Sequential Order Research Articles

Assessing the effectiveness of static heuristics for scheduling lumber orders in the sawmilling production process

Although optimization models can be used to plan the production process, in most cases static heuristics, such as earliest due date (E), longest processing time (L), and shortest processing time (S), are used because of their simplicity. This study aims to analyze the production cost of the static heuristics and to determine how this cost relates to the size of the production orders in the sawmilling industry. We set a planning problem with different orders and due dates and solved it using two cost-minimization models to compare their solutions. The first was a planning model (PL) where orders were split up into products demand by period, and the second, a planning scheduling (PS) where the sequence of processing orders based on static heuristics was assumed as known. In the latter, the minimum production cost for each static heuristic was found. In both models, the same resource constraints were assumed. The costs showed no significant changes based on order sizes. However, 0,5 % of orders were delayed using PS-E, and 17 % of orders were delayed using PL. PL was an efficient solution method when changing the orders´ size and when looking for the best static heuristic to process the orders. However, PS-E showed the ability to reduce the backlog close to zero while the PL backlog ratio was 17 %. No penalties were applied to backlogs due to their subjective nature; however, when shortages occurred, the demand was unmet or backlogged with substantial costs. Thus, in case the proposed method is adopted using a conservative backlog cost, a sawmill producing under the cut-to-order environment that produces 300000 m3 /year would reduce backlogged orders by 51000 m3. If the holding lumber cost is 2 $/m3, annual savings would be $408000.

UBAP2L ensures homeostasis of nuclear pore complexes at the intact nuclear envelope.

Assembly of macromolecular complexes at correct cellular sites is crucial for cell function. Nuclear pore complexes (NPCs) are large cylindrical assemblies with eightfold rotational symmetry, built through hierarchical binding of nucleoporins (Nups) forming distinct subcomplexes. Here, we uncover a role of ubiquitin-associated protein 2-like (UBAP2L) in the assembly and stability of properly organized and functional NPCs at the intact nuclear envelope (NE) in human cells. UBAP2L localizes to the nuclear pores and facilitates the formation of the Y-complex, an essential scaffold component of the NPC, and its localization to the NE. UBAP2L promotes the interaction of the Y-complex with POM121 and Nup153, the critical upstream factors in a well-defined sequential order of Nups assembly onto NE during interphase. Timely localization of the cytoplasmic Nup transport factor fragile X-related protein 1 (FXR1) to the NE and its interaction with the Y-complex are likewise dependent on UBAP2L. Thus, this NPC biogenesis mechanism integrates the cytoplasmic and the nuclear NPC assembly signals and ensures efficient nuclear transport, adaptation to nutrient stress, and cellular proliferative capacity, highlighting the importance of NPC homeostasis at the intact NE.

Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents.

Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

Study of the Agricultural Applications of the PageRank Algorithm

As a traditional agricultural country, agriculture is the foundation of China's economic and social development. Therefore, promoting the development of agriculture is a necessary way to realize common prosperity. Applying the PageRank algorithm to agriculture can not only liberate the labor force, but also improve the crop yield to achieve economic optimization and promote social development and progress. By exploring the advantages and disadvantages of the PageRank algorithm, based on the concept of graph theory, different weights are assigned to the links according to the attribute characteristics of the links themselves. Then according to the data validation, experimental analysis, and the results of weight size, match and screen the corresponding web pages, and according to the matching degree and importance of the sequential order, and then collect data. Then the relevant knowledge of graph theory is used to illustrate the crop growth environment and growth factors, and the growth status of the target crops is observed in real-time to optimize the growth conditions at any time. Thus, the optimal growing environment is determined, and the yield of crops is improved to promote economic development.

