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Accumulating evidence suggests that some microRNAs (miRNAs) are involved in papillary thyroid carcinoma (PTC) progression. However, it remains necessary to elucidate the underlying molecular mechanisms involved. In the present study, we investigated the role of microRNA-101 (miR-101) in PTC via targeting of Ras-related C3 botulinum toxin substrate 1 (Rac1). The results showed that miR-101 was significantly downregulated in PTC tissues compared with adjacent normal tissues. Restoration of miR-101 expression significantly inhibited cell proliferation in the K1 PTC cell line. Moreover, algorithm-based and experimental strategies verified Rac1 as a direct target of miR-101 in the K1 cell line. Taken together, these findings suggest that miR-101 inhibited PTC growth via the downregulation of Rac1 expression, providing a better understanding of miRNA-modulated signaling networks for future cancer therapeutics. [ABSTRACT FROM AUTHOR]

Infection of Helicobacter pylori (H. pylori) changed the proliferation of gastric epithelial cells and decreased the expression of heat shock protein 70 (HSP70). However, the effects of H. pylori on the proliferation of gastric epithelial cells and the roles of HSP70 duringthe progress need further investigation. Objective. To investigate the effects of Helicobacter pylori (H. pylori) and heat shock protein 70 (HSP70) on the proliferation of human gastric epithelial cells. Methods. H. pylori and a human gastric epithelial cell line (AGS) were cocultured. The proliferation of AGS cells was quantitated by an MTT assay, and the expression of HSP70 in AGS cells was detected by Western blotting. HSP70 expression in AGS cells was silenced by small interfering RNA (siRNA) to investigate the role of HSP70. The siRNA-treated AGS cells were cocultured with H. pylori and cell proliferation was measured by an MTT assay. Results. The proliferation of AGS cells was accelerated by coculturing with H. pylori for 4 and 8 h, but was suppressed at 24 and 48 h. HSP70 expression was decreased in AGS cells infected by H. pylori for 48 h. The proliferation in HSP70-silenced AGS cells was inhibited after coculturing with H. pylori for 24 and 48 h compared with the control group. Conclusions. Coculture of H. pylori altered the proliferation of gastric epithelial cells and decreased HSP70 expression. HSP70 knockdown supplemented the inhibitory effect of H. pylori on proliferation of epithelial cells. These results indicate that the effects of H. pylori on the proliferation of gastric epithelial cells at least partially depend on the decreased expression of HSP70 induced by the bacterium. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that the expression of miR-34a is significantly upregulated and associated with cell apoptosis in pancreatic β-cell treated with palmitate. Nevertheless, the underlying detailed mechanism is largely unknown. Here, we showed that miR-34a was significantly induced inMin6 pancreatic β-cell upon palmitate treatment. Elevated miR-34a promoted Min6 cell apoptosis. Intriguingly, ectopic expression of miR-34a lowered the expression of Bcl-2, an antiapoptotic protein. Luciferase reporter assay indicated the direct interaction of miR-34a with the Bcl-2 3'-UTR. Moreover, downregulated expression of Bcl-2 induced by palmitate could be restored by inhibition of miR-34a. We conclude that direct suppression of Bcl-2 by miR-34a accounts for palmitate-induced increased apoptosis rate in pancreatic β-cell. [ABSTRACT FROM AUTHOR]

