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World Journal of Methodology Dec 2012The purpose of this overview is to provide a concise introduction to the methodology and current advances in molecular dynamics (MD) simulations. MD simulations emerged... (Review)
Review
The purpose of this overview is to provide a concise introduction to the methodology and current advances in molecular dynamics (MD) simulations. MD simulations emerged as a powerful and popular tool to study dynamic behavior of proteins and macromolecule complexes at the atomic resolution. This approach can extend static structural data, such as X-ray crystallography, into dynamic domains with realistic timescales (up to millisecond) and high precision, therefore becoming a veritable computational microscope. This perspective covers current advances and methodology in the simulation of protein folding and drug design as illustrated by several important published examples. Overall, recent progress in the simulation field points to the direction that MD will have significant impact on molecular biology and pharmaceutical science.
PubMed: 25237616
DOI: 10.5662/wjm.v2.i6.42 -
Frontiers in Neuroscience 2021Across sleep and wakefulness, brain function requires inter-neuronal interactions lasting beyond seconds. Yet, most studies of neural circuit connectivity focus on... (Review)
Review
Across sleep and wakefulness, brain function requires inter-neuronal interactions lasting beyond seconds. Yet, most studies of neural circuit connectivity focus on millisecond-scale interactions mediated by the classic fast transmitters, GABA and glutamate. In contrast, neural circuit roles of the largest transmitter family in the brain-the slow-acting peptide transmitters-remain relatively overlooked, or described as "modulatory." Neuropeptides may efficiently implement sustained neural circuit connectivity, since they are not rapidly removed from the extracellular space, and their prolonged action does not require continuous presynaptic firing. From this perspective, we review actions of evolutionarily-conserved neuropeptides made by brain-wide-projecting hypothalamic neurons, focusing on lateral hypothalamus (LH) neuropeptides essential for stable consciousness: the orexins/hypocretins. Action potential-dependent orexin release inside and outside the hypothalamus evokes slow postsynaptic excitation. This excitation does not arise from modulation of classic neurotransmission, but involves direct action of orexins on their specific G-protein coupled receptors (GPCRs) coupled to ion channels. While millisecond-scale, GABA/glutamate connectivity within the LH may not be strong, re-assessing LH microcircuits from the peptidergic viewpoint is consistent with slow local microcircuits. The sustained actions of neuropeptides on neuronal membrane potential may enable core brain functions, such as temporal integration and the creation of lasting permissive signals that act as "eligibility traces" for context-dependent information routing and plasticity. The slowness of neuropeptides has unique advantages for efficient neuronal processing and feedback control of consciousness.
PubMed: 33776641
DOI: 10.3389/fnins.2021.644313 -
American Family Physician Feb 2014Pacemakers are indicated in patients with certain symptomatic bradyarrhythmias caused by sinus node dysfunction, and in those with frequent, prolonged sinus pauses.... (Review)
Review
Pacemakers are indicated in patients with certain symptomatic bradyarrhythmias caused by sinus node dysfunction, and in those with frequent, prolonged sinus pauses. Patients with third-degree or complete atrioventricular (AV) block benefit from pacemaker placement, as do those with type II second-degree AV block because of the risk of progression to complete AV block. The use of pacemakers in patients with type I second-degree AV block is controversial. Patients with first-degree AV block generally should not receive a pacemaker except when the PR interval is significantly prolonged and the patient is symptomatic. Although some guidelines recommend pacemaker implantation for patients with hypersensitive carotid sinus syndrome, recent evidence has not shown benefit. Some older patients with severe neurocardiogenic syncope may benefit from pacemakers, but most patients with this disorder do not. Cardiac resynchronization therapy improves mortality rates and some other disease-specific measures in patients who have a QRS duration of 150 milliseconds or greater and New York Heart Association class III or IV heart failure. Patients with class II heart failure and a QRS of 150 milliseconds or greater also appear to benefit, but there is insufficient evidence to support the use of cardiac resynchronization therapy in patients with class I heart failure. Cardiac resynchronization therapy in patients with a QRS of 120 to 150 milliseconds does not reduce rates of hospitalization or death.
Topics: Bradycardia; Cardiac Resynchronization Therapy; Electrocardiography; Humans
PubMed: 24695448
DOI: No ID Found -
Optics Express Nov 2023Two decades after its introduction, optogenetics - a biological technique to control the activity of neurons or other cell types with light - remains a cutting edge and...
