The relationship between self-awareness of attentional status, behavioral performance and oscillatory brain rhythms

High-level cognitive factors, including self-awareness, are believed to play an important role in human visual perception. The principal aim of this study was to determine whether oscillatory brain rhythms play a role in the neural processes involved in self-monitoring attentional status. To do so we measured cortical activity using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) while participants were asked to self-monitor their internal status, only initiating the presentation of a stimulus when they perceived their attentional focus to be maximal. We employed a hierarchical Bayesian method that uses fMRI results as soft-constrained spatial information to solve the MEG inverse problem, allowing us to estimate cortical currents in the order of millimeters and milliseconds. Our results show that, during self-monitoring of internal status, there was a sustained decrease in power within the 7-13 Hz (alpha) range in the rostral cingulate motor area (rCMA) on the human medial wall, beginning approximately 430 msec after the trial start (p < 0.05, FDR corrected). We also show that gamma-band power (41-47 Hz) within this area was positively correlated with task performance from 40-640 msec after the trial start (r = 0.71, p < 0.05). We conclude: (1) the rCMA is involved in processes governing self-monitoring of internal status; and (2) the qualitative differences between alpha and gamma activity are reflective of their different roles in self-monitoring internal states. We suggest that alpha suppression may reflect a strengthening of top-down interareal connections, while a positive correlation between gamma activity and task performance indicates that gamma may play an important role in guiding visuomotor behavior. © 2013 Yamagishi et al

LRP-1 Promotes Cancer Cell Invasion by Supporting ERK and Inhibiting JNK Signaling Pathways

Background: The low-density lipoprotein receptor-related protein-1 (LRP-1) is an endocytic receptor mediating the clearance of various extracellular molecules involved in the dissemination of cancer cells. LRP-1 thus appeared as an attractive receptor for targeting the invasive behavior of malignant cells. However, recent results suggest that LRP-1 may facilitate the development and growth of cancer metastases in vivo, but the precise contribution of the receptor during cancer progression remains to be elucidated. The lack of mechanistic insights into the intracellular signaling networks downstream of LRP-1 has prevented the understanding of its contribution towards cancer. Methodology/Principal Findings: Through a short-hairpin RNA-mediated silencing approach, we identified LRP-1 as a main regulator of ERK and JNK signaling in a tumor cell context. Co-immunoprecipitation experiments revealed that LRP-1 constitutes an intracellular docking site for MAPK containing complexes. By using pharmacological agents, constitutively active and dominant-negative kinases, we demonstrated that LRP-1 maintains malignant cells in an adhesive state that is favorable for invasion by activating ERK and inhibiting JNK. We further demonstrated that the LRP-1-dependent regulation of MAPK signaling organizes the cytoskeletal architecture and mediates adhesive complex turnover in cancer cells. Moreover, we found that LRP-1 is tethered to the actin network and to focal adhesion sites and controls ERK and JNK targeting to talin-rich structures. Conclusions: We identified ERK and JNK as the main molecular relays by which LRP-1 regulates focal adhesion disassembly of malignant cells to support invasion

Neural Correlates of Visual Motion Prediction

Predicting the trajectories of moving objects in our surroundings is important for many life scenarios, such as driving, walking, reaching, hunting and combat. We determined human subjects’ performance and task-related brain activity in a motion trajectory prediction task. The task required spatial and motion working memory as well as the ability to extrapolate motion information in time to predict future object locations. We showed that the neural circuits associated with motion prediction included frontal, parietal and insular cortex, as well as the thalamus and the visual cortex. Interestingly, deactivation of many of these regions seemed to be more closely related to task performance. The differential activity during motion prediction vs. direct observation was also correlated with task performance. The neural networks involved in our visual motion prediction task are significantly different from those that underlie visual motion memory and imagery. Our results set the stage for the examination of the effects of deficiencies in these networks, such as those caused by aging and mental disorders, on visual motion prediction and its consequences on mobility related daily activities