BDCore: Bidirectional Decoding with Co-graph Representation for Joint Entity and Relation Extraction

Relation extraction has become a crucial step for the automatic construction of Knowledge Graph (KG). Recently, researchers leverage Sequence-to-Sequence (Seq2Seq) models for Joint Entity and Relation Extraction (JERE). Nevertheless, traditional decoding methods entail the generation of the target sequence incrementally from left to right by the decoder, without the ability to revise earlier predictions when errors occur. This limitation becomes evident when decoding errors manifest prior to the current decoding step. Furthermore, the interrelations among triplets originating from the same sentence exhibit a robust correlation, which has been overlooked. In this paper, we propose Bidirectional Decoding with Co-graph representation (BDCore) to address the issues mentioned above. Specifically, we first introduce a backward decoder to decode the target sequence in a reverse order. Then, the forward decoder introduces two attention mechanisms to simultaneously considering the hidden states of the encoder and the backward decoder. Thus, the backward decoding information helps to alleviate the negative impact of the forward decoding errors. Besides, we construct a relation co-occurrence graph (Co-graph) and exploit Graph Convolutional Network (GCN) to capture the relation correlation. The extensive experiments demonstrate the benefits of the proposed bidirectional decoding and co-graph representation for relation extraction. Compared to the previous methods, our approach significantly outperforms the baselines on the NYT benchmark.

Simplified matching pursuits applied to 3D nuclear reactor temperature distribution construction

Autonomous control systems can enhance the economic viability of complex systems such as nuclear microreactors. Advanced forms of these control systems benefit from techniques for high-resolution field data reconstruction from sensor data. Basis projection methods present a useful set of methodologies for nonparametric reconstruction of these field data. In this work, high fidelity multiphysics simulations are used to generate microreactor temperature distributions that are then used to evaluate the viability of a basis projection method which employs a generalized set of basis functions, or dictionaries. Additionally, metrics for evaluating the accuracy of the temperature distribution are presented that are motivated both from the fields of traditional signal processing and statistics. The performance of a method based on matching pursuits is compared to a method that uses the sequential ordering of basis functions. The matching pursuits-based method gives improved performance for highly sparse representations of temperature distributions. Additionally, accuracy is analyzed for multiple temperature distributions which represent different potential reactor operation configurations. Overall, the results from this work should be considered as an upper bound on the performance of basis projection methods which employ generalized basis functions for real time reactor control.

Time-resolved profiling of RNA binding proteins throughout the mRNA life cycle

mRNAs continually change their protein partners throughout their lifetimes, yet our understanding of mRNA-protein complex (mRNP) remodeling is limited by a lack of temporal data. Here, we present time-resolved mRNA interactome data by performing pulse metabolic labeling with photoactivatable ribonucleoside in human cells, UVA crosslinking, poly(A)+ RNA isolation, and mass spectrometry. This longitudinal approach allowed the quantification of over 700 RNA binding proteins (RBPs) across ten time points. Overall, the sequential order of mRNA binding aligns well with known functions, subcellular locations, and molecular interactions. However, we also observed RBPs with unexpected dynamics: the transcription-export (TREX) complex recruited posttranscriptionally after nuclear export factor 1 (NXF1) binding, challenging the current view of transcription-coupled mRNA export, and stress granule proteins prevalent in aged mRNPs, indicating roles in late stages of the mRNA life cycle. To systematically identify mRBPs with unknown functions, we employed machine learning to compare mRNA binding dynamics with Gene Ontology (GO) annotations. Our data can be explored at chronology.rna.snu.ac.kr.

Specific Real-Time PCR Assay Targeting D-loop Gene and Short Amplicon Sequencing for Identification of Monkey Meat in Beef Meatballs

Macaque monkey (Macaca fascicularis) meat (MM) has been reported to be consumed as meatball and soup products in Indonesia. MM is not allowed to be traded in Indonesia and is considered not halal meat; therefore, MM is not allowed to be consumed by Muslim communities. In this study, species-specific primer (SSP) targeting on mitochondrial displacement (D-loop) region coupled with real-time PCR assay was used to identify monkey meat in beef meatballs. The PCR product was also subjected to sequencing in order to ensure the adulteration practice of MM in beef meatballs. The primers were designed and subjected to in silico specificity test using BLAST. The used primers were: forward: 5’-TGACTCCCACCACATCCC-3’ and reverse: 5’-GTGTGGAGCTAGAATATTGAACCG-3’. Real-time PCR assay using SSP targeting on mt-D-loop primers was capable of identifying MM in meatball products, specifically with a detection limit of 0.0078 ng corresponding to 1% MM in beef meatballs. The developed method can be proposed as the standard method for detecting MM in food products intended for halal authentication analysis, provided that DNAs are available in food products.