Two decades after its introduction, optogenetics - a biological technique to control the activity of neurons or other cell types with light - remains a cutting edge and promising tool to study biological processes. Its increasing usage in research varies widely from causally exploring biological mechanisms and neural computations, to neurostimulation and sensory restauration. To stimulate neurons in the brain, a variety of approaches have been developed to generate precise spatiotemporal light patterns. Yet certain constrains still exists in the current optical techniques to activate a neuronal population with both cellular resolution and millisecond precision. Here, we describe an experimental setup allowing to stimulate a few tens of neurons in a plane at sub-millisecond rates using 2-photon activation. A liquid crystal on silicon spatial light modulator (LCoS-SLM) was used to generate spatial patterns in 2 dimensions. The image of the patterns was formed on the plane of a digital micromirror device (DMD) that was used as a fast temporal modulator of each region of interest. Using fluorescent microscopy and patch-clamp recording of neurons in culture expressing the light-gated ion channels, we characterized the temporal and spatial resolution of the microscope. We described the advantages of combining the LCoS-SLM with the DMD to maximize the temporal precision, modulate the illumination amplitude, and reduce background activation. Finally, we showed that this approach can be extended to patterns in 3 dimensions. We concluded that the methodology is well suited to address important questions about the role of temporal information in neuronal coding.
Topics: Photons; Photic Stimulation; Holography; Neurons; Brain
PubMed: 38018006
DOI: 10.1364/OE.498644 -
Current Opinion in Neurobiology Apr 2011Synapses exhibit several forms of short-term plasticity that play a multitude of computational roles. Short-term depression suppresses neurotransmitter release for... (Review)
Review
Synapses exhibit several forms of short-term plasticity that play a multitude of computational roles. Short-term depression suppresses neurotransmitter release for hundreds of milliseconds to tens of seconds; facilitation and post-tetanic potentiation lead to synaptic enhancement lasting hundreds of milliseconds to minutes. Recent advances have provided insight into the mechanisms underlying these forms of plasticity. Vesicle depletion, as well as inactivation of both release sites and calcium channels, contribute to synaptic depression. Mechanisms of short-term enhancement include calcium channel facilitation, local depletion of calcium buffers, increases in the probability of release downstream of calcium influx, altered vesicle pool properties, and increases in quantal size. Moreover, there is a growing appreciation of the heterogeneity of vesicles and release sites and how they can contribute to use-dependent plasticity.
Topics: Animals; Calcium Channels; Humans; Neuronal Plasticity; Presynaptic Terminals; Synaptic Vesicles
PubMed: 21353526
DOI: 10.1016/j.conb.2011.02.003 -
Neuron Oct 2013During an action potential, Ca(2+) entering a presynaptic terminal triggers synaptic vesicle exocytosis and neurotransmitter release in less than a millisecond. How does... (Review)
Review
During an action potential, Ca(2+) entering a presynaptic terminal triggers synaptic vesicle exocytosis and neurotransmitter release in less than a millisecond. How does Ca(2+) stimulate release so rapidly and precisely? Work over the last decades revealed that Ca(2+) binding to synaptotagmin triggers release by stimulating synaptotagmin binding to a core fusion machinery composed of SNARE and SM proteins that mediates membrane fusion during exocytosis. Complexin adaptor proteins assist synaptotagmin by activating and clamping this core fusion machinery. Synaptic vesicles containing synaptotagmin are positioned at the active zone, the site of vesicle fusion, by a protein complex containing RIM proteins. RIM proteins activate docking and priming of synaptic vesicles and simultaneously recruit Ca(2+) channels to active zones, thereby connecting in a single complex primed synaptic vesicles to Ca(2+) channels. This architecture allows direct flow of Ca(2+) ions from Ca(2+) channels to synaptotagmin, which then triggers fusion, thus mediating tight millisecond coupling of an action potential to neurotransmitter release.
Topics: Animals; Membrane Fusion; Models, Neurological; Neurons; Neurotransmitter Agents; SNARE Proteins; Synaptic Transmission; Synaptic Vesicles
PubMed: 24183019
DOI: 10.1016/j.neuron.2013.10.022 -
Analytical Chemistry Dec 2022In Parkinson's disease and other synucleinopathies, α-synuclein misfolds and aggregates. Its intrinsically disordered nature, however, causes it to adopt several...
In Parkinson's disease and other synucleinopathies, α-synuclein misfolds and aggregates. Its intrinsically disordered nature, however, causes it to adopt several meta-stable conformations stabilized by internal hydrogen bonding. Because they interconvert on short timescales, monomeric conformations of disordered proteins are difficult to characterize using common structural techniques. Few techniques can measure the conformations of monomeric α-synuclein, including millisecond hydrogen/deuterium-exchange mass spectrometry (HDX-MS). Here, we demonstrate a new approach correlating millisecond HDX-MS data with aggregation kinetics to determine the localized structural dynamics that underpin the self-assembly process in full-length wild-type monomeric α-synuclein. Our custom instrumentation and software enabled measurement of the amide hydrogen-exchange rates on the millisecond timescale for wild-type α-synuclein monomer up to residue resolution and under physiological conditions, mimicking those in the extracellular, intracellular, and lysosomal cellular compartments. We applied an empirical correction to normalize measured hydrogen-exchange rates and thus allow comparison between drastically different solution conditions. We characterized the aggregation kinetics and morphology of the resulting fibrils and correlate these with structural changes in the monomer. Applying a correlative approach to connect molecular conformation to aggregation in α-synuclein for the first time, we found that the central C-terminal residues of α-synuclein are driving its nucleation and thus its aggregation. We provide a new approach to link the local structural dynamics of intrinsically disordered proteins to functional attributes, which we evidence with new details on our current understanding of the relationship between the local chemical environment and conformational ensemble bias of monomeric α-synuclein.
