Probabilistic Models of Motor Production

N. Bernstein defined the ability of the central neural system (CNS) to control many degrees of freedom of a physical body with all its redundancy and flexibility as the main problem in motor control. He pointed at that man-made mechanisms usually have one, sometimes two degrees of freedom (DOF); when the number of DOF increases further, it becomes prohibitively hard to control them. The brain, however, seems to perform such control effortlessly. He suggested the way the brain might deal with it: when a motor skill is being acquired, the brain artificially limits the degrees of freedoms, leaving only one or two. As the skill level increases, the brain gradually "frees" the previously fixed DOF, applying control when needed and in directions which have to be corrected, eventually arriving to the control scheme where all the DOF are "free". This approach of reducing the dimensionality of motor control remains relevant even today. One the possibles solutions of the Bernstetin's problem is the hypothesis of motor primitives (MPs) - small building blocks that constitute complex movements and facilitite motor learnirng and task completion. Just like in the visual system, having a homogenious hierarchical architecture built of similar computational elements may be beneficial. Studying such a complicated object as brain, it is important to define at which level of details one works and which questions one aims to answer. David Marr suggested three levels of analysis: 1. computational, analysing which problem the system solves; 2. algorithmic, questioning which representation the system uses and which computations it performs; 3. implementational, finding how such computations are performed by neurons in the brain. In this thesis we stay at the first two levels, seeking for the basic representation of motor output. In this work we present a new model of motor primitives that comprises multiple interacting latent dynamical systems, and give it a full Bayesian treatment. Modelling within the Bayesian framework, in my opinion, must become the new standard in hypothesis testing in neuroscience. Only the Bayesian framework gives us guarantees when dealing with the inevitable plethora of hidden variables and uncertainty. The special type of coupling of dynamical systems we proposed, based on the Product of Experts, has many natural interpretations in the Bayesian framework. If the dynamical systems run in parallel, it yields Bayesian cue integration. If they are organized hierarchically due to serial coupling, we get hierarchical priors over the dynamics. If one of the dynamical systems represents sensory state, we arrive to the sensory-motor primitives. The compact representation that follows from the variational treatment allows learning of a motor primitives library. Learned separately, combined motion can be represented as a matrix of coupling values. We performed a set of experiments to compare different models of motor primitives. In a series of 2-alternative forced choice (2AFC) experiments participants were discriminating natural and synthesised movements, thus running a graphics Turing test. When available, Bayesian model score predicted the naturalness of the perceived movements. For simple movements, like walking, Bayesian model comparison and psychophysics tests indicate that one dynamical system is sufficient to describe the data. For more complex movements, like walking and waving, motion can be better represented as a set of coupled dynamical systems. We also experimentally confirmed that Bayesian treatment of model learning on motion data is superior to the simple point estimate of latent parameters. Experiments with non-periodic movements show that they do not benefit from more complex latent dynamics, despite having high kinematic complexity. By having a fully Bayesian models, we could quantitatively disentangle the influence of motion dynamics and pose on the perception of naturalness. We confirmed that rich and correct dynamics is more important than the kinematic representation. There are numerous further directions of research. In the models we devised, for multiple parts, even though the latent dynamics was factorized on a set of interacting systems, the kinematic parts were completely independent. Thus, interaction between the kinematic parts could be mediated only by the latent dynamics interactions. A more flexible model would allow a dense interaction on the kinematic level too. Another important problem relates to the representation of time in Markov chains. Discrete time Markov chains form an approximation to continuous dynamics. As time step is assumed to be fixed, we face with the problem of time step selection. Time is also not a explicit parameter in Markov chains. This also prohibits explicit optimization of time as parameter and reasoning (inference) about it. For example, in optimal control boundary conditions are usually set at exact time points, which is not an ecological scenario, where time is usually a parameter of optimization. Making time an explicit parameter in dynamics may alleviate this

Single-atom imaging of fermions in a quantum-gas microscope

Single-atom-resolved detection in optical lattices using quantum-gas microscopes has enabled a new generation of experiments in the field of quantum simulation. Fluorescence imaging of individual atoms has so far been achieved for bosonic species with optical molasses cooling, whereas detection of fermionic alkaline atoms in optical lattices by this method has proven more challenging. Here we demonstrate single-site- and single-atom-resolved fluorescence imaging of fermionic potassium-40 atoms in a quantum-gas microscope setup using electromagnetically-induced-transparency cooling. We detected on average 1000 fluorescence photons from a single atom within 1.5s, while keeping it close to the vibrational ground state of the optical lattice. Our results will enable the study of strongly correlated fermionic quantum systems in optical lattices with resolution at the single-atom level, and give access to observables such as the local entropy distribution and individual defects in fermionic Mott insulators or anti-ferromagnetically ordered phases.Comment: 7 pages, 5 figures; Nature Physics, published online 13 July 201

Cardiovascular care of patients with stroke and high risk of stroke: The need for interdisciplinary action: A consensus report from the European Society of Cardiology Cardiovascular Round Table.