UV-aging reduces the effects of biodegradable microplastics on soil sulfamethoxazole degradation and sul genes development

In recent years, the biodegradable plastics has extensively used in industry, agriculture, and daily life. Herein, the effects of two biodegradable microplastics (BMPs), poly(butyleneadipate-co-terephthalate) (PBAT) and polyhydroxyalkanoate (PHA), on soil sulfamethoxazole (SMX) degradation and sul genes development were comparatively studied based on the type, dosage, and state. The addition of virgin BMPs significantly increased soil DOC following a sequential order PBAT > PHA and high dose > low dose. Meanwhile virgin PBAT significantly reduced soil pH. In general, the addition of BMPs not only promoted soil SMX degradation but also increased the abundance of sul genes, with an exception that pH reduction in virgin PBAT inhibited the proliferation of sul genes. The driving effects of BMPs on soil microbial diversity following the same order as that on DOC. Specific bacteria stimulated by BMPs, such as Arthrobacter and two genera affiliated with phylum TM7, accounted for the accelerated degradation of SMX. Intriguingly, UV-aging hindered the release of DOC from BMPs and the reduction in pH, mitigated the stimulation of microbial communities, and ultimately reduced the promotion effect of BMPs on SMX degradation and sul genes proliferation. Our results suggest that more attention should be paid to the proliferation risk of ARGs in the environment affected by BMPs and UV-aging can be employed sometimes to reduce this risk.

Virulence genes, resistome and mobilome of Streptococcus suis strains isolated in France.

Streptococcus suis is a leading cause of infection in pigs, causing extensive economic losses. In addition, it can also infect wild fauna, and can be responsible for severe infections in humans. Increasing antimicrobial resistance (AMR) has been described in S. suis worldwide and most of the AMR genes are carried by mobile genetic elements (MGEs). This contributes to their dissemination by horizontal gene transfer. A collection of 102 strains isolated from humans, pigs and wild boars in France was subjected to whole genome sequencing in order to: (i) study their genetic diversity, (ii) evaluate their content in virulence-associated genes, (iii) decipher the mechanisms responsible for their AMR and their association with MGEs, and (iv) study their ability to acquire extracellular DNA by natural transformation. Analysis by hierarchical clustering on principal components identified a few virulence-associated factors that distinguish invasive CC1 strains from the other strains. A plethora of AMR genes (n=217) was found in the genomes. Apart from the frequently reported erm(B) and tet(O) genes, more recently described AMR genes were identified [vga(F)/sprA, vat(D)]. Modifications in PBPs/MraY and GyrA/ParC were detected in the penicillin- and fluoroquinolone-resistant isolates respectively. New AMR gene-MGE associations were detected. The majority of the strains have the full set of genes required for competence, i.e for the acquisition of extracellular DNA (that could carry AMR genes) by natural transformation. Hence the risk of dissemination of these AMR genes should not be neglected.

Memory-Based Self-Ordering FFT for Efficient I/O Scheduling

A complex-valued self-ordering radix-2 memory-based Fast Fourier Transform (FFT) architecture suitable for low end Field Programmable Gate Arrays (FPGA) is presented. Employing a self-ordering algorithm within the data flow, both input and output data are kept in normal sequential order, not in digit-reversed-order. This way, with an appropriate scheduling, last stage of the FFT and I/O operations are performed in parallel with no wait states. Self-ordering FFT algorithms are generally designed for software implementations. We designed and implemented one on FPGA (hardware), showing that considerable number of clock cycle savings can be obtained compared to unordered FFT counterparts. The approach is implemented on various FPGAs. The results are compared with similar radix-2 architectures in terms of required clock cycles and resource usage, confirming the advantage of the approach.

