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Biophysical Journal Oct 2020Biological cells deform on a nanometer scale when their transmembrane voltage changes, an effect that has been visualized during the action potential using quantitative...
Biological cells deform on a nanometer scale when their transmembrane voltage changes, an effect that has been visualized during the action potential using quantitative phase imaging. Similar changes in the optical path length have been observed in photoreceptor outer segments after a flash stimulus via phase-resolved optical coherence tomography. These optoretinograms reveal a fast, millisecond-scale contraction of the outer segments by tens of nanometers, followed by a slow (hundreds of milliseconds) elongation reaching hundreds of nanometers. Ultrafast measurements of the contractile response using line-field phase-resolved optical coherence tomography show a logarithmic increase in amplitude and a decreasing time to peak with increasing stimulus intensity. We present a model that relates the early receptor potential to these deformations based on the voltage-dependent membrane tension-the mechanism observed earlier in neurons and other electrogenic cells. The early receptor potential is caused by conformational changes in opsins after photoisomerization, resulting in the fractional shift of the charge across the disk membrane. Lateral repulsion of the ions on both sides of the membrane affects its surface tension and leads to its lateral expansion. Because the volume of the disks does not change on a millisecond timescale, their lateral expansion leads to an axial contraction of the outer segment. With increasing stimulus intensity and the resulting tension, the area expansion coefficient of the disk membrane also increases as thermally induced fluctuations are pulled flat, resisting further expansion. This leads to the logarithmic saturation observed in measurements as well as the peak shift in time. This imaging technique therefore relates the structural changes in the photoreceptor to the underlying neurological function of transducing light into electrical signals. Such label-free optical monitoring of neural activity using fast interferometry may be applicable not only to optoretinography but also to neuroscience in general.
Topics: Action Potentials; Interferometry; Ions; Neurons; Photoreceptor Cells
PubMed: 33031739
DOI: 10.1016/j.bpj.2020.09.005 -
Annual International Conference of the... Aug 2016Brain-machine interfaces (BMI) have vastly used a single scale of neural activity, e.g., spikes or electrocorticography (ECoG), as their control signal. New technology...
Brain-machine interfaces (BMI) have vastly used a single scale of neural activity, e.g., spikes or electrocorticography (ECoG), as their control signal. New technology allows for simultaneous recording of multiple scales of neural activity, from spikes to local field potentials (LFP) and ECoG. These advances introduce the new challenge of modeling and decoding multiple scales of neural activity jointly. Such multi-scale decoding is challenging for two reasons. First, spikes are discrete-valued and ECoG/LFP are continuous-valued, resulting in fundamental differences in statistical characteristics. Second, the time-scales of these signals are different, with spikes having a millisecond time-scale and ECoG/LFP having much slower time-scales on the order of tens of milliseconds. Here we develop a new multiscale modeling and decoding framework that addresses these challenges. Our multiscale decoder extracts information from ECoG/LFP in addition to spikes, while operating at the fast time-scale of the spikes. The multiscale decoder specializes to a Kalman filter (KF) or to a point process filter (PPF) when no spikes or ECoG/LFP are available, respectively. Using closed-loop BMI simulations, we show that compared to PPF decoding of spikes alone or KF decoding of LFP/ECoG alone, the multiscale decoder significantly improves the accuracy and error performance of BMI control and runs at the fast millisecond time-scale of the spikes. This new multiscale modeling and decoding framework has the potential to improve BMI control using simultaneous multiscale neural activity.
Topics: Algorithms; Brain-Computer Interfaces; Electrophysiological Phenomena; Models, Neurological; Motor Cortex; Time Factors
PubMed: 28269704
DOI: 10.1109/EMBC.2016.7592183 -
Journal of Visualized Experiments : JoVE Jun 2022Alpha-synuclein (aSyn) is an intrinsically disordered protein whose fibrillar aggregates are abundant in Lewy bodies and neurites, which are the hallmarks of Parkinson's...
