the derived numerical findings and the analytical ones was observed. Lastly, utilizing time histories and response curves to compare analytical and numerical solutions was fascinating and significant.

Host or the Hosted? Effects of Non-Nutritive Sweeteners on Intestinal and Microbial Mechanisms of Glycemic Control.

Background/Objective: High habitual consumption of non-nutritive sweeteners (NNS) is linked to increased incident type 2 diabetes, with emerging clinical evidence that effects on gut microbiota may, in part, drive this risk. However, the precise contribution of the effects of NNS on gut microbiota to host glycemic responses remains unclear. Methods: Ten-week-old male C57BL/6 mice (N = 10 per group) were randomized to drinking water with or without combined NNS (sucralose 1.5 mg/mL plus acesulfame-K 2.5 mg/mL) and with or without antibiotics to deplete gut microbiota (ABX, 1 mg/mL ampicillin and neomycin) over two weeks. Oral glucose tolerance tests (OGTT, 2 g/kg) were conducted on days -1 and 12. On day 14, mice underwent a jejunal infusion of glucose (300 mg) with 3-O-methyl glucose (30 mg, 3-OMG, a marker of glucose absorption) in 1.5 mL for 30 min, followed by blood collection and bioassays. Data were analyzed using ANOVA with NNS and ABX as factors. Results: Jejunal glucose absorption was augmented in NNS+ mice relative to NNS- (31%; 3-OMG T30; p ≤ 0.05) independent of ABX. ABX attenuated OGTT responses independent of NNS supplementation (-35%; incremental AUC, p ≤ 0.001). NNS+ ABX+ mice had augmented GLP-1 responses to intrajejunal glucose relative to other groups (69-108%, p < 0.05). Conclusions: These findings demonstrate that sub-acute NNS supplementation augments glucose absorption independent of gut microbiota in mice but does not disrupt glycemic responses. Antibiotic depletion of gut microbiota markedly increased glucose tolerance in mice, which may involve the actions of GLP-1.

CURRENT CHALLENGES AND PROSPECTS OF LEGAL REGULATION OF PUBLIC ADMINISTRATION OF THE SOCIAL SPHERE IN THE TERRITORIAL COMMUNITIES OF UKRAINE

The article defines that public administration is a system of activities of state authorities aimed at optimizing the use of resources to achieve the priority goals of social policy. It is emphasized that the social sphere covers a wide range of services that ensure the well-being of citizens, including health care, education, social protection and other critically important elements. The study of the problems of public management of the social sphere in territorial communities reveals a number of challenges, such as insufficient financial support, the absence of a clear legal framework, and a low level of public involvement in decision-making processes. Analysis of modern approaches to legal regulation in this area showed that effective management of social policy requires the integration of innovative methods, in particular digitalization of processes, which will contribute to the transparency and accountability of local self-government bodies. As a result of the research, it was found that the public management of the social sphere in the territorial communities of Ukraine is a complex, multifaceted process that requires a comprehensive analysis and a comprehensive approach to its improvement. The development of recommendations for improving management mechanisms should become a priority for researchers and practitioners in this important field. Effective management of the social sphere requires systematic control over the implementation of state policy. This involves not only an internal audit of the activities of local self-government bodies, but also mechanisms of public control that would allow residents to actively participate in the processes of evaluating the effectiveness of social programs. The study showed that the key factors in the effectiveness of public management of the social sphere in territorial communities are: adaptability of management mechanisms; integration of modern technologies; formation of partnership relations; personnel training and development; community involvement in decision-making processes, etc. Legal regulation of public management of the social sphere in territorial communities of Ukraine is conditioned by the need to create effective management mechanisms that meet modern challenges. Among the prospects for the development of legal regulation of public management of the social sphere in the territorial communities of Ukraine, the need for: improvement of the legal framework was emphasized; strengthening of financial autonomy; development of professional training; integration of modern technologies; community involvement in decision-making processes; focus on inclusiveness; monitoring and evaluation of efficiency; cooperation with international organizations; adaptation to changes in the socio-economic environment; increasing the level of trust in the authorities, etc. It is emphasized that the successful implementation of public policy in the social sphere depends on the effective interaction of all interested parties, which in turn will ensure sustainable development and increase the quality of life of the population.

