Journals
2012 EN
Feng Chen · Yingmei Feng · Kaier Zheng
+12 more
A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.
Public Library of Science
Journals
2012 EN
Audrey Maille · Lucie Engelhart · Marie Bourjade
+1 more
Background Although gestural communication is widespread in primates, few studies focused on the cognitive processes underlying gestures produced by monkeys. Methodology/Principal Findings The present study asked whether red-capped mangabeys ( Cercocebus torquatus ) trained to produce visually based requesting gestures modify their gestural behavior in response to human’s attentional states. The experimenter held a food item and displayed five different attentional states that differed on the basis of body, head and gaze orientation; mangabeys had to request food by extending an arm toward the food item (begging gesture). Mangabeys were sensitive, at least to some extent, to the human’s attentional state. They reacted to some postural cues of a human recipient: they gestured more and faster when both the body and the head of the experimenter were oriented toward them than when they were oriented away. However, they did not seem to use gaze cues to recognize an attentive human: monkeys begged at similar levels regardless of the experimenter’s eyes state. Conclusions/Significance These results indicate that mangabeys lowered their production of begging gestures when these could not be perceived by the human who had to respond to it. This finding provides important evidence that acquired begging gestures of monkeys might be used intentionally.
Public Library of Science
Journals
2012 EN
L.H. Pereira · Roxana Zamudio · Giordano B. SoaresSouza
+14 more
Gastric cancer is one of the most lethal types of cancer and its incidence varies worldwide, with the Andean region of South America showing high incidence rates. We evaluated the genetic structure of the population from Lima (Peru) and performed a case-control genetic association study to test the contribution of African, European, or Native American ancestry to risk for gastric cancer, controlling for the effect of non-genetic factors. A wide set of socioeconomic, dietary, and clinic information was collected for each participant in the study and ancestry was estimated based on 103 ancestry informative markers. Although the urban population from Lima is usually considered as mestizo (i.e., admixed from Africans, Europeans, and Native Americans), we observed a high fraction of Native American ancestry (78.4% for the cases and 74.6% for the controls) and a very low African ancestry (<5%). We determined that higher Native American individual ancestry is associated with gastric cancer, but socioeconomic factors associated both with gastric cancer and Native American ethnicity account for this association. Therefore, the high incidence of gastric cancer in Peru does not seem to be related to susceptibility alleles common in this population. Instead, our result suggests a predominant role for ethnic-associated socioeconomic factors and disparities in access to health services. Since Native Americans are a neglected group in genomic studies, we suggest that the population from Lima and other large cities from Western South America with high Native American ancestry background may be convenient targets for epidemiological studies focused on this ethnic group.
Public Library of Science
Journals
2012 EN
Andrew K. Davis · Jean Chi · Catherine A. Bradley
+1 more
The distinctive orange and black wings of monarchs ( Danaus plexippus ) have long been known to advertise their bitter taste and toxicity to potential predators. Recent work also showed that both the orange and black coloration of this species can vary in response to individual-level and environmental factors. Here we examine the relationship between wing color and flight performance in captive-reared monarchs using a tethered flight mill apparatus to quantify butterfly flight speed, duration and distance. In three different experiments (totaling 121 individuals) we used image analysis to measure body size and four wing traits among newly-emerged butterflies prior to flight trials: wing area, aspect ratio (length/width), melanism, and orange hue. Results showed that monarchs with darker orange (approaching red) wings flew longer distances than those with lighter orange wings in analyses that controlled for sex and other morphometric traits. This finding is consistent with past work showing that among wild monarchs, those sampled during the fall migration are darker in hue (redder) than non-migratory monarchs. Together, these results suggest that pigment deposition onto wing scales during metamorphosis could be linked with traits that influence flight, such as thorax muscle size, energy storage or metabolism. Our results reinforce an association between wing color and flight performance in insects that is suggested by past studies of wing melansim and seasonal polyphenism, and provide an important starting point for work focused on mechanistic links between insect movement and color.