Our previous study has demonstrated that dietary arginine supplementation during early pregnancy enhanced embryo implantation in rats. However, the mechanism was not clear. The objective of this study was to determine the mechanism that arginine enhanced embryo implantation during early pregnancy. Rats were fed the basal diets supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) once pregnancy. On d4 of pregnancy, rats were given intrauterine injection of L-NG-nitro arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), a-difluoromethylornithine (DFMO, polyamine synthesis inhibitor), wortmannin (PI3K inhibitor), or rapamycin (mTOR inhibitor). On d7 of pregnancy, rats were killed. Intrauterine injection of L-NAME decreased the implantation sites, while dietary arginine supplementation increased the implantation sites. Intrauterine injection of DFMO decreased the pregnancy rate, which was reversed by dietary arginine supplementation. Intrauterine injection of rapamycin or wortmannin inhibited embryo implantation. However, dietary arginine supplementation did not reverse this inhibition.Western blot analysis revealed that the expression of uterine p-PKB and p-S6K1 was greater in rats fed the arginine-supplemented diet in the presence of L-NAME treatment compared with rats fed the control diet. In the presence of DFMO treatment, the expression of uterine iNOS and eNOS was significantly enhanced in the arginine group compared with the control group. Similarly, intrauterine injection of wortmannin or rapamycin decreased the expression of uterine iNOS and eNOS, which was enhanced by dietary arginine supplementation. These data indicated that dietary arginine supplementation during early pregnancy could enhance embryo implantation through stimulation of PI3K/PKB/mTOR/NO signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Epigenetic mechanisms mainly include DNA methylation, post-translational modifications of histones, chromatin remodeling and non-coding RNAs. All of these processes are mediated and controlled by enzymes. Abnormalities of the enzymes are involved in a variety of complex human diseases. Recently, potent natural or synthetic chemicals are utilized to establish the quantitative contributions of epigenetic regulation through the enzymes and provide novel insight for developing new therapeutics. However, the development of more specific and effective epigenetic therapeutics requires a more complete understanding of the chemical epigenomic landscape. Description: Here, we present a human epigenetic enzyme and modulator database (HEMD), the database which provides a central resource for the display, search, and analysis of the structure, function, and related annotation for human epigenetic enzymes and chemical modulators focused on epigenetic therapeutics. Currently, HEMD contains 269 epigenetic enzymes and 4377 modulators in three categories (activators, inhibitors, and regulators). Enzymes are annotated with detailed description of epigenetic mechanisms, catalytic processes, and related diseases, and chemical modulators with binding sites, pharmacological effect, and therapeutic uses. Integrating the information of epigenetic enzymes in HEMD should allow for the prediction of conserved features for proteins and could potentially classify them as ideal targets for experimental validation. In addition, modulators curated in HEMD can be used to investigate potent epigenetic targets for the query compound and also help chemists to implement structural modifications for the design of novel epigenetic drugs. Conclusions: HEMD could be a platform and a starting point for biologists and medicinal chemists for furthering research on epigenetic therapeutics. HEMD is freely available at http://mdl.shsmu.edu.cn/HEMD/. [ABSTRACT FROM AUTHOR]

Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol-OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling trans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT-copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs. [ABSTRACT FROM AUTHOR]

Background: The molecular network sustained by different types of interactions among proteins is widely manifested as the fundamental driving force of cellular operations. Many biological functions are determined by the crosstalk between proteins rather than by the characteristics of their individual components. Thus, the searches for protein partners in global networks are imperative when attempting to address the principles of biology. Results: We have developed a web-based tool ''Sequence-based Protein Partners Search'' (SPPS) to explore interacting partners of proteins, by searching over a large repertoire of proteins across many species. SPPS provides a database containing more than 60,000 protein sequences with annotations and a protein-partner search engine in two modes (Single Query and Multiple Query). Two interacting proteins of human FBXO6 protein have been found using the service in the study. In addition, users can refine potential protein partner hits by using annotations and possible interactive network in the SPPS web server. Conclusions: SPPS provides a new type of tool to facilitate the identification of direct or indirect protein partners which may guide scientists on the investigation of new signaling pathways. The SPPS server is available to the public at http://mdl. shsmu.edu.cn/SPPS/. [ABSTRACT FROM AUTHOR]