The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk

Proteins containing a caveolin-binding domain (CBD), such as the Rho-GTPases, can interact with caveolin-1 (Cav1) through its caveolin scaffold domain. Rho-GTPases are important regulators of p130Cas, which is crucial for both normal cell migration and Src kinase-mediated metastasis of cancer cells. However, although Rho-GTPases (particularly RhoC) and Cav1 have been linked to cancer progression and metastasis, the underlying molecular mechanisms are largely unknown. To investigate the function of Cav1–Rho-GTPase interaction in metastasis, we disrupted Cav1–Rho-GTPase binding in melanoma and mammary epithelial tumor cells by overexpressing CBD, and examined the loss-of-function of RhoC in metastatic cancer cells. Cancer cells overexpressing CBD or lacking RhoC had reduced p130Cas phosphorylation and Rac1 activation, resulting in an inhibition of migration and invasion in vitro. The activity of Src and the activation of its downstream targets FAK, Pyk2, Ras and extracellular signal-regulated kinase (Erk)1/2 were also impaired. A reduction in α5-integrin expression, which is required for binding to fibronectin and thus cell migration and survival, was observed in CBD-expressing cells and cells lacking RhoC. As a result of these defects, CBD-expressing melanoma cells had a reduced ability to metastasize in recipient mice, and impaired extravasation and survival in secondary sites in chicken embryos. Our data indicate that interaction between Cav1 and Rho-GTPases (most likely RhoC but not RhoA) promotes metastasis by stimulating α5-integrin expression and regulating the Src-dependent activation of p130Cas/Rac1, FAK/Pyk2 and Ras/Erk1/2 signaling cascades

Rho-Regulatory Proteins in Breast Cancer Cell Motility and Invasion

The importance of the Rho-GTPases in cancer progression, particularly in the area of metastasis, is becoming increasingly evident. This review will provide an overview of the role of the Rho-regulatory proteins in breast cancer metastatis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44220/1/10549_2004_Article_5264599.pd

The Influence of Gatekeeping and Utilization Review on Patient Satisfaction

OBJECTIVE: To examine the influence of utilization review and denial of specialty referrals on patient satisfaction with overall medical care, willingness to recommend one’s physician group to a friend, and desire to disenroll from the health plan. DESIGN: Two cross-sectional questionnaires: one of physician groups and one of patient satisfaction. SETTING: Eighty-eight capitated physician groups in California. PARTICIPANTS: Participants were 11,710 patients enrolled in a large California network-model HMO in 1993 who received care in one of the 88 physician groups. MEASUREMENTS AND MAIN RESULTS: Our main measures were how groups conducted utilization review for specialty referrals and tests, patient-reported denial of specialty referrals, and patient satisfaction with overall medical care. Patients in groups that required preauthorization for access to many types of specialists were significantly (p≤ .001) less satisfied than patients in groups that had few preauthorization requirements, even after adjusting for patient and other group characteristics. Patients who had wanted to see a specialist in the previous year but did not see one were significantly less satisfied than those who had wanted to see a specialist and actually saw one (p < .001). In addition, patients who did not see a specialist when desired were more likely to want to disenroll from the health plan than patients who saw the specialist (40% vs 18%, p≤ .001) and more likely not to recommend their group to a friend (38% vs 13%, p≤ .001). CONCLUSIONS: Policies that limited direct access to specialists, and especially denial of patient-desired referrals, were associated with significantly lower patient satisfaction, increased desire to disenroll, and lower likelihood of recommending the group to a friend. Health plans and physician groups need to take these factors into account when designing strategies to reduce specialty care use

CCL2 disrupts the adherens junction: implications for neuroinflammation

Alterations to blood-brain barrier (BBB) adhesion molecules and junctional integrity during neuroinflammation can promote central nervous system (CNS) pathology. The chemokine CCL2 is elevated during CNS inflammation and is associated with endothelial dysfunction. The effects of CCL2 on endothelial adherens junctions (AJs) have not been defined. We demonstrate that CCL2 transiently induces Src-dependent disruption of human brain microvascular endothelial AJ. β-Catenin is phosphorylated and traffics from the AJ to PECAM-1 (platelet endothelial cell adhesion molecule-1), where it is sequestered at the membrane. PECAM-1 is also tyrosine-phosphorylated, an event associated with recruitment of the phosphatase SHP-2 (Src homology 2 domain-containing protein phosphatase) to PECAM-1, β-catenin release from PECAM-1, and reassociation of β-catenin with the AJ. Surface localization of PECAM-1 is increased in response to CCL2. This may enable the endothelium to sustain CCL2-induced alterations in AJ and facilitate recruitment of leukocytes into the CNS. Our novel findings provide a mechanism for CCL2-mediated disruption of endothelial junctions that may contribute to BBB dysfunction and increased leukocyte recruitment in neuroinflammatory diseases

v-SRC'S hold over actin and cell adhesions

The oncoprotein v-Src and its cellular homologue (c-Src) are tyrosine kinases that modulate the actin cytoskeleton and cell adhesions. Through the concerted action of their protein-interaction and kinase domains, they are targeted to cell–matrix integrin adhesions or cadherin-dependent junctions between epithelial cells, where they phosphorylate substrates that induce adhesion turnover and actin re-modelling. Recent experiments have defined some of the key targets and effector pathways that mediate the pleiotropic oncogenic effects of v-Src