Sampling Real-Time Atomic Dynamics in Metal Nanoparticles by Combining Experiments, Simulations, and Machine Learning.

Even at low temperatures, metal nanoparticles (NPs) possess atomic dynamics that are key for their properties but challenging to elucidate. Recent experimental advances allow obtaining atomic-resolution snapshots of the NPs in realistic regimes, but data acquisition limitations hinder the experimental reconstruction of the atomic dynamics present within them. Molecular simulations have the advantage that these allow directly tracking the motion of atoms over time. However, these typically start from ideal/perfect NP structures and, suffering from sampling limits, provide results that are often dependent on the initial/putative structure and remain purely indicative. Here, by combining state-of-the-art experimental and computational approaches, how it is possible to tackle the limitations of both approaches and resolve the atomistic dynamics present in metal NPs in realistic conditions is demonstrated. Annular dark-field scanning transmission electron microscopy enables the acquisition of ten high-resolution images of an Au NP at intervals of 0.6 s. These are used to reconstruct atomistic 3D models of the real NP used to run ten independent molecular dynamics simulations. Machine learning analyses of the simulation trajectories allow resolving the real-time atomic dynamics present within the NP. This provides a robust combined experimental/computational approach to characterize the structural dynamics of metal NPs in realistic conditions.

Instrumented assessment of gait disturbance in PMM2-CDG adults: a feasibility analysis.

BACKGROUND: Congenital disorders of glycosylation (CDG) are genetic diseases caused by impaired synthesis of glycan moieties linked to glycoconjugates. Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent CDG, is characterized by prominent neurological involvement. Gait disturbance is a major cause of functional disability in patients with PMM2-CDG. However, no specific gait assessment for PMM2-CDG is available. This study analyses gait-related parameters in PMM2-CDG patients using a standardized clinical assessment and instrumented gait analysis (IGA). RESULTS: Seven adult patients with a molecular diagnosis of PMM2-CDG were followed-up from February 2021 to December 2022 and compared to a group of healthy control (HC) subjects, matched for age and sex. Standardized assessment of disease severity including ataxia and peripheral neuropathy along with isometric muscle strength and echo-biometry measurements at lower limbs were performed. IGA spatiotemporal parameters were obtained by means of a wearable sensor in basal conditions. PMM2-CDG patients displayed lower gait speed, stride length, cadence and symmetry index, compared to HC. Significant correlations were found among the used clinical scales and between disease severity (NCRS) scores and the gait speed measured by IGA. Variable reduction of knee extension strength and a significant decrease of lower limb muscle thickness with conserved echo intensity were found in PMM2-CDG compared to HC. CONCLUSIONS: The study elucidates different components of gait disturbance in PMM2-CDG patients and shows advantages of using wearable sensor-based IGA in this frame. IGA parameters may potentially serve as quantitative measures for follow-up or outcome quantification in PMM2-CDG.

Time course of surface electromyography during walking of children with spastic cerebral palsy treated with botulinum toxin type A and its rehabilitation implications.

BACKGROUND: The timing of the effects of botulinum toxin A on spastic muscles is not yet fully clarified. The goal of this study was to follow the temporal changes of surface electromyographic activity of lower limb muscles during walking, after a therapeutic dose of botulinum toxin A injected into the calf muscles of children with spastic cerebral palsy. METHODS: A group of children with spastic equinus foot was administered botulinum toxin A into the gastrocnemius medialis and lateralis muscles. Surface electromyographic activity of the tibialis anterior, gastrocnemius medialis, rectus femoris and medial hamstrings, was recorded before botulinum toxin A injections and after 4, 8, and 16 weeks. Children walked on ground and on a treadmill at an incline of 0% and 12%. The area of electromyographic activity and the index of muscle co-contraction were calculated for specific segments of gait cycle. FINDINGS: Botulinum toxin A did not modify the speed of gait on ground. ANOVA showed significant differences in electromyography during the stance phase segments with a maximum decrease between 4 and 8 weeks' post botulinum toxin A and a full recovery at 16 weeks. A significant co-contraction of rectus femoris/gastrocnemius medialis, between 0 and 20% and 35-50% of the gait cycle, was observed from the 4th to the 8th week post- botulinum toxin A for both treadmill settings. INTERPRETATION: The temporal identification of deterioration/recovery of electromyographic activity as well as of muscle co-contractions, could be key elements in a rehabilitation program planning combined with botulinum toxin A.

