A Robust Optimization Approach to Emergency Vehicle Scheduling

The emergency vehicle scheduling problem is studied under the objective function to minimize the total transportation time with uncertain road travel time. Firstly, we build a stochastic programming model considering the constrained chance. Then, we analyze the model based on robust optimization method and get its equivalent set of uncertainty constraint, which has good mathematical properties with consideration of the robustness of solutions. Finally, we implement a numerical example to compare the results of robust optimization method and that of the particle swarm optimization algorithm. The case study shows that the proposed method achieves better performance on computational complexity and stability

The changes of CD4+CD25+/CD4+ proportion in spleen of tumor-bearing BALB/c mice

CD4+CD25+ regulatory T lymphocytes (T(R)) constitute 5–10% of peripheral CD4+ T cells in naive mice and humans, and play an important role in controlling immune responses. Accumulating evidences show that T(R )cells are involved in some physiological processes and pathologic conditions such as autoimmune diseases, transplantation tolerance and cancer, and might be a promising therapeutic target for these diseases. To evaluate the change of CD4+CD25+ T(R )cells in mouse tumor models, CD4+CD25+ subset in peripheral blood and spleen lymphocytes from normal or C26 colon-carcinoma-bearing BABL/c mice were analyzed by flow cytometry using double staining with CD4 and CD25 antibodies. The proportion of CD4+CD25+/CD4+ in spleen lymphocytes was found to be higher than that in peripheral blood lymphocytes in normal mice. No difference was observed in the proportion in peripheral blood lymphocytes between tumor bearing mice and normal mice, while there was a significant increase in the proportion in spleen lymphocytes in tumor bearing mice as compared with normal mice. Moreover, the proportion increased in accordance with the increase in the tumor sizes. The increase in the proportion was due to the decrease in CD4+ in lymphocytes, which is resulted from decreased CD4+CD25- subset in lymphocytes. Our observation suggests the CD4+CD25+/CD4+ proportion in spleen lymphocytes might be a sensitive index to evaluate the T(R )in tumor mouse models, and our results provide some information on strategies of antitumor immunotherapy targeting CD4+CD25+ regulatory T lymphocytes

Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis

BACKGROUND: It is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism. METHODS: Mice received an intracerebroventricular fusion of Aβ(25-35). Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform. RESULTS: Our results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ(25-35)-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ(1-42 )production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9. CONCLUSIONS: Pinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD

Poly[[hemi-μ4-oxalato-hemi-μ2-oxalato-bis­(μ3-pyrazine-2-carboxyl­ato)erbium(III)silver(I)] monohydrate]

The asymmetric unit of the title complex, {[AgEr(C5H3N2O2)2(C2O4)]·H2O}n, contains one ErIII atom, one AgI atom, two pyrazine-2-carboxyl­ate (pyc) ligands, two half oxalate ligands (each lying on an inversion center) and one uncoordinated water mol­ecule. The ErIII atom is coordinated by two O atoms and two N atoms from two pyc ligands, one O atom from a third pyc ligand and four O atoms from two oxalate ligands in a distorted monocapped square-anti­prismatic geometry. The AgI atom is coordinated by two N atoms from two pyc ligands, one O atom from a third pyc ligand and one O atom from one oxalate ligand. The crystal structure exhibits a three-dimensional heterometallic polymeric network. O—H⋯O hydrogen bonding between the uncoordinated water mol­ecule and carboxyl­ate O atoms is observed

Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer

BACKGROUND: Accumulating evidence indicates that the long non-coding RNA HOTAIR plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of HOTAIR in gastric carcinogenesis remains largely unknown. METHODS: HOTAIR expression was measured in 78 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation (RIP). The positive HOTAIR/HER2 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis. RESULTS: HOTAIR upregulation was associated with larger tumor size, advanced pathological stage and extensive metastasis, and also correlated with shorter overall survival of gastric cancer patients. Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of gastric carcinoma cells, while HOTAIR depletion inhibited both cell invasion and cell viability, and induced growth arrest in vitro and in vivo. In particular, HOTAIR may act as a ceRNA, effectively becoming a sink for miR-331-3p, thereby modulating the derepression of HER2 and imposing an additional level of post-transcriptional regulation. Finally, the positive HOTAIR/HER2 correlation was significantly associated with advanced gastric cancers. CONCLUSIONS: HOTAIR overexpression represents a biomarker of poor prognosis in gastric cancer, and may confer malignant phenotype to tumor cells. The ceRNA regulatory network involving HOTAIR and the positive interaction between HOTAIR and HER2 may contribute to a better understanding of gastric cancer pathogenesis and facilitate the development of lncRNA-directed diagnostics and therapeutics against this disease

