Numerical Study Research Articles

Resveratrol: Targeting cancer stem cells and ncRNAs to overcome cancer drug resistance.

A major challenge in treating cancer is the development of drug resistance, which can result in treatment failure and tumor recurrence. Targeting cancer stem cells (CSCs) and non-coding RNAs (ncRNAs) with a polyphenolic substance called resveratrol has the ability to combat this problem by lowering cancer resistance to drugs and opening up new therapeutic options. Resveratrol alters the expression of genes related to self-renewal, modulating important signaling pathways involved in cancer initiation and CSC control. Additionally, resveratrol affects non-coding RNAs (ncRNAs), including Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs which are essential for stemness, drug resistance, and other cancer-related activities. Numerous studies have shown that resveratrol has the potential to be an effective anticancer drug when used in combination therapy, but issues with absorption and pharmacokinetics still need to be resolved before it can be used in clinical applications. Reducing chemotherapy resistance by better understanding the intricate mechanisms by which resveratrol affects cancer cells and CSCs, as well as its impact on ncRNA expression, could eventually contribute to more effective cancer treatments. To completely understand these pathways and optimize the utilization of resveratrol in combination treatments, additional study is necessary.

Systematic literature review on the holistic integration of e-learning in universities: Policy, human, financial, and technical perspectives

This systematic literature review (SLR) explores the integration of e-learning in universities, emphasizing a comprehensive approach that intertwines various mainstream perspectives. Despite numerous studies on e-learning implementation evaluation, few have holistically considered financial, human, technical, and policy factors. This review used PRISMA guidelines and sources from Scopus, Google Scholar, ERIC, SAGE, and ProQuest. Of 26 analyzed studies, seven core themes emerged: Policy, financial, technical, human, institutional factors, others, and an integrated perspective, further distilled into 13 sub-themes. Findings highlight the importance of an integrative framework for evaluating e-learning, underscoring the interplay between macro and institutional policies. Additionally, the authors recommend cross-national comparisons and data synthesis from stakeholders, including students, educators and directors, to fully grasp e-learning implementation dynamics. Distinctively, it adopts an integrated perspective, filling the research gap by emphasizing overlooked financial considerations and presenting a comprehensive view through an SLR. By drawing insights from human, finance, technical, and policy perspective, the study provides a multidimensional lens on e-learning. This forward-looking approach not only captures the current state of e-learning integration but also charts future research directions, establishing its originality and significance in higher education.

Robust Parameter Design on Dual Stochastic Response Models With Constrained Bayesian Optimization

In engineering system design, minimizing the variations of the quality measurements while guaranteeing their overall quality up to certain levels, namely the robust parameter design (RPD), is crucial. Recent works have dealt with the design of a system whose response-control variables relationship is a deterministic function with a complex shape and function evaluation is expensive. In this work, we propose a Bayesian optimization method for the RPD of stochastic functions. Dual stochastic response models are carefully designed for stochastic functions. The heterogeneous variance of the sample mean is addressed by the predictive mean of the log variance surrogate model in a two-step approach. We establish an acquisition function that favors exploration across the feasible and optimality-improvable regions to effectively and efficiently solve the stochastic constrained optimization problem. The performance of our proposed method is demonstrated by the extensive numerical and case studies. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —Many manufacturing processes involve undesirable variations, which create variations in the final products. For example, many emerging manufacturing processes, such as nanomanufacturing, involve complex physical and chemical dynamics and transformation, creating variations in the manufacturing output. In such processes, it is crucial to design the manufacturing processes or products so that they have minimum variations in their quality. Meanwhile, it is also important to maintain the overall quality of the designed processes or products. Furthermore, acquiring data from many advanced manufacturing processes is often very costly, especially in the designing stage. In this work, we propose a data-driven method that automatically finds the best setting of manufacturing processes or products with the minimum variations of quality and a given constraint on the average quality satisfied. Our proposed method is used before conducting every experiment; It analyzes the historical data from previous experiments and provides a setting to be used in the next experiment. Our proposed method efficiently utilizes the historical data, and thus finds the best robust setting by conducting only a small number of experiments.