Machine learning of atomic dynamics and statistical surface identities in gold nanoparticles.

It is known that metal nanoparticles (NPs) may be dynamic and atoms may move within them even at fairly low temperatures. Characterizing such complex dynamics is key for understanding NPs' properties in realistic regimes, but detailed information on, e.g., the stability, survival, and interconversion rates of the atomic environments (AEs) populating them are non-trivial to attain. In this study, we decode the intricate atomic dynamics of metal NPs by using a machine learning approach analyzing high-dimensional data obtained from molecular dynamics simulations. Using different-shape gold NPs as a representative example, an AEs' dictionary allows us to label step-by-step the individual atoms in the NPs, identifying the native and non-native AEs and populating them along the MD simulations at various temperatures. By tracking the emergence, annihilation, lifetime, and dynamic interconversion of the AEs, our approach permits estimating a "statistical equivalent identity" for metal NPs, providing a comprehensive picture of the intrinsic atomic dynamics that shape their properties.

Innate dynamics and identity crisis of a metal surface unveiled by machine learning of atomic environments.

Metals are traditionally considered hard matter. However, it is well known that their atomic lattices may become dynamic and undergo reconfigurations even well below the melting temperature. The innate atomic dynamics of metals is directly related to their bulk and surface properties. Understanding their complex structural dynamics is, thus, important for many applications but is not easy. Here, we report deep-potential molecular dynamics simulations allowing to resolve at an atomic resolution the complex dynamics of various types of copper (Cu) surfaces, used as an example, near the Hüttig (∼1/3 of melting) temperature. The development of deep neural network potential trained on density functional theory calculations provides a dynamically accurate force field that we use to simulate large atomistic models of different Cu surface types. A combination of high-dimensional structural descriptors and unsupervized machine learning allows identifying and tracking all the atomic environments (AEs) emerging in the surfaces at finite temperatures. We can directly observe how AEs that are non-native in a specific (ideal) surface, but that are, instead, typical of other surface types, continuously emerge/disappear in that surface in relevant regimes in dynamic equilibrium with the native ones. Our analyses allow estimating the lifetime of all the AEs populating these Cu surfaces and to reconstruct their dynamic interconversions networks. This reveals the elusive identity of these metal surfaces, which preserve their identity only in part and in part transform into something else under relevant conditions. This also proposes a concept of "statistical identity" for metal surfaces, which is key to understanding their behaviors and properties.

Balance impairment in cerebrotendinous xanthomatosis: Ankle strategy deficit. A case study.

BACKGROUND: Cerebrotendinous xanthomatosis is a rare autosomal-recessive lipid storage disorder causing an elevation in cholestanol and cholesterol levels and their deposition in the central nervous system and tendons with consequent posture and gait disturbances. METHODS: This report shows the case of a 36-year-old male affected by Cerebrotendinous xanthomatosis with static and dynamic instability. We aimed to provide an instrumented quantification of quiet upright standing using a piezoelectric force platform measuring the variations of center of pressure with the foot position 10 cm and 20 cm apart or extra-rotated with an opening angle of 30°, with eyes open or closed. The area of center of pressure and the length of its trajectory in the anterior-posterior and medial-lateral directions were computed. The temporal variability of center of pressure was evaluated by means of the Root Mean Square. FINDINGS: In comparison with a control group, the area, the trajectory length of center of pressure in anterior-posterior and medial-lateral directions and the temporal variability increased in all static conditions. Intra-patient comparison showed that foot position 10 cm apart was the position that most influenced stability causing a marked worsening of area and trajectory length of center of pressure in both anterior-posterior and medial-lateral directions, particularly for the eyes closed condition. INTERPRETATION: We found a large static instability due to internal neural and biomechanical constraints causing an insufficiency of ankle strategy. A physical therapy program based on instrumented proprioceptive exercises is to be implemented to teach the use of a hip strategy.

Anti-inflammatory role of vitamin D in muscle dysfunctions of patients with chronic obstructive pulmonary disease: a comprehensive review.