Immobilization mechanisms of Sr(II), Ni(II), and Cd(II) on glomalin-related soil protein in mangrove sediments at the microscopic scale

Glomalin-related soil protein (GRSP) is a significant component in the sequestration of heavy metal in soils, but its mechanisms for metal adsorption are poorly known. This study combined spectroscopic data with molecular docking simulations to reveal metal adsorption onto GRSP's surface functional groups at the molecular level. The EXAFS combined with FTIR and XPS analyses indicated that the adsorption of Cd(II), Sr(II), and Ni(II) by GRSP occurred mainly through the coordination of –OH and –COOH groups with the metal. The –COOH and –OH groups bound to the metal as electron donors and the electron density of the oxygen atom decreased, suggesting that electrostatic attraction might be involved in the adsorption process. Two-dimensional correlation spectroscopy revealed that preferential adsorption occurred on GRSP for the metal in sequential order of –COOH groups followed by –OH groups. The presence of the Ni–C shell in the Ni EXAFS spectrum suggested that Ni formed organometallic complexes with the GRSP surface. However, Sr–C and Cd–C were absent in the second shell of the Sr and Cd spectra, which was attributed to the adsorption of Sr and Cd ions with large hydration ion radius by GRSP to form outer-sphere complexes. Through molecular docking simulations, negatively charged residues such as ASP151 and ASP472 in GRSP were found to provide electrostatic attraction and ligand combination for the metal adsorption, which was consistent with the spectroscopic analyses. Overall, these findings provided new insights into the interaction mechanisms between GRSP and metals, which will help deepen our understanding of the ecological functions of GRSP in metal sequestration.

Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccine regimen plus Ad26.ZEBOV booster at 1 year versus 2 years in health-care and front-line workers in the Democratic Republic of the Congo: secondary and exploratory outcomes of an open-label, randomised, phase 2 trial

Health-care providers and front-line workers are at risk of contracting Ebola virus disease during an Ebola virus outbreak and consequently of becoming drivers of the disease. We aimed to assess the long-term immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen and the safety of and immune memory response to an Ad26.ZEBOV booster vaccination at 1 year or 2 years after the first dose in this at-risk population. This open-label, single-centre, randomised, phase 2 trial was conducted at one study site within a hospital in Boende, Democratic Republic of the Congo. Adult health-care providers and front-line workers, excluding those with a known history of Ebola virus disease, were vaccinated with a two-dose heterologous regimen administered at a 56-day interval via a 0·5 mL intramuscular injection in the deltoid muscle, comprising Ad26.ZEBOV as the first dose and MVA-BN-Filo as the second dose. After the initial vaccination on day 1, participants were randomly assigned (1:1) via randomisation envelopes, opened in a sequential order, to receive an Ad26.ZEBOV booster vaccination at 1 year (group 1) or 2 years (group 2) after the first dose. We present the secondary and exploratory objectives of the trial-results of the primary objective have been published elsewhere. We measured immunogenicity at six timepoints per group as geometric mean concentrations (GMCs) of Ebola virus glycoprotein-specific IgG binding antibodies, using the Filovirus Animal Non-Clinical Group ELISA. We assessed serious adverse events occurring up to 6 months after the last dose and local and systemic solicited and unsolicited adverse events reported for 7 days after the booster vaccination. Antibody responses were analysed per protocol, serious adverse events per full analysis set (FAS), and adverse events for all boosted FAS participants. This trial is registered as completed on ClinicalTrials.gov (NCT04186000). Between Dec 18, 2019, and Feb 8, 2020, 699 health-care providers and front-line workers were enrolled and 698 were randomly assigned (350 to group 1 and 348 to group 2 [FAS]); 534 (77%) participants were male and 164 (23%) were female. 319 in group 1 and 317 in group 2 received the booster. 29 (8%) in group 1 and 26 (7%) in group 2 did not complete the study, mostly due to loss to follow-up or moving out of the study area. In both groups, injection-site pain or tenderness (87 [27%] of 319 group 1 participants vs 90 [28%] of 317 group 2 participants) and headache (91 [29%] vs 93 [29%]) were the most common solicited adverse events related to the investigational product. One participant (in group 2) had a related serious adverse event after booster vaccination (fever of ≥40·0°C). Before booster vaccination, Ebola virus glycoprotein-specific IgG binding antibody GMCs were 279·9 ELISA units (EU) per mL (95% CI 250·6-312·7) in 314 group 1 participants (1 year after first dose) and 274·6 EU/mL (242·1-311·5) in 310 group 2 participants (2 years after first dose). These values were 5·2 times higher in group 1 and 4·9 times higher in group 2 than before vaccination on day 1. 7 days after booster vaccination, these values increased to 10 781·6 EU/mL (9354·4-12 426·4) for group 1 and 10 746·9 EU/mL (9208·7-12 542·0) for group 2, which were approximately 39 times higher than before booster vaccination in both groups. 1 year after booster vaccination in 299 group 1 participants, a GMC that was 7·6-times higher than before booster vaccination was still observed (2133·1 EU/mL [1827·7-2489·7]). Overall, the vaccine regimen and booster dose were well tolerated. A similar and robust humoral immune response was observed for participants boosted 1 year and 2 years after the first dose, supporting the use of the regimen and flexibility of booster dose administration for prophylactic vaccination in at-risk populations. Innovative Medicines Initiative 2 Joint Undertaking and Coalition for Epidemic Preparedness Innovations.

