GC-Content Dependence of Elastic and Overstretching Properties of DNA:RNA Hybrid Duplexes.

DNA:RNA hybrid duplex plays important roles in various biological processes. Both its structural stability and interactions with proteins are highly sequence dependent. In this study, we utilize homebuilt optical tweezers to investigate how GC contents in the sequence influence the structural and mechanical properties of DNA:RNA hybrid by measuring its contour length, elasticities, and overstretching dynamics. Our results support that the DNA:RNA hybrid adopts a conformation between the A- and B-form helix, and the GC content does not affect its structural and elastic parameters obviously when varying from 40 to 60% before the overstretching transition of DNA:RNA hybrid occurs. In the overstretching transition, however, our study unravels significant heterogeneity and strong sequence dependence, suggesting the presence of a highly dynamic competition between the two processes, namely the S-form duplex formation (nonhysteretic) and the unpeeling (hysteretic). Analyzing the components left in DNA:RNA hybrid after the overstretching transition suggests that the RNA strand is more easily unpeeled than the DNA strand, whereas an increase in the GC content from 40 to 60% can significantly reduce unpeeling. Large hysteresis is observed between the stretching and relaxation processes, which is also quantitatively correlated with the percentage of unpeeling in the DNA:RNA duplex. Increasing in both the salt concentration and GC content can effectively reduce the hysteresis with the latter being more significant. Together, our study reveals that the mechanical properties of DNA:RNA hybrid duplexes are significantly different from double-stranded DNA and double-stranded RNA, and its overstretching behavior is highly sequence dependent. These results should be taken into account in the future studies on DNA:RNA-hybrid-related functional structures and motor proteins.

Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome.

INTRODUCTION: The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients. METHODS: We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups. RESULTS: Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected = 0.002; older age: HR 1.034, p-corrected = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV ≥ 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037). CONCLUSION: Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.

Study of Foveal Avascular Zone Growth in Individuals With Mild Diabetic Retinopathy by Optical Coherence Tomography.

Purpose: The purpose of this study was to investigate the association between foveal vessels and retinal thickness in individuals with diabetic retinopathy (DR) and control subjects, and to reveal foveal avascular zone (FAZ) growth in early individuals with DR. Methods: The regions with a thickness less than 60 µm were marked from the intima thickness maps and named FAZThic. The avascular zones extracted from the deep vascular plexus were designated as FAZAngi. The boundary of the two FAZ forms a ring region, which we called FAZRing. The FAZ growth rate was defined as the ratio of the FAZRing area to the FAZThic area. Thirty healthy controls and 30 individuals with mild nonproliferative DR were recruited for this study. Results: The FAZThic area in individuals with mild DR and control subjects showed similar distribution. The FAZAngi area in individuals with mild DR are higher than that in control subjects on the whole, but there was no significant difference (P > 0.05). The FAZRing area in individuals with mild DR was significantly higher than that in control subjects (P < 0.001). However, there is still a small amount of overlap data between the two groups. For the FAZ growth rate, the individuals with mild DR were also significantly larger than the control subjects (P < 0.001). But there were no overlapping data between the two groups. Conclusions: The growth of FAZ in individuals with mild DR can be inferred by comparing FAZAngi with FAZThic. This method minimizes the impact of individual variations and helps researchers to understand the progression mechanism of DR more deeply.

Automated retinal boundary segmentation of optical coherence tomography images using an improved Canny operator.

Retinal segmentation is a prerequisite for quantifying retinal structural features and diagnosing related ophthalmic diseases. Canny operator is recognized as the best boundary detection operator so far, and is often used to obtain the initial boundary of the retina in retinal segmentation. However, the traditional Canny operator is susceptible to vascular shadows, vitreous artifacts, or noise interference in retinal segmentation, causing serious misdetection or missed detection. This paper proposed an improved Canny operator for automatic segmentation of retinal boundaries. The improved algorithm solves the problems of the traditional Canny operator by adding a multi-point boundary search step on the basis of the original method, and adjusts the convolution kernel. The algorithm was used to segment the retinal images of healthy subjects and age-related macular degeneration (AMD) patients; eleven retinal boundaries were identified and compared with the results of manual segmentation by the ophthalmologists. The average difference between the automatic and manual methods is: 2-6 microns (1-2 pixels) for healthy subjects and 3-10 microns (1-3 pixels) for AMD patients. Qualitative method is also used to verify the accuracy and stability of the algorithm. The percentage of "perfect segmentation" and "good segmentation" is 98% in healthy subjects and 94% in AMD patients. This algorithm can be used alone or in combination with other methods as an initial boundary detection algorithm. It is easy to understand and improve, and may become a useful tool for analyzing and diagnosing eye diseases.

Vividness of mental imagery: individual variability can be measured objectively.

When asked to imagine a visual scene, such as an ant crawling on a checkered table cloth toward a jar of jelly, individuals subjectively report different vividness in their mental visualization. We show that reported vividness can be correlated with two objective measures: the early visual cortex activity relative to the whole brain activity measured by functional magnetic resonance imaging (fMRI) and the performance on a novel psychophysical task. These results show that individual differences in the vividness of mental imagery are quantifiable even in the absence of subjective report.

