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1.
Transl Stroke Res ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32036560

RESUMO

CD8+ T cells are recognized as key players in exacerbation of ischemic stroke; however, the underlying mechanism in modulating the function of CD8+ T cells has not been completely elucidated. Here, we uncovered that FasL enhanced the cytotoxicity of CD8+ T cells to neurons after ischemic stroke. Inactivation of FasL specific on CD8+ T cells protected against brain damage and neuron loss. Proteomic analysis identified that PDPK1 functioned downstream of FasL signaling and inhibition of PDPK1 effectively reduced cytotoxicity of CD8+ T cells and improved ischemic neurological deficits. Taken together, these results highlight an intrinsic FasL-PDPK1 pathway regulating the cytotoxicity of CD8+ T cells in ischemic stroke.

2.
Sci Adv ; 6(4): eaay8514, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010790

RESUMO

Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol-based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders. Systemically administered PEGOL-60 crosses impaired CNS barriers and specifically targets activated microglia/macrophages at the injured site in diverse animal models for cerebral palsy, glioblastoma, and age-related macular degeneration, demonstrating its potential to overcome impaired blood-brain, blood-tumor-brain, and blood-retinal barriers and target key cells in the CNS. PEGOL-60 also exhibits powerful intrinsic anti-oxidant and anti-inflammatory effects in inflamed microglia in vitro. Therefore, PEGOL-60 is an effective vehicle to specifically deliver therapies to sites of CNS injury for enhanced therapeutic outcomes in a range of neuroinflammatory diseases.

3.
Am J Sports Med ; : 363546519900158, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32027514

RESUMO

BACKGROUND: Anterior tibial subluxation (ATS) in extension after anterior cruciate ligament (ACL) injury highlights an increased anterior position of the tibia relative to the femur. Recent studies demonstrated that subluxation is sometimes irreducible and the normal tibiofemoral relationship is not restored by ACL reconstruction (ACLR), which raises concerns regarding clinical outcomes after ACLR. HYPOTHESIS: Excessive preoperative ATS in extension is associated with inferior knee stability after anatomic ACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: From March 2016 to January 2017, a total of 487 consecutive patients with clinically diagnosed noncontact ACL injuries who underwent primary anatomic ACLR were retrospectively analyzed. Of these patients, 430 met the criteria for inclusion in this study. Anterior subluxation of the lateral and medial compartments (ASLC and ASMC) in extension relative to the femoral condyles was measured on preoperative magnetic resonance imaging. Twenty patients (study group) who demonstrated excessive (>10 mm) ASLC and ASMC in extension were matched 1:2 to 40 participants (control group) who showed minimal or no (<3 mm) ASLC and ASMC in extension. The amount of ASLC and ASMC in extension relative to the femoral condyles at 2 years postoperatively was the primary outcome. Moreover, the Lysholm score, IKDC grade (International Knee Documentation Committee), and stability assessments (pivot-shift test and KT-1000 arthrometer side-to-side difference) were evaluated preoperatively and at the last follow-up visit. RESULTS: The preoperative mean ASLC and ASMC in extension of the study group were both significantly larger than those of the control group (study group vs control group: ASLC, 13.5 mm vs 1.2 mm; ASMC, 12.4 mm vs 1.0 mm; P < .05). Moreover, patients in the study group showed significantly larger posterior tibial slope than the patients in the control group (17.8°± 2.5° vs 9.5°± 1.5°; P < .05). At the final follow-up visit, the mean ASLC and ASMC of the study group were 8.1 mm and 7.3 mm, which were significantly larger than those of the control group (ASLC, 0.9 mm; ASMC, 0.7 mm; P < .05). In addition, the study group showed inferior knee stability when compared with the control group in terms of both the pivot-shift test (study group vs control group: 2 grade 2, 10 grade 1, and 8 grade 0 vs 1 grade 1 and 39 grade 0; P < .05) and the KT-1000 arthrometer side-to-side difference (study group vs control group: 4.4 ± 1.2 mm vs 1.5 ± 0.6 mm; P < .05). Furthermore, the study group showed significantly lower mean Lysholm score (study group vs control group: 80.3 ± 6.3 vs 93.3 ± 4.3, P < .05) and IKDC grading results (study group vs control group: 3 grade C, 16 grade B, and 1 grade A vs 3 grade B and 37 grade A; P < .05) as compared with the control group. CONCLUSION: In this short-term study, the excessive (>10 mm) preoperative ATS in extension after ACL injury was associated with inferior knee stability after anatomic ACLR.