Alpha-synuclein (aSyn) is an intrinsically disordered protein whose fibrillar aggregates are abundant in Lewy bodies and neurites, which are the hallmarks of Parkinson's disease. Yet, much of its biological activity, as well as its aggregation, centrally involves the soluble monomer form of the protein. Elucidation of the molecular mechanisms of aSyn biology and pathophysiology requires structurally highly resolved methods and is sensitive to biological conditions. Its natively unfolded, meta-stable structures make monomeric aSyn intractable to many structural biology techniques. Here, the application of one such approach is described: hydrogen/deuterium-exchange mass spectrometry (HDX-MS) on the millisecond timescale for the study of proteins with low thermodynamic stability and weak protection factors, such as aSyn. At the millisecond timescale, HDX-MS data contain information on the solvent accessibility and hydrogen-bonded structure of aSyn, which are lost at longer labeling times, ultimately yielding structural resolution up to the amino acid level. Therefore, HDX-MS can provide information at high structural and temporal resolutions on conformational dynamics and thermodynamics, intra- and inter-molecular interactions, and the structural impact of mutations or alterations to environmental conditions. While broadly applicable, it is demonstrated how to acquire, analyze, and interpret millisecond HDX-MS measurements in monomeric aSyn.
Topics: Deuterium; Deuterium Exchange Measurement; Hydrogen; Hydrogen Deuterium Exchange-Mass Spectrometry; Protein Conformation; alpha-Synuclein
PubMed: 35815971
DOI: 10.3791/64050 -
Optometry and Vision Science : Official... Jul 2023To better understand the implication of a potential cognitive change in glaucoma, patients were stimulated in central visual areas considered functionally normal to...
SIGNIFICANCE
To better understand the implication of a potential cognitive change in glaucoma, patients were stimulated in central visual areas considered functionally normal to discard an effect due to the loss of vision during an attentional task. The outcome might improve the follow-up on the impact of the pathology.
PURPOSE
This study aimed to evaluate the effect of primary open-angle glaucoma on the visual attention system by recording responses of behavioral and oculomotor strategies.
METHODS
We included 20 individuals with primary open-angle glaucoma (62.1 ± 7.2 years old), 18 age-matched control subjects (58.4 ± 7.2 years old), and 20 young control subjects (25.7 ± 3.5 years old). The procedure consisted of visual (eye-tracking recordings) and manual detection of a target. All participants had to detect a square with a vertical bar within distractors (squares, triangles, and circles with a horizontal or vertical bar) of identical size of 1.6 × 1.6° visual angle. The shapes were displayed concentrically on a radius of 5° of visual angle. All participants were tested to ensure that their visual field sensitivity was normal within ±5° central vision.
RESULTS
In responding manually, glaucoma participants were slower than age-matched control subjects (1723 ± 488 vs. 1263 ± 385 milliseconds; P < .01). Eye-tracking recordings showed that glaucoma participants found the target within the same time frame as age-matched control subjects. Compared with the young group, the scanpath length and average fixation duration on distractors were significantly longer for the glaucoma patients (+235 pixels, +104 milliseconds) and the age-matched control participants (+120 pixels, +39 milliseconds). Impaired contrast sensitivity was correlated with longer response time, longer scanpath, and longer fixation on distractors.
CONCLUSIONS
Glaucoma affects the manual response times in a visual attention task, but patients can visually detect the target as quickly as age-matched control subjects. Different clinical factors predicted the performances. The age of the patients was associated with longer scanpath. The visual field loss (mean deviation) was linked with longer visual response time. The loss of contrast sensitivity predicted the behavioral change on fixation duration to the distractors, global response time, visual response time, and scanpath length.
PubMed: 37399242
DOI: 10.1097/OPX.0000000000002036 -
International Journal of Sports... Mar 2022(1) To analyze the associations between serve velocity (SV) and various single-joint upper-limb isometric force-time curve parameters, (2) to develop a prediction...