Numerical Simulation Study on Optimizing the Conical Cutter Bit to Break Deep Strata

Background: Methods that are used to obtain oil and gas resources by penetrating deep strata are gradually being developed. The complex lithology of deep strata causes difficulties for traditional drill bits to cut into the rock effectively, which affects the drilling efficiency. Objective: The goal of this work is to optimize the bit structure and design a patented drill bit for more efficient rock breaking. Methods: Through a series of tests, the rock mechanics parameters of deep strata in a block of Jilin Oilfield were measured, and the drill bit model XFXR5195 was selected to best match the lithology of the formation by using the Virtual Strength Index and the Technique for Order Preference by Similarity to an Ideal Solution. Simulation of the rock breaking process of the conical PDC cutter and cylindrical PDC cutter with the finite element method. Results: The simulation results show that the pre-crushing of the conical cutter can effectively reduce the difficulty of the subsequent cylindrical cutter in breaking and cutting rocks under 100 MPa compressive strength rocks; under 50 MPa compressive strength rocks, the combination of the conical cutter and cylindrical cutter are not effective with regards to drilling. Conclusion: The conical PDC cutter has a more uniform force range and more concentrated stress on the rock than the cylindrical PDC cutter. The rock-breaking ability of the conical PDC cutter is higher than that of the cylindrical PDC cutter under different compressive strength rocks and especially in high compressive strength rocks.

Magnetic Nanoparticles with Aspects of their Use in Cancer Therapy

Abstract: Cancers remain the leading cause of death worldwide, despite significant advances in their diagnosis and treatment. The inadequacy and ineffectiveness of standard treatments (chemotherapy, radiotherapy, and surgery), their severe side effects, and the resistance of tumor cells to chemotherapeutics have forced researchers to investigate alternative therapeutic strategies. Magnetic nanoparticles (MNPs) have been evaluated as one of the promising strategies in treating cancers, a major public health problem. Due to their intrinsic magnetic properties, MNPs are tools that can be designed to be multifunctional in medicine, including cancer therapy. Multifunctionality can be achieved with various drug/agent loadings, such as chemotherapeutic drugs, radionuclides, nucleic acids, and antibodies. This provides a multimodal theranostics platform for cancer diagnosis, monitoring, and therapy. These substances can then be delivered to the tumor tissue using an external magnetic field (EMF). Magnetic or photothermal applications kill cancer cells at the tumor site by inducing local hyperthermia, whereas photodynamic therapy kills them by producing reactive oxygen species. MNP applications also prevent drug resistance. In addition, alone or with different combination options, MNP applications provide synergistic effects and reduce side effects. Functionalized MNPs can be used to remove unwanted cells from blood, including circulating tumor cells (CTCs), which are key factors in the metastatic process and leukemia cells. Despite numerous successful studies, there are some unpredictable obstacles to be discovered in routine usage. This review focuses mainly on the application of MNPs in cancer treatment, covering future perspectives and challenges.

Numerical Study of the Piezocone Test in Sandy Soil under Different Drainage Conditions Using a Hypoplastic Constitutive Model

Numerical Study of the Piezocone Test in Sandy Soil under Different Drainage Conditions Using a Hypoplastic Constitutive Model

Curcumin as a Potential Phytoconstituent used for Cancer Treatment: An Overview

Background:: Cancer is one of the leading causes of death worldwide. Therapy for cancer has remained a challenge for a very long period of time, though developments of various treatment strategies have been introduced. However, Curcuma longa L (Turmeric) attains major attention to cure cancer due to its phytoconstituents which can be used in the treatment of various cancers. Due to the wide availability and minimal adverse effects, curcumin has become a source of significant interest in research for cancer treatment which can lead to heavy cost cut off in the treatment. Objective:: In this review article, the anti-cancer properties of curcumin in the treatment of cancer are highlighted. Conclusion:: Scientists from all over the world have been interested in curcumin, a polyphenol isolated from Curcuma longa, for its biological properties, the most well-known of which is its ability to fight cancer. It is one of the most promising classes of bioactive natural substances, particularly in the treatment of various cancer types. Curcumin demonstrates anticancer properties. To overcome the limitation of curcumin numerous studies, analysis, and research has been already completed and many are still going on. The use of curcumin either alone or in combination might alter the treatment of cancer.