4.
Nanoscale ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016234

RESUMO

Self-assembled Mn0.06Ge0.94 quantum dots (QDs) on a Si substrate or GexSi1-x virtual substrate (VS) were grown by molecular beam epitaxy. The GexSi1-x VS of different thicknesses and Ge compositions x were utilized to modulate the ferromagnetic properties of the above QDs. The MnGe QDs on GexSi1-x VS show a significantly enhanced ferromagnetism with a Curie temperature above 220 K. On the basis of the microstructural and magnetization results, the ferromagnetic properties of the QDs on GexSi1-x VS are believed to come from the intrinsic MnGe ferromagnetic phase rather than any intermetallic ferromagnetic compounds of Mn and Ge. At the same time, we found that by increasing the Ge composition x of GexSi1-x VS, the ferromagnetism of QDs grown on VS will markedly increase due to the improvements of hole concentration and Ge composition inside the QDs. These results are fundamentally important in the understanding and especially in the realization of high Curie temperature MnGe diluted magnetic semiconductors.

5.
Phytomedicine ; 68: 153172, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-32004989

RESUMO

BACKGROUND: Aberrant activation of STAT3 is frequently encountered and promotes survival, cellular proliferation, migration, invasion and angiogenesis in tumor cell. Convallatoxin, triterpenoid ingredient, exhibits anticancer pharmacological properties. PURPOSE: In this work, we investigated the anticancer potential of convallatoxin and explored whether convallatoxin mediates its effect through interference with the STAT3 activation in colorectal cancer cells. METHODS: In vitro, the underlying mechanisms of convallatoxin at inhibiting STAT3 activation were investigated by homology modeling and molecular docking, luciferase reporter assay, MTT assay, RT-PCR, Western blotting and immunofluorescence assays. Changes in cellular proliferation, apoptosis, migration, invasion and angiogenesis were analyzed by EdU labeling assay, colony formation assay, flow cytometry assay, wound-healing assay, matrigel transwell invasion assay and tube formation assays. And in vivo, antitumor activity of convallatoxin was assessed in a murine xenograft model of HCT116 cells. RESULTS: Convallatoxin decreased the viability of colorectal cancer lines. Moreover, convallatoxin reduced the P-STAT3 (T705) via the JAK1, JAK2, and Src pathways and inhibited serine-727 phosphorylation of STAT3 via the PI3K-AKT-mTOR-STAT3 pathways in colorectal cancer cells. Interestingly, we discovered the crosstalk between mTOR and JAK2 in mTOR/STAT3 and JAK/STAT3 pathways, which collaboratively regulated STAT3 activation and convallatoxin play a role in it. Convallatoxin also downregulated the expression of target genes involved cell survival (e.g., Survivin, Bcl-xl, Bcl-2), proliferation (e.g., Cyclin D1), metastasis (e.g., MMP-9), and angiogenesis (e.g., VEGF). Indeed, we found that convallatoxin inhibited tube formation, migration, and invasion of endothelial cells, and inhibited the proliferation. Finally, in vivo observations were confirmed by showing antitumor activity of convallatoxin in a murine xenograft model. CONCLUSION: The result of the current study show that convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer cells and indicate that convallatoxin could be a valuable candidate for the development of colorectal cancer therapeutic.