PURPOSE
(1) To analyze the associations between serve velocity (SV) and various single-joint upper-limb isometric force-time curve parameters, (2) to develop a prediction model based on the relationship between these variables, and (3) to determine whether these factors are capable of discriminating between tennis players with different SV performances.
METHOD
A total of 17 high-performance tennis players performed 8 isometric tests of joints and movements included in the serve kinetic chain (wrist and elbow flexion [EF] and extension; shoulder flexion [SHF] and extension [SHE], internal [SHIR] and external rotation). Isometric force (IF), rate of force development (RFD), and impulse (IMP) at different time intervals (0-250 ms) were obtained for analysis.
RESULTS
Significant (P < .05 to P < .01) and moderate to very large correlations were found between SV and isometric force (IF), RFD and impulse (IMP) at different time intervals in all joint positions tested (except for the EF). Stepwise multiple regression analysis highlighted the importance of RFD in the SHIR from 0 to 50 milliseconds and isometric force (IF) in the SHF at 250 milliseconds on SV performance. Moreover, the discriminant analyses established SHIR RFD from 0 to 30 milliseconds as the most important factor discriminating players with different serve performances.
CONCLUSIONS
Force-time parameters in upper-limb joints involved in the serve moderate to very largely influence SV. Findings suggest that the capability to develop force in short periods of time (<250 ms), especially in the shoulder joint, seems relevant to develop high SV in competition tennis players.
Topics: Humans; Range of Motion, Articular; Shoulder; Shoulder Joint; Tennis; Upper Extremity
PubMed: 34794120
DOI: 10.1123/ijspp.2021-0254 -
Journal of Neurophysiology Sep 2022Neurons are embedded in complex networks, where they participate in repetitive, coordinated interactions with other neurons. Neuronal spike timing is thus predictably...
Neurons are embedded in complex networks, where they participate in repetitive, coordinated interactions with other neurons. Neuronal spike timing is thus predictably constrained by a range of ionic currents that shape activity at both short (milliseconds) and longer (tens to hundreds of milliseconds) timescales, but we lack analytical tools to rigorously identify these relationships. Here, we innovate a modeling approach to test the relationship between oscillations in the local field potential (LFP) and neuronal spike timing. We use kernel density estimation to relate single neuron spike timing and the phase of LFP rhythms (in simulated and hippocampal CA1 neuronal spike trains). We then combine phase and short (3 ms) spike history information within a logistic regression framework ("phaseSH models"), and show that models that leverage refractory constraints and oscillatory phase information can effectively test whether-and the degree to which-rhythmic currents (as measured from the LFP) reliably explain variance in neuronal spike trains. This approach allows researchers to systematically test the relationship between oscillatory activity and neuronal spiking dynamics as they unfold over time and as they shift to adapt to distinct behavioral conditions. Statistical models that incorporate neural spiking history and relationships to the phase of ongoing oscillations in the local field potential robustly capture and predict neuronal engagement in rhythmic processes. These models constitute a powerful tool to systematically test explicit hypotheses regarding the specific rhythmic currents that constrain neural spiking activity over time and during different behaviors.
Topics: Action Potentials; Hippocampus; Models, Neurological; Neurons
PubMed: 35858125
DOI: 10.1152/jn.00423.2021 -
JACC. Clinical Electrophysiology Dec 2022Takotsubo syndrome is associated with life threatening arrhythmias, and the apical ballooning pattern is characterized by a peculiar QT prolongation and particularly... (Review)
Review
BACKGROUND
Takotsubo syndrome is associated with life threatening arrhythmias, and the apical ballooning pattern is characterized by a peculiar QT prolongation and particularly high-risk of arrhythmias.
OBJECTIVES
The aim of the study was to determine the association of QT interval on electrocardiogram for ventricular arrhythmic complications in patients with apical ballooning Takotsubo syndrome in a diverse population at a large urban hospital in the U.S.