Vitamin D deficiency is involved in the etiology of a broad range of diseases. Recently, some studies have shown a link between vitamin D and susceptibility to the onset of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation and irreversible airway obstruction. Systemic inflammation in COPD patients is associated with a decline in lung function. In addition, inflammation causes various extra-pulmonary symptoms, including muscle deterioration that leads to reduced strength and fatigue endurance, especially in muscles of the lower limb. In COPD the pathophysiological changes related to the inflammatory state affect oxidant-antioxidant balance, which is one of the main mechanisms promoting the progression of this disease and exacerbations. Vitamin D exerts beneficial effects and exhibits anti-inflammatory actions. Vitamin D deficiency in COPD patients affects inflammation, oxidative stress and mitochondrial impairment and can generate the development of skeletal atrophy. This systematic review offers a better understanding of the molecular mechanisms linking vitamin D deficiency to COPD and muscle weakness, and aims to establish whether vitamin D supplementation could be useful to mitigate inflammation in COPD patients.

Reconstructing reactivity in dynamic host-guest systems at atomistic resolution: amide hydrolysis under confinement in the cavity of a coordination cage.

Spatial confinement is widely employed by nature to attain unique efficiency in controlling chemical reactions. Notable examples are enzymes, which selectively bind reactants and exquisitely regulate their conversion into products. In an attempt to mimic natural catalytic systems, supramolecular metal-organic cages capable of encapsulating guests in their cavity and of controlling/accelerating chemical reactions under confinement are attracting increasing interest. However, the complex nature of these systems, where reactants/products continuously exchange in-and-out of the host, makes it often difficult to elucidate the factors controlling the reactivity in dynamic regimes. As a case study, here we focus on a coordination cage that can encapsulate amide guests and enhance their hydrolysis by favoring their mechanical twisting towards reactive molecular configurations under confinement. We designed an advanced multiscale simulation approach that allows us to reconstruct the reactivity in such host-guest systems in dynamic regimes. In this way, we can characterize amide encapsulation/expulsion in/out of the cage cavity (thermodynamics and kinetics), coupling such host-guest dynamic equilibrium with characteristic hydrolysis reaction constants. All computed kinetic/thermodynamic data are then combined, obtaining a statistical estimation of reaction acceleration in the host-guest system that is found in optimal agreement with the available experimental trends. This shows how, to understand the key factors controlling accelerations/variations in the reaction under confinement, it is necessary to take into account all dynamic processes that occur as intimately entangled in such host-guest systems. This also provides us with a flexible computational framework, useful to build structure-dynamics-property relationships for a variety of reactive host-guest systems.

Identifying the Effects of Age and Speed on Whole-Body Gait Symmetry by Using a Single Wearable Sensor.

Studies on gait symmetry in healthy population have mainly been focused on small range of age categories, neglecting Teenagers (13-18 years old) and Middle-Aged persons (51-60 years old). Moreover, age-related effects on gait symmetry were found only when the symmetry evaluation was based on whole-body acceleration than on spatiotemporal parameters of the gait cycle. Here, we provide a more comprehensive analysis of this issue, using a Symmetry Index (SI) based on whole-body acceleration recorded on individuals aged 6 to 84 years old. Participants wore a single inertial sensor placed on the lower back and walked for 10 m at comfortable, slow and fast speeds. The SI was computed using the coefficient of correlation of whole-body acceleration measured at right and left gait cycles. Young Adults (19-35 years old) and Adults (36-50 years old) showed stable SI over the three speed conditions, while Children (6-12 years old), Teenagers (13-18 years old), Middle-Aged persons and Elderly (61-70 and 71-84 years old) exhibited lower SI values when walking at fast speed. Overall, this study confirms that whole-body gait symmetry is lower in Children and in Elderly persons over 60 years of age, showing, for the first time, that asymmetries appear also during teenage period and in Middle-Aged persons (51-60 years old).

Is the Power Spectrum of Electromyography Signal a Feasible Tool to Estimate Muscle Fiber Composition in Patients with COPD?