DiPri : Distance-based Seed Prioritization for Greybox Fuzzing

Greybox fuzzing is a powerful testing technique. Given a set of initial seeds, greybox fuzzing continuously generates new test inputs to execute the program under test and drives executions with code coverage as feedback. Seed prioritization is an important step of greybox fuzzing that helps greybox fuzzing choose promising seeds for input generation in priority. However, mainstream greybox fuzzers like AFL++ and Zest tend to neglect the importance of seed prioritization. They may pick seeds plainly according to the sequential order of the seeds being queued or an order produced with a random-based approach, which may consequently degrade their performance in exploring code and exposing bugs. In the meantime, existing state-of-the-art techniques like Alphuzz and K-Scheduler adopt complex strategies to schedule seeds. Although powerful, such strategies also inevitably incur great overhead and will reduce the scalability of the proposed technique. In this paper, we propose a novel distance-based seed prioritization approach named DiPri to facilitate greybox fuzzing. Specifically, DiPri evaluates the queued seeds according to seed distances and chooses the outlier ones, which are the farthest from the others, in priority to improve the probabilities of discovering previously unexplored code regions. To make a profound evaluation of DiPri , we prototype DiPri on AFL++ and conduct large-scale experiments with four baselines and 24 C/C++ fuzz targets, where eight are from widely adopted real-world projects, eight are from the coverage-based benchmark FuzzBench, and eight are from the bug-based benchmark Magma. The results obtained through a fuzzing exceeding 50,000 CPU hours suggest that DiPri can (1) insignificantly influence the host fuzzer’s capability of code coverage by slightly improving the branch coverage on the eight targets from real-world projects and slightly reducing the branch coverage on the eight targets from FuzzBench, and (2) improve the host fuzzer’s capability of finding bugs by triggering five more Magma bugs. Besides the evaluation with the three C/C++ benchmarks, we integrate DiPri into the Java fuzzer Zest and conduct experiments on a Java benchmark composed of five real-world programs for more than 8,000 CPU hours to empirically study the scalability of DiPri . The results with the Java benchmark demonstrate that DiPri is pretty scalable and can help the host fuzzer find bugs more consistently.

The content of patients' emotional expressions during follow-up consultations for chronic diseases.

In this article, we seek to extract the themes that patients share when they express negative emotions in the context of follow-up consultation of chronic illness. We are mainly interested in patients with chronic illnesses, as these pathologies have a significant emotional overload leading to a significant deterioration of the patient's quality of life. Our corpus included audio recordings of 12 chronic disease follow-up consultations conducted by physicians practicing in neurology, nutrition, internal medicine and infectiology. The 12 patients participating suffer from various chronic diseases: Parkinson's, HIV, diabetes, etc. We performed thematic content analyses on the emotional sequences in order to extract the themes underlying these emotional expressions. The 10 themes we have extracted are related to physical aspects, psychological aspects, the healthcare system and/or the healthcare provider, prognostic elements, social life, family life, aspects of professional life, issues of daily life, treatments and finally, aspects related to objectives and disease progress. Our results show that follow-up consultations for chronic illnesses are consultations during which patients express emotions for different purposes. These emotional expressions concern particular themes that are not found in other forms of medical consultations. We will compare these results in the discussion part of this article.