METHODS
We reviewed 105 cases of apical ballooning Takotsubo syndrome in patients admitted between 2011 and 2017. Two cardiologists reviewed the electrocardiograms to measure QT interval, adjusted for rate using the Fridericia formula (QTF), and ventricular arrhythmic complications during the hospitalization. Data are reported as median and interquartile range or number and percentage.
RESULTS
Of the 105 patients, 86 (82%) were female, and 34 (32%) were self-reported Black or African American. The mean age was 65 years (range: 58-72 years). Left ventricular ejection fraction was 25% (range: 25%-35%). Heart rate was 101 beats/min (range: 83-121 beats/min). Ten (11%) patients experienced a ventricular arrhythmic complication and had significantly longer QTF (470 [range: 422-543] milliseconds) than did those without complications (417 [range: 383-456] milliseconds, P = 0.031). The area under the curve for QTF was 0.708 (95% CI: 0.536-0.880; P = 0.031). Twenty-eight (27%) patients had a QTF ≥460 milliseconds and significantly more arrhythmic complications (21% vs 5%, odds ratio 4.997 [95% CI: 1.288-19.237], P = 0.021). QTF was an independent predictor of ventricular arrhythmias: odds ratio 1.090 for each 10-millisecond increase in QTF (95% CI: 1.004-1.183; P = 0.040, corrected for sex).
CONCLUSIONS
In a diverse population of patients with apical ballooning Takotsubo syndrome admitted to a large urban hospital in the United States, QTF at admission ≥460 milliseconds identifies patients at high risk for in-hospital arrhythmic complications. Further studies are needed to determine strategies aimed at shortening QT interval to potentially prevent life-threatening arrhythmic events.
Topics: Humans; Female; Aged; Male; Takotsubo Cardiomyopathy; Stroke Volume; Ventricular Function, Left; Long QT Syndrome; Arrhythmias, Cardiac; Hospitals
PubMed: 36543499
DOI: 10.1016/j.jacep.2022.08.010 -
Journal of the American Chemical Society Apr 2022Deciphering the molecular mechanisms of enzymatic allosteric regulation requires the structural characterization of functional states and also their time evolution...
Deciphering the molecular mechanisms of enzymatic allosteric regulation requires the structural characterization of functional states and also their time evolution toward the formation of the allosterically activated ternary complex. The transient nature and usually slow millisecond time scale interconversion between these functional states hamper their experimental and computational characterization. Here, we combine extensive molecular dynamics simulations, enhanced sampling techniques, and dynamical networks to describe the allosteric activation of imidazole glycerol phosphate synthase (IGPS) from the substrate-free form to the active ternary complex. IGPS is a heterodimeric bienzyme complex whose HisH subunit is responsible for hydrolyzing glutamine and delivering ammonia for the cyclase activity in HisF. Despite significant advances in understanding the underlying allosteric mechanism, essential molecular details of the long-range millisecond allosteric activation of IGPS remain hidden. Without using information of the active state, our simulations uncover how IGPS, with the allosteric effector bound in HisF, spontaneously captures glutamine in a catalytically inactive HisH conformation, subsequently attains a closed HisF:HisH interface, and finally forms the oxyanion hole in HisH for efficient glutamine hydrolysis. We show that the combined effector and substrate binding dramatically decreases the conformational barrier associated with oxyanion hole formation, in line with the experimentally observed 4500-fold activity increase in glutamine hydrolysis. The allosteric activation is controlled by correlated time-evolving dynamic networks connecting the effector and substrate binding sites. This computational strategy tailored to describe millisecond events can be used to rationalize the effect of mutations on the allosteric regulation and guide IGPS engineering efforts.
Topics: Allosteric Regulation; Aminohydrolases; Binding Sites; Glutamine
PubMed: 35412310
DOI: 10.1021/jacs.1c12629 -
Immunogenic Cell Death in Electroporation-Based Therapies Depends on Pulse Waveform Characteristics.Vaccines May 2023Traditionally, electroporation-based therapies such as electrochemotherapy (ECT), gene electrotransfer (GET) and irreversible electroporation (IRE) are performed with...