A greater proportion of glycolytic muscle fibers is a manifestation of skeletal muscle dysfunction in Chronic Obstructive Pulmonary Disease (COPD). Here, we propose to use the spectral analysis of the electromyographic signal as a non-invasive approach to investigate the fiber muscle composition in COPD. We recorded the electromyographic activity of Rectus Femoris (RF), Vastus Lateralis (VL), Vastus Medialis (VM) and Biceps Femoris (BF) muscles, in ten patients and ten healthy individuals, during non-fatiguing, flexion-extension leg movements. The mean (MNF) and median frequencies (MDF) were calculated, and the most common profiles of electromyographic power spectrum were characterized by using the principal component analysis. Frequency parameters showed higher values in patients with COPD than in the control group for the RF (+25% for MNF; +21% for MNF), VL (+16% for MNF; 16% for MNF) and VM (+22% for MNF; 22% for MNF) muscles during the extension movements and for the BF (+26% for MNF; 34% for MNF) muscle during flexion movements. Spectrum profiles of the COPD patients shifted towards the higher frequencies, and the changes in frequency parameters were correlated with the level of disease severity. This shift of frequencies may indicate an increase in glycolytic muscle fibers in patients with COPD. These results, along with the non-fatigable nature of the motor task and the adoption of a non-invasive method, encourage to use electromyographic spectral analysis for estimating muscle fiber composition in patients with COPD.

Impact of chronic obstructive pulmonary disease on passive viscoelastic components of the musculoarticular system.

Chronic obstructive pulmonary disease (COPD) produces skeletal muscle atrophy and weakness, leading to impairments of exercise performance. The mechanical work needed for movement execution is also provided by the passive tension developed by musculoarticular connective tissue. To verify whether COPD affects this component, the passive viscoelastic properties of the knee joint were evaluated in 11 patients with COPD and in 11 healthy individuals. The levels of stiffness and viscosity were assessed by means of the pendulum test, consisting in a series of passive leg oscillations. In addition, to explore the contribution of passive tension in the mechanical output of a simple motor task, voluntary leg flexion-extension movements were performed. Patients with COPD showed a statistically significant reduction in stiffness and viscosity compared to controls. Voluntary execution of flexion-extension movements revealed that the electromyographic activity of the Rectus Femoris and Biceps Femoris was lower in patients than in controls, and the low viscoelastic tension in the patients conditioned the performance of active movements. These results provide novel insights on the mechanism responsible for the movement impairments associated with COPD.

Critical spatiotemporal gait parameters for individuals with dementia: A systematic review and meta-analysis.

Instrumented gait analysis allows for the identification of walking parameters to predict cognitive decline and the worsening of dementia. The aim of this study was to perform a meta-analysis to better clarify which gait parameters are affected or modified with the progression of the dementia in a larger sample, as well as which gait assessment conditions (single-task or dual-task conditions) would be more sensitive to reflect the influence of dementia. Literature searches were conducted with the keywords "quantitative gait" OR "gait analysis" AND "dementia" AND "single-task" AND "dual-task," and for "quantitative gait" OR "gait analysis" AND "dementia" AND "fall risk" on PubMed, EMBASE, the Cochrane Library, Scopus, and Web of Science. The results were used to perform a systematic review focussing on instrumental quantitative assessment of the walking of patients with dementia, during both single and dual tasks. The search was performed independently by two authors (C. R. and C. M.) from January 2018 to April 2020 using the PICOS criteria. Nine publications met the inclusion criteria and were included in the systematic review. Our meta-analysis showed that during a single task, most of the spatiotemporal parameters of gait discriminated best between patients with dementia and healthy controls, including speed, cadence, stride length, stride time, stride time variability, and stance time. In dual tasks, only speed, stride length, and stride time variability discriminated between the two groups. In addition, compared with spatial parameters (e.g. stride length), some temporal gait parameters were more correlated to the risk of falls during the comfortable walking in a single task, such as cadence, stride time, stride time variability, and stance time. During a dual task, only the variability of stride time was associated with the risk of falls.

Use of a Single Wearable Sensor to Evaluate the Effects of Gait and Pelvis Asymmetries on the Components of the Timed Up and Go Test, in Persons with Unilateral Lower Limb Amputation.