Design of reliable standalone utility-scale pumped hydroelectric storage powered by PV/Wind hybrid renewable system

With a target of 35 % renewable energy in the country’s energy mix by 2030, the goal of this research is to support the Libyan government’s plan to maximize the use of environmentally friendly and sustainable energy sources. This will be accomplished by making effective use of the region’s plentiful natural resources. The feasibility of wind and solar energy has been established by local research, and the presence of highlands that can store pumped hydropower (PHS) makes hybrid renewable energy systems (HRES) even more feasible. These systems might offer a sizable edge over competitors in the regional energy market. In this study, PHS was utilized to stabilize electricity production in addition to storing energy. A hydropower turbine provides electricity to the load, and the PHS system is powered by a PV/wind supply. By lowering the volatility of wind and photovoltaic power generation, the suggested system could offer a more dependable renewable energy source without requiring complicated control mechanisms. This strategy could encourage a wider adoption of renewable energy, which could be especially advantageous for developing nations. Under particular load and climate conditions, the energy production of different solar PV array and wind turbine farm configurations was estimated using the System Advisor Model (SAM) software. The ideal HRES configuration consists of a 290 MW wind farm, a 154 MW solar PV field, and a 508 MW PHS system. This configuration will provide 100 % of the annual electrical demand of 513 GWh, plus a 20 % safety margin. The levelized cost of energy (LCOE), estimated at $211.65/MWh, is reduced by this configuration. It is anticipated that the $929.02 million initial investment will be recovered in 11 years, and the system will turn a profit in the following 9 years. Also, the planned HRES will stop 532.17 tons of CO2 emissions from being released each year.

Controllable Human Trajectory Generation Using Profile-Guided Latent Diffusion

Trajectory generation is a vital element in AI applications. Firstly, it enables simulation such as traffic simulation and epidemic spreading modeling. Secondly, it can provide synthetic privacy-preserving data for training AI models. Notably, trajectory generation featuring controllable user profiles holds substantial value in generating customized mobility trajectories tailored to diverse requirements. However, relevant work is still lacking. On the one hand, traditional deep generative models fall short in guiding controllable trajectory generation due to the statistical nature of human mobility patterns and the corresponding insufficient control mechanisms. On the other hand, though the diffusion model has demonstrated strong generative capabilities in many fields, to achieve controllable generation on discrete trajectory data, we still need to redesign the structure of the continuous diffusion model. In this paper, we introduce a controllable trajectory generation framework that leverages a continuous diffusion model and classifier guidance for more robust condition control. Our proposed framework comprises two modules: a latent trajectory diffusion model and a trajectory classifier for profile guidance. Experiments on two real-world mobility datasets consistently demonstrate its capability of generating trajectories matching given user profiles and conforming to human mobility patterns. Our source code and trained models are released at https://github.com/tsinghua-fib-lab/User-Profile-Guided-Latent-Diffusion .

Influence of reservoir water saturation on coalbed methane development: Based on multi-field coupling numerical simulation

Water in coal reservoirs serves as both the driving force of reservoir fluid and the resistance to coalbed methane (CBM) migration. However, the impact and control mechanism of water saturation on CBM development in the field have not been revealed yet. The evolution of reservoir dynamics and gas production rate under various initial water saturation conditions is simulated based on the COMSOL multiphysics numerical simulation software. The simulation results show that the reduction of initial water saturation can significantly enhance the effective permeability of the reservoir gas phase, which can be increased by up to 4764%. This increases the rate of gas production, which is the main mechanism for controlling production by water saturation in the reservoir. For high water saturation reservoirs, the positive effect of inter-well interference should be reasonably utilized, and high well network density should be used to rapidly increase gas-effective permeability. For low water saturation reservoirs, the negative effect of inter-well interference should be avoided, and low well network density should be used to increase the control of single well reserves.