Exponential Synchronization of Markovian Jump Neural Networks Based on Asynchronous Delayed-Feedback Controller With Uncertain Hidden Information.

Due to the complex network environment, the feedback information cannot be timely received by the controller. This article proposes a method on the exponential synchronization for the Markovian jump neural networks, which is achieved by designing a new asynchronous delayed-feedback controller, with its feedback delay taken into account. The quantized relationship between the exponential synchronization and the feedback delay is derived from a new designed Lyapunov functional, to acquire delay boundaries. With the help of a hidden-Markov process, the designed controller shows asynchrony, which allows controller modes to run free. In particular, the detection probability is assumed to be bounded known, marking a breakthrough over existing results. Moreover, the proposed method proves to be applicable in both synchronous and asynchronous cases. By using the proposed method, the computation freedom of the controller gain matrix can be substantially augmented. Further, comparative numerical studies are implemented to validate the effectiveness and superiority of the proposed method.

Menstrual Phase Identification Questionnaire (MPIQ): Development and validation of a cross-sectional survey to identify follicular and luteal phases.

Evidence continues to accumulate on the influence of the menstrual phase on several biobehavioral outcomes (e.g., substance misuse). Expansion of this knowledge is limited due to the burdensomeness of accurate menstrual phase assessment. Thus, we sought to create and validate a questionnaire that can be used as a stand-alone item within low-resource settings and numerous study designs (e.g., cross-sectional) to accurately identify both the follicular phase (FP) and the luteal phase (LP). Participants completed the self-administered four-item Menstrual Phase Identification Questionnaire (MPIQ) in two recently completed clinical trials. We assessed the accuracy of two MPIQ scoring criteria (less restrictive and more restrictive), as compared to self-report of onset of menses alone, with progesterone confirmation via dried blood spots. Participants (n = 59) were, on average, 33.7 (standard deviation [SD]: ± 4.3) years old and provided a total of 83 responses. Assessing FP and LP using the self-reported onset of menses alone classified 65.1% of the responses with an overall phase identification accuracy of 60.2%. While the more restrictive MPIQ scoring classified 100% of the responses, it yielded a similar accuracy (68.4%). In contrast, the less restrictive MPIQ scoring classified 100% of the responses and also significantly improved phase identification accuracy to 92.1% (p < .001). The MPIQ, as a stand-alone item, allows all cross-sectional responses to be classified with a high level of accuracy. This low-burden questionnaire can be used alone to identify FP and LP in studies that may be otherwise limited by study design, finances, and/or participant burden. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Joint Effects of Winds and Tides on Near-Inertial Internal Waves in the Northern South China Sea: A Three-Dimensional Numerical Study

Abstract Joint effects of winds and tides on near-inertial internal waves (NIWs) are numerically investigated via a series of three-dimensional quasi-realistic simulations in the northern South China Sea (NSCS). Model results demonstrate that in the presence of wind-induced NIWs, more tidal energy is transferred to NIWs, while in the presence of tide-induced NIWs, the extreme wind (cyclone) would inject less near-inertial kinetic energy (NIKE). The interaction between wind-induced and tide-induced NIWs produces total NIKE more (or less) than a linear superposition of that generated by wind and tide forcing alone at different sites in the NSCS. Specifically, near the Luzon Strait, both tides and winds make positive contributions to the local near-inertial energy input, resulting in more than 30% enhancement of total NIKE (&gt;0.5 kJ m−2). However, in some deep-water regions along the cyclone paths, energy is transferred from cyclones to NIWs and also from NIWs to internal tides. Due to this “energy pipeline” effect, tide- and wind-induced NIWs contribute to weakening of total NIKE (∼0.3 kJ m−2 or 30%). Additionally, sensitivity experiments with varying initial tidal phases indicate that the interaction between wind-induced NIKE and tide-induced NIKE is robust in most of the model domain (over 80%) under different phase alignments between wind- and tide-induced NIWs. From the perspective of cyclones, tide-induced NIKE is comparable to wind-induced NIKE in the Luzon Strait before the arrival of cyclones, while tide-induced NIKE is two orders of magnitude smaller than wind-induced NIKE in most of the NSCS after the arrival of cyclones. Overall, our results highlight the joint effects of wind and tide forcing on the local NIW dynamics in the NSCS. Significance Statement Near-inertial internal waves (NIWs) are ubiquitous phenomena in stratified water, which can significantly influence the ocean mixing, especially across the thermocline. NIWs are generated mainly by wind forcing near the sea surface, but also by internal tide breaking in the ocean interior. Hence, a question that arises is whether winds or tides play dominant roles in generating NIWs. In fact, due to the interaction between wind- and tide-induced NIWs, the total near-inertial kinetic energy (NIKE) is not merely a linear superposition of that generated by winds and tides forcing alone. By carrying out numerical experiments, we find that extreme winds can help to transfer more energy from tides to NIWs, while tides would suppress energy transferring from winds to NIWs. As a result, this fact is crucial in accurately reproducing NIW dynamics in a targeted region, thereby determining redistribution of local ocean mixing intensity.