The Timed Up and Go (TUG) test quantifies physical mobility by measuring the total performance time. In this study, we quantified the single TUG subcomponents and, for the first time, explored the effects of gait cycle and pelvis asymmetries on them. Transfemoral (TF) and transtibial (TT) amputees were compared with a control group. A single wearable inertial sensor, applied to the back, captured kinematic data from the body and pelvis during the 10-m walk test and the TUG test. From these data, two categories of symmetry indexes (SI) were computed: One SI captured the differences between the antero-posterior accelerations of the two sides during the gait cycle, while another set of SI quantified the symmetry over the three-dimensional pelvis motions. Moreover, the total time of the TUG test, the time of each subcomponent, and the velocity of the turning subcomponents were measured. Only the TF amputees showed significant reductions in each SI category when compared to the controls. During the TUG test, the TF group showed a longer duration and velocity reduction mainly over the turning subtasks. However, for all the amputees there were significant correlations between the level of asymmetries and the velocity during the turning tasks. Overall, gait cycle and pelvis asymmetries had a specific detrimental effect on the turning performance instead of on linear walking.

Effects of Functional Electrical Stimulation Cycling of Different Duration on Viscoelastic and Electromyographic Properties of the Knee in Patients with Spinal Cord Injury.

The benefits of functional electrical stimulation during cycling (FES-cycling) have been ascertained following spinal cord injury. The instrumented pendulum test was applied to chronic paraplegic patients to investigate the effects of FES-cycling of different duration (20-min vs. 40-min) on biomechanical and electromyographic characterization of knee mobility. Seven adults with post-traumatic paraplegia attended two FES-cycling sessions, a 20-min and a 40-min one, in a random order. Knee angular excursion, stiffness and viscosity were measured using the pendulum test before and after each session. Surface electromyographic activity was recorded from the rectus femoris (RF) and biceps femoris (BF) muscles. FES-cycling led to reduced excursion (p < 0.001) and increased stiffness (p = 0.005) of the knee, which was more evident after the 20-min than 40-min session. Noteworthy, biomechanical changes were associated with an increase of muscle activity and changes in latency of muscle activity only for 20-min, with anticipated response times for RF (p < 0.001) and delayed responses for BF (p = 0.033). These results indicate that significant functional changes in knee mobility can be achieved by FES-cycling for 20 min, as evaluated by the pendulum test in patients with chronic paraplegia. The observed muscle behaviour suggests modulatory effects of exercise on spinal network aimed to partially restore automatic neuronal processes.

Age-Related Changes in Mobility Evaluated by the Timed Up and Go Test Instrumented through a Single Sensor.

Mobility across people with a large range of age was evaluated, for the first time, by using an instrumented timed up and go test (iTUG) based on signals acquired by a single wearable inertial sensor. Eighty healthy participants, from childhood to old age, performed the test, covering walking distances of 3 m and 7 m. Total time, temporal, and velocity parameters of linear and turning subcomponents of the test were quantified. While children, adults, and senior adults exhibited similar values for all the parameters, older adults showed increases in duration and reductions in velocity during the turning phases when compared with the other groups. an increase in velocity was observed during mid turning when the test was performed along the longer distance. Similarity across children, adults, and senior adults indicates that healthy individuals develop the abilities performed in the iTUG early, while the slowing down shown during the turning phases by the older adults may reflect the need to implement adaptive adjustments to face changes of direction. These results emphasize the idea that reducing equipment to a single sensor provides an appropriate quantification when the iTUG is used to investigate a broader age range or different levels of complexity.

Relationship between accuracy and complexity when learning underarm precision throwing.

Learning precision ball throwing was mostly studied to explore the early rapid improvement of accuracy, with poor attention on possible adaptive processes occurring later when the rate of improvement is reduced. Here, we tried to demonstrate that the strategy to select angle, speed and height at ball release can be managed during the learning periods following the performance stabilization. To this aim, we used a multivariate linear model with angle, speed and height as predictors of changes in accuracy. Participants performed underarm throws of a tennis ball to hit a target on the floor, 3.42 m away. Two training sessions (S1, S2) and one retention test were executed. Performance accuracy increased over the S1 and stabilized during the S2, with a rate of changes along the throwing axis slower than along the orthogonal axis. However, both the axes contributed to the performance changes over the learning and consolidation time. A stable relationship between the accuracy and the release parameters was observed only during S2, with a good fraction of the performance variance explained by the combination of speed and height. All the variations were maintained during the retention test. Overall, accuracy improvements and reduction in throwing complexity at the ball release followed separate timing over the course of learning and consolidation.

