Online and post-trial feedback differentially affect implicit adaptation to a visuomotor rotation

Multiple motor learning processes can be discriminated in visuomotor rotation paradigms. At least four processes have been proposed: Implicit adaptation updates an internal model based on prediction errors. Model-free reinforcement reinforces actions that achieve task success. Use-dependent learning favors repetition of prior movements, and strategic learning uses explicit knowledge about the task. The current experiment tested whether the processes involved in motor learning differ when visual feedback is altered. Specifically, we hypothesized that online and post-trial feedback would cause different amounts of implicit adaptation. Twenty subjects performed drawing movements to targets under a 45° counterclockwise visuomotor rotation while aiming at a clockwise adjacent target. Subjects received visual feedback via a cursor on a screen. One group saw the cursor throughout the movement (online feedback), while the other only saw the final position after movement execution (post-trial feedback). Both groups initially hit the target by applying the strategy. After 80 trials, subjects with online feedback had drifted in clockwise direction [mean direction error: 15.1° (SD 11.2°)], thus overcompensating the rotation. Subjects with post-trial feedback remained accurate [mean: 0.7° (SD 2.0°), TIME × GROUP: F = 3.926, p = 0.003]. We interpret this overcompensation to reflect implicit adaptation isolated from other mechanisms, because it is driven by prediction error rather than task success (model-free reinforcement) or repetition (use-dependent learning). The current findings extend previous work (e.g., Mazzoni and Krakauer in J Neurosci 26:3642–3645, 2006; Hinder et al. in Exp Brain Res 201:191–207, 2010) and suggest that online feedback promotes more implicit adaptation than does post-trial feedback.     

MOLECULAR IDENTIFICATION OF Bartonella henselae IN A SERONEGATIVE CAT SCRATCH DISEASE PATIENT WITH AIDS IN RIO DE JANEIRO, BRAZIL

Bartonella henselae is associated with a wide spectrum of clinical manifestations, including cat scratch disease, endocarditis and meningoencephalitis, in immunocompetent and immunocompromised patients. We report the first molecularly confirmed case of B. henselae infection in an AIDS patient in state of Rio de Janeiro, Brazil. Although DNA sequence of B. henselae has been detected by polymerase chain reaction in a lymph node biopsy, acute and convalescent sera were nonreactive.     

Increased metabolic rate and insulin sensitivity in male mice lacking the carcino-embryonic antigen-related cell adhesion molecule 2

Aims/hypothesis

The carcino-embryonic antigen-related cell adhesion molecule (CEACAM)2 is produced in many feeding control centres in the brain, but not in peripheral insulin-targeted tissues. Global Ceacam2 null mutation causes insulin resistance and obesity resulting from hyperphagia and hypometabolism in female Ceacam2 homozygous null mutant mice (Cc2 [also known as Ceacam2]^?/?) mice. Because male mice are not obese, the current study examined their metabolic phenotype.

Methods

The phenotype of male Cc2 ^?/? mice was characterised by body fat composition, indirect calorimetry, hyperinsulinaemic?Ceuglycaemic clamp analysis and direct recording of sympathetic nerve activity.

Results

Despite hyperphagia, total fat mass was reduced, owing to the hypermetabolic state in male Cc2 ^?/? mice. In contrast to females, male mice also exhibited insulin sensitivity with elevated ??-oxidation in skeletal muscle, which is likely to offset the effects of increased food intake. Males and females had increased brown adipogenesis. However, only males had increased activation of sympathetic tone regulation of adipose tissue and increased spontaneous activity. The mechanisms underlying sexual dimorphism in energy balance with the loss of Ceacam2 remain unknown.

Conclusions/interpretation

These studies identified a novel role for CEACAM2 in the regulation of metabolic rate and insulin sensitivity via effects on brown adipogenesis, sympathetic nervous outflow to brown adipose tissue, spontaneous activity and energy expenditure in skeletal muscle.     

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.     

Enhanced cellulose degradation by targeted integration of a cohesin-fused β-glucosidase into the Clostridium thermocellum cellulosome

The conversion of recalcitrant plant-derived cellulosic biomass into biofuels is dependent on highly efficient cellulase systems that produce near-quantitative levels of soluble saccharides. Similar to other fungal and bacterial cellulase systems, the multienzyme cellulosome system of the anaerobic, cellulolytic bacterium Clostridium thermocellum is strongly inhibited by the major end product cellobiose. Cellobiose-induced inhibition can be relieved via its cleavage to noninhibitory glucose by the addition of exogenous noncellulosomal enzyme β-glucosidase; however, because the cellulosome is adsorbed to the insoluble substrate only a fraction of β-glucosidase would be available to the cellulosome. Towards this end, we designed a chimeric cohesin-fused β-glucosidase (BglA-CohII) that binds directly to the cellulosome through an unoccupied dockerin module of its major scaffoldin subunit. The β-glucosidase activity is thus focused at the immediate site of cellobiose production by the cellulosomal enzymes. BglA-CohII was shown to retain cellobiase activity and was readily incorporated into the native cellulosome complex. Surprisingly, it was found that the native C. thermocellum cellulosome exists as a homooligomer and the high-affinity interaction of BglA-CohII with the scaffoldin moiety appears to dissociate the oligomeric state of the cellulosome. Complexation of the cellulosome and BglA-CohII resulted in higher overall degradation of microcrystalline cellulose and pretreated switchgrass compared to the native cellulosome alone or in combination with wild-type BglA in solution. These results demonstrate the effect of enzyme targeting and its potential for enhanced degradation of cellulosic biomass.