Experimental and Numerical Study of Grout Effectiveness and Force-Transfer Mechanism in Socket Connections

Experimental and Numerical Study of Grout Effectiveness and Force-Transfer Mechanism in Socket Connections

3D Numerical Study of Scour around a Pile Group in the Staggered Arrangement under Combined Wave-Current Flows

3D Numerical Study of Scour around a Pile Group in the Staggered Arrangement under Combined Wave-Current Flows

Bitcoin in Blockchain Technology and Ethereum In Smart Contracts

Abstract: Blockchain is one of the most trending technologies which plays a major role in online transactions using cryptocurrencies. The blockchain is a chain of blocks that consists of allthe transactions up to the size of 1MB. This blockchain has many properties such as decentralization, immutability, transparency, and audibility, making transactions more secure and tamper-proof. It is tamper-proof because there is no possibility to tampera block as every block in the blockchain has the hash of the previous block. And among cryptocurrencies, bitcoin is one ofthe most popular... In fact, blockchain was introduced to theworld because of bitcoins. Apart from cryptocurrency, blockchain technology can be used in financial, NYC, and social services, risk management, food, healthcare facilities, and so on. Numerous studies have examined the potential that blockchain offers inmultiple application sectors, as well as the benefits and different kinds of blockchain. This paper presents a comparative studyof bitcoins in blockchain technology and the workflow of thebitcoin, compares bitcoin and Ethereum, and provides the use of smart contracts in this emerging technology. The methodology considered for this research is the Ethereum blockchain in smart contracts using a solidity programming language.

Borderline Bireylerde Kendine Zarar Verme Davranışı ve İntihar Girişimine Yönelik Psikolojik Müdahaleler: Sistematik Derleme

Self-harm behaviour and suicide attempts are considered maladaptive coping mechanisms by individuals with a diagnosis of borderline personality disorder (BPD). Numerous studies have demonstrated that individuals with BPD are at a heightened risk for self-harm behaviour and suicide. Therefore, there is a need for intervention efforts aimed at reducing self-harm and suicide attempts in this population by promoting more functional coping strategies. No systematic review has been conducted to explore the effectiveness of such interventions. A systematic review was performed to identify randomized controlled trials of interventions to reduce self-harm and suicide attempts among individuals with BPD, published between 2012 and 2022. PsycARTICLES, PubMed, Web of Science, Science Direct, and Taylor &amp; Francis databases were examined in the review. A total of 6,760 studies were initially screened, only 13 were selected for review based on the inclusion and exclusion criteria. The results indicated that the standard dialectical behaviour therapy protocol, with the addition of psychological intervention components such as skills training, exposure and acceptance, statistically significantly increased recovery. Statistically significant results have been obtained from various psychotherapeutic intervention groups such as schema therapy, cognitive behavioural therapy and emotion regulation therapy However, it was noted that existing protocols might be inadequate in preventing relapse and addressing potential negative outcomes such as premature termination of therapy.

