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Muscle spindles provide critical information about movement position and velocity. They have been shown to act as stretch receptors in passive muscle, however, during active movements their behavior is less clear. In particular, spindle responses have been shown to be out-of-phase or phase advanced with respect to their expected muscle length-sensitivity. Whether this apparent discrepancy of spindle responses between passive and active movements is due to fusimotor (γ-drive) remains unresolved, since the activity of fusimotor neurons during voluntary non-locomotor movements are largely unknown. We developed a computational model to predict fusimotor activity and to investigate whether fusimotor activity could explain the empirically observed phase advance of spindle responses. The model links a biomechanical wrist model to length- and γ-drive-dependent transfer functions of type Ia and type II muscle spindle activity. Our simulations of two wrist-movement tasks suggest that (i) experimentally observed type Ia and type II activity profiles can to a large part be explained by appropriate, i.e. strongly modulated and task-dependent, γ-drive. That (ii) the empirically observed phase advance of type Ia or of type II profiles during active movement can be similarly explained by appropriate γ-drive. In summary, the simulation predicts that a highly task-modulated activation of the γ-system is instrumental in producing a large part of the empirically observed muscle spindle activity for voluntary wrist movements.

Background: Abnormal cortical processing of sensory inputs has been found bilaterally in writer's cramp (WC). This study tested the hypothesis that patients with WC have an impaired ability to adjust grip forces according to visual and somatosensory cues in both hands., Methods: A unimanual visuomotor force-tracking task and a bimanual sense of effort force-matching task were performed by WC patients and healthy controls., Results: In visuomotor tracking, WC patients showed increased error, greater variability, and longer release duration than controls. In the force-matching task, patients underestimated, whereas controls overestimated, the force applied in the other hand. Visuomotor tracking and force matching were equally impaired in both the symptomatic and nonsymptomatic hand in WC patients., Conclusions: This study provides evidence of bilaterally impaired grip-force control in WC, when using visual or sense of effort cues. This suggests a generalized subclinical deficit in sensorimotor integration in WC., (Copyright © 2013 Movement Disorder Society.)

Color is a ubiquitous perceptual stimulus that is often considered in terms of aesthetics. Here we review theoretical and empirical work that looks beyond color aesthetics to the link between color and psychological functioning in humans. We begin by setting a historical context for research in this area, particularly highlighting methodological issues that hampered earlier empirical work. We proceed to overview theoretical and methodological advances during the past decade and conduct a review of emerging empirical findings. Our empirical review focuses especially on color in achievement and affiliation/attraction contexts, but it also covers work on consumer behavior as well as food and beverage evaluation and consumption. The review clearly shows that color can carry important meaning and can have an important impact on people's affect, cognition, and behavior. The literature remains at a nascent stage of development, however, and we note that considerable work on boundary conditions, moderators, and real-world generalizability is needed before strong conceptual statements and recommendations for application are warranted. We provide suggestions for future research and conclude by emphasizing the broad promise of research in this area.

Lipid nanoparticles (LNPs) encapsulating short interfering RNAs that target hepatic genes are advancing through clinical trials, and early results indicate the excellent gene silencing observed in rodents and nonhuman primates also translates to humans. This success has motivated research to identify ways to further advance this delivery platform. Here, we characterize the polyethylene glycol lipid (PEG-lipid) components, which are required to control the self-assembly process during formation of lipid particles, but can negatively affect delivery to hepatocytes and hepatic gene silencing in vivo. The rate of transfer from LNPs to plasma lipoproteins in vivo is measured for three PEG-lipids with dialkyl chains 14, 16, and 18 carbons long. We show that 1.5 mol % PEG-lipid represents a threshold concentration at which the chain length exerts a minimal effect on hepatic gene silencing but can still modify LNPs pharmacokinetics and biodistribution. Increasing the concentration to 2.5 and 3.5 mol % substantially compromises hepatocyte gene knockdown for PEG-lipids with distearyl (C18) chains but has little impact for shorter dimyristyl (C14) chains. These data are discussed with respect to RNA delivery and the different rates at which the steric barrier disassociates from LNPs in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e139; doi:10.1038/mtna.2013.66; published online 17 December 2013.

Contrary to predictions from Expected Utility Theory and Game Theory, when making economic decisions in interpersonal situations, people take the interest of others into account and express various forms of solidarity, even in one-shot interactions with anonymous strangers. Research in other-regarding behavior is dominated by behavioral economical and evolutionary biological approaches. Psychological theory building, which addresses mental processes underlying other-regarding behavior, is rare. Based on Relational Models Theory (RMT, [1]) and Relationship Regulation Theory (RRT, [2]) it is proposed that moral motives influence individuals' decision behavior in interpersonal situations via conscious and unconscious (automatic) processes. To test our propositions we developed the 'Dyadic Solidarity Game' and its solitary equivalent, the 'Self-Insurance Game'. Four experiments, in which the moral motives "Unity" and "Proportionality" were manipulated, support the propositions made. First, it was shown that consciously activated moral motives (via framing of the overall goal of the experiment) and unconsciously activated moral motives (via subliminal priming) influence other-regarding behavior. Second, this influence was only found in interpersonal, not in solitary situations. Third, by combining the analyses of the two experimental games the extent to which participants apply the Golden Rule ("treat others how you wish to be treated") could be established. Individuals with a "Unity" motive treated others like themselves, whereas individuals with a "Proportionality" motive gave others less then they gave themselves. The four experiments not only support the assumption that morals matter in economic games, they also deliver new insights in how morals matter in economic decision making.

