Role of the medial part of the intraparietal sulcus in implementing movement direction

The contribution of the posterior parietal cortex (PPC) to visually guided movements has been originally inferred from observations made in patients suffering from optic ataxia. Subsequent electrophysiological studies in monkeys and functional imaging data in humans have corroborated the key role played by the PPC in sensorimotor transformations underlying goal-directed movements, although the exact contribution of this structure remains debated. Here, we used transcranial magnetic stimulation (TMS) to interfere transiently with the function of the left or right medial part of the intraparietal sulcus (mIPS) in healthy volunteers performing visually guided movements with the right hand. We found that a "virtual lesion" of either mIPS increased the scattering in initial movement direction (DIR), leading to longer trajectory and prolonged movement time, but only when TMS was delivered 100-160 ms before movement onset and for movements directed toward contralateral targets. Control experiments showed that deficits in DIR consequent to mIPS virtual lesions resulted from an inappropriate implementation of the motor command underlying the forthcoming movement and not from an inaccurate computation of the target localization. The present study indicates that mIPS plays a causal role in implementing specifically the direction vector of visually guided movements toward objects situated in the contralateral hemifield

ERK Activation and Cell Growth Require CaM Kinases in MCF-7 Breast Cancer Cells

Previous studies on MCF-7 breast cancer cells have shown that the G-protein coupled receptor (GPCR) agonist carbachol increases intracellular calcium levels and the activation of extracellular signal-regulated kinase (ERK). Calcium and calmodulin regulate the calcium/calmodulin- dependent kinase (CaM kinase) family of proteins that have been proposed to regulate ERK and gene transcription. Our results suggest that both estrogen (E2) and carbachol treatment of MCF-7 breast cancer cells trigger phosphorylation of ERK I /2 and the transcription factor Elk-1. Carbachol and estrogen triggered nearly a four- to sixfold increase in MCF-7 cell proliferation by 96 h, respectively. Carbachol-stimulated ERK activation and cell growth was completely blocked by the Muscarinic M3- subtype GPCR inhibitor, 4-DAMP, and siRNA against the M3-subtype GPCR. Interestingly, blockade of CaM KK with the selective inhibitor ST0-609 prevented carbachol activation CaM KI, ERK, Elk-1 , and cell gro\vth. Consistent with these observations, knockdown of CaM KKa and CaM Kly with shRNA-containing plas1nids blocked ERK activation by carbachol. In addition, Elk-I phosphorylation and luciferase activity in response to carbachol treat1nent was also dependent upon CaM kinases and was inhibited by U0126, ST0-609, and siRNA knockdown of CaM kinases and ERK2. Finally, blockade of either CaM KK (with ST0-609) or ERK (with U0126) activities resulted in the inhibition of carbachol- and estrogen-mediated cyclin Dl expression and MCF-7 cell growth. Taken together, our results suggest that carbachol treatment of MCF-7 cells activates CaM KI, ERK, the transcription factor Elk-1 , cyclin D 1, and cell grovvth through CaM KK

Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target

Cholangiocarcinoma is the second most common primary liver cancer and responds poorly to existing therapies. Intrahepatic cholangiocarcinoma (ICC) likely originates from the biliary tree and develops within the hepatic parenchyma. We have generated a flexible orthotopic allograft mouse model of ICC that incorporates common genetic alterations identified in human ICC and histologically resembles the human disease. We examined the utility of this model to validate driver alterations in ICC and tested their suitability as therapeutic targets. Specifically, we showed that the fused-in-glioblastoma-c- ros-oncogene1 (FIG-ROS1(S); FIG- ROS) fusion gene dramatically accelerates ICC development and that its inactivation in established tumors has a potent antitumor effect. Our studies establish a versatile model of ICC that will be a useful preclinical tool and validate ROS1 fusions as potent oncoproteins and therapeutic targets in ICC and potentially other tumor types

Dissociable contribution of the parietal and frontal cortex to coding movement direction and amplitude

