Economic principles motivating social attention in humans

We know little about the processes by which we evaluate the opportunity to look at another person. We propose that behavioural economics provides a powerful approach to understanding this basic aspect of social attention. We hypothesized that the decision process culminating in attention to another person follows the same economic principles that govern choices about rewards such as food, drinks and money. Specifically, such rewards are discounted as a function of time, are tradable for other rewards, and reinforce work. Behavioural and neurobiological evidence suggests that looking at other people can also be described as rewarding, but to what extent these economic principles apply to social orienting remains unknown. Here, we show that the opportunity to view pictures of the opposite sex is discounted by delay to viewing, substitutes for money and reinforces work. The reward value of photos of the opposite sex varied with physical attractiveness and was greater in men, suggesting differential utility of acquiring visual information about the opposite sex in men and women. Together, these results demonstrate that choosing whom to look at follows a general set of economic principles, implicating shared neural mechanisms in both social and non-social decision making.     

Shared as well as distinct roles of EHD proteins revealed by biochemical and functional comparisons in mammalian cells and <Emphasis Type="Italic">C. elegans</Emphasis>

Background  

The four highly homologous human EHD proteins (EHD1-4) form a distinct subfamily of the Eps15 homology domain-containing protein family and are thought to regulate endocytic recycling. Certain members of this family have been studied in different cellular contexts; however, a lack of concurrent analyses of all four proteins has impeded an appreciation of their redundant versus distinct functions.     

Novel diarylheptanoids as inhibitors of TNF-α production

Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α) production is described in the present article. The key reactions involve the formation of a β-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,β-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings indicate that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.     

Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality

A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ～70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% (n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% (n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.     

Senescence marker protein 30 (SMP30) expression in eukaryotic cells: existence of multiple species and membrane localization

Senescence marker protein (SMP30), also known as regucalcin, is a 34 kDa cytosolic marker protein of aging which plays an important role in intracellular Ca(2+) homeostasis, ascorbic acid biosynthesis, oxidative stress, and detoxification of chemical warfare nerve agents. In our goal to investigate the activity of SMP30 for the detoxification of nerve agents, we have produced a recombinant adenovirus expressing human SMP30 as a fusion protein with a hemaglutinin tag (Ad-SMP30-HA). Ad-SMP30-HA transduced the expression of SMP30-HA and two additional forms of SMP30 with molecular sizes ～28 kDa and 24 kDa in HEK-293A and C3A liver cells in a dose and time-dependent manner. Intravenous administration of Ad-SMP30-HA in mice results in the expression of all the three forms of SMP30 in the liver and diaphragm. LC-MS/MS results confirmed that the lower molecular weight 28 kDa and 24 kDa proteins are related to the 34 kDa SMP30. The 28 kDa and 24 kDa SMP30 forms were also detected in normal rat liver and mice injected with Ad-SMP30-HA suggesting that SMP30 does exist in multiple forms under physiological conditions. Time course experiments in both cell lines suggest that the 28 kDa and 24 kDa SMP30 forms are likely generated from the 34 kDa SMP30. Interestingly, the 28 kDa and 24 kDa SMP30 forms appeared initially in the cytosol and shifted to the particulate fraction. Studies using small molecule inhibitors of proteolytic pathways revealed the potential involvement of β and γ-secretases but not calpains, lysosomal proteases, proteasome and caspases. This is the first report describing the existence of multiple forms of SMP30, their preferential distribution to membranes and their generation through proteolysis possibly mediated by secretase enzymes.     

Proanthocyanidin exposure to B6C3F1 mice significantly attenuates dimethylnitrosamine-induced liver tumor induction and mortality by differentially modulating programmed and unprogrammed cell deaths

Proanthocyanidins are of current interest as chemopreventive agents. The potential of the pre-, post- and co-exposure of proanthocyanidin-rich grape seed extract (GSPE) in preventing, reducing and/or delaying dimethylnitrosamine (N-nitrosodimethylamine, DMN)-induced liver tumorigenesis, carcinogenesis and mortality in male B6C3F1 mice was determined. Animals were divided into six groups: I—control, II—GSPE alone, III—DMN alone, IV—GSPE + DMN, V—DMN exposure (3 months) followed by GSPE diet (9 months) and VI—GSPE diet (3 months) + DMN (3 months) + control diet (6 months). DMN exposure (0–8 weeks: 5 mg/kg; 8–12 weeks: 10 mg/kg, i.p.) was limited to a total period of 3 months. GSPE was incorporated in laboratory chow (ADI: 100 mg/kg b.w.). Animals were sacrificed at 3 month intervals, and serum chemistry, liver histopathology, integrity of hepatic genomic DNA, antioxidant status, and rates of apoptotic and necrotic cell deaths were determined. DMN-induced liver tumor formation (85%) and animal lethality (38%) were powerfully antagonized by co-administration of GSPE + DMN (tumor positive: 45%; death: 11%). More than 75% of the DMN-treated animals had numerous tumors (five or more), which were significantly reduced in the GSPE + DMN group (35%). GSPE also negatively influenced other protocols specifically designed to test initiation and progression phases. Thus, GSPE was instrumental in modulating metabolic cascades and regulated orchestration of cell death processes involved during the multistage tumorigenic process. These results unraveled that long-term exposure to proanthocyanidin-rich grape seed extract may serve as a potent barrier to all three stages of DMN-induced liver carcinogenesis and tumorigenesis by selectively altering oxidative stress, genomic integrity and cell death patterns in vivo.     