Objectives: To investigate median nerve structure in patients with recurrent carpal tunnel syndrome (CTS) using diffusion tensor imaging (DTI) and to relate DTI changes to anatomical MRI and to measures of median nerve function., Methods: Median nerve structure was quantified according to DTI in patients with recurrent CTS and in healthy controls of similar age. Anatomical MRI was used to identify the presence of nerve compression and fibrosis. Median nerve function was measured using electromyography, a force-tracking task (accuracy of precision grip control) and clinical measures., Results: Patients showed reduced apparent diffusion coefficient (ADC), reduced axial diffusivity (AD) and radial diffusivity (RD) along the median nerve compared with controls (P < 0.001). Patients with endoneural fibrosis had the greatest reductions in ADC and in RD. ADC and AD correlated positively with nerve conduction velocity (R = 0.54 and R = 0.68, respectively) and fractional anisotropy correlated negatively with error during force-tracking (R = -0.58)., Conclusions: A specific pattern of DTI changes in the median nerve was identified in patients with recurrent CTS. Fibrosis may be underlying these structural changes. The correlations with nerve conduction velocity and accuracy of force control suggest that DTI is a promising technique in the study of median nerve structure in recurrent CTS., Key Points: • Diffusion tensor imaging (DTI) offers further possibilities in musculoskeletal magnetic resonance imaging. • DTI reveals median nerve changes in recurrent carpal tunnel syndrome. • DTI changes were greater with signs of median nerve fibrosis. • DTI parameters correlated with nerve conduction and force control measures. • DTI is a promising technique in recurrent carpal tunnel syndrome.

In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available.

The responses of individual primate corticospinal neurons to localized electrical stimulation of primary motor (M1) and of ventral premotor cortex (area F5) are poorly documented. To rectify this and to study interactions between responses from these areas, we recorded corticospinal axons, identified by pyramidal tract stimulation, in the cervical spinal cord of three chloralose-anesthetized macaque monkeys. Single stimuli (≤400 μA) were delivered to the hand area of M1 or F5 through intracortical microwire arrays. Only 14/112 (13%) axons showed responses to M1 stimuli that indicated direct intracortical activation of corticospinal neurons (D-responses); no D-responses were seen from F5. In contrast, 62 axons (55%) exhibited consistent later responses to M1 stimulation, corresponding to indirect activation (I-responses), showing that single-pulse intracortical stimulation of motor areas can result in trans-synaptic activation of a high proportion of the corticospinal output. A combined latency histogram of all axon responses was nonperiodic, clearly different from the periodic surface-recorded corticospinal volleys. This was readily explained by correcting for conduction velocities of individual axons. D-responding axons, taken as originating in neurons close to the M1 stimulating electrodes, showed more I-responses from M1 than those without a D-response, and 8/10 of these axons also responded to F5 stimulation. Altogether, 33% of tested axons responded to F5 stimulation, most of which also showed I-responses from M1. These excitatory effects are in keeping with facilitation of hand muscles evoked from F5 being relayed via M1. This was further demonstrated by facilitation of test responses from M1 by conditioning F5 stimuli.

Non-healing wounds represent a challenging problem for physicians and patients alike. Although treatment strategies are aimed at specific causes, there are basic management principles that apply to all wounds. The purpose of this article is to review these core management principles as they apply to lower extremity wounds. Key points include a multidisciplinary approach and individualized plans of care as per specific patient needs. A comprehensive treatment plan will lead to faster healing and improved outcomes.

Francis (2013) tested for and found evidence of publication bias in 1 of the 3 focal relations examined in Elliot et al. (2010), that between red and attractiveness. He then called into question the research as a whole and the field of experimental psychology more generally. Our reply has 3 foci. First, we attend to the bottom line regarding the red-attractiveness effect; it has already been replicated and extended by several independent laboratories. Second, we note that the test applied to our research is an exploratory test meant to be used cautiously and highlight ways in which the application to our research seems incautious. Third, we place the critique in the broader context of the prevailing norms and practices of the field and suggest that the preferred approach to reevaluating and revising the system currently in place is the frank, creative exchange of ideas already underway., (2013 APA, all rights reserved)

Objectives: Spinal canal stenosis is often measured on anatomical magnetic resonance imaging (MRI) to estimate the degree of spinal cord compression. This study examined whether two quantitative measures of spinal canal stenosis taken from anatomical MRI are related to spinal cord white-matter integrity in patients with cervical spondylosis measured by diffusion tensor imaging (DTI)., Patients and Methods: DTI and T2-weighted MRI of the cervical spinal cord were performed in 15 patients with cervical spondylosis and ten healthy control subjects of similar age. Severity of stenosis was calculated using Pavlov's ratio and the space-available-for-cord (SAC) technique., Results: Patients had significantly lower Pavlov's ratios and SAC (C2-C3, C4-C5 and C6-C7), lower fractional anisotropy (FA; C2-C3 and C4-C5) and higher radial diffusivity (C2-C3, C4-C5 and C6-C7) than the controls. In patients, only Pavlov's ratio correlated with mean FA (R=0.66, P=0.008). Variations in Pavlov's ratio and FA also showed a similar pattern across cervical levels., Conclusion: Pavlov's ratio is a better predictor of spinal cord integrity than the SAC and, therefore, may be more relevant clinically for the evaluation of stenosis in patients with cervical spondylosis., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Special (lipid) delivery: The role of the ionizable lipid pK(a) in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pK(a) value and silencing of the mouse FVII gene (FVII ED(50) ) was found, with an optimal pK(a) range of 6.2-6.5. The most potent cationic lipid from this study has ED(50) levels around 0.005 mg kg(-1) in mice and less than 0.03 mg kg(-1) in non-human primates., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The present research sought to extend the nascent literature on color and psychological functioning by examining whether perception of the color green facilitates creativity. In four experiments, we demonstrated that a brief glimpse of green prior to a creativity task enhances creative performance. This green effect was observed using both achromatic (white, gray) and chromatic (red, blue) contrast colors that were carefully matched on nonhue properties, and using both picture-based and word-based assessments of creativity. Participants were not aware of the purpose of the experiment, and null effects were obtained on participants' self-reported mood and positive activation. These findings indicate that green has implications beyond aesthetics and suggest the need for sustained empirical work on the functional meaning of green.