Peripheral group II metabotropic glutamate receptors (mGluR2/3) regulate prostaglandin E2-mediated sensitization of capsaicin responses and thermal nociception.

Previous studies have shown that group II metabotropic glutamate receptors (mGluRs) are present on the peripheral terminals of primary sensory neurons, suggesting that they might be involved in nociception. In this study, we investigated the modulation of nociception by peripheral group II mGluRs and the molecular basis of this modulation. Subcutaneous injection of a group II mGluR agonist, 2R,4R 4-aminopyrrolidine-2,4-dicarboxylate (APDC), did not alter thermal sensitivity but blocked prostaglandin E2 (PGE2)-induced thermal hyperalgesia. This effect was blocked by (2s)-2-amino-2-[(1s,2s)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid, a selective group II mGluR antagonist. In cultured primary sensory neurons, APDC blocked PGE2-induced potentiation of capsaicin responses, which was abolished when neurons were pretreated with pertussis toxin. Similar potentiating effects induced by forskolin but not 8-bromo-cAMP were also blocked by the activation of group II mGluRs. These results indicate that peripheral group II mGluRs act via inhibition of adenylyl cyclase to reverse the sensitization of capsaicin receptors and the thermal hyperalgesia induced by PGE2, and suggest that peripheral group II mGluRs might be targeted for therapeutic intervention in inflammatory pain states.

Peripheral group II metabotropic glutamate receptors mediate endogenous anti-allodynia in inflammation.

We previously demonstrated that activation of peripheral group II mGluRs inhibits PGE2-induced thermal hyperalgesia. In the present study we examined the role of peripheral group II mGluRs in inflammation-induced mechanical allodynia in CD1 mice. Subcutaneous injection of group II mGluR agonists or antagonists into the plantar surface of the mouse hind paw did not alter mechanical thresholds, suggesting that peripheral group II mGluRs did not modulate basal mechanical sensation. We then used either PGE2 or carrageenan to induce mechanical allodynia and investigated the effects of activating or inhibiting peripheral group II mGluRs. PGE2-injected mice showed an 87+/-1% decrease of mechanical thresholds 75 min after the injection, whereas mice injected with group II mGluR agonists had no increase in sensitivity compared to vehicle-injected mice. In the carrageenan-induced inflammation model, 3 h after carrageenan injection the mechanical thresholds of mice injected with group II mGluR agonist APDC fully recovered to baseline levels while vehicle-injected mice showed only 43+/-8% recovery. The application of group II mGluR antagonist (LY341495) alone delayed the recovery of PGE2- and carrageenan-induced mechanical allodynia. Three hours after injection of carrageenan, LY341495-injected mice showed little or no recovery with mechanical thresholds 8+/-1% of pre-carrageenan baselines, compared to 57+/-8% of pre-carrageenan baselines in vehicle-injected mice at the same time point. Our results suggest that activation of peripheral group II mGluRs reduces inflammation-induced mechanical allodynia and that peripheral group II mGluRs may mediate endogenous anti-allodynia effects, which speed recovery from inflammation-induced hypersensitivity.

Group II metabotropic glutamate receptors inhibit cAMP-dependent protein kinase-mediated enhancemednt of tetrodotoxin-resistant sodium currents in mouse dorsal root ganglion neurons.

Tetrodotoxin (TTX)-resistant sodium currents are important in nociception and nociceptive sensitization, which is partially due to their cAMP/protein kinase A (PKA)-mediated enhancement. Here we studied the effects of group II mGluR activation on TTX-resistant sodium currents in cultured mouse dorsal root ganglion (DRG) neurons. Activation of adenylyl cyclase with forskolin caused an increase in the amplitude of TTX-R currents and a leftward shift of the activation curve. When neurons were treated with ammonium pyrrolidinedithiocarbamate (APDC), a selective group II mGluR agonist, both the forskolin-induced increase in current amplitude and the shift of activation curve were blocked. LY341495, a group II mGluR antagonist, prevented these inhibitory effects of APDC. Our results suggest that group II mGluRs can negatively regulate TTX-R sodium currents in mouse DRG neurons.

Implicit signals in small group settings and their impact on the expression of cognitive capacity and associated brain responses.

Measures of intelligence, when broadcast, serve as salient signals of social status, which may be used to unjustly reinforce low-status stereotypes about out-groups' cultural norms. Herein, we investigate neurobehavioural signals manifest in small (n = 5) groups using functional magnetic resonance imaging and a 'ranked group IQ task' where implicit signals of social status are broadcast and differentiate individuals based on their expression of cognitive capacity. We report an initial overall decrease in the expression of cognitive capacity in the small group setting. However, the environment of the 'ranked group IQ task' eventually stratifies the population into two groups ('high performers', HP and 'low performers', LP) identifiable based on changes in estimated intelligence quotient and brain responses in the amygdala and dorsolateral prefrontal cortex. In addition, we demonstrate signals in the nucleus accumbens consistent with prediction errors in expected changes in status regardless of group membership. Our results suggest that individuals express diminished cognitive capacity in small groups, an effect that is exacerbated by perceived lower status within the group and correlated with specific neurobehavioural responses. The impact these reactions have on intergroup divisions and conflict resolution requires further investigation, but suggests that low-status groups may develop diminished capacity to mitigate conflict using non-violent means.