There has been renewed interest in the role of strategies in sensorimotor learning. The combination of new behavioral methods and computational methods has begun to unravel the interaction between processes related to strategic control and processes related to motor adaptation. These processes may operate on very different error signals. Strategy learning is sensitive to goal-based performance error. In contrast, adaptation is sensitive to prediction errors between the desired and actual consequences of a planned movement. The former guides what the desired movement should be, whereas the latter guides how to implement the desired movement. Whereas traditional approaches have favored serial models in which an initial strategy-based phase gives way to more automatized forms of control, it now seems that strategic and adaptive processes operate with considerable independence throughout learning, although the relative weight given the two processes will shift with changes in performance. As such, skill acquisition involves the synergistic engagement of strategic and adaptive processes.
motor learning; motor adaptation; motor skills; cognition
Deep brain stimulation was introduced as a treatment for patients with Parkinsonism and other movement disorders in the early 1990s. The technique rapidly became the treatment of choice for these conditions, and is now also being explored for other diseases, including Tourette syndrome, gait disorders, epilepsy, obsessive-compulsive disorder, and depression. Although the mechanism of action of DBS remains unclear, it is recognized that DBS works through focal modulation of functionally specific circuits. The fact that that the same DBS parameters and targets can be used in multiple diseases suggests that DBS does not counteract the pathophysiology of any specific disorder, but acts to replace pathologic activities in disease-affected brain circuits with activity that is more easily tolerated. Despite the progress made in the use of DBS, much remains to be done to fully realize the potential of this therapy. We describe some of the most active areas of research in this field, both in terms of exploration of new targets and stimulation parameters, and in terms of new electrode or stimulator designs.
Parkinson’s disease; dystonia; subthalamic nucleus; internal pallidal segment; pedunculopontine nucleus; segregated circuits
Glycosylation affects many essential T cell processes and is intrinsically controlled throughout the lifetime of a T cell. CD43 and CD45 are the two most abundant glycoproteins on the T cell surface and are decorated with O- and N-glycans. Global T cell glycosylation and specific glycosylation of CD43 and CD45 are modulated during thymocyte development and T cell activation; T cells control the type and abundance of glycans decorating CD43 and CD45 by regulating expression of glycosyltransferases and glycosidases. Additionally, T cells regulate glycosylation of CD45 by expressing alternatively spliced isoforms of CD45 that have different glycan attachment sites. The glycophenotype of CD43 and CD45 on T cells influences how T cells interact with the extracellular environment, including how T cells interact with endogenous lectins. This review focuses on changes in glycosylation of CD43 and CD45 occurring throughout T cell development and activation and the role that glycosylation plays in regulating T cell processes, such as migration, T cell receptor signaling, and apoptosis.
glycosylation; T cell; CD43; CD45
genetic and epigenetic programming; fetal development; toxicity
Multimodal CT/MRI has dramatically changed the approach to ischemic stroke management, as noninvasive CT/MRI images detail brain tissue or parenchyma, angiography or vessel status, and collateral perfusion or blood flow in regions of the brain vulnerable to ischemic injury. Such snapshots of the dynamic process of cerebral ischemia may be used to gauge reversibility and therapeutic opportunities. Treatment of acute stroke may be rapidly tailored to clinical scenarios based on imaging correlation of ischemia, vessel status, and perfusion. Serial or repeated imaging from the initial presentation to later stages of the hospital course may illustrate infarct growth, persisting occlusion, reocclusion, recanalization, reperfusion, and hemorrhagic transformation. From acute stroke to rehabilitation phases and subsequent prevention, multimodal CT/MRI has emerged as a key tool to track the process of stroke and the impact of our therapeutic interventions.
stroke; acute ischemia; imaging; thrombolysis; collateral circulation; hemodynamics
This paper reviews and synthesizes functional imaging research that over the past decade has begun to offer new insights into the brain mechanisms underlying emotion regulation. Towards that end, the first section of the paper outlines a model of the processes and neural systems involved in emotion generation and regulation. The second section surveys recent research supporting and elaborating the model, focusing primarily on studies of the most commonly investigated strategy, which is known as reappraisal. At its core, the model specifies how prefrontal and cingulate control systems modulate activity in perceptual, semantic and affect systems as a function of one's regulatory goals, tactics, and the nature of the stimuli and emotions being regulated. This section also shows how the model can be generalized to understand the brain mechanisms underlying other emotion regulation strategies as well as a range of other allied phenomena. The third and last section considers directions for future research, including how basic models of emotion regulation can be translated to understand changes in emotion across the lifespan and in clinical disorders.