© 2015 Davare, Zénon, Desmurget and Olivier. To reach for an object, we must convert its spatial location into an appropriate motor command, merging movement direction and amplitude. In humans, it has been suggested that this visuo-motor transformation occurs in a dorsomedial parieto-frontal pathway, although the causal contribution of the areas constituting the “reaching circuit” remains unknown. Here we used transcranial magnetic stimulation (TMS) in healthy volunteers to disrupt the function of either the medial intraparietal area (mIPS) or dorsal premotor cortex (PMd), in each hemisphere. The task consisted in performing step-tracking movements with the right wrist towards targets located in different directions and eccentricities; targets were either visible for the whole trial (Target-ON) or flashed for 200 ms (Target-OFF). Left and right mIPS disruption led to errors in the initial direction of movements performed towards contralateral targets. These errors were corrected online in the Target-ON condition but when the target was flashed for 200 ms, mIPS TMS manifested as a larger endpoint spreading. In contrast, left PMd virtual lesions led to higher acceleration and velocity peaks—two parameters typically used to probe the planned movement amplitude—irrespective of the target position, hemifield and presentation condition; in the Target-OFF condition, left PMd TMS induced overshooting and increased the endpoint dispersion along the axis of the target direction. These results indicate that left PMd intervenes in coding amplitude during movement preparation. The critical TMS timings leading to errors in direction and amplitude were different, namely 160–100 ms before movement onset for mIPS and 100–40 ms for left PMd. TMS applied over right PMd had no significant effect. These results demonstrate that, during motor preparation, direction and amplitude of goal-directed movements are processed by different cortical areas, at distinct timings, and according to a specific hemispheric organization.ARC (Actions de Recherche Concertées, Communauté Française de Belgique); Fondation Médicale Reine Elisabeth (FMRE) and from the Fonds de la Recherche Scientifique (FNRS–FDP); BBSRC David Phillips fellowship (UK), the Royal Society (UK); FWO Odysseus project (Fonds WetenschappelijkOnderzoek,Belgium).AZisaSeniorResearch AssociatesupportedbyINNOVIRIS

Grasp-specific motor resonance is influenced by the visibility of the observed actor

Motor resonance is the modulation of M1 corticospinal excitability induced by observation of others' actions. Recent brain imaging studies have revealed that viewing videos of grasping actions led to a differential activation of the ventral premotor cortex depending on whether the entire person is viewed versus only their disembodied hand. Here we used transcranial magnetic stimulation (TMS) to examine motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) during observation of videos or static images in which a whole person or merely the hand was seen reaching and grasping a peanut (precision grip) or an apple (whole hand grasp). Participants were presented with six visual conditions in which visual stimuli (video vs static image), view (whole person vs hand) and grasp (precision grip vs whole hand grasp) were varied in a 2 × 2 × 2 factorial design. Observing videos, but not static images, of a hand grasping different objects resulted in a grasp-specific interaction, such that FDI and ADM MEPs were differentially modulated depending on the type of grasp being observed (precision grip vs whole hand grasp). This interaction was present when observing the hand acting, but not when observing the whole person acting. Additional experiments revealed that these results were unlikely to be due to the relative size of the hand being observed. Our results suggest that observation of videos rather than static images is critical for motor resonance. Importantly, observing the whole person performing the action abolished the grasp-specific effect, which could be due to a variety of PMv inputs converging on M1