6.
Medicine (Baltimore) ; 99(7): e19066, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049807

RESUMO

Previous work suggests that the long noncoding RNA HCC associated long non-coding RNA (HANR) is associated with hepatocellular carcinoma (HCC) progression, but its significance in the context of colorectal cancer (CRC) remains to be determined. Therefore, in this study we assessed the prognostic and diagnostic value of HANR in patients suffering from CRC.The HANR expression in 165 pairs of CRC cancer and adjacent non-cancerous prostate tissues was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Student t test was conducted for intergroup comparison. Pearson correlation test was used for correlation analysis. Survival curves were carried out by the Kaplan-Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affected the prognosis of CRC patients.In this study, levels of HANR were significantly higher in CRC tumor samples relative to adjacent normal tissue samples (P < .001). A ROC analysis suggested HANR expression could be reliably used to differentiate between normal and CRC tumor tissue. In addition, elevated HANR expression was positively correlated with more advanced and aggressive CRC features, such as a larger tumor size (P = .003), increased invasion depth (P = .012), and more advanced TNM stage (P = .011). Survival analyses revealed that elevated HANR expression was correlated with worse overall survival (P = .002) and disease-free survival (P = .003). A multivariate analysis further confirmed the relevance of HANR as an independent predictor of CRC patient outcomes.In summary, these results indicate that the lncRNA HANR is a promising prognostic indicator in CRC patients.

7.
Inorg Chem ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017542

RESUMO

The directing effect of coordinating ligands in the formation of uranium molecular complexes has been well established, but the role of counterions in metal-ligand interactions remains ambiguous and requires further investigation. In this work, we describe the targeted isolation, through the choice of alkali-metal ions, of a family of tetravalent uranium sulfates, showing the influence of the overall topology and, unexpectedly, the UIV nuclearity upon the inclusion of such countercations. Analyses of the structures of uranium(IV) oxo/hydroxosulfate oligomeric species isolated from consistent synthetic conditions reveal that the incorporation of Na+ and Rb+ promotes the crystallization of 0D discrete clusters with a hexanuclear [U6O4(OH)4(H2O)4]12+ core, whereas the larger Cs+ ion allows for the isolation of a 2D-layered oligomer with a less condensed trinuclear [U3(O)]10+ center. This finding expands the prevalent view that counterions play an innocent role in molecular complex synthesis, affecting only the overall packing but not the local oligomerization. Interestingly, trends in nuclearity appear to correlate with the hydration enthalpies of alkali-metal cations, such that the alkali-metal cations with larger hydration enthalpies correspond to more hydrated complexes and cluster cores. These findings afford new insights into the mechanism of nucleation of UIV, and they also open a new path for the rational design and synthesis of targeted molecular complexes.

8.
J Am Chem Soc ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32053353

RESUMO

Topological defects, such as vortices and skyrmions, provide a wealth of splendid possibilities to new nanoscale devices because of their marvelous electronic, magnetic, and mechanical behaviors. Recently, great advances have been made in the study of ferroelectric vortex in conventional perovskite oxides, such as BaTiO3, and BiFeO3. Despite extensive interest, however, no intriguing ferroelectric vortex structures have yet been found in organic-inorganic hybrid perovskites (OIHPs), which are desirable for their mechanical flexibility, ease of fabrication, and low acoustical impedance. We observed the robust vortex-antivortex topological configurations in a two-dimensional (2D) layered OIHP ferroelectric (4,4-DFPD)2PbI4 (4,4-DFPD is 4,4-difluoropiperidinium). This provides future directions to the study of perovskites, and makes it a promising alternative for nanoscale ferroelectric devices in medical, micromechanical, and biomechani-cal applications.