emotion; emotion regulation; cognitive control; amygdala; prefrontal cortex
Humans differ in their ability to quit using addictive substances, including nicotine, the major psychoactive ingredient in tobacco. For tobacco smoking, a substantial body of evidence, largely derived from twin studies, indicates that approximately half of these individual differences in ability to quit are heritable [1, 2], genetic influences that likely overlap with those for other addictive substances . Both twin and molecular genetic studies support overlapping influences on nicotine addiction vulnerability and smoking cessation success, although there is little formal analysis of the twin data that supports this important point [2, 3]. None of the current datasets provides clear data concerning which heritable factors might provide robust dimensions around which individuals differ in ability to quit smoking. One approach to this problem is to test mice with genetic variations in genes that contain human variants that alter quit-success. This review considers which features of quit success should be included in a comprehensive approach to elucidating the genetics of quit success, and how those features may be modeled in mice.
Nicotine; smoking cessation; quit success; genetics
Autosomal dominant hyper-IgE syndrome (AD-HIES) or Job’s syndrome is a primary immunodeficiency with a wide array of clinical features caused by dominant negative mutations in STAT3. In recent years, not only the clinical phenotype of the disease has been expanded with recognition of features such as arterial aneurysms, but also our understanding of the pathogenesis of the disease has greatly improved.
autosomal dominant hyper-IgE syndrome; Job’s syndrome; signal transducer and activator of transcription 3; Th17 cells
Efficient cardiac regeneration post-infarction (MI) requires the replacement of lost cardiomyocytes, formation of new coronary vessels and appropriate modulation of the inflammatory response. However, insight into how to stimulate repair of the human heart is currently limited. Utilising the embryonic paradigm of regeneration, we demonstrated that the actin-binding peptide Thymosin β4 (Tβ4), required for epicardium-derived coronary vasculogenesis, can recapitulate its embryonic role and activate quiescent adult epicardial cells (EPDCs). Once stimulated, EPDCs facilitate neovascularisation of the ischaemic adult heart and, moreover, contribute bona fide cardiomyocytes. EPDC-derived cardiomyocytes structurally and functionally integrate with resident muscle, to regenerate functional myocardium, limiting pathological remodelling and effecting an improvement in cardiac function. Alongside pro-survival and anti-inflammatory properties, these regenerative roles, via EPDCs, markedly expand the range of therapeutic benefits of Tβ4 to sustain and repair the myocardium after ischaemic damage.
Thymosin β4; EPDCs; epicardium; Wt1; myocardial regeneration; de novo cardiomyocytes
Enteropathogenic E. coli (EPEC) infection is a major cause of infantile diarrhea in the developing world. Using a type-three secretion system, bacterial effector proteins are transferred to the host cell cytosol where they affect multiple physiological functions, ultimately leading to diarrheal disease. Disruption of intestinal epithelial cell tight junctions is a major consequence of EPEC infection and is mediated by multiple effector proteins, among them EspG1 and its homologue EspG2. EspG1/G2 contribute to loss of barrier function via an undefined mechanism that may be linked to their disruption of microtubule networks. Recently new investigations have identified additional roles for EspG. Sequestration of active ADP-ribosylating factor (ARF) proteins and promotion of p21-activated kinase (PAK) activity as well as inhibition of Golgi-mediated protein secretion have all been linked to EspG. In this review, we examine the functions of EspG1/G2 and discuss potential mechanisms of EspG-mediated tight junction disruption.
EPEC; tight junctions; EspG; microtubules; ARF; PAK
β-lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-β-lactamases are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs including carbapenems. This diversity is reflected in the observation that the enzyme mechanisms differ based on whether one or two zincs are bound in the active site which, in turn, is dependent on the subclass of β-lactamase. The dissemination of the genes encoding these enzymes among Gram-negative bacteria has made them an important cause of resistance. In addition, there are currently no clinically available inhibitors to block metallo-β-lactamase action. This review summarizes the numerous studies that have yielded insights into the structure, function, and mechanism of action of these enzymes.
