How We Choose One over Another: Predicting Trial-by-Trial Preference Decision

Preference formation is a complex problem as it is subjective, involves emotion, is led by implicit processes, and changes depending on the context even within the same individual. Thus, scientific attempts to predict preference are challenging, yet quite important for basic understanding of human decision making mechanisms, but prediction in a group-average sense has only a limited significance. In this study, we predicted preferential decisions on a trial by trial basis based on brain responses occurring before the individuals made their decisions explicit. Participants made a binary preference decision of approachability based on faces while their electrophysiological responses were recorded. An artificial neural network based pattern-classifier was used with time-frequency resolved patterns of a functional connectivity measure as features for the classifier. We were able to predict preference decisions with a mean accuracy of 74.3±2.79% at participant-independent level and of 91.4±3.8% at participant-dependent level. Further, we revealed a causal role of the first impression on final decision and demonstrated the temporal trajectory of preference decision formation.     

T2384, a novel antidiabetic agent with unique peroxisome proliferator-activated receptor gamma binding properties

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays central roles in adipogenesis and glucose homeostasis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARgamma by TZDs improves insulin sensitivity; however, this is accompanied by the induction of several undesirable side effects. We have identified a novel synthetic PPARgamma ligand, T2384, to explore the biological activities associated with occupying different regions of the receptor ligand-binding pocket. X-ray crystallography studies revealed that T2384 can adopt two distinct binding modes, which we have termed "U" and "S", interacting with the ligand-binding pocket of PPARgamma primarily via hydrophobic contacts that are distinct from full agonists. The different binding modes occupied by T2384 induced distinct patterns of coregulatory protein interaction with PPARgamma in vitro and displayed unique receptor function in cell-based activity assays. We speculate that these unique biochemical and cellular activities may be responsible for the novel in vivo profile observed in animals treated systemically with T2384. When administered to diabetic KKAy mice, T2384 rapidly improved insulin sensitivity in the absence of weight gain, hemodilution, and anemia characteristics of treatment with rosiglitazone (a TZD). Moreover, upon coadministration with rosiglitazone, T2384 was able to antagonize the side effects induced by rosiglitazone treatment alone while retaining robust effects on glucose disposal. These results are consistent with the hypothesis that interactions between ligands and specific regions of the receptor ligand-binding pocket might selectively trigger a subset of receptor-mediated biological responses leading to the improvement of insulin sensitivity, without eliciting less desirable responses associated with full activation of the receptor. We suggest that T2384 may represent a prototype for a novel class of PPARgamma ligand and, furthermore, that molecules sharing some of these properties would be useful for treatment of type 2 diabetes.     

Isolation and characterization of tri‐ and tetranucleotide microsatellite loci in the Asian elephant,Elephas maximus

Asian elephants (Elephas maximus) are an endangered species. Their future survival depends on intensive conservation and management, based on in‐depth knowledge of particular populations. Molecular genetic methods, especially microsatellite analysis through noninvasive sampling, provides an effective means of obtaining such information. The use of tri‐ and tetranucleotide microsatellite markers is advantageous in noninvasive sampling through dung analysis. Here we describe the isolation and characterization of five tri‐ and tetranucleotide markers in the Asian elephant. All five loci were found to be polymorphic in a sample of 20 Asian elephants from Sri Lanka.     

Lipolysis in Adipocytes Isolated from Deep and Superficial Subcutaneous Adipose Tissue

Objective: Abdominal subcutaneous adipose tissue (SAT) occurs in two depots separated by a fascial plane: deep SAT and superficial SAT. In a recent study it was demonstrated that the amount of deep SAT has a much stronger relationship to insulin resistance than does superficial SAT. Because insulin resistance may be related to fatty acid release from adipose tissue, we hypothesized that the two SAT depots may have a different lipolytic activity. Research Methods and Procedures: To test this hypothesis, we obtained samples of deep and superficial SAT from patients undergoing elective abdominal surgery. The rate of lipolysis was determined in the collagenase‐digested adipocytes obtained from the two fat depots by measuring glycerol release in the presence and absence of isoproterenol. In addition, the relative concentration of hormone‐sensitive lipase was determined in both SAT depots by Western blot analysis. Results: Our results showed that the rate of isoproterenol‐stimulated lipolysis was ～20% higher in cells from deep SAT compared with those from superficial SAT, indicating that the deep SAT is more lipolytically active. The concentration of hormone‐sensitive lipase did not differ between the two adipose tissue depots. Discussion: These findings suggest that the higher lipolytic activity of deep SAT may account for its stronger association with insulin resistance. The mechanism seems to be independent of differences in hormone‐sensitive lipase concentration.     