Mitigation of chronic unpredictable stress–induced cognitive deficits in mice by Lycium barbarum L (Solanaceae) polysaccharides

Purpose: To investigate the neuroprotective effects of Lycium barbarum polysaccharide (LBP) against concomitant cognitive dysfunction and changes in hippocampal CREB-BDNF signaling pathway in chronically unpredictable stressed mice.Methods: The mice were subjected to different unpredictable stressors for a period of 4 weeks. Behavioral tests, including open field (OFT) and Morris water maze (MWMT) tests were used to evaluate pharmacological effects. Serum corticosterone levels, protein expression level of BDNF and pCREB/CREB in hippocampus were assessed by ELISA, Western blot and immunohistochemistry methods, respectively. Morphological changes in pyramidal neurons in the hippocampus were studied by Nissl staining.Results: LBP improved mice performance in MWMT, indicating that it reversed chronic unpredictable stress (CUS)-induced cognitive deficits. LBP treatment reduced serum corticosterone levels and prevented neuron loss in the hippocampus. It maintained expression levels of BDNF and phosphorylation of CREB in hippocampus during CUS procedure.Conclusion: Lycium barbarum polysaccharide protects CREB-BDNF signaling pathway in hippocampus and relieves CUS-induced cognitive deficits. These results suggest that Lycium barbarum polysaccharides is potentially an alternative neuro-protective agent against stress-induced psychopathological dysfunction.Keywords: Lycium barbarum, Polysaccharide, Chronic unpredictable stress, Cognitive deficits, Brainderived neurotrophic factor, Calcium/cyclic-AMP responsive binding protei

NF-κB mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons

<p>Abstract</p> <p>Background</p> <p>Inflammatory processes play important roles in both neuropathic and inflammatory pain states, but the effects of inflammation <it>per se </it>within the sensory ganglia are not well understood. The cytokine growth-related oncogene (GRO/KC; CXCL1) shows strong, rapid upregulation in dorsal root ganglion (DRG) in both nerve injury and inflammatory pain models. We examined the direct effects of GRO/KC on small diameter DRG neurons, which are predominantly nociceptive. Whole cell voltage clamp technique was used to measure voltage-activated potassium (K) currents in acutely cultured adult rat small diameter sensory neurons. Fluorescently labeled isolectin B4 (IB4) was used to classify cells as IB4-positive or IB4-negative.</p> <p>Results</p> <p>In IB4-negative neurons, voltage-activated K current densities of both transient and sustained components were increased after overnight incubation with GRO/KC (1.5 nM), without marked changes in voltage dependence or kinetics. The average values for the slow and fast decay time constants at 20 mV were unchanged by GRO/KC. The amplitude of the fast inactivating component increased significantly with no large shifts in the voltage dependence of inactivation. The increase in K currents was completely blocked by co-incubation with protein synthesis inhibitor cycloheximide (CHX) or NF-κB inhibitors pyrrolidine dithiocarbamate (PDTC) or quinazoline (6-Amino-4-(4-phenoxypheny lethylamino;QNZ). In contrast, the voltage-activated K current of IB4-positive neurons was unchanged by GRO/KC. GRO/KC incubation caused no significant changes in the expression level of eight selected voltage-gated K channel genes in quantitative PCR analysis.</p> <p>Conclusion</p> <p>The results suggest that GRO/KC has important effects in inflammatory processes via its direct actions on sensory neurons, and that activation of NF-κB is involved in the GRO/KC-induced enhancement of K currents.</p

Clinical Significance of Potential Unidentified HLA-G Isoforms Without α1 Domain but Containing Intron 4 in Colorectal Cancer Patients