11.
Sci Rep ; 10(1): 2306, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041987

RESUMO

Azadirachtin exhibits excellent bioactivities against several hundred arthropods. However, current knowlege of its biochemical effect on B. dorsalis larvae is not deep enough. In this study, integrated LC-MS and GC-MS-based untargeted metabolomics were used to analyze the changes of endogenous metabolites and the biochemical effects of azadirachtin on B. dorsalis larvae. Azadirachtin has excellent bioactivities against B. dorsalis larvae in this study, leading to a longer developmental duration, lower survival rate, and low pupa weight. The effect of azadirachtin was investigated on a total of 22 and 13 differentially abundant metabolites in the LC-MS and GC-MS-based metabolomics results, are selected respectively. Pathway analysis indicated that 14 differentially enriched metabolic pathways, including seven influential pathways, are worthy of attention. Further integrated key metabolic pathway analysis showed that histidine metabolism, D-glutamine and D-glutamate metabolism, biotin metabolism, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and alanine, aspartate and glutamate metabolism in B. dorsalis larvae are significantly relevant pathways affected by azadirachtin. Although extrapolating the bioactivity results in this study to the practical project of B. dorsalis pest management in the field has limitations, it was found that azadirachtin has a significant effect on the primary metabolism of B. dorsalis larvae.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32013027

RESUMO

Remediation of soil heavy metal by biochar has been extensively studied. However, few studies focused on the role of biochar on the co-immobilization of cadmium (Cd(II)) and arsenate (As(V)) and related soil nutrient availability. Remediation tests were conducted with three types of pristine and ferric trichloride (FeCl3) modified biochar (rice, wheat, and corn straw biochar) in Cd-As co-contaminated soil, with application rates of 1, 5, and 10% (w/w) and the incubation of 1, 7, 10, and 15 days. Using TCLP (Toxicity Characteristic Leaching Procedure) method, 10% of FeCl3 modified corn-straw derived biochar (FCB) had the highest immobilization efficiency of Cd(II) (63.21%) and As(V) (95.10%) after 10 days of the incubation. Iron-modified biochar immobilized higher fractions of water-soluble (F1) and surface-absorbed (F2) metal fractions than pristine biochar. For FCB amendment, Cd was mostly presented in the organic matter (OM) and sulfides associated (F4) and residual (F5) fractions (88.52%), as was found in the Fe-Al (oxides and hydroxides) (F3), F4, and F5 fractions (75.87%). FCB amendment increased soil pH values and available iron contents (p < 0.05), while no changes in soil available phosphorus content (p > 0.05). This study showed that FCB application reduces the environmental mobility of metals in Cd-As contaminated soil, while it also increases soil pH and available nutrient mobility, improving soil environmental quality and reducing remediation costs.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32052539

RESUMO

Reported here is a molecular-Lego synthetic strategy for macrocycles with functional skeletons, involving one-pot and high-yielding condensation between bis(2,4-dimethoxyphenyl)arene monomers and paraformaldehyde. By changing the blocks, variously functional units (naphthalene, pyrene, anthraquinone, porphyrin, et. al.) can be conveniently introduced into the backbone of macrocycles. Interestingly, the macrocyclization can be tuned by the geometrical configuration of monomeric blocks. Linear (180 o ) monomer yield cyclic trimers and pentamers, while V-shaped (120 o , 90 o and 60 o ) monomers tend to form dimers. More significantly, even heterogeneous macrocycles are obtained in moderate yield by co-oligomerization of different monomers. This series of macrocycles have the potential to be considerably prosperous in the near future.

14.
Neuropeptides ; : 102023, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-32005500

RESUMO

Cocaine-regulated and amphetamine-regulated transcript (CART) is a neuropeptide with reported neuroprotective effects in ischemic cerebral injury. However, its mechanism has not yet been elucidated. Herein, we investigated the role and mechanism of CART in synaptic plasticity in neurons after ischemic cerebral stroke. We found that the survival rate of the oxygen-glucose deprivation (OGD) neurons was increased after CART treatment. Moreover, CART treatment significantly attenuated ischemia-induced neuronal synaptic damage and increased synaptophysin expression. In addition, the number of presynaptic vesicles was increased and the postsynaptic density (PSD) was thickened after CART treatment. Mechanistically, CART treatment enhanced the expression of Arc mRNA in a cAMP response element binding protein (CREB) dependent manner in OGD neurons, and blockade of CREB by KG-501 eliminated the protective effect of CART. Collectively, CART protected the synaptic structure in neurons after ischemic cerebral injury by increasing the Arc expression via upregulating p-CREB.