Public Library of Science
Journals
2012 EN
Belvin Gong · Catherine Kielar · A. Jennifer Morton
Abnormal insoluble ubiqitinated protein aggregates are found in the brains of Huntington’s disease (HD) patients and in mice transgenic for the HTT mutation. Here, we describe the earliest stages of visible NII formation in brains of R6/2 mice killed between 2 and 6 weeks of age. We found that huntingtin-positive aggregates formed rapidly (within 24–48 hours) in a spatiotemporal manner similar to that we described previously for ubiquitinated inclusions. However, in most neurons, aggregates are not ubiquitinated when they first form. It has always been assumed that mutant huntingtin is recognised as ‘foreign’ and consequently ubiquitinated and targeted for degradation by the ubiquitin-proteasome system pathway. Our data, however, suggest that aggregation and ubiquitination are separate processes, and that mutant huntingtin fragment is not recognized as ‘abnormal’ by the ubiquitin-proteasome system before aggregation. Rather, mutant Htt appears to aggregate before it is ubiquitinated, and then either aggregated huntingtin is ubiquitinated or ubiquitinated proteins are recruited into aggregates. Our findings have significant implications for the role of the ubiquitin-proteasome system in the formation of aggregates, as they suggest that this system is not involved until after the first aggregates form.
Public Library of Science
Journals
2012 EN
Catherine TétardJones · Michael A. Kertesz · Richard F. Preziosi
Plants simultaneously interact with a plethora of species both belowground and aboveground, which can result in indirect effects mediated by plants. Studies incorporating plant genetic variation indicate that indirect effects mediated by plants may be a significant factor influencing the ecology and evolution of species within a community. Here, we present findings of a Quantitative Trait Locus (QTL) mapping study, where we mapped a rhizobacteria-aphid indirect effect onto the barley genome. We measured the size of aphid populations on barley when the barley rhizosphere either was or was not supplemented with a rhizobacterial species. Using a QTL mapping subset, we located five regions of the barley genome associated with the rhizobacteria-aphid indirect effect. Rhizobacterial supplementation led to an increase in aphid population size (mapped to three barley QTL), or a decrease in aphid population size (mapped to two barley QTL). One QTL associated with plant resistance to aphids was affected by a significant QTL-by-environment interaction, because it was not expressed when rhizobacteria was supplemented. Our results indicated that rhizobacterial supplementation of barley roots led to either increased or reduced aphid population size depending on plant genotype at five barley QTL. This indicates that the direction of a rhizobacteria-aphid indirect effect could influence the selection pressure on plants, when considering species that affect plant fitness. Further research may build on the findings presented here, to identify genes within QTL regions that are involved in the indirect interaction.
Public Library of Science
Journals
2012 EN
Katriina Tiira · Osmo Hakosalo · Lauri Kareinen
+5 more
Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disorder observed both in humans and animals. Examples of Canine Compulsive Disorder (CD) include excessive tail chasing (TC), light/shadow chasing and flank sucking. We performed a questionnaire survey to investigate the characteristics of compulsive (TC) and its possible associations with environmental correlates and personality in a pet population of 368 dogs from four dog breeds. We observed an early onset of TC at 3–6 months of age and a large variation in TC frequency in all breeds, with an overrepresentation of milder cases. Almost half of the TC dogs showed lowered responsiveness during bouts and displayed also other types of compulsions more often than the controls. Interestingly, dogs that received dietary supplements, especially vitamins and minerals, expressed less TC compared to dogs that did not receive any supplements. Neutered females had less TC, suggesting an influence of ovarian hormones on TC. Tail chasers were shyer and had separated earlier from their mothers than the controls. Finally, our genetic study did not find an association between TC and CDH2, a locus previously associated with the canine flank sucking compulsion. In conclusion, the early-onset and the variable nature of the repetitive behaviour, which is affected by environmental factors such as micronutrients, neutering and maternal care, share several similar components between canine and human compulsions and supports canine TC as a model for human OCD.