Topics: Humans; alpha-Synuclein; Deuterium; Hydrogen Deuterium Exchange-Mass Spectrometry; Deuterium Exchange Measurement; Parkinson Disease; Protein Conformation
PubMed: 36413494
DOI: 10.1021/acs.analchem.2c03183 -
IUCrJ Sep 2021Time-resolved crystallography of biomolecules in action has advanced rapidly as methods for serial crystallography have improved, but the large number of crystals and...
Time-resolved crystallography of biomolecules in action has advanced rapidly as methods for serial crystallography have improved, but the large number of crystals and the complex experimental infrastructure that are required remain serious obstacles to its widespread application. Here, millisecond mix-and-quench crystallography (MMQX) has been developed, which yields millisecond time-resolved data using far fewer crystals and routine remote synchrotron data collection. To demonstrate the capabilities of MMQX, the conversion of oxaloacetic acid to phosphoenolpyruvate by phosphoenolpyruvate carboxy-kinase (PEPCK) is observed with a time resolution of 40 ms. By lowering the entry barrier to time-resolved crystallography, MMQX should enable a broad expansion in structural studies of protein dynamics.
PubMed: 34584739
DOI: 10.1107/S2052252521007053 -
Philosophical Transactions of the Royal... May 2015We discuss the importance of timing in brain function: how temporal dynamics of the world has left its traces in the brain during evolution and how we can monitor the... (Review)
Review
We discuss the importance of timing in brain function: how temporal dynamics of the world has left its traces in the brain during evolution and how we can monitor the dynamics of the human brain with non-invasive measurements. Accurate timing is important for the interplay of neurons, neuronal circuitries, brain areas and human individuals. In the human brain, multiple temporal integration windows are hierarchically organized, with temporal scales ranging from microseconds to tens and hundreds of milliseconds for perceptual, motor and cognitive functions, and up to minutes, hours and even months for hormonal and mood changes. Accurate timing is impaired in several brain diseases. From the current repertoire of non-invasive brain imaging methods, only magnetoencephalography (MEG) and scalp electroencephalography (EEG) provide millisecond time-resolution; our focus in this paper is on MEG. Since the introduction of high-density whole-scalp MEG/EEG coverage in the 1990s, the instrumentation has not changed drastically; yet, novel data analyses are advancing the field rapidly by shifting the focus from the mere pinpointing of activity hotspots to seeking stimulus- or task-specific information and to characterizing functional networks. During the next decades, we can expect increased spatial resolution and accuracy of the time-resolved brain imaging and better understanding of brain function, especially its temporal constraints, with the development of novel instrumentation and finer-grained, physiologically inspired generative models of local and network activity. Merging both spatial and temporal information with increasing accuracy and carrying out recordings in naturalistic conditions, including social interaction, will bring much new information about human brain function.
Topics: Brain; Brain Mapping; Electroencephalography; Humans; Magnetoencephalography; Nerve Net; Time Factors
PubMed: 25823867
DOI: 10.1098/rstb.2014.0170 -
Current Biology : CB Aug 2019Monovision is a common prescription lens correction for presbyopia [1]. Each eye is corrected for a different distance, causing one image to be blurrier than the other....
Monovision is a common prescription lens correction for presbyopia [1]. Each eye is corrected for a different distance, causing one image to be blurrier than the other. Millions of people have monovision corrections, but little is known about how interocular blur differences affect motion perception. Here, we report that blur differences cause a previously unknown motion illusion that makes people dramatically misperceive the distance and three-dimensional direction of moving objects. The effect occurs because the blurry and sharp images are processed at different speeds. For moving objects, the mismatch in processing speed causes a neural disparity, which results in the misperceptions. A variant of a 100-year-old stereo-motion phenomenon called the Pulfrich effect [2], the illusion poses an apparent paradox: blur reduces contrast, and contrast reductions are known to cause neural processing delays [3-6], but our results indicate that blurry images are processed milliseconds more quickly. We resolve the paradox with known properties of the early visual system, show that the misperceptions can be severe enough to impact public safety, and demonstrate that the misperceptions can be eliminated with novel combinations of non-invasive ophthalmic interventions. The fact that substantial perceptual errors are caused by millisecond differences in processing speed highlights the exquisite temporal calibration required for accurate perceptual estimation. The motion illusion-the reverse Pulfrich effect-and the paradigm we use to measure it should help reveal how optical and image properties impact temporal processing, an important but understudied issue in vision and visual neuroscience.
Topics: Adult; Depth Perception; Female; Humans; Illusions; Male; Motion; Motion Perception; Presbyopia; Vision, Monocular; Young Adult
PubMed: 31353183
DOI: 10.1016/j.cub.2019.06.070