Adequate grip force modulation is critical to manual dexterity and often impaired in hemiparetic stroke patients. Previous studies in hemiparetic patients suggest that aspects of grip force control may be differently affected by the lesion. We developed a visuomotor power grip force-tracking task allowing quantification of tracking error, force variability and release duration. We investigated force control in 24 chronic stroke patients with varying severity of hemiparesis and in healthy control subjects. Force tracking was performed at 10, 20, and 30% maximal voluntary contraction (MVC). Control subjects were also tested at absolute force levels similar to those of the patients. Patients tracking with their paretic hand at similar relative (%MVC) grip force levels showed increased error, force variability and release duration, but surprisingly, there was no difference in tracking error or variability between patients and control subjects performing at similar absolute force levels. Furthermore, patients improved their tracking performance across repeated blocks similar to control subjects. Release duration, however, was increased (also in the non-paretic hand), was force-independent and did not correlate with MVC strength. Of the three performance measures, only release duration explained some of the variance in arm and hand function (Frenchay Arm Test score), independent of MVC strength. The findings show (i) that hemiparetic stroke patients preserve the ability to modulate (generate and maintain) power grip force within their limited force range and (ii) that MVC grip strength and duration of grip release are differently affected and are two complementary predictors of arm function after stroke., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This paper describes a computational model of use-dependent recovery of movement strength following a stroke. The model frames the problem of strength recovery as that of learning appropriate activations of residual corticospinal neurons to their target motoneuronal pools. For example, for an agonist/antagonist muscle pair, we assume the motor system must learn to activate preserved agonist-exciting corticospinal neurons and deactivate preserved antagonist-exciting corticospinal neurons. The model incorporates a biologically plausible reinforcement learning algorithm for adjusting cell activation patterns-stochastic search-using generated limb force as the teaching signal to adjust the synaptic weights that determine cell activations. The model makes predictions consistent with clinical and brain imaging data, such as that patients can achieve an increase in strength after appearing to reach a recovery plateau (i.e., "residual capacity"), that the differential effect of a dose of movement practice will be greater earlier in recovery, and that force-related brain activation will increase in secondary motor areas following a stroke. An interesting prediction that could be explored clinically is that temporarily inhibiting subpopulations of more powerfully connected corticospinal neurons during late movement training will allow the motor system to optimize corticospinal neurons with a weaker influence, whose optimization was blocked by the rapid optimization of more strongly connected neurons early in training., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: A basic premise of the recently proffered color-in-context model is that the influence of color on psychological functioning varies as a function of the psychological context in which color is perceived. Some research has examined the appetitive and aversive implications of viewing the color red in romance- and achievement-relevant contexts, respectively, but in all existing empirical work approach and avoidance behavior has been studied in separate tasks and separate experiments. Research is needed to directly test whether red influences the same behavior differently depending entirely on psychological context., Methodology/principal Findings: The present experiment was designed to put this premise to direct test in romance- and achievement-relevant contexts within the same experimental paradigm involving walking behavior. Our results revealed that exposure to red (but not blue) indeed has differential implications for walking behavior as a function of the context in which the color is perceived. Red increased the speed with which participants walked to an ostensible interview about dating (a romance-relevant context), but decreased the speed with which they walked to an ostensible interview about intelligence (an achievement-relevant context)., Conclusions/significance: These results are the first direct evidence that the influence of red on psychological functioning in humans varies by psychological context. Our findings contribute to both the literature on color psychology and the broader, emerging literature on the influence of context on basic psychological processes.

Recent brain-machine interfaces (BMI) have demonstrated the use of intracortical signals for the kinematic control of robotic arms. However, for potential restoration of manual dexterity, two issues remain to be addressed: (1) Can hand and digit movements for dexterous manipulation be controlled in a similar way to arm movements? (2) Can the potentially large signal space for decoding of the many degrees of freedom (dof) of hand and digit movements be minimized? The first question addresses BMI control of dexterous prosthetic devices, while the second addresses the problem of whether few, but identified, neurons might provide adequate decoding. Asynchronous decoding of precision grip finger movement kinematics from identified corticomotoneuronal (CM) cell activity was performed with an artificial neural network (ANN). After training over a given session, the ANNs successfully decoded trial-by-trial movement kinematics. Average accuracy over sessions was in the order of 80% and 50% for data sets of two monkeys respectively. Decoding accuracy increased as a function of (1) number of simultaneously recorded CM cells used for prediction, and (2) size of the sliding input window. Subsequently, a robot digit actuated by pneumatic artificial muscles, fed with the predicted trajectory, mimicked the recorded movement offline. Furthermore, CM cell signals were used for decoding of time-varying hand muscle EMG activity. The performance of EMG prediction tended to increase if CM cells that facilitated this particular muscle (compared to CM cells that facilitated other muscles) were used. These results provide evidence that an anthropomorphic robot finger can be controlled offline by spike trains recorded from identified corticospinal neurons. This represents a step towards neuroprosthetic devices for dexterous hand movements.