Public Library of Science
Journals
2012 EN
Marc Guéroult · Olivier Boittin · Oliver Mauffret
+2 more
This study investigates the effect of Mg 2+ bound to the DNA major groove on DNA structure and dynamics. The analysis of a comprehensive dataset of B-DNA crystallographic structures shows that divalent cations are preferentially located in the DNA major groove where they interact with successive bases of (A/G)pG and the phosphate group of 5′-CpA or TpG. Based on this knowledge, molecular dynamics simulations were carried out on a DNA oligomer without or with Mg 2+ close to an ApG step. These simulations showed that the hydrated Mg 2+ forms a stable intra-strand cross-link between the two purines in solution. ApG generates an electrostatic potential in the major groove that is particularly attractive for cations; its intrinsic conformation is well-adapted to the formation of water-mediated hydrogen bonds with Mg 2+ . The binding of Mg 2+ modulates the behavior of the 5′-neighboring step by increasing the BII (ε-ζ>0°) population of its phosphate group. Additional electrostatic interactions between the 5′-phosphate group and Mg 2+ strengthen both the DNA-cation binding and the BII character of the 5′-step. Cation binding in the major groove may therefore locally influence the DNA conformational landscape, suggesting a possible avenue for better understanding how strong DNA distortions can be stabilized in protein-DNA complexes.
Public Library of Science
Journals
2012 EN
Zhongxiao Wan · Ian Ritchie · MarieSoleil Beaudoin
+3 more
Background Glyceroneogenesis is an important step in the control of fatty acid re-esterification with PEPCK and PDK4 being identified as key enzymes in this process. We have previously shown that glyceroneogenic enzymes such as PDK4 are rapidly induced in white adipose tissue during exercise. Recent studies have suggested that IL-6 regulates adipose tissue metabolism and gene expression during exercise. Interestingly, IL-6 has been reported to directly decrease PEPCK expression. The purpose of this investigation was to determine the role of IL-6 in modulating the effects of exercise on the expression of glyceroneogenic enzymes in mouse adipose tissue. We hypothesized that the exercise-mediated induction of PDK4 and PEPCK would be greater in adipose tissue from IL-6 deficient mice compared to wild type controls. Methodology and Principle Findings Treatment of cultured epididymal adipose tissue (eWAT) with IL-6 (150 ng/ml) increased the phosphorylation of AMPK, ACC and STAT3 and induced SOCS3 mRNA levels while decreasing PEPCK and PDK4 mRNA. AICAR decreased the expression of PDK4 and PEPCK. The activation of AMPK by IL-6 was independent of increases in lipolysis. An acute bout of treadmill running (15 meters/minute, 5% incline, 90 minutes) did not induce SOCS3 or increase phosphorylation of STAT3 in eWAT, indicating that IL-6 signalling was not activated. Exercise-induced increases in PEPCK and PDK4 mRNA expression were attenuated in eWAT from IL-6 −/− mice in parallel with a greater relative increase in AMPK phosphorylation compared to exercised WT mice. These changes occurred independent of alterations in beta-adrenergic signalling in adipose tissue from IL-6 −/− mice. Conclusions and Significance Our findings question the role of IL-6 signalling in adipose tissue during exercise and suggest an indirect effect of this cytokine in the regulation of adipose tissue gene expression during exercise.
Public Library of Science
Journals
2012 EN
Lowri A. Griffiths · Jennifer Doig · A. M. D. Churchhouse
+4 more
Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype “wasted” ( wst ). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal. Although the mutation is said to be recessive, aged heterozygous mice have never been examined in detail; a number of other mouse models of motor neuron degeneration have recently been shown to have similar, albeit less severe, phenotypic abnormalities in the heterozygous state. We therefore examined the effects of ageing on a cohort of heterozygous +/wst mice and control mice, in order to establish whether a presumed 50% reduction in eEF1A2 expression was compatible with normal function. We evaluated the grip strength assay as a way of distinguishing between wasted and wild-type mice at 3–4 weeks, and then performed the same assay in older +/wst and wild-type mice. We also used rotarod performance and immunohistochemistry of spinal cord sections to evaluate the phenotype of aged heterozygous mice. Heterozygous mutant mice showed no deficit in neuromuscular function or signs of spinal cord pathology, in spite of the low levels of eEF1A2.
Public Library of Science