Comprehensive stroke care is an interdisciplinary challenge. Close collaboration of cardiologists and stroke physicians is critical to ensure optimum utilisation of short- and long-term care and preventive measures in patients with stroke. Risk factor management is an important strategy that requires cardiologic involvement for primary and secondary stroke prevention. Treatment of stroke generally is led by stroke physicians, yet cardiologists need to be integrated care providers in stroke units to address all cardiovascular aspects of acute stroke care, including arrhythmia management, blood pressure control, elevated levels of cardiac troponins, valvular disease/endocarditis, and the general management of cardiovascular comorbidities. Despite substantial progress in stroke research and clinical care has been achieved, relevant gaps in clinical evidence remain and cause uncertainties in best practice for treatment and prevention of stroke. The Cardiovascular Round Table of the European Society of Cardiology together with the European Society of Cardiology Council on Stroke in cooperation with the European Stroke Organisation and partners from related scientific societies, regulatory authorities and industry conveyed a two-day workshop to discuss current and emerging concepts and apparent gaps in stroke care, including risk factor management, acute diagnostics, treatments and complications, and operational/logistic issues for health care systems and integrated networks. Joint initiatives of cardiologists and stroke physicians are needed in research and clinical care to target unresolved interdisciplinary problems and to promote the best possible outcomes for patients with stroke

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases

Neuroinflammation is a process characterised by drastic changes in microglial morphology and by marked upregulation of the 18-kDa translocator protein (TSPO) on the mitochondria. The continual increase in incidence of neuroinflammation and neurodegenerative diseases poses a major health issue in many countries, requiring more innovative diagnostic and monitoring tools. TSPO expression may constitute a biomarker for brain inflammation that could be monitored by using TSPO tracers as neuroimaging agents. From medical imaging perspectives, this review focuses on the current concepts related to the TSPO, and discusses briefly on the status of its PET imaging related to neuroinflammation and neurodegenerative diseases in humans

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis

Molecular Architectures of Trimeric SIV and HIV-1 Envelope Glycoproteins on Intact Viruses: Strain-Dependent Variation in Quaternary Structure

The initial step in target cell infection by human, and the closely related simian immunodeficiency viruses (HIV and SIV, respectively) occurs with the binding of trimeric envelope glycoproteins (Env), composed of heterodimers of the viral transmembrane glycoprotein (gp41) and surface glycoprotein (gp120) to target T-cells. Knowledge of the molecular structure of trimeric Env on intact viruses is important both for understanding the molecular mechanisms underlying virus-cell interactions and for the design of effective immunogen-based vaccines to combat HIV/AIDS. Previous analyses of intact HIV-1 BaL virions have already resulted in structures of trimeric Env in unliganded and CD4-liganded states at ∼20 Å resolution. Here, we show that the molecular architectures of trimeric Env from SIVmneE11S, SIVmac239 and HIV-1 R3A strains are closely comparable to that previously determined for HIV-1 BaL, with the V1 and V2 variable loops located at the apex of the spike, close to the contact zone between virus and cell. The location of the V1/V2 loops in trimeric Env was definitively confirmed by structural analysis of HIV-1 R3A virions engineered to express Env with deletion of these loops. Strikingly, in SIV CP-MAC, a CD4-independent strain, trimeric Env is in a constitutively “open” conformation with gp120 trimers splayed out in a conformation similar to that seen for HIV-1 BaL Env when it is complexed with sCD4 and the CD4i antibody 17b. Our findings suggest a structural explanation for the molecular mechanism of CD4-independent viral entry and further establish that cryo-electron tomography can be used to discover distinct, functionally relevant quaternary structures of Env displayed on intact viruses

Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study

In a retrospective cohort study, Gabriel Chodick and colleagues find a significant association between persistence with statin therapy and reduced risk of developing rheumatoid arthritis, but only a modest decrease in risk of osteoarthritis

Determination of the Proteolytic Cleavage Sites of the Amyloid Precursor-Like Protein 2 by the Proteases ADAM10, BACE1 and γ-Secretase

Regulated intramembrane proteolysis of the amyloid precursor protein (APP) by the protease activities α-, β- and γ-secretase controls the generation of the neurotoxic amyloid β peptide. APLP2, the amyloid precursor-like protein 2, is a homolog of APP, which shows functional overlap with APP, but lacks an amyloid β domain. Compared to APP, less is known about the proteolytic processing of APLP2, in particular in neurons, and the cleavage sites have not yet been determined. APLP2 is cleaved by the β-secretase BACE1 and additionally by an α-secretase activity. The two metalloproteases ADAM10 and ADAM17 have been suggested as candidate APLP2 α-secretases in cell lines. Here, we used RNA interference and found that ADAM10, but not ADAM17, is required for the constitutive α-secretase cleavage of APLP2 in HEK293 and SH-SY5Y cells. Likewise, in primary murine neurons knock-down of ADAM10 suppressed APLP2 α-secretase cleavage. Using mass spectrometry we determined the proteolytic cleavage sites in the APLP2 sequence. ADAM10 was found to cleave APLP2 after arginine 670, whereas BACE1 cleaves after leucine 659. Both cleavage sites are located in close proximity to the membrane. γ-secretase cleavage was found to occur at different peptide bonds between alanine 694 and valine 700, which is close to the N-terminus of the predicted APLP2 transmembrane domain. Determination of the APLP2 cleavage sites enables functional studies of the different APLP2 ectodomain fragments and the production of cleavage-site specific antibodies for APLP2, which may be used for biomarker development