Motor skill acquisition in the lower limb may induce modifications of spinal network excitability. We hypothesized that short-term motor adaptation in precision grip tasks would also induce modifications of cervical spinal network excitability. In a first series of experiments, we studied the impact of two different precision grip force control tasks (a visuomotor force-tracking task and a control force task without visual feedback) on cervical spinal network excitability in healthy subjects. We separately tested the efficacy of two key components of the spinal circuitry: (i) presynaptic inhibition on flexor carpi radialis (FCR) Ia terminals, and (ii) disynaptic inhibition directed from extensor carpi radialis (ECR) to FCR. We found that disynaptic inhibition decreased temporarily after both force control tasks, independently of the presence of visual feedback. In contrast, the amount of presynaptic inhibition on FCR Ia terminals decreased only after the visuomotor force tracking task. This temporary decrease was correlated with improved tracking accuracy during the task (i.e. short-term motor adaptation). A second series of experiments confirmed these results and showed that the visuomotor force-tracking task resulted also in an increase of the Hmax/Mmax ratio and the slope of the ascending part of the H-reflex recruitment curve. In order to address the role of presynaptic inhibition in the motor adaptation process, we conducted a third series of experiments during which presynaptic inhibition was recorded before and after two consecutive sessions of visuomotor force tracking. The results showed that (i) improved tracking accuracy occurred during both sessions, and (ii) presynaptic inhibition decreased only after the first session of visuomotor force tracking. Taken together, these results suggest thus that the nature of the motor task performed has a specific impact on the excitability of these cervical spinal circuits. These findings also suggest that early motor adaptation is associated with a modulation of presynaptic Ia inhibition in the upper limb.

This letter presents a novel unsupervised sensory matching learning technique for the development of an internal representation of three-dimensional information. The representation is invariant with respect to the sensory modalities involved. Acquisition of the internal representation is demonstrated with a neural network model of a sensorimotor system of a simple model creature, consisting of a tactile-sensitive body and a multiple-degrees-of-freedom arm with proprioceptive sensitivity. Acquisition of the 3D representation as well as a distributed representation of the body scheme, occurs through sensorimotor interactions (i.e., the sensory-motor experience of the creature). Convergence of the learning is demonstrated through computer simulations for the model creature with a 7-DoF arm and a spherical body covered by 20 tactile fields.

We have previously demonstrated that conjugation of small molecule ligands to small interfering RNAs (siRNAs) and anti-microRNAs results in functional siRNAs and antagomirs in vivo. Here we report on the development of an efficient chemical strategy to make oligoribonucleotide-ligand conjugates using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) or click reaction. Three click reaction approaches were evaluated for their feasibility and suitability for high-throughput synthesis: the CuAAC reaction at the monomer level prior to oligonucleotide synthesis, the solution-phase postsynthetic "click conjugation", and the "click conjugation" on an immobilized and completely protected alkyne-oligonucleotide scaffold. Nucleosides bearing 5'-alkyne moieties were used for conjugation to the 5'-end of the oligonucleotide. Previously described 2'- and 3'-O-propargylated nucleosides were prepared to introduce the alkyne moiety to the 3' and 5' termini and to the internal positions of the scaffold. Azido-functionalized ligands bearing lipophilic long chain alkyls, cholesterol, oligoamine, and carbohydrate were utilized to study the effect of physicochemical characteristics of the incoming azide on click conjugation to the alkyne-oligonucleotide scaffold in solution and on immobilized solid support. We found that microwave-assisted click conjugation of azido-functionalized ligands to a fully protected solid-support bound alkyne-oligonucleotide prior to deprotection was the most efficient "click conjugation" strategy for site-specific, high-throughput oligonucleotide conjugate synthesis tested. The siRNA conjugates synthesized using this approach effectively silenced expression of a luciferase gene in a stably transformed HeLa cell line.

Background and Purpose: wallerian degeneration (WD) in descending motor tracts after stroke is described at the level of the internal capsule and the brainstem. We investigated whether diffusion tensor imaging (DTI) can detect degeneration in the lateral cervical spinal cord after stroke., Methods: DTI at 1.5 T of the cervical spinal cord was performed in 4 chronic hemiparetic patients after ischemic stroke. Stroke lesions included the corticospinal tract. DTI was also performed in 12 healthy controls. Diffusion parameters were obtained for left and right (i) half and (ii) lateral spinal cord extending from C2 to C7., Results: relative fractional anisotropy (FA) in the lateral tracts on the affected side compared with the unaffected side (left/right) was reduced in stroke patients as compared with controls (P= .007). FA was lowest in patients with severe upper limb hemiparesis. Relative apparent diffusion coefficient in the lateral tracts was increased in the patients (P= .03)., Conclusions: this study provides preliminary evidence that DTI at 1.5 T can be used for identification and quantification of WD in the lateral cervical spinal cord in stroke patients. This may prove useful for prognosis of motor outcome after stroke.

Novel non-nucleoside alkyne monomers compatible with oligonucleotide synthesis were designed, synthesized, and efficiently incorporated into RNA and RNA analogues during solid-phase synthesis. These modifications allowed site-specific conjugation of ligands to the RNA oligonucleotides through copper-assisted (CuAAC) and copper-free strain-promoted azide-alkyne cycloaddition (SPAAC) reactions. The SPAAC click reactions of cyclooctyne-oligonucleotides with various classes of azido-functionalized ligands in solution phase and on solid phase were efficient and quantitative and occurred under mild reaction conditions. The SPAAC reaction provides a method for the synthesis of oligonucleotide-ligand conjugates uncontaminated with copper ions.

During RNA-induced silencing complex (RISC) assembly the guide (or antisense) strand has to separate from its complementary passenger (or sense) strand to generate the active RISC complex. Although this process was found to be facilitated through sense strand cleavage, there is evidence for an alternate mechanism, in which the strands are dissociated without prior cleavage. Here we show that the potency of siRNA can be improved by modulating the internal thermodynamic stability profile with chemical modifications. Using a model siRNA targeting the firefly luciferase gene with subnanomolar IC50, we found that placement of thermally destabilizing modifications, such as non-canonical bases like 2,4-difluorotoluene or single base pair mismatches in the central region of the sense strand (9-12 nt), significantly improve the potency. For this particular siRNA, the strongest correlation between the decrease in thermal stability and the increase in potency was found at position 10. Controls with stabilized sugar-phosphate backbone indicate that enzymatic cleavage of the sense strand prior to strand dissociation is not required for silencing activity. Similar potency-enhancing effects were observed as this approach was applied to other functional siRNAs targeting a different site on the firefly luciferase transcript or endogenously expressed PTEN.