Low power coordination in wireless ad-hoc networks

ABSTRACT Distributed wireless ad-hoc networks @WANs) pose numerous technical Among them, two are widely conthese problems, two are of dominating importance: (i) low energy and Operation and (ii) autonomous localized operation and decision making. Recent studies have shown sidered as crucial: autonomous localized operation and minimization of energy consumption. We address the fundamental problem of how to maximize life-time of the network by using only local information while preserving network connectivity, We start by introducing the Care-Ree Sleep (CS) Theorem that provides provably optimal necessary and nodes are not required for addressing the current network cient conditions for a node to turn off its radio while ensuring and Although there have been a number of efforts to deterthat global connectivity is not affected. The cS theorem is the basis for an efficient localized almine the conditions for a node to enter sleep state using gorithm that decides which node will turn its radio off, and only locally available information while preserving the overfor how long, The effectiveness of the approach is demonall connectivity of the network, only heuristic answers have sleep coordination problem. The sleep coordination problem the algorithm over a wide range of network parameters. is interesting and challenging from several view points: 0 Complexity of the Problem. The nodes that stay Categories and Subject Descriptors awake to preserve the connectivity of the network form a [ C O M P U T E R -C O M M U N I C A T I O N N E T W O R K S ] : connected dominating set on the network graph. Finding Network Protocols; C.4 [ P E R F O R M A N C E OF S Y S - the minimum connected dominating set can be proven to be TEMS]: [Reliability, availability, and serviceability] NP-complete. Therefore, even in cases where we do have the complete graph information about the whole network, finding the optimal solution in polynomial time is unlikely. Furthermore, setting the proper sleep times t o the nodes to maximize the overall network's lifetime, adds a new dimension to the NP-complete minimum connected dominating 0 Scope of the Problem. For a sleep coordination procedure, making a globally sound decision using only local information is a challenging task. Changing the status of even one node can potentially impact any node in the network ill terms Of its CODneCtiVity and energy consumption. 0 Guaranteed Connectivity. There is a need to determine under which conditions, a Particular node can sleep, while still guaranteeing that the network is connected. 0 Protocol Design. The autonomous operation of the nodes in DWANs has several advantages including fault tolerance, fast response to changes, and non-PrePlanned network structure. However, interaction and collaboration between the nodes and existence of shared resources, dictates a need for a protocol that can handle concurrency and synchronization of the autonomous ad-hoc node decisions. The power saving coordination strategy introduced here attempts to address these challenges. we start by introducing the care-nee sleep (CS) theorem that establishes provably optimal necessary and sufficient conditions for a given node to enter sleep state without disconnecting the network. strated using numerous simulations of the performance of been Presented [17, 3~ ' 1. we refer to this Problem as the General Terms Algorithms, Design, Performance Keywords set problem. Wireless ad-hoc network, low-power, coordinatio

Stimulation of PPC affects the mapping between motion and force signals for stiffness perception but not motion control

How motion and sensory inputs are combined to assess an object’s stiffness is still unknown. Here, we provide evidence for the existence of a stiffness estimator in the human posterior parietal cortex (PPC). We showed previously that delaying force feedback with respect to motion when interacting with an object caused participants to underestimate its stiffness. We found that applying theta-burst transcranial magnetic stimulation (TMS) over the PPC, but not the dorsal premotor cortex, enhances this effect without affecting movement control. We explain this enhancement as an additional lag in force signals. This is the first causal evidence that the PPC is not only involved in motion control, but also has an important role in perception that is disassociated from action. We provide a computational model suggesting that the PPC integrates position and force signals for perception of stiffness and that TMS alters the synchronization between the two signals causing lasting consequences on perceptual behavior

Long-latency modulation of motor cortex excitability by ipsilateral posterior inferior frontal gyrus and pre-supplementary motor area

The primary motor cortex (M1) is strongly influenced by several frontal regions. Dual-site transcranial magnetic stimulation (dsTMS) has highlighted the timing of early (<40 ms) prefrontal/premotor influences over M1. Here we used dsTMS to investigate, for the first time, longer-latency causal interactions of the posterior inferior frontal gyrus (pIFG) and pre-supplementary motor area (pre-SMA) with M1 at rest. A suprathreshold test stimulus (TS) was applied over M1 producing a motor-evoked potential (MEP) in the relaxed hand. Either a subthreshold or a suprathreshold conditioning stimulus (CS) was administered over ipsilateral pIFG/pre-SMA sites before the TS at different CS-TS inter-stimulus intervals (ISIs: 40-150 ms). Independently of intensity, CS over pIFG and pre-SMA (but not over a control site) inhibited MEPs at an ISI of 40 ms. The CS over pIFG produced a second peak of inhibition at an ISI of 150 ms. Additionally, facilitatory modulations were found at an ISI of 60 ms, with supra-but not subthreshold CS intensities. These findings suggest differential modulatory roles of pIFG and pre-SMA in M1 excitability. In particular, the pIFG-but not the pre-SMA-exerts intensity-dependent modulatory influences over M1 within the explored time window of 40-150 ms, evidencing fine-tuned control of M1 output