Diverse perspectives in zebrafish seizure models: An exploration of chemical inducers

Numerous studies have investigated seizures in zebrafish, employing diverse methods to induce and observe epilepsy. Chemical inducers have become indispensable tools for precisely manipulating neural activity in controlled experiments. This research is dedicated to a meticulous comparison and analysis of various seizure-inducing chemicals in zebrafish. The selected chemical inducers include pentylenetetrazole (PTZ), kainic acid (KA), picrotoxin (PTX), pilocarpine, and other substances. The primary mechanism of these inducers involves altering neurotransmitter receptors, particularly GABA and glutamate, at inhibitory or excitatory synapses. This alteration creates an imbalance between inhibitory and excitatory signals in the brain, contributing to epileptogenesis. The resulting hyperactivity in the zebrafish brain disrupts metabolism, elevates reactive oxygen species (ROS), and causes neuronal damage. Chemical induction offers valuable insights into the neurological activity of zebrafish, enabling the observation of behaviors such as whole-body contractions, loss of posture, or freezing. Various parameters can be adjusted to examine the effects of chemical inducers on zebrafish development and to replicate various types of seizures, such as status epilepticus and temporal lobe epilepsy. Despite the array of options available, many chemical inducers remain underutilized in zebrafish studies. To ensure the successful induction of models, monitoring gene expression markers such as c-fos, which represents neuronal activity, becomes crucial. Additionally, a scoring system is employed to analyze seizure severity and identify treatment efficacy. The existing gaps in utilizing chemical inducers present great opportunities for future model development. This chemically-induced seizure model in zebrafish is pivotal for unraveling seizure mechanisms, contributing significantly to advancements in neurological research.

Numerical Analysis of the Effects of Fuel Injection Duration and Spray Angle on the Combustion Process in a Compression Ignition Engine

The changes in injection strategies for diesel engines have a major impact on the performance and pollutant emission characteristics of diesel engines. If injection strategies like injection duration, injection timing, injection pressure and spray angle are properly adjusted, combustion can be improved. The engine performance will increase and emissions will decrease with the combustion improvement. In this work, the influences of injection duration and spray angle on the combustion characteristics of single cylinder, natural aspirated, electronically controlled injection, compression ignition engine were investigated. In the first stage of the work, experiments were executed on a single cylinder CI engine using a Cussons P8160 DC dynamometer. After the experiments, the piston bowl geometry of the engine was modeled and numerical simulation studies were achieved at 7 different injection durations and 7 different spray angles using Converge CFD software. As a result of this study, it was observed that there is a good match between experimental and simulation data of heat release rate (HRR) and in-cylinder pressure. In-cylinder pressure decreased with longer injection duration. The highest max. in-cylinder pressure was roughly 101.0 bar at 4°CA injection duration and the lowest max. in-cylinder pressure was roughly 82.0 bar at 10°CA injection duration. When the HRR data were analyzed, it was seen that as the injection duration increased, the amount of heat released by combustion decreased. When examining the results of the spray angle analysis, it was concluded that there were not very large differences in-cylinder pressure and HRR data, and there was a difference of 1.4 bar between the highest and lowest max. in-cylinder pressure values. In addition, the highest in-cylinder pressure of approximately 86.7 bar was obtained at a spray angle of 77°. It was observed that the CA50 value was obtained at angles closer to the top dead center by increasing the spray angle and decreasing the injection duration. Moreover, the longest combustion durations were realized at 60° spray angle and 10°CA injection duration.

The Contribution of Double-strand Break Repair Radiation Sensitive Protein 51 Genotypes to Lung Cancer in Taiwan.

Numerous studies have reported the over-expression of the radiation-sensitive protein 51 (RAD51) in various types of cancer. However, the role of RAD51 genotypes in lung cancer remains largely unknown. This study aimed to assess the impact of the common variant RAD51 rs1801320 (G-135C) genotypes on the risk of lung cancer in Taiwan. The contribution of RAD51 rs1801320 genotypes to lung cancer risk was investigated in a cohort comprising 358 lung cancer patients and 716 age- and sex-matched healthy controls, utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. The analysis revealed that among the control subjects, the percentages of GG, CG, and CC genotypes of RAD51 rs1801320 were 73.2%, 24.3%, and 2.5%, respectively. Among the lung cancer patients, these percentages were 71.0%, 25.1%, and 3.9%, respectively (p for trend=0.4075). Allelic frequency distributions showed no significant association between the C allele of RAD51 rs1801320 and lung cancer risk determination (p=0.2987). Specifically, the RAD51 rs1801320 CC genotypes were associated with an elevated risk of lung cancer among males [adjusted odds ratio (aOR)=2.28, 95% confidence interval (95%CI)=1.03-4.87] and smokers (aOR=2.93, 95%CI=1.23-5.87), but not among females and non-smokers. The RAD51 rs1801320 CC genotype was identified as a risk factor for elevated lung cancer risk in males and smokers. This genotype may serve as a molecular biomarker at the DNA level for early detection and prediction of lung cancer in Taiwan.