In many nonhuman species of vertebrates, females are attracted to red on male conspecifics. Red is also a signal of male status in many nonhuman vertebrate species, and females show a mating preference for high-status males. These red-attraction and red-status links have been found even when red is displayed on males artificially. In the present research, we document parallels between human and nonhuman females' response to male red. Specifically, in a series of 7 experiments we demonstrate that women perceive men to be more attractive and sexually desirable when seen on a red background and in red clothing, and we additionally show that status perceptions are responsible for this red effect. The influence of red appears to be specific to women's romantic attraction to men: Red did not influence men's perceptions of other men, nor did it influence women's perceptions of men's overall likability, agreeableness, or extraversion. Participants showed no awareness that the research focused on the influence of color. These findings indicate that color not only has aesthetic value but can carry meaning and impact psychological functioning in subtle, important, and provocative ways., (2010 APA, all rights reserved)

Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) to hepatocytes in vivo; however, the precise mechanism by which this efficient delivery occurs has yet to be elucidated. We found that apolipoprotein E (apoE), which plays a major role in the clearance and hepatocellular uptake of physiological lipoproteins, also acts as an endogenous targeting ligand for ionizable LNPs (iLNPs), but not cationic LNPs (cLNPs). The role of apoE was investigated using both in vitro studies employing recombinant apoE and in vivo studies in wild-type and apoE(-/-) mice. Receptor dependence was explored in vitro and in vivo using low-density lipoprotein receptor (LDLR(-/-))-deficient mice. As an alternative to endogenous apoE-based targeting, we developed a targeting approach using an exogenous ligand containing a multivalent N-acetylgalactosamine (GalNAc)-cluster, which binds with high affinity to the asialoglycoprotein receptor (ASGPR) expressed on hepatocytes. Both apoE-based endogenous and GalNAc-based exogenous targeting appear to be highly effective strategies for the delivery of iLNPs to liver.

Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2'-3'-cyclic nucleotide 3'-phosphodiesterase) in oligodendrocytes. Cholesterol-conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

A peptide nucleic acid (PNA) targeting a splice junction of the murine PTEN primary transcript was covalently conjugated to various basic peptides. When systemically administered to healthy mice, the conjugates displayed sequence-specific alteration of PTEN mRNA splicing as well as inhibition of full length PTEN protein expression. Correlating activity with drug concentration in various tissues indicated strong tissue-dependence, with highest levels of activity observed in adipose tissue. While the presence of a peptide carrier was found to be crucial for efficient delivery to tissue, little difference was observed between the various peptides evaluated. A second PNA-conjugate targeting the murine insulin receptor primary transcript showed a similar activity profile, suggesting that short basic peptides can generally be used to effectively deliver peptide nucleic acids to adipose tissue.

Diffusion tensor imaging (DTI) can be used to elucidate relations between CNS structure and function. We hypothesized that the degree of spinal white matter organization relates to the accuracy of control of grip force. Healthy subjects of different age were studied using DTI and visuomotor tracking of precision grip force. The latter is a prime component of manual dexterity. A regional analysis of spinal white matter [fractional anisotropy (FA)] across multiple cervical levels (C2-C3, C4-C5, and C6-C7) and in different regions of interest (left and right lateral or medial spinal cord) was performed. FA was highest at the C2-C3 level, higher on the right than the left side, and higher in the lateral than in the medial spinal cord (p < 0.001). FA of whole cervical spinal cord (C2-C7) was lower in subjects with high tracking error (r = -0.56, p = 0.004) and decreased with age (r = -0.63, p = 0.001). A multiple regression analysis revealed an independent contribution of each predictor (semipartial correlations: age, r = -0.55, p < 0.001; tracking error, r = -0.49, p = 0.003). The closest relation between FA and tracking error was found at the C6-C7 level in the lateral spinal cord, in which the corticospinal tract innervates spinal circuitry controlling hand and digit muscles. FA of the medial spinal cord correlated consistently with age across all cervical levels, whereas FA of the lateral spinal cord did not. The results suggest (1) a functionally relevant specialization of lateral spinal cord white matter and (2) an increased sensitivity to age-related decline in medial spinal cord white matter in healthy subjects.

We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.

Color may not only be pleasing to the eye, but may also carry important associations relevant for psychological functioning. Two experiments were conducted to test for basic hue-meaning associations, controlling for lightness and chroma. Specifically, we used a reaction time paradigm to test for links between red and green, and words that varied in achievement content (failure and success) or valence more generally. Results revealed that red was positively associated with failure and general negative words, and was negatively associated with success and general positive words, whereas green was positively associated with success words only. These findings directly document that hue carries psychologically relevant meaning. Implications both within and beyond the achievement domain are discussed.

Three experiments were conducted on color preference using a spontaneous selection paradigm with infant participants. Experiment 1 demonstrated that participants prefer red over green in a friendly laboratory environment. Experiment 2 demonstrated that participants' preference for red varies with the context in which the color is presented: Red is preferred in a hospitable context (following a happy face), but not in a hostile context (following an angry face). The opposite pattern was found for the control color green. Experiment 3 used the same context manipulation, but a second control color, gray, was added to clearly examine whether context affects preference for red only. As predicted, given a second alternative choice, context-dependent preference for red, but not green or gray, was found. These results represent the first evidence of context moderation in the color preference literature.