15.
Mol Pharm ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32058727

RESUMO

Chemotherapy still accounts for a large proportion in the treatments of tumors, but the drug resistance and side effects caused by long-term chemotherapy should not be underestimated. In this work, the drug combination strategy has been widely developed to overcome the side effects brought by the use of single drugs and improve the therapeutic effect. However, in clinical applications, co-delivery of drugs is very difficult, and different in vivo kinetics due to different drug properties will lead to a decrease in efficacy. Thus, the design of novel anti-tumor therapeutic agents, including new platinum agents represent an area in need of urgent attention. Our investigation implies a promising strategy for the design of a platinum prodrug to enhance the treatment of breast cancer. Dual-drug delivery nanoparticle was developed for enhanced treatment of breast cancer based on two-into-one co-delivery strategy. Through the synergistic effect of released cisplatin hydrate and tolfenamic acid (COX-2 inhibitor) from the coordination prodrug, tumor growth is significantly suppressed, and survival time is greatly extended in breast tumor-bearing mice.

16.
Am J Sports Med ; : 363546520902150, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32058797

RESUMO

BACKGROUND: The lateral meniscus posterior root (LMPR) lesion further decreases dynamic knee stability after anterior cruciate ligament (ACL) injury owing to the loss of the "wedge effect" maintained by the posterior horn of the lateral meniscus. However, the effect of LMPR lesions on the static tibiofemoral relationship in extension after ACL injuries is not determined. PURPOSE: To (1) determine the effect of LMPR lesions on anterior tibial subluxation of the lateral compartment (ATSLC) in extension in patients with ACL injuries and to (2) identify the LMPR-related factors associated with excessive ATSLC in extension. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between January 2015 and December 2017, 405 consecutive patients with diagnosed ACL injuries who underwent primary ACL reconstructions were retrospectively reviewed. Among them, 45 patients with combined ACL injuries and LMPR lesions (ACL+LMPR group) and 51 patients with isolated ACL injuries (ACL group) were identified. Values of ATSLC in extension were measured on preoperative supine magnetic resonance imaging and classified into high grade (≥6 mm) and low grade (<6 mm). The mean ATSLC in extension and the proportion of patients with high-grade ATSLC in extension were compared between the groups by univariate analysis. In the ACL+LMPR group, predictors of high-grade ATSLC in extension-including age, sex, body mass index, affected side, cause of injury, period from injury (<12 or ≥12 weeks), LMPR lesion pattern (radial tear or root avulsion), and meniscofemoral ligament integrity (intact or impaired)-were assessed by univariate analysis and multivariate logistic regression analysis. RESULTS: The mean ATSLC in extension in the ACL+LMPR group was significantly greater than that in the ACL group (5.6 mm vs 3.1 mm; P = .001). The proportion of patients with high-grade ATSLC in extension in the ACL+LMPR group was also significantly larger than that in the ACL group (44.4% vs 15.7%; P = .002). In addition, the root avulsion (instead of radial tear) (odds ratio, 28.750; 95% CI, 2.344-352.549; P = .009) and the period from injury ≥12 weeks (odds ratio, 17.095; 95% CI, 1.207-242.101; P = .036) were determined to be the 2 independent predictors of high-grade ATSLC in extension. However, age, sex, body mass index, affected side, cause of injury, and meniscofemoral ligament integrity were not. CONCLUSION: After ACL injuries, concomitant LMPR lesion further increased ATSLC in extension. Chronic LMPR avulsion was associated with high-grade ATSLC in extension.