The ectopic HLA-G expression in malignancies has been extensively explored and clinical significance of the molecule was widely acknowledged. Besides previously well-documented seven isoforms (HLA-G1~-G7), other novel isoforms of HLA-G have been reported but their clinical relavenace remians evaluated. In this study, lesion HLA-G expression in 379 case-matched serial section primary colorectal cancers (CRC) were evaluated with mAb 4H84 (recognizing an epitope in HLA-G α1 domain), and mAb 5A6G7 (recognizing an epitope encoded by intron 4), respectively. Data showed that HLA-G positive staining with mAbs 4H84 and 5A6G7 was 70.7 and 60.4%, respectively. When percentage of HLA-G expression detected with mAb 4H84 subtracted that with mAb 5A6G7, the difference (ΔHLA-G) with negative (ΔHLA-Gneg), comparable (ΔHLA-Gcom) and positive (ΔHLA-Gpos) were observed in 64 (16.9%), 159 (42.0%), and 156 (41.2%) cases, respectively. Noteworthy, unexpected immunostaining was observed in 44 (11.6%) lesions that no staining was detected with mAb 4H84 but positive with mAb 5A6G7 (4H84neg5A6G7pos). This staining pattern was unpredictable because all seven known HLA-G isoforms containing the α 1 domain could be recognized by the mAb 4H84. Moreover, patients with ΔHLA-Gneg had obviously better survival than those with ΔHLA-Gcom and ΔHLA-Gpos (p = 0.017), and ΔHLA-G could be an independent prognostic factor for CRC patients (p = 0.008). Our findings provides the first report that potential unidentified HLA-G isoforms is of distinct clinical significance in CRC patients

Prognostic and Risk Stratification Value of Lesion MACC1 Expression in Colorectal Cancer Patients

The up-regulated metastasis-associated in colon cancer 1 (MACC1) expression and its clinical significance has been explored in a varity of malignancies. In this study, lesion MACC1 expression in 503 CRC patients (Ncolon = 332, Nrectal = 171) were analyzed with immunohistochemistry, and its correlation with clinical parameters, patient survival, and its impact on prognostic stratification were evaluated. Data revealed the survival of patient with MACC1high is markedly worse than that of MACC1low (mean overall survival: 80.1 vs. 90.4 months; p = 0.001) and is an independent prognostic predictor (hazard ratio = 1.533; p = 0.005). More importantly, for the first time, we demonstrated that MACC1 status exhibited a significantly prognostic power for stratified clinical parameters such as patient age and gender, particular TNM status, and distinct AJCC disease stage. In summary, our findings indicated that MACC1 is a valuable prognostic and risk stratification biomarker for colorectal cancer patients

KLF7-transfected Schwann cell graft transplantation promotes sciatic nerve regeneration

Our former study demonstrated that Krüppel-like Factor 7 (KLF7) is a transcription factor that stimulates axonal regeneration after peripheral nerve injury. Currently, we used a gene therapy approach to overexpress KLF7 in Schwann cells (SCs) and assessed whether KLF7-transfected SCs graft could promote sciatic nerve regeneration. SCs were transfected by adeno-associated virus 2 (AAV2)-KLF7 in vitro. Mice were allografted by an acellular nerve (ANA) with either an injection of DMEM (ANA group), SCs (ANA + SCs group) or AAV2-KLF7-transfected SCs (ANA + KLF7-SCs group) to assess repair of a sciatic nerve gap. The results indicate that KLF7 overexpression promoted the proliferation of both transfected SCs and native SCs. The neurite length of the dorsal root ganglia (DRG) explants was enhanced. Several beneficial effects were detected in the ANA + KLF7-SCs group including an increase in the compound action potential amplitude, sciatic function index score, enhanced expression of PKH26-labeling transplant SCs, peripheral myelin protein 0, neurofilaments, S-100, and myelinated regeneration nerve. Additionally, HRP-labeled motoneurons in the spinal cord, CTB-labeled sensory neurons in the DRG, motor endplate density and the weight ratios of target muscles were increased by the treatment while thermal hyperalgesia was diminished. Finally, expression of KLF7, NGF, GAP43, TrkA and TrkB were enhanced in the grafted SCs, which may indicate that several signal pathways may be involved in conferring the beneficial effects from KLF7 overexpression. We concluded that KLF7-overexpressing SCs promoted axonal regeneration of the peripheral nerve and enhanced myelination, which collectively proved KLF-SCs as a novel therapeutic strategy for injured nerves