Estimation with extended sequential order statistics: A link function approach

AbstractThe model of extended sequential order statistics (ESOS) comprises of two valuable characteristics making the model powerful when modelling multi‐component systems. First, components can be assumed to be heterogeneous and second, component lifetime distributions can change upon failure of other components. This degree of flexibility comes at the cost of a large number of parameters. The exact number depends on the system size and the observation depth and can quickly exceed the number of observations available. Consequently, the model would benefit from a reduction in the dimension of the parameter space to make it more readily applicable to real‐world problems. In this article, we introduce link functions to the ESOS model to reduce the dimension of the parameter space while retaining the flexibility of the model. These functions model the relation between model parameters of a component across levels. By construction the proposed ‘link estimates’ conveniently yield ordered model estimates. We demonstrate how those ordered estimates lead to better results compared to their unordered counterparts, particularly when sample sizes are small.

Are radiographs overutilized in pediatric orthopaedic emergency room care?

BackgroundIt is estimated that $12.8 billion to $28.6 billion is wasted annually on unnecessary imaging studies and treatment in the United States. This is especially important to the pediatric population, which is unable to make decisions for themselves and vulnerable to radiation exposure. We hypothesized that a significant number of unnecessary radiographs are performed in the pediatric emergency department, leading to excessive time, cost, and radiation exposure to pediatric patients. MethodsWe retrospectively reviewed 406 patients who were evaluated in a pediatric emergency department (ED) for possible fracture at a single institution during the 2020 calendar year. Records were reviewed for demographics, history and physical exams, as well as the sequential order that radiographs were performed. All radiographs were evaluated by the senior author to determine if they resulted in a change in management. All data was recorded and analyzed by the senior author and our statistician using Student’s t-test. Results406 patient encounters were included. 2807 radiographs were deemed unnecessary, with an average of 6.9 radiographs per patient. $454,734 were spent on radiographs that ultimately did not change management. A total of 216 hours and 43 minutes were spent in the x-ray suite alone, for an average of 32 minutes per patient. The estimated amount of radiation exposure that did not change management was potentially as high as 69 millirem per patient. ConclusionsThere is an excessive amount of monetary waste, radiation exposure, and encounter time spent in pediatric orthopedic patients in the ED. There are several potential strategies to alleviate this problem, which we hope can be taken into consideration to help address this widespread healthcare issue.

Sequencing heterogeneous orders in Bucket Brigade order-picking lines

Bucket Brigade (BB) is a common approach for dynamic work-sharing in order-picking lines. Differently from typical analysis, we assume heterogeneous orders, which creates blockages and reduced efficiency. The problem is how to sequence entering orders with the aim of minimizing this potential inefficiency. The proposed framework models order-picking lines with workload distributed along the picking aisle according to the number of items to be picked in each pick face. We propose a measure for quantifying the generated blockage inefficiency (BI) as a proxy for the makespan. As the BI depends on the sequence of orders, several strategies are proposed to identify sequences with no-blockage or with minimal BI. We provide several practical sequencing policies. Sequencing based on no-blockage notions and steady-state hand-off positions is proved useful, and no-blockage is implied by first-order distributional dominance sequencing. Traveling salesman problem and Hamiltonian path modeling is proposed as an exact computational method of item-specific sequences with minimal or no blockage in a strong sense. A simple policy ensures low BI for large sets of orders, for which we show an asymptotic result: the BI of any efficient sequence approaches zero in the limit as the sequence length tends to infinity. In general, sequencing orders is a practically relevant and effective managerial strategy, as it typically substantially reduces the BI and often eliminates it entirely.