Background Mutations in the insulin receptor (IR) gene are known to cause severe insulin resistance. Although clinical features due to a mutation can be diverse, hypoglycaemia is found in some cases. A family with a female proband diagnosed with type A insulin resistance syndrome was studied. Clinical characteristics were compared with the Arginine1174Glutamine (R1174N) mutation reported in the literature. Methods The proband was a 16-year-old girl who was presented with intermittent hypoglycaemia, hirsutism, darkened skin, acne and oligomenorrhoea. A 5-h oral glucose tolerance test (OGTT), intravenous glucose tolerance test and continuous glucose monitoring system were performed for evaluation of glucose metabolism and insulin secretion. Results from a hyperinsulinaemic euglycaemic clamp on the proband were compared to nine normal glucose tolerance (NGT) controls. The IR gene of the proband, along with her parents and two dizygotic twin brothers were scanned for mutations by direct sequencing. Results Elevated serum insulin and insulin : C-peptide ratios were found in the proband, the father and one of the twin brothers, carried a heterozygous missense mutation of Arginine1174Tryptophan (R1174W) in exon20 of the IR gene. The clamp study showed that the nonoxidative glucose disposal rates of the proband were near zero, and that the metabolic clearance rate for insulin was markedly reduced. Conclusions R1174 of the IR gene may be a candidate locus for hyperinsulinaemic hypoglycaemia. Clinical heterogeneity is not uncommon within families as well as among mutation carriers with different amino acid replacements. More pedigrees and long-term follow-up data are needed to document the evolution of β-cell function and clarify the role of R1174 on insulin resistance and hyperinsulinaemic hypoglycaemia. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To investigate whether long-term optimal glycemic control can be achieved without medication by transient continuous subcutaneous insulin infusion (CSII) and the possible mechanisms responsible for this remission. RESEARCH DESIGN AND METHODS -- Newly diagnosed type 2 diabetic patients (n = 138, fasting glucose >11.1mmol/l) were hospitalized and treated with CSII for 2 weeks. Intravenous glucose tolerance tests (IVGTTs) were performed, and blood glucose, HbA[sub1c], lipid profiles, proinsulin, insulin, and C-peptide were measured before and after CSII. Patients were followed longitudinally on diet alone after withdrawal of insulin. RESULTS -- Optimal glycemic control was achieved within 6.3 ± 3.9 days by CSII in 126 patients. The remission rates (percentages maintaining near euglycemia) at the third, sixth, twelfth, and twenty-fourth month were 72.6, 67.0, 47.1, and 42.3%, respectively. Patients who maintained glycemic control >12 months (remission group) had greater recovery of β-cell function than those who did not (nonremission group) when assessed immediately after CSII. Homeostasis model assessment of β-cell function (HOMA-B) and the area under the curve (AUC) of insulin during IVGTT were higher in the remission group (145.4 ± 89.6 vs. 78.5 ± 68.5, P = 0.002, and 1,423.4 ± 523.2 vs. 1,159.5 ± 476.8 pmol ⋅ l[sup-1] ⋅ min[sup-1], P = 0.044). Change in acute insulin response was also greater in the remission group than that in the nonremission group (621.8 ± 430.4 vs. 387.3 ± 428.8 pmol ⋅ 1[sup-1] ⋅ min[sup-1], P = 0.033). CONCLUSIONS -- Short-term intensive insulin therapy can induce long-term glycemic control in newly diagnosed type 2 diabetic patients with severe hyperglycemia. The improvement of β-cell function, especially the restoration of first-phase insulin secretion, could be responsible for the remission. [ABSTRACT FROM AUTHOR]

Consider a single machine processing multiproducts situation when only the mean and standard deviation of processing time for each product are available. The bounds of optimal commit delivery time range are obtained. A decision of the robust commit delivery time is suggested. An extension to the situation with information of orders in queue is also discussed. Numerical examples show that the suggested decision performs well. The expected value of additional information, which measures the maximum amount a decision maker is willing to pay for knowledge of true distribution information, is small, and that further demonstrates the worthiness of the suggested robust decision. [ABSTRACT FROM AUTHOR]

In the literature of cooperative (co-op) advertising, the focus of the research is on a relationship in which a manufacturer is the leader and retailers are followers. This relationship implies the dominance of the manufacturer over retailers. Recent market trends have shown a shift in power from manufacturers to retailers. Retailers, as a result, may possess equal or even greater power than a manufacturer in some instances when it comes to retailing. Based on this new market phenomenon, we intend to explore the role of co-op advertising in a manufacturer-retailer supply chain through brand name investments, local advertising expenditures, and sharing rules of advertising expenses. Two co-op advertising models are developed and compared. The first co-op advertising model is based on the traditional leader-follower relationship of a manufacturer and a retailer. The second model incorporates partnership into co-op advertising coordination. Business examples and managerial implications of the models have been discussed. A cooperative bargaining technique is utilized to implement the partnership co-op advertising model. [ABSTRACT FROM AUTHOR]

Allostery allows for the fine-tuning of protein function. Targeting allosteric sites is gaining increasing recognition as a novel strategy in drug design. The key challenge in the discovery of allosteric sites has strongly motivated the development of computational methods and thus high-quality, publicly accessible standard data have become indispensable. Here, we report benchmarking data for experimentally determined allosteric sites through a complex process, including a 'Core set' with 235 unique allosteric sites and a 'Core-Diversity set' with 147 structurally diverse allosteric sites. These benchmarking sets can be exploited to develop efficient computational methods to predict unknown allosteric sites in proteins and reveal unique allosteric ligand--protein interactions to guide allosteric drug design. [ABSTRACT FROM AUTHOR]

The traditional quantity discount problem is analyzed from the perspective of game theory, including both noncooperative and cooperative models. For the noncooperative case, the Stackelberg equilibrium is derived. For the cooperative case, the Pareto Optimality criteriaare used to find a group of optimal strategies. Both scenarios are illustrated through an example which quantifies the benefits resulting from cooperation between the buyer and the seller for game-theoretic solutions using geometric programming. [ABSTRACT FROM AUTHOR]