17.
Nat Cell Biol ; 22(2): 167-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029896

RESUMO

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

18.
Mol Med Rep ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32016481

RESUMO

The relationship between osteoblasts and angiogenesis is vital for bone regeneration, especially mandibular and maxillary bones. Transforming growth factor ß1 (TGF­ß1) and vascular endothelial growth factor (VEGF) are closely related to angiogenesis; however, the regulatory mechanism between them remains unknown. The present study aimed to reveal this mechanism to provide novel insight for development of potential therapeutic opportunities. Western blotting and reverse transcription­quantitative PCR was used to assess the protein and mRNA expression levels in MC3T3­E1 preosteoblast cells and HUVECs, ELISAs were used to detect the expression levels of secreted VEGF, MTT assays were used to assess the viability of the cells, migratory ability was assessed using Transwell assays, angiogenesis assays were used to analyze the formation of blood vessels, and TGF­ß1 regulation was confirmed using a dual­luciferase reporter assay. The overexpression of specificity protein 1 (SP1) or TGF­ß1 increased VEGF expression levels and secretion, and promoted angiogenesis of co­cultured HUVECs. SP1 also promoted SMAD2 phosphorylation. These effects of SP1 were all reversed by the TGF­ß1 inhibitor. The VEGF inhibitor bevacizumab also reduced the SP1/TGF­ß1/SMAD2 pathway­induced angiogenesis of preosteoblasts. In conclusion, it was demonstrated that SP1 promoted TGF­ß1 expression, activated the SMAD2 pathway and induced VEGF secretion, which may enhance angiogenic processes in preosteoblasts.

19.
IEEE Trans Cybern ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031961

RESUMO

The resource-constrained project scheduling problem (RCPSP) is a basic problem in project management. The net present value (NPV) of discounted cash flow is used as a criterion to evaluate the financial aspects of RCPSP in many studies. But while most existing studies focused on only the contractor's NPV, this article addresses a practical extension of RCPSP, called the payment scheduling negotiation problem (PSNP), which considers both the interests of the contractor and the client. To maximize NPVs of both sides and achieve a win-win solution, these two participants negotiate together to determine an activity schedule and a payment plan for the project. The challenges arise in three aspects: 1) the client's NPV and the contractor's NPV are two conflicting objectives; 2) both participants have special preferences in decision making; and 3) the RCPSP is nondeterministic polynomial-time hard (NP-Hard). To overcome these challenges, this article proposes a new approach with the following features. First, the problem is reformulated as a biobjective optimization problem with preferences. Second, to address the different preferences of the client and the contractor, a strategy of multilevel region interest is presented. Third, this strategy is integrated in the nondominated sorting genetic algorithm II (NSGA-II) to solve the PSNP efficiently. In the experiment, the proposed algorithm is compared with both the double-level optimization approach and the multiobjective optimization approach. The experimental results validate that the proposed method can focus on searching in the region of interest (ROI) and provide more satisfactory solutions.

20.
Cell Signal ; 69: 109433, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31982551

RESUMO

In mammals, 24-h rhythms of behaviour and physiology are regulated by the circadian clock. The circadian clock is controlled by a central clock in the brain's suprachiasmatic nucleus (SCN) that synchronizes peripheral clocks in peripheral tissues. Clock genes in the SCN are primarily entrained by light. Increasing evidence has shown that peripheral clocks are also regulated by light and hormones independent of the SCN. How the peripheral clocks deal with internal signals is dependent on the relevance of a specific cue to a specific tissue. In different tissues, most genes that are under circadian control are not overlapping, revealing the tissue-specific control of peripheral clocks. We will discuss how different signals control the peripheral clocks in different peripheral tissues, such as the liver, gastrointestinal tract, and pancreas, and discuss the organ-to-organ communication between the peripheral clocks at the molecular level.

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