β-lactamase; antibiotic resistance; carbapenem; zinc metallo-enzyme
Antimuscle specific kinase (anti-MuSK) myasthenia (AMM) differs from antiacetylcholine receptor myasthenia gravis in exhibiting more focal muscle involvement (neck, shoulder, facial, and bulbar muscles) with wasting of the involved, primarily axial, muscles. AMM is not associated with thymic hyperplasia and responds poorly to anticholinesterase treatment. Animal models of AMM have been induced in rabbits, mice, and rats by immunization with purified xenogeneic MuSK ectodomain, and by passive transfer of large quantities of purified serum IgG from AMM patients into mice. The models have confirmed the pathogenic role of the MuSK antibodies in AMM and have demonstrated the involvement of both the presynaptic and postsynaptic components of the neuromuscular junction. The observations in this human disease and its animal models demonstrate the role of MuSK not only in the formation of this synapse but also in its maintenance.
animal models; autoimmune; muscle-specific kinase; muscle wasting; MuSK; myasthenia; neuromuscular junction; synapse
Unlike their protein “roommates” and their nucleic acid “cousins,” carbohydrates remain an enigmatic arm of biology. The central reason for the difficulty in fully understanding how carbohydrate structure and biological function are tied is the nontemplate nature of their synthesis and the resulting heterogeneity. The goal of this collection of expert reviews is to highlight what is known about how carbohydrates and their binding partners—the microbial (non-self), tumor (altered-self), and host (self)—cooperate within the immune system, while also identifying areas of opportunity to those willing to take up the challenge of understanding more about how carbohydrates influence immune responses. In the end, these reviews will serve as specific examples of how carbohydrates are as integral to biology as are proteins, nucleic acids, and lipids. Here, we attempt to summarize general concepts on glycans and glycan-binding proteins (mainly C-type lectins, siglecs, and galectins) and their contributions to the biology of immune responses in physiologic and pathologic settings.
glycobiology; glycoimmunology; glycans; lectins; C-type lectins; siglecs; galectins
Many Gram-negative and Gram-positive bacteria recycle a significant proportion of the peptidoglycan components of their cell walls during their growth and septation. In many—and quite possibly all—bacteria, the peptidoglycan fragments are recovered and recycled. While cell-wall recycling is beneficial for the recovery of resources, it also serves as a mechanism to detect cell-wall–targeting antibiotics and to regulate resistance mechanisms. In several Gram-negative pathogens, anhydro-MurNAc-peptide cell-wall fragments regulate AmpC β-lactamase induction. In some Gram-positive organisms, short peptides derived from the cell wall regulate the induction of both β-lactamase and β-lactam-resistant penicillin-binding proteins. The involvement of peptidoglycan recycling with resistance regulation suggests that inhibitors of the enzymes involved in the recycling might synergize with cell-wall-targeted antibiotics. Indeed, such inhibitors improve the potency of β-lactams in vitro against inducible AmpC β-lactamase-producing bacteria. We describe the key steps of cell-wall remodeling and recycling, the regulation of resistance mechanisms by cell-wall recycling, and recent advances toward the discovery of cell-wall recycling inhibitors.
AmpD; AmpG; AmpR; autolysin; BlaR1; Escherichia coli; lytic transglycosylase; MRSA; NagZ; PBP2a; Staphylococcus aureus
The bactericidal, cell membrane-targeting lipopeptide antibiotic daptomycin (DAP) is an important agent in treating invasive Staphylococcus aureus infections. However, there have been numerous recent reports of development of daptomycin-resistance (DAP-R) during therapy with this agent. The mechanisms of DAP-R in S. aureus appear to be quite diverse. DAP-R strains often exhibit progressive accumulation of single nucleotide polymorphisms in the multipeptide resistance factor gene (mprF) and the yycFG components of the yycFGHI operon. Both loci are involved in key cell membrane (CM) events, with mprF being responsible for the synthesis and outer CM translocation of the positively-charged phospholipid, lysyl-phosphotidylglycerol (L-PG), while the yyc operon is involved in the generalized response to stressors such as antimicrobials. In addition, other perturbations of the CM have been identified in DAP-R strains including: extremes in CM order; resistance to CM depolarization and permeabilization; and reduced surface binding of DAP. Moreover, modifications of the cell wall (CW) appear to also contribute to DAP-R, including enhanced expression of the dlt operon (involved in D-alanylation of CW teichoic acids) and progressive CW thickening.