METTL3-mediated m6A modification increases Hspa1a stability to inhibit osteoblast aging

Senile osteoporosis is mainly caused by osteoblasts attenuation, which results in reduced bone mass and disrupted bone remodeling. Numerous studies have focused on the regulatory role of m6A modification in osteoporosis; however, most of the studies have investigated the differentiation of bone marrow mesenchymal stem cells (BMSCs), while the direct regulatory mechanism of m6A on osteoblasts remains unknown. This study revealed that the progression of senile osteoporosis is closely related to the downregulation of m6A modification and methyltransferase-like 3 (METTL3). Overexpression of METTL3 inhibits osteoblast aging. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that METTL3 upregulates the stability of Hspa1a mRNA, thereby inhibiting osteoblast aging. Moreover, the results demonstrated that METTL3 enhances the stability of Hspa1a mRNA via m6A modification to regulate osteoblast aging. Notably, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) participates in stabilizing Hspa1a mRNA in the METTL3-mediated m6A modification process, rather than the well-known degradation function. Mechanistically, METTL3 increases the stability of Hspa1a mRNA in a YTHDF2-dependent manner to inhibit osteoblast aging. Our results confirmed the significant role of METTL3 in osteoblast aging and suggested that METTL3 could be a potential therapeutic target for senile osteoporosis.

Investigation of combined parallel and triple-pass v-corrugated solar air heater: A numerical and experimental study

Renewable and safe energy sources have been used more in recent years because of rising energy needs and finite fossil fuel resources. A solar air heater (SAH) is a device that utilizes solar energy to warm air for diverse applications, including room heating, drying procedures, or ventilation. The major aim of the current study is investigating the performance of the combined utilization of grooved absorber and triple-flow air channel modification in a SAH using numerical modeling. Accordingly, CFD method has been used to model the heat and flow characteristics inside a parallel-flow v-grooved SAH (PFVSAH), a triple-flow v-grooved SAH (TFVSAH), and a combined-SAH. The experimental and numerical evaluation of PFVSAH was conducted under different climatic conditions and mass flow rates of 0.019 kg/s, 0.015 kg/s, and 0.012 kg/s. Additionally, a numerical comparison was made between PFVSAH, TFVSAH and combined-SAH. According to the numerical results, the calculated temperature differences in a TFVSAH are greater than those in a PFVSAH and less than in a combined-SAH. According to the experimental results, when the mass flow rate is 0.012 kg/s, the PFVSAH shows average thermal and exergy efficiencies of 59.51% and 29.09%, respectively. In PFVSAH, the highest temperature difference between the outlet and the inlet was 28 °C. The recorded values for the top heat loss coefficient (THLC) of the PFVSAH varied between 4.3 and 8.93 W/m2.

Exploring the acoustic potential of 3D printed micro-perforated panels: A comparative analysis

In the present study, the sound absorption performance of inhomogeneous Micro-Perforated Panels (MPPs) with multiple cavities is investigated. Two models, a three-cavity system and a four-cavity system, are proposed and a numerical study is performed using MATLAB. The models are validated through experimental analysis in an impedance tube. The study meticulously varies the geometrical parameters, including pore diameter, thickness of the MPP, perforation ratio, and back-cavity length. It is found that MPPs with a greater number of sub-cavities have a better sound absorption coefficient than two-cavity systems. The results suggest that the back air cavity is predominantly responsible for multiple peaks, ensuring wideband sound absorption. It is also found that smaller perforation ratios for sub-cavities with larger pore diameters improve sound absorption performance in the lower frequency region. The study indicates that a pore diameter of less than 0.5 mm should be used for better sound absorption above the range of 800–850 Hz, and back cavity length has greater control than pore diameter between 850 Hz and 2000 Hz to make the curve smooth with less fluctuation. The findings have significant implications for the design of MPPs for real-world applications.