When a visual stimulus is quickly followed in time by a second visual stimulus, we are normally unable to perceive it consciously. This study examined how affective states influence this temporal limit of conscious perception. Using a masked visual perception task, we found that the temporal threshold for access to consciousness is decreased in negative mood and increased in positive mood. To identify the brain mechanisms associated with this effect, we analysed brain oscillations. The mood-induced differences in perception performance were associated with differences in ongoing alpha power (around 10 Hz) before stimulus presentation. Additionally, after stimulus presentation, the better performance during negative mood was associated with enhanced global coordination of neuronal activity of theta oscillations (around 5 Hz). Thus, the effect of mood on the speed of conscious perception seems to depend on changes in oscillatory brain activity, rendering the cognitive system more or less sensitive to incoming stimuli.

Area F5, in the ventral premotor cortex of the macaque monkey, plays a critical role in determining the hand shape appropriate for grasp of a visible object. F5 neurones show increased firing for particular types of grasp, and inactivation of F5 produces deficits in visually guided grasp. But how is F5 activity transformed into the appropriate pattern of hand muscle activity for efficient grasp? Here we investigate the pathways that may be involved by testing the effect of single stimuli delivered through microwires chronically implanted in area F5 and in primary motor cortex (M1) of two macaque monkeys. The EMG responses from M1 test (T) stimulation were recorded from 4-11 contralateral hand, digit and arm muscles during reach-to-grasp of visually presented objects. Conditioning (C) stimulation of F5, at intensities subthreshold for motor effects, caused strong modulation (over twofold) of M1 test (T) responses. The pattern of facilitation was specific. First, facilitation of the T response was particularly evident at short C-T intervals of -1 to 1 ms. Second, this facilitation was only present in some muscles and during reach-to-grasp of a subset of objects; it did not appear to be simply related to the level of EMG activity in the muscles at the moment of cortical stimulation or indeed to the upcoming contribution of that muscle during grasp. At later C-T intervals (1-6 ms), F5 stimulation caused significant suppression of the test M1 response. The results are in keeping with the concept that during visually guided grasp, F5 modulates corticospinal outputs from M1 in a muscle- and grasp-specific manner.

This research tests whether the perception of red in an achievement context evokes avoidance behavior without conscious awareness and also examines the context specificity of the hypothesized red effect. In Experiment 1, participants were briefly shown red or green on the cover of an analogies test that they would ostensibly take (an achievement context) or rate on likability of (a nonachievement context) in an adjacent lab. Those shown red, relative to those shown green, knocked fewer times on the door of the adjacent lab in the achievement context; no red-green difference in knocking was observed in the nonachievement context. In Experiment 2, participants were briefly shown red, green, or gray on the cover of an IQ test that they would ostensibly take. Those shown red moved their body away from the test cover to a greater degree than did those shown green or gray. This research contributes to incipient work on color psychology and to the more established literature on the automatic link between evaluation and behavior.

We investigated age related changes in the control of precision grip in 29 healthy adults spanning early adulthood to middle age (21-67 years). Subjects performed a visually guided, isometric precision grip ramp-and-hold force-tracking task. Target force levels were 3, 6, and 9 N. Precision and performance of force regulation was quantified. Larger errors were made during the ramp than during the hold phase. Age correlated positively with the amount of error at the lowest (3 N) force level in both phases. Force onsets were systematically earlier in middle-aged subjects and the average slope of the force during the ramp decreased with increasing age. The results show that precision during low grip force control decreases already during middle age and those subjects may modify their force generation strategies to compensate for early and subtle degenerative changes in the motor system before decline in grip strength is apparent.

Different dose-matched, upper extremity rehabilitation training techniques, including robotic and non-robotic techniques, can result in similar improvement in movement ability after stroke, suggesting they may elicit a common drive for recovery. Here we report experimental results that support the hypothesis of a common drive, and develop a computational model of a putative neural mechanism for the common drive. We compared weekly motor control recovery during robotic and unassisted movement training techniques after chronic stroke (n = 27), as assessed with quantitative measures of strength, speed, and coordination. The results showed that recovery in both groups followed an exponential time course with a time constant of about 4-5 weeks. Despite the greater range and speed of movement practiced by the robot group, motor recovery was very similar between the groups. The premise of the computational model is that improvements in motor control are caused by improvements in the ability to activate spared portions of the damaged corticospinal system, as learned by a biologically plausible search algorithm. Robot-assisted and unassisted training would in theory equally drive this search process.

This research examines the hypothesis that an attentional process grounded in avoidance motivation-local relative to global processing-mediates the negative effect of red on intellectual performance. This hypothesis was tested in a series of experiments using two approaches to documenting mediation. Experiment 1 established that the perception of red undermines IQ test performance. Experiments 2a and 2b documented mediation via the experimental causal chain approach, and Experiment 3 documented mediation via the measurement of mediation approach. This represents the first demonstration of a mediational process in the domain of color psychology. A call is made to broaden priming research to include color stimuli.

In common with other secondary motor areas, the macaque ventral premotor cortex (PMv) gives rise to corticospinal projections; it also makes numerous reciprocal corticocortical connections with the primary motor cortex (M1). Repetitive intracortical microstimulation (rICMS) of the PMv gives rise to movements of the hand and digits. To investigate whether these motor effects are dependent on the corticocortical interactions with M1, the effect of reversible inactivation of the M1 hand area was tested in three macaque monkeys with chronically implanted intracortical electrodes in the hand representations of M1 and PMv (rostral division, area F5). Monkeys were lightly sedated. Test EMG responses to rICMS were recorded from intrinsic hand muscles before and after microinjection of the GABA agonist muscimol in the M1 hand area. This not only greatly reduced EMG responses evoked from M1, but also reduced or abolished responses from F5, over a similar time course (20-50 min). Muscimol in M1 reduced the level of background EMG activity in the contralateral hand, which was paretic for several hours after injection. However, because EMG responses to direct activation of the corticospinal tract were significantly less affected than the responses to F5 stimulation, it is unlikely that reduced motoneuronal excitability explained the loss of the evoked responses from F5. Finally, muscimol injections in M1 greatly reduced the corticospinal volleys evoked by rICMS in F5. The results suggest that the motor effects evoked from F5 depend, at least in part, on corticocortical interactions with M1, leading to activation of M1 corticospinal outputs to hand muscles.