Staphylococcus aureus; daptomycin; antibiotic resistance; endocarditis
The development of invasive aspergillosis is a feared complication for immunocompromised patients. Despite the use of antifungal agents with excellent bioactivity, the morbidity and mortality rate for invasive aspergillosis remains unacceptably high. Defects within the innate immune response portend the highest risk for patients, but detailed knowledge of molecular pathways in neutrophils and macrophages in response to this fungal pathogen is lacking. Phagocytosis of fungal spores is a key step that places the pathogen into a phagosome, a membrane-delimited compartment that undergoes maturation and ultimately delivers antigenic material to the class II MHC pathway. We review the role of Toll-like receptor 9 (TLR9) in phagosome maturation of Aspergillus fumigates–containing phagosomes. Advanced imaging modalities and the development of fungal like particles are promising tools that will aid in the dissection of the molecular mechanism to fungal immunity.
innate immunity; Dectin-1; Toll-like receptor; phagosome; macrophage; TLR9
Forkhead box P3 (FOXP3)+ is a transcription factor necessary for the function of regulatory T cells (Treg cells). Treg cells maintain immune homeostasis and self-tolerance, and play an important role in the prevention of autoimmune disease. Here, we discuss the role of Treg cells in the pathogenesis of myasthenia gravis (MG) and review evidence indicating that a significant defect in Treg cell in vitro suppressive function exists in MG patients, without an alteration in circulating frequency. This functional defect is associated with a reduced expression of key functional molecules such as FOXP3 on isolated Treg cells and appears to be more pronounced in immunosuppression-naive MG patients. In vitro administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced the suppressive function of Treg cells and up-regulated FOXP3 expression. These findings indicate a clinically relevant Treg cell–intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target.
myasthenia gravis; regulatory T cells; FOXP3; GM-CSF
The deep sequencing of an mRNA population, RNA-seq, is a very successful application of next-generation sequencing technologies (NGSTs). RNA-seq takes advantage of two key NGST features: (1) samples can be mixtures of different DNA pieces, and (2) sequencing provides both qualitative and quantitative information about each DNA piece analyzed. We recently used RNA-seq to study the transcriptome of Aspergillus fumigatus, a deadly human fungal pathogen. Analysis of the RNA-seq data indicates that there are likely tens of unannotated and hundreds of novel genes in the A. fumigates transcriptome, mostly encoding for small proteins. Inspection of transcriptome-wide variation between two isolates reveals thousands of single nucleotide polymorphisms. Finally, comparison of the transcriptome profiles of one isolate in two different growth conditions identified thousands of differentially-expressed genes. These results demonstrate the utility and potential of RNA-seq for functional genomics studies in A. fumigatus and other fungal human pathogens.
novel genes; annotation; population structure; differential expression; transcriptome profiling
Complement plays an important role in the pathophysiology of experimental autoimmune myasthenia gravis (EAMG). The deposition of IgG at the neuromuscular junction, followed by the activation and observance of C3 at the site, and finally the insertion of the membrane attack complex, which results in the destruction of the plasma membrane at the neuromuscular junction. Animal models’ of complement-deficient components show the importance of the mediated lysisin EAMG. These events have regulators that allow for the limitation in the cascade and the ability of the cell to inhibit complement at many places along the pathway. The complement regulatory proteins have many roles in reducing the activation of the complement cascade and the inflammatory pathways. Mice deficient in complement regulatory proteins, decay accelerating factor and CD59, demonstrate a significant increase in the destruction at the neuromuscular junction. Inhibition of complement-mediated lysis is an attractive therapeutic in MG.
complement; complement regulators; myasthenia gravis; C5; autoimmunity
Presynaptic active zones are synaptic vesicle release sites that playessential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The molecular mechanisms of active zone organization utilize presynaptic voltage-dependent calcium channels (VDCCs) in NMJs as scaffolding proteins. VDCCs interact extracellularly with the muscle-derived synapse organizer, laminin β2, and interact intracellularly with active zone-specific proteins, such as Bassoon, CAST/Erc2/ELKS2alpha, ELKS, Piccolo, and RIMs. These molecular mechanisms are supported by studies in P/Q- and N-type VDCCs double-knockout mice, and they are consistent with the pathological conditions of Lambert-Eaton myasthenic syndrome and Pierson syndrome, which are caused by autoantibodies against VDCCs or by a laminin β2 mutation. During normal postnatal maturation, NMJs maintain the density of active zones, while NMJs triple their size. However, active zones become impaired during aging. Propitiously, muscle exercise ameliorates the active zone impairment in aged NMJs, which suggests the potential for therapeutic strategies.