Epigallocatechin gallate suppresses mitotic clonal expansion and adipogenic differentiation of preadipocytes through impeding JAK2/STAT3-mediated transcriptional cascades

BackgroundMitotic clonal expansion (MCE) is a prerequisite for preadipocyte differentiation and adipogenesis. Epigallocatechin gallate (EGCG) has been shown to inhibit preadipocyte differentiation. However, the exact molecular mechanisms are still elusive. PurposeThis study investigated whether EGCG could inhibit adipogenesis and lipid accumulation by regulating the cell cycle in the MCE phase of adipogenesis and its underlying molecular mechanisms. Method3T3-L1 preadipocytes were induced to differentiate by a differentiation cocktail (DMI) and were treated with EGCG (25–100 μM) for 9, 18, and 24 h to examine the effect on MCE, or eight days to examine the effect on terminal differentiation. C57BL/6 mice were fed a high-fat diet (HFD) for three months to induce obesity and were given EGCG (50 or 100 mg/kg) daily by gavage. ResultsWe showed that EGCG significantly inhibited terminal adipogenesis and lipid accumulation in 3T3-L1 cells and decreased expressions of PPARγ, C/EBPα, and FASN. Notably, at the MCE phase, EGCG regulated the cell cycle in sequential order, induced G0/G1 arrest at 18 h, and inhibited the G2/M phase at 24 h upon DMI treatment. Meanwhile, EGCG regulated the expressions of cell cycle regulators (cyclin D1, cyclin E1, CDK4, CDK6, cyclin B1, cyclin B2, p16, and p27), and decreased C/EBPβ, PPARγ, and C/EBPα expressions at MCE. Mechanistic studies using STAT3 agonist Colivelin and antagonist C188–9 revealed that EGCG-induced cell cycle arrest in the MCE phase and terminal adipocyte differentiation was mediated by the inhibition of JAK2/STAT3 signaling cascades and STAT3 (Tyr705) nuclear translocation. Furthermore, EGCG significantly protected mice from HFD-induced obesity, reduced body weight and lipid accumulations in adipose tissues, reduced hyperlipidemia and leptin levels, and improved glucose intolerance and insulin sensitivity. Moreover, RNA sequencing (RNA-seq) analysis showed that the cell cycle changes in epididymal white adipose tissue (eWAT) were significantly enriched upon EGCG treatment. We further verified that EGCG treatment significantly reduced expressions of adipogenic factors, cell cycle regulators, and p-STAT3 in eWAT. ConclusionEGCG inhibits MCE, resulting in the inhibition of early and terminal adipocyte differentiation and lipid accumulation, which were mediated by inhibiting p-STAT3 nucleus translocation and activation.

Tilt Angle Effect on Natural Convection Heat Transfer from an Inclined Array of Square Cylinders

Natural convection heat transfer from an inclined array of square cross-section cylinders is experimentally studied. Three cylinders of side length D = 0.02 m and 1 m length are used to form the inclined array. Three-cylinder axis inclination angles to the horizontal of 30°, 45°, and 60° are considered. The cylinders are heated using an internal heating element of constant heat flux. Surface temperatures are measured along the three surfaces of each cylinder; upper, lower, and the front side at nine points spaced evenly by 10 cm. The local circumference average temperature is obtained at each point. Four center-to-center distances to side length S/D = 1.25, 1.75, 2.25, and 2.75 are used. Local Nusselt numbers and the modified Rayleigh numbers are obtained for each cylinder at each circumference averaged temperature point. Results show that the lower cylinder heat transfer is least affected by the array compared to that of its single one followed by the middle and the upper cylinder for all S/D and the inclination angles used. The Nusselt number is degraded from that of the single cylinder at a small S/D and that degradation decreases as the S/D increases for all angles. It is observed that the Nusselt number enhances at the small cylinder axis tilt angle of 30°, followed by 45°, and 60°, especially at high modified Rayleigh numbers. New novel general empirical correlations for Nusselt numbers are obtained for each S/D using the cylinder axis tilt angle, the modified Rayleigh numbers, and the cylinder number in the array as parameters. A new general correlation is obtained for the array using the modified Rayleigh number, S/D, the cylinder axis tilt angle, and the cylinder sequential order number as parameters. These new correlations will help any engineering applications using such a configuration of the array.