Objective: The aim of this prospective and longitudinal study was to characterize EEG patterns during the first weeks of life in extremely premature infants., Methods: Twenty-five extremely premature infants were included and weekly EEG recordings were obtained between 24 and 36 weeks of conceptional age (CA)., Results: Central (rolandic) positive slow waves (CPSW) were found to be the most reliable and characteristic pattern. CPSWs were frequent at 24 weeks CA and progressively diminished and disappeared around 34 weeks CA. CPSWs appeared isolated or in sequences, they occurred during periods of continuous or discontinuous EEG activity, during bursts or during intervals of discontinuous activity, and unilaterally or bilaterally. Temporal positive slow waves and theta rhythms occurred less often and did not decrease as a function of CA. In addition, the amount of discontinuity progressively decreased until 36 weeks CA. The duration of bursts stayed constant, while inter-burst intervals decreased as a function of CA., Conclusions: Central positive slow waves are characteristic features of the EEG in the extremely premature infant., Significance: The presence of CPSWs and their progressive disappearance until 34 weeks CA may represent a maturational marker in the EEG.

This research focuses on the relation between color and psychological functioning, specifically, that between red and performance attainment. Red is hypothesized to impair performance on achievement tasks, because red is associated with the danger of failure in achievement contexts and evokes avoidance motivation. Four experiments demonstrate that the brief perception of red prior to an important test (e.g., an IQ test) impairs performance, and this effect appears to take place outside of participants' conscious awareness. Two further experiments establish the link between red and avoidance motivation as indicated by behavioral (i.e., task choice) and psychophysiological (i.e., cortical activation) measures. The findings suggest that care must be taken in how red is used in achievement contexts and illustrate how color can act as a subtle environmental cue that has important influences on behavior., (((c) 2007 APA, all rights reserved).)

Short interfering RNA (siRNA) duplexes are currently being evaluated as antisense agents for gene silencing. Chemical modification of siRNAs is widely expected to be required for therapeutic applications in order to improve delivery, biostability and pharmacokinetic properties. Beyond potential improvements in the efficacy of oligoribonucleotides, chemical modification may also provide insight into the mechanism of mRNA downregulation mediated by the RNA-protein effector complexes (RNA-induced silencing complex or RISC). We have studied the in vitro activity in HeLa cells of siRNA duplexes against firefly luciferase with substitutions in the guide strand of U for the apolar ribo-2,4-difluorotoluyl nucleotide (rF) [Xia, J. et al. (2006) ACS Chem. Biol., 1, 176-183] as well as of C for rF. Whereas an internal rF:A pair adjacent to the Ago2 ('slicer' enzyme) cleavage site did not affect silencing relative to the native siRNA duplex, the rF:G pair and other mismatches such as A:G or A:A were not tolerated. The crystal structure at atomic resolution determined for an RNA dodecamer duplex with rF opposite G manifests only minor deviations between the geometries of rF:G and the native U:G wobble pair. This is in contrast to the previously found, significant deviations between the geometries of rF:A and U:A pairs. Comparison between the structures of the RNA duplex containing rF:G and a new structure of an RNA with A:G mismatches with the structures of standard Watson-Crick pairs in canonical duplex RNA leads to the conclusion that local widening of the duplex formed by the siRNA guide strand and the targeted region of mRNA is the most likely reason for the intolerance of human Ago2 (hAgo2), the RISC endonuclease, toward internal mismatch pairs involving native or chemically modified RNA. Contrary to the influence of shape, the thermodynamic stabilities of siRNA duplexes with single rF:A, A:A, G:A or C:A (instead of U:A) or rF:G pairs (instead of C:G) show no obvious correlation with their activities. However, incorporation of three rF:A pairs into an siRNA duplex leads to loss of activity. Our structural and stability data also shed light on the role of organic fluorine as a hydrogen bond acceptor. Accordingly, UV melting (T(M)) data, osmotic stress measurements, X-ray crystallography at atomic resolution and the results of semi-empirical calculations are all consistent with the existence of weak hydrogen bonds between fluorine and the H-N1(G) amino group in rF:G pairs of the investigated RNA dodecamers.

A dynamic and recurrent artificial neural network was used to investigate the functional properties of firing patterns observed in the primary motor (M1) and the primary somatosensory (S1) cortex of the behaving monkey during control of precision grip force. In the behaving monkey it was found that neurons in M1 and in S1 increase their firing activity with increasing grip force, as do the intrinsic and extrinsic hand muscles implicated in the task. However, some neurons also decreased their activity as a function of increasing force. The functional implication of these latter neurons is not clear and has not been elucidated so far. In order to explore their functional implication, we therefore simulated patterns of neural activity in artificial neural networks that represent cortical, spinal and afferent neural populations and tested whether particular activity profiles would emerge as a function of the input and of the connectivity of these networks. The functional implication of units with emergent or imposed decreasing activity was then explored. Decreasing patterns of activity in M1 units did not emerge from the networks. However, the same networks generated decreasing activity if imposed as target patterns. As indicated by the emerging weight space, M1 projection units with decreasing patterns are functionally less involved in driving alpha motoneurons than units with increasing profiles. Furthermore, these units did not provide significant fusimotor drive, whereas those with increasing profiles did. Fusimotor drive was a function of the (imposed) form of muscle spindle afferent activity: with gamma (fusimotor) drive, muscle spindle afferents provided signals other than muscle length (as observed experimentally). The network solutions thus predict a functional dichotomy between increasing and decreasing M1 neurons: the former primarily drive alpha and gamma motoneurons, the latter only weakly alpha motoneurons.