Bassoon; calcium channel; exercise; laminin; motor neuron; synapse
In myasthenia gravis (MG) and experimental autoimmune MG (EAMG), many pathologically significant autoantibodies are directed to the main immunogenic region (MIR) of muscle nicotinic acetylcholine receptors (AChRs), a conformation-dependent region at the extracellular tip of α1 subunits of AChRs. Human muscle AChR α1 MIR sequences were integrated into Aplesia ACh-binding protein (AChBP). The chimera potently induced EAMG. AChBP induced EAMG much less potently. AChBP is a water-soluble protein resembling the extracellular domain of AChRs, yet rats immunized with chimeras developed autoantibodies to both extracellular and cytoplasmic domains of muscle AChRs. We propose that an initial autoimmune response directed at the MIR leads to an autoimmune response sustained by muscle AChRs. Autoimmune stimulation sustained by endogenous muscle AChR may be a target for specific immunosuppression. These studies show that the α1 MIR is highly myasthenogenic, and that AChR-like proteins distantly related to muscle AChR can induce EAMG and, potentially, MG.
nicotinic acetylcholine receptor; AChR; MG; EAMG; antigenic structure
An appropriate density of acetylcholine receptors (AChRs) and Na+ channels (NaChs) in the normal neuromuscular junction (NMJ) determines the magnitude of safety factor (SF) that guarantees fidelity of neuromuscular transmission. In myasthenia gravis (MG), an overall simplification of the postsynaptic folding secondary to NMJ destruction results in AChRs and NaChs depletion. Loss of AChRs and NaChs accounts respectively for 59% and 40% reduction of the SF at the endplate, which manifests as neuromuscular transmission failure. The extraocular muscles (EOM) have physiologically less developed postsynaptic folding, hence a lower baseline SF, which predisposes them to dysfunction in MG and development of fatigue during “high performance” eye movements, such as saccades. However, saccades in MG show stereotyped, conjugate initial components, similar to normal, which might reflect preserved neuromuscular transmission fidelity at the NMJ of the fast, pale global fibers, which have better developed postsynaptic folding than other extraocular fibers.
safety factor; extraocular muscles; saccades; neuromuscular junction
During the past 5 years an increasing number of patients were diagnosed with congenital myasthenic syndromes (CMS) and a number of novel syndromes were recognized and investigated. This presentation focuses on the CMS caused by defects in choline acetyltransferase, novel fast-channel syndromes that hinder isomerization of the acetylcholine receptor from the closed to the open state, the consequences of deleterious mutations in the intermediate filament linker plectin, altered neuromuscular transmission in a centronuclear myopathy, and two recently identified CMS caused by congenital defects in glycosylation.
congenital myasthenic syndromes; acetylcholine receptor; fast-channel syndromes; choline acetyltransferase; plectin; centronuclear myopathy; GFPT1; DPAGT1
Biomarkers are defined as characteristics (proteins, RNA, single nucleotide polymorphisms, imaging) that are objectively measured and evaluated as an indicator of pathogenic processes or pharmacologic responses to a therapeutic intervention. Biomarkers are important in clinical trials where the robust biomarker reflects the underlying disease process in a sensitive and reliable manner. For myasthenia gravis (MG), acetylcholine receptor and muscle specific kinase antibodies, as well as single fiber electromyography, serve as excellent biomarkers for diagnosis but do not adequately substitute for clinical evaluations to predict treatment response. New technologies are emerging that enable broad biomarker discovery in biological fluids. Biomarker evaluation is ideally done in the context of longitudinal clinical trials. The MGTX trial has collected plasma and serum for RNA and protein analysis and thymus, which will allow robust biomarker discovery. The ultimate goal will be to identify candidates for a reliable substitute for a clinically meaningful endpoint that is a direct measure of the effectiveness of a therapy in the context of a continuum of disease natural history and a patient's overall well-being.
biomarkers; myasthenia gravis; surrogate endpoint; Prentice criteria