Identifying money laundering risk indicators: Evidence from Bulgaria

The study of the fight against money laundering in Bulgaria takes on a heightened significance due to the country's unique geopolitical and economic context. As a member of the European Union and a key regional player, Bulgaria assumes a pivotal role in preventing cross-border crimes, including money laundering. The present study aims to analyze how modern technologies can bolster this crucial role, facilitating monitoring and analysis processes to enhance the effectiveness of audit and tax inspections in the country. The research applied practical methods involving digital tools and technological solutions such as artificial intelligence and machine learning. These tools were used to identify risk patterns and anomalies in transaction data, demonstrating their real-world application and effectiveness. They enable fast and accurate analysis of large volumes of data, which is particularly important in the context of sophisticated money laundering schemes. The results of the study underscore the potential benefits of technological innovation in the field of financial audits. With the aid of digital technologies, supervisory authorities in Bulgaria stand to significantly enhance their ability to detect financial abuses, including money laundering and tax evasion. In conclusion, the study reiterates the pressing need for further integration of modern technological solutions in the practices of audit and tax services in Bulgaria. This integration is crucial to ensure the effectiveness of control mechanisms and the country's ability to respond to current and future challenges in the fight against crimes in the financial sphere, underscoring the urgency of this matter.

Arabidopsis uses a molecular grounding mechanism and a biophysical circuit breaker to limit floral abscission signaling

Abscission is the programmed separation of plant organs. It is widespread in the plant kingdom with important functions in development and environmental response. In Arabidopsis, abscission of floral organs (sepals, petals, and stamens) is controlled by two receptor-like protein kinases HAESA (HAE) and HAESA LIKE-2 (HSL2), which orchestrate the programmed dissolution of the abscission zone connecting floral organs to the developing fruit. In this work, we use single-cell RNA sequencing to characterize the core HAE/HSL2 abscission gene expression program. We identify the MAP KINASE PHOSPHATASE-1/MKP1 gene as a negative regulator of this pathway. MKP1 acts prior to activation of HAE/HSL2 signaling to establish a signaling threshold required for the initiation of abscission. Furthermore, we use single-cell data to identify genes expressed in two subpopulations of abscission zone cells: those proximal and those distal to the plane of separation. We identify INFLORESCENCE DEFICIENT IN ABSCISSION/IDA family genes, encoding activating ligands of HAE/HSL2, as enriched in distal abscission zone cells at the base of the abscising organs. We show how this expression pattern forms a biophysical circuit breaker whereby, when the organ is shed, the source of the IDA peptides is removed, leading to cessation of HAE/HSL2 signaling. Overall, this work provides insight into the multiple control mechanisms acting on the abscission-signaling pathway.

An Efficient Competitive Control Mechanism for Negative Information Spread in Online Social Networks

An Efficient Competitive Control Mechanism for Negative Information Spread in Online Social Networks

Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML.

Abnormal Notch1 expression has an important role in tumorigenesis. However, upstream control mechanisms for Notch1 are still insufficiently understood. Acute myeloid leukemia (AML) is one of the most common and lethal blood malignancies with limited possibilities for treatment. Thus, new therapeutic targets are urgently needed to improve current ineffective therapies. Herein, high Annexin A1 (ANXA1) expression is found correlated with hyperproliferation of AML cells, and then ANXA1 is identified as a novel negative regulator of Notch1 function in AML. Mechanistically, ANXA1 directly bound to the intracellular domain of Notch1 (NICD) to target this tumor suppressor for degradation. Furthermore, NICD executed its tumor suppressive function through activation of the p15 promoter. Thus, ablation of the Notch1-p15-mediated tumor suppression by ANXA1 provided a novel mechanism of AML proliferation. In human AML patients, a mutual exclusive relation is discovered between ANXA1 and Notch1/p15, corroborating mechanistic discovery. On the basis of these results, it is reasonably speculated that targeting ANXA1 would provide an effective approach for treatment of AML. In support of this new therapeutic paradigm, provided proof-of-concept data by antagonizing ANXA1 using NICD inhibitory peptides.