Pareto-Koopmans efficiency in Data Envelopment Analysis (DEA) is extended to stochastic inputs and outputs via probabilistic input-output vector comparisons in a given empirical production (possibility) set. In contrast to other approaches which have used Chance Constrained Programming formulations in DEA, the emphasis here is on "joint chance constraints." An assumption of arbitrary but known probability distributions leads to the P-Model of chance constrained programming. A necessary condition for a DMU to be stochastically efficient and a sufficient condition for a DMU to be non-stochastically efficient are provided. Deterministic equivalents using the zero order decision rules of chance constrained programming and multivariate normal distributions take the form of an extended version of the additive model of DEA. Contacts are also maintained with all of the other presently available deterministic DEA models in the form of easily identified extensions which can be used to formalize the treatment of efficiency when stochastic elements are present. [ABSTRACT FROM AUTHOR]

DEA (Data Envelopment Analysis) models and concepts are formulated here in terms of the ‘P-Models’ of Chance Constrained Programming, which are then modified to contact the ‘satisficing concepts’ of H.A. Simon. Satisficing is thereby added as a third category to the efficiency/inefficiency dichotomies that have heretofore prevailed in DEA. Formulations include cases in which inputs and outputs are stochastic, as well as cases in which only the outputs are stochastic. Attention is also devoted to situations in which variations in inputs and outputs are related through a common random variable. Extensions include new developments in goal programming with deterministic equivalents for the corresponding satisficing models under chance constraints. [ABSTRACT FROM AUTHOR]

Substantial research literature has been developed over the years on the subject of inventory. The more recent literature has examined the fundamental relationships between inventory control and price theory. A significant portion of this literature assumes the ultimate consumer demand as a constant and characterizes the relationship between a manufacturer and a retailer as a leader-follower problem. A primary assumption in these studies is that the manufacturer, as the leader, exerts almost complete control over the behavior of the retailer. However, in practice, the retailer does exert some control over the manufacturer. This paper develops a framework that integrates inventory control with constant demand and the economic relationship between consumer demand and retail price. Within this framework, the impact of order quantity, wholesale price and retail price on the behavior of both the manufacturer and the retailer is investigated. Furthermore, this paper explores the issues and conclusions that result from coordinating the relationship between the manufacturer and the retailer. Our analyses demonstrate that channel coordination can be achieved by utilizing well-known bargaining models. A numerical example is provided to illustrate our theoretical findings. [ABSTRACT FROM AUTHOR]

The sugarcane field excitation, cutting forces and the engine excitation constitute complicated excitations acting on sugarcane harvesters. In this study, the sugarcane cutting mechanism under complicated excitations was analyzed. The dynamics and the mathematical models of sugarcane harvesters were established and simulated. Based on theoretical analysis, sugarcane cutting experiments were done on a self-built sugarcane harvester test platform (SHTP), designed as single-factor and the orthogonal experiments. Effects of the sugarcane field excitation characterized by the sugarcane field excitation device (SFED) output frequency, the engine excitation characterized by the actuating engine output frequency, the cutter rotating speed, the sugarcane harvester travelling speed simulated through the sugarcane transporting speed of the SHTP and the cutter inclination angle on the cutting quality of sugarcane harvesters were studied. Effects of the axial cutter vibration on three-directional cutting forces and the sugarcane cutting quality (SCQ) as well as effects of three-directional cutting forces on the SCQ were further studied. It is shown that the sugarcane field excitation, the axial cutter vibration amplitude and frequency as well as the three-directional cutting forces have significantly negative monotonic correlated effects on the SCQ while the cutter rotating speed, the sugarcane harvester travelling speed and the cutter inclination angle have significantly positive monotonic correlated effects on the SCQ. Significance levels of effects on three-directional cutting forces and the SCQ form high to low are as follow, the axial cutter vibration, the sugarcane field excitation, the cutter rotating speed, the engine excitation, the cutter inclination angle, the sugarcane harvester travelling speed. The theoretical analysis results were verified through experiment and an optimal combination was obtained with the cutter rotating speed of 700 r/min, sugarcane harvester travelling speed of 0.6 m/s and cutter inclination angle of 8°. This study can provide a reference for setting cutting parameters of sugarcane harvesters with a good SCQ. [ABSTRACT FROM AUTHOR]