Activin disrupts somitogenesis in cultured chick embryos

The anatomical and cell biological aspects of somite formation in the chick embryo have been rather well studied. Molecular regulation of somitogenesis in vertebrates is just beginning to be understood. We have studied the effects of human recombinant activin on somitogenesis in gastrulating chick embryos cultured in vitro with a view to assessing the possible role of activin-related molecules in this phenomenon. Activin disrupted somitogenesis in treated embryos, resulting in the formation of abnormal, split or ectopic somites. Light microscopic examination indicated that the ability of activin to interfere with somitogenesis might be partly due to initiation of somite formation at ectopic sites. We show that these cells are indeed somitogenic by their expression of one of the earliest somite-specific marker genes, Pax3. Scanning electron microscopic examination of control and treated embryos revealed direct effects of activin on cell-cell interactions. Cells from treated embryos exhibited disrupted intercellular adhesion leading to large intercellular spaces, altered cell shapes and modification of cell surface protrusions. The effects of activin on somitogenesis appear to be specific, since the neural structures, which are generally more susceptible to chemical insults during gastrulation, were relatively less affected. The results clearly point to a role of activin-related molecules in somitogenesis in the chick embryo.     

Krt6a-Positive Mammary Epithelial Progenitors Are Not at Increased Vulnerability to Tumorigenesis Initiated by ErbB2

While most breast cancers are thought to arise from the luminal layer of the breast tissue, it remains unclear which specific cells in the luminal layer are the cells of origin of breast cancer. We have previously reported that WAP-positive luminal epithelial cells are at increased susceptibility to tumor initiation by ErbB2 compared to the bulk population, while the mammary cells with canonical Wnt signaling activity fail to evolve into tumors upon ErbB2 activation. Here, we used retrovirus to introduce ErbB2 into the Krt6a-positive mammary progenitor subset of the luminal epithelium and, for comparison, into the mammary luminal epithelium indiscriminately. Tumors developed from both groups of cells with a similar latency. These data indicate that the Krt6a-positive subset of mammary epithelial cells can be induced to form cancer by ErbB2 but it is not more susceptible to tumorigenesis initiated by ErbB2 than the bulk population of the luminal epithelium.     

Ferrous-iron induces lipid peroxidation with little damage to energy transduction in mitochondria

Addition of ferrous sulfate, but not ferric chloride, in micromolar concentrations to rat liver mitochondria induced high rates of consumption of oxygen. The oxygen consumed was several times in excess of the reducing capacity of ferrous-iron (O: Fe ratios 5–8). This occurred in the absence of NADPH or any exogenous oxidizable substrate. The reaction terminated on oxidation of ferrous ions. Malondialdehyde (MDA), measured as thiobarbituric acid-reacting material, was produced indicating peroxidation of lipids. The ratio of O₂: MDA was about 4: 1. Pretreatment of mitochondria with ferrous sulfate decreased the rate of oxidation (state 3) with glutamate (+malate) as the substrate by about 40% but caused little damage to energy tranduction process as represented by ratios of ADP: O and respiratory control, as well as calcium-stimulated oxygen uptake and energy-dependent uptake of [⁴⁵Ca]-calcium. Addition of succinate or ubiquinone decreased ferrous iron-induced lipid peroxidation in intact mitochondria. In frozen-thawed mitochondria, addition of succinate enhanced lipid peroxidation whereas ubiquinone had little effect. These results suggest that ferrous-iron can cause peroxidation of mitochondrial lipids without affecting the energy transduction systems, and that succinate and ubiquinone can offer protection from damage due to such ferrous-iron released from the stores within the cells.     

Phospho‐Proteomic Analysis of Cardiac Dyssynchrony and Resynchronization Therapy

Cardiac dyssynchrony arises from conduction abnormalities during heart failure and worsens morbidity and mortality. Cardiac resynchronization therapy (CRT) re‐coordinates contraction using bi‐ventricular pacing, but the cellular and molecular mechanisms involved remain largely unknown. The aim is to determine how dyssynchronous heart failure (HF_dys) alters the phospho‐proteome and how CRT interacts with this unique phospho‐proteome by analyzing Ser/Thr and Tyr phosphorylation. Phospho‐enriched myocardium from dog models of Control, HF_dys, and CRT is analyzed via MS. There were 209 regulated phospho‐sites among 1761 identified sites. Compared to Con and CRT, HF_dys is hyper‐phosphorylated and tyrosine phosphorylation is more likely to be involved in signaling that increased with HF_dys and was exacerbated by CRT. For each regulated site, the most‐likely targeting‐kinase is predicted, and CK2 is highly specific for sites that are “fixed” by CRT, suggesting activation of CK2 signaling occurs in HF_dys that is reversed by CRT, which is supported by western blot analysis. These data elucidate signaling networks and kinases that may be involved and deserve further study. Importantly, a possible role for CK2 modulation in CRT has been identified. This may be harnessed in the future therapeutically to compliment CRT, improving its clinical effects.     

On Second Order Efficiency of Estimators Derived by Generalised χ2 Distance Functions

Taylor (1953) proposed a distance function in connection with the logit χ² estimator. For product (associated) multinomial distributions, he showed that minimization of the distance function yields BAN estimators. Aithal (1986) and Rao (1989) considered a modified version of Taylor's distance function and showed that a member belonging to this class leads to a second order efficient estimator. In this paper we consider Taylor's distance function and show that a member belonging to this class produces a second order efficient estimator. In addition to the above two, the m.l. estimator is also second order efficient. In order to compare these three second order efficient estimators, the small sample variances of the estimators are estimated through a simulation study. The results indicate that the variance of the m.l. estimator is the smallest in most of the cases.     

Tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives as microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors: SAR and in vivo efficacy in hyperalgesia pain model

A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE₂ release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F = 33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.