Traditionally, electroporation-based therapies such as electrochemotherapy (ECT), gene electrotransfer (GET) and irreversible electroporation (IRE) are performed with different but typical pulse durations-100 microseconds and 1-50 milliseconds. However, recent in vitro studies have shown that ECT, GET and IRE can be achieved with virtually any pulse duration (millisecond, microsecond, nanosecond) and pulse type (monopolar, bipolar-HFIRE), although with different efficiency. In electroporation-based therapies, immune response activation can affect treatment outcome, and the possibility of controlling and predicting immune response could improve the treatment. In this study, we investigated if different pulse durations and pulse types cause different or similar activations of the immune system by assessing DAMP release (ATP, HMGB1, calreticulin). Results show that DAMP release can be different when different pulse durations and pulse types are used. Nanosecond pulses seems to be the most immunogenic, as they can induce the release of all three main DAMP molecules-ATP, HMGB1 and calreticulin. The least immunogenic seem to be millisecond pulses, as only ATP release was detected and even that assumingly occurs due to increased permeability of the cell membrane. Overall, it seems that DAMP release and immune response in electroporation-based therapies can be controlled though pulse duration.
PubMed: 37376425
DOI: 10.3390/vaccines11061036 -
Accounts of Chemical Research May 2023ConspectusNanoparticles have witnessed immense development in the past several decades due to their intriguing physicochemical properties. The modern chemist is...
ConspectusNanoparticles have witnessed immense development in the past several decades due to their intriguing physicochemical properties. The modern chemist is interested not only in methods of synthesizing nanoparticles with tunable properties but also in the chemistry that nanoparticles can drive. While several methods exist to synthesize nanoparticles, it is often advantageous to put nanoparticles on a variety of conductive substrates for multiple applications (such as energy storage and conversion). Despite enjoying over 200 years of development, electrodeposition of nanoparticles suffers from a lack of control over nanoparticle size and morphology. There have been heroic efforts to address these issues over time. With an understanding that structure-function studies are imperative to understand the chemistry of nanoparticles, new methods are necessary to electrodeposit a variety of nanoparticles with control over macromorphology and also microstructure.This Account details our group's efforts in overcoming challenges of classical nanoparticle electrodeposition by electrodepositing nanoparticles from water nanodroplets. When a nanodroplet full of metal salt precursor is incident on the electrode biased sufficiently negative to drive electroplating, nanoparticles form at a fast rate (on the order of microseconds to milliseconds). We start with the general nuts-and-bolts of the experiment (nanodroplet formation and methods for electrodeposition). The deposition of new nanomaterials often requires one to develop new methods of measurement, and we detail new measurement tools for quantifying nanoparticle porosity and nanopore tortuosity within single nanoparticles. We achieve nanopore characterization by using Focused Ion Beam milling and Scanning Electron Microscopy. Owing to the small size of the nanodroplets and fast mass transfer (the contents of a femtoliter droplet can be electrolyzed in only a few milliseconds), the use of nanodroplets also allows the electrodeposition of high entropy alloy nanoparticles at room temperature.We detail how a deep understanding of ion transfer mechanisms can be used to expand the library of possible metals that can be deposited. Furthermore, simple ion changes in the dispersed droplet phase can decrease the cost per experiment by orders of magnitude. Finally, electrodeposition in aqueous nanodroplets can also be combined with stochastic electrochemistry for a variety of interesting studies. We detail the quantification of the growth kinetics of single nanoparticles in single aqueous nanodroplets. Nanodroplets can also be used as tiny reactors to trap only a few molecules of a metal salt precursor. Upon reduction to the zerovalent metal, electrocatalysis at very small metal clusters can be probed and evaluated with time using steady-state electrochemical measurements. Overall, this burgeoning synthetic tool is providing unexpected avenues of tunability of metal nanoparticles on conductive substrates.
PubMed: 37155578
DOI: 10.1021/acs.accounts.3c00050