Integration of the viral cDNA into host chromosomes is required for viral replication. Human immunodeficiency virus integrase catalyzes two sequential reactions, 3'-processing (3'-P) and strand transfer (ST). The first integrase inhibitors are undergoing clinical trial, but interactions of inhibitors with integrase and DNA are not well understood in the absence of a co-crystal structure. To increase our understanding of integrase interactions with DNA, we examined integrase catalysis with oligonucleotides containing DNA backbone, base, and groove modifications placed at unique positions surrounding the 3'-processing site. 3'-Processing was blocked with substrates containing constrained sugars and alpha-anomeric residues, suggesting that integrase requires flexibility of the phosphodiester backbone at the 3'-P site. Of several benzo[a]pyrene 7,8-diol 9,10-epoxide (BaP DE) adducts tested, only the adduct in the minor groove at the 3'-P site inhibited 3'-P, suggesting the importance of the minor groove contacts for 3'-P. ST occurred in the presence of bulky BaP DE DNA adducts attached to the end of the viral DNA suggesting opening of the active site for ST. Position-specific effects of these BaP DE DNA adducts were found for inhibition of integrase by diketo acids. Together, these results demonstrate the importance of DNA structure and specific contacts with the viral DNA processing site for inhibition by integrase inhibitors.

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security "by proxy". Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.

Cellular permeation peptides have been used successfully for the delivery of a variety of cargoes across cellular membranes, including large hydrophilic biomolecules such as proteins, oligonucleotides, or plasmid DNA. For the present work, a series of short amphipathic peptides was designed to elucidate the structural requirements for efficient and nontoxic delivery of peptide nucleic acids (PNAs). On the basis of an idealized alpha-helical structure, the helical parameters were modulated systematically to yield peptides within a certain range of hydrophobicity and amphipathicity. The corresponding PNA conjugates were synthesized and characterized in terms of secondary structure, enzymatic stability, and antisense activity. The study revealed correlations between the physicochemical and biophysical properties of the conjugates and their biological activity and led to the development of potent peptide vectors for the cellular delivery of antisense PNAs. Two representative compounds were radiolabeled and evaluated for their biodistribution in healthy mice.

Improving cellular uptake and biodistribution remains one of the major obstacles for a successful and broad application of peptide nucleic acids (PNAs) as antisense therapeutics. Recently, we reported the identification and functional characterization of an antisense PNA, which redirects splicing of murine CD40 pre-mRNA. In this context, it was discovered that a simple octa(l-lysine) peptide covalently linked to the PNA is capable of promoting free uptake of the conjugate into BCL1 cells as well as primary murine macrophages. On the basis of this peptide motif, the present study aimed at identifying the structural features, which define effective peptide carriers for cellular delivery of PNA. While the structure-activity relationship study revealed some clear correlations, only a few modifications actually led to an overall improvement as compared to the parent octa(l-lysine) conjugate. In a preliminary PK/tissue distribution study in healthy mice, the parent conjugate exhibited relatively broad tissue distribution and only modest elimination via excretion within the time frame of the study.

We analyzed the adaptability of human thumb and index finger movement kinematics and dynamics to variations of precision grip aperture and movement velocity. Six subjects performed precision grip opening and closing movements under different conditions of movement velocity and movement aperture (thumb and index finger tip-to-tip distance). Angular motion of the thumb and index finger joints was recorded with a CyberGlove and a three-dimensional biomechanical model was used for solving the inverse dynamics problem during precision grip movements, i.e., for calculating joint torques from experimentally obtained angular variations. The time-varying joint angles and joint torques were analyzed by principal-component analysis to quantify the contributions of individual joints in kinematic and dynamic synergies. At the level of movement kinematics, we found subject-specific angular contributions. However, the adaptation to large aperture, achieved by an increase of the relative contribution of the proximal joints, was subject-invariant. At the level of movement dynamics, the adaptation of thumb-index finger movements to task constraints was similar among all subjects and required the linear scaling of joint torques, the synchronization of joint torques under high velocity conditions, and a flexible redistribution of joint torques between the proximal joint of the thumb and that of the index finger. This work represents one of the first attempts at calculating the joint torques during human precision-grip movements and indicates that the dynamic synergies seem to be remarkably simple compared with the synergies found for movement kinematics.

Dynamic recurrent neural networks were derived to simulate neuronal populations generating bidirectional wrist movements in the monkey. The models incorporate anatomical connections of cortical and rubral neurons, muscle afferents, segmental interneurons and motoneurons; they also incorporate the response profiles of four populations of neurons observed in behaving monkeys. The networks were derived by gradient descent algorithms to generate the eight characteristic patterns of motor unit activations observed during alternating flexion-extension wrist movements. The resulting model generated the appropriate input-output transforms and developed connection strengths resembling those in physiological pathways. We found that this network could be further trained to simulate additional tasks, such as experimentally observed reflex responses to limb perturbations that stretched or shortened the active muscles, and scaling of response amplitudes in proportion to inputs. In the final comprehensive network, motor units are driven by the combined activity of cortical, rubral, spinal and afferent units during step tracking and perturbations. The model displayed many emergent properties corresponding to physiological characteristics. The resulting neural network provides a working model of premotoneuronal circuitry and elucidates the neural mechanisms controlling motoneuron activity. It also predicts several features to be experimentally tested, for example the consequences of eliminating inhibitory connections in cortex and red nucleus. It also reveals that co-contraction can be achieved by simultaneous activation of the flexor and extensor circuits without invoking features specific to co-contraction.