Behavioral coping strategies in a cichlid fish: the role of social status and acute stress response in direct and displaced aggression

The African cichlid fish, Astatotilapia burtoni, has a complex social system with a sophisticated social hierarchy that offers unique opportunities to understand how social rank and its physiological substrates relate to behavioral strategies. In A. burtoni, a small fraction of the males are dominant (T, territorial), as distinguished by being large, brightly colored, reproductively active, and aggressively defending territories. In contrast, the majority of males are non-dominant (NT, non-territorial), being smaller, drably colored, sexually immature, and typically schooling with females. The social system is regulated by aggressive interactions between males and behavioral responses to aggression can be direct or displaced with respect to the animal that acts. To determine whether direct and displaced behaviors are differentially exhibited by T and NT males, individuals were shown a video presentation of a dominant male displaying aggressively. Analysis of aggressive acts toward the video display and displaced activity toward a tank mate revealed that T males exhibited more direct behavior (toward the video display), while NT males engaged in more displaced behavior (toward tank mates). Because similar experiments with primates suggest that shifts in behavioral strategies are linked to changes in the stress response (as measured by circulating cortisol levels), we measured cortisol levels of T and NT males following exposure to the aggressive stimulus. Although in some animals subordinate males are reported to have higher cortisol levels, here we show that in A. burtoni the endocrine response to specific situations can vary considerably even among animals of the same status. Interestingly, NT males with intermediate cortisol levels showed more directed behavior while NT males with both high and low cortisol levels showed more displaced. This suggests an optimal physiological stress response in NT males that predisposes them to challenge aggressors perhaps making it more likely for them to ascend in status.     

Evidence for retro-translocation of pokeweed antiviral protein from endoplasmic reticulum into cytosol and separation of its activity on ribosomes from its activity on capped RNA

Pokeweed antiviral protein (PAP) is a single-chain ribosome inactivating protein (RIP) that binds to ribosomes and depurinates the highly conserved alpha-sarcin/ricin loop (SRL) of the large subunit rRNA. Catalytic depurination of a specific adenine has been proposed to result in translation arrest and cytotoxicity. Here, we show that both precursor and mature forms of PAP are localized in the endoplasmic reticulum (ER) in yeast. The mature form is retro-translocated from the ER into the cytosol where it escapes degradation unlike the other substrates of the retro-translocation pathway. A mutation of a highly conserved asparagine residue at position 70 (N70A) delays ribosome depurination and the onset of translation arrest. The ribosomes are eventually depurinated, yet cytotoxicity and loss of viability are markedly absent. Analysis of the variant protein, N70A, does not reveal any decrease in the rate of synthesis, subcellular localization, or the rate of transport into the cytosol. N70A destabilizes its own mRNA, binds to cap, and blocks cap dependent translation, as previously reported for the wild-type PAP. However, it cannot depurinate ribosomes in a translation-independent manner. These results demonstrate that N70 near the active-site pocket is required for depurination of cytosolic ribosomes but not for cap binding or mRNA destabilization, indicating that the activity of PAP on capped RNA can be uncoupled from its activity on rRNA. These findings suggest that the altered active site of PAP might accommodate a narrower range of substrates, thus reducing ribotoxicity while maintaining potential therapeutic benefits.     

Phosphorylation of Enoyl-Acyl Carrier Protein Reductase InhA Impacts Mycobacterial Growth and Survival

InhA, the primary target for the first line anti-tuberculosis drug isoniazid, is a key enzyme of the fatty-acid synthase II system involved in mycolic acid biosynthesis in Mycobacterium tuberculosis. In this study, we show that InhA is a substrate for mycobacterial serine/threonine protein kinases. Using a novel approach to validate phosphorylation of a substrate by multiple kinases in a surrogate host (Escherichia coli), we have demonstrated efficient phosphorylation of InhA by PknA, PknB, and PknH, and to a lower extent by PknF. Additionally, the sites targeted by PknA/PknB have been identified and shown to be predominantly located at the C terminus of InhA. Results demonstrate in vivo phosphorylation of InhA in mycobacteria and validate Thr-266 as one of the key sites of phosphorylation. Significantly, our studies reveal that the phosphorylation of InhA by kinases modulates its biochemical activity, with phosphorylation resulting in decreased enzymatic activity. Co-expression of kinase and InhA alters the growth dynamics of Mycobacterium smegmatis, suggesting that InhA phosphorylation in vivo is an important event in regulating its activity. An InhA-T266E mutant, which mimics constitutive phosphorylation, is unable to rescue an M. smegmatis conditional inhA gene replacement mutant, emphasizing the critical role of Thr-266 in mediating post-translational regulation of InhA activity. The involvement of various serine/threonine kinases in modulating the activity of a number of enzymes of the mycolic acid synthesis pathway, including InhA, accentuates the intricacies of mycobacterial signaling networks in parallel with the changing environment.     

Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy

Cisplatin is a widely used antineoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show not only that mitochondrial dysfunction is a feature of cisplatin nephrotoxicity, but also that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin's antineoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Because similar compounds seem to be safe in humans, mitochondrially targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.