Selective improvements in balancing associated with offline periods of spaced training.

Benefits from post-training memory processing have been observed in learning many procedural skills. Here, we show that appropriate offline periods produce a performance gain during learning to stand on a multiaxial balance board. The tilt angle and the area of sway motion of the board were much more reduced in participants performing a training spaced by an interval of one day with respect to participants executing the same amount of practice over a concentrated period. In particular, offline memory encoding was specifically associated with the motion along the anterior-posterior direction, the spatio-temporal dynamics, and the frequency contents of the board sway. Overall, quantification of spaced learning in a whole-body postural task reveals that offline memory processes enhance the performance by encoding single movement components. From a practical perspective, we believe that the amount of practice and the length of inter-session interval, adopted in this study, may provide objective insights to develop appropriate programs of postural training.

Binding Free Energies of Host-Guest Systems by Nonequilibrium Alchemical Simulations with Constrained Dynamics: Illustrative Calculations and Numerical Validation.

In the companion article (Giovannelli et al., 10.1021/acs.jctc.7b00594), we presented an alchemical approach, based on nonequilibrium molecular dynamics simulations, to compute absolute binding free energies of a generic host-guest system. Two alternative computational routes, called binded-domain and single-point alchemical-path schemes, have been proposed. This study is addressed to furnish numerical validation and illustrative examples of the above-mentioned alchemical schemes. Validation is provided by comparing binding free-energy data relative to two poses of a Zn(II)·anion complex with those recovered from an alternative approach, based on steered molecular dynamics simulations. We illustrate important technical and theoretical aspects for a good practice in applying both alchemical schemes, not only through the calculations on the Zn(II)·anion complex, but also estimating absolute binding free energies of 1:1 complexes of ß-cyclodextrin with aromatic compounds (benzene and naphthalene). Comparison with experimental data and previous molecular dynamics simulation studies further confirms the validity of the present nonequilibrium-alchemical methodology.

Relationships between Muscle Architecture of Rectus Femoris and Functional Parameters of Knee Motion in Adults with Down Syndrome.

This study was designed to measure in vivo muscle architecture of the rectus femoris in adults with Down syndrome, testing possible relationships with functional parameters of the knee motion. Ten adults with Down syndrome and ten typically developed participated in the study. Pennation angle and thickness of the rectus femoris and subcutaneous layer of the thigh were measured via ultrasound imaging. Knee kinematics and electromyographic activity of the rectus femoris were recorded during free leg dropping. Muscle thickness was reduced and subcutaneous layer was thicker in persons with Down syndrome with respect to typically developed adults, but there were no differences in the pennation angle. The area of the rectus femoris EMG activity during the leg flexion was greater in Down syndrome with respect to typically developed adults. The leg movement velocity was lower in Down people than in controls, but the knee excursion was similar between the groups. Functional parameters correlated with pennation angle in the persons with Down syndrome and with muscle thickness in typically developed persons. The description of muscle architecture and the relationships between morphological and functional parameters may provide insights on the limits and the opportunities to overcome the inherent biomechanical instability in Down syndrome.

Quantitative analysis of upright standing in adults with late-onset Pompe disease.

Pompe disease is a rare disorder producing muscle weakness and progressive impairments in performing daily motor activities, such as walking and standing. Most studies have focused on dysfunctions at cellular level, restricting the examination of gross motor functions to qualitative or subjective rating scales evaluations. With the aim of providing an instrumented quantification of upright standing in Pompe disease, we used a force platform to measure the center of pressure over three foot positions and with eyes open and closed. Amplitude and variability of body sway were measured to determine the level of postural stability, while power spectrum analysis and nonlinear computations were performed to explore the structure of the postural control. In comparison with healthy participants, patients with Pompe disease showed a reduced level of postural stability, but irrelevant variations in frequency content and spatio-temporal structure of the sway motion were detected. Changes in foot position did not increase the postural instability associated with Pompe disease, but prominent worsening occurred in the patients when they stand with eyes closed, particularly along the anterior-posterior direction. These results provide objective elements to monitor deficiencies of upright standing in Pompe disease, emphasizing the specific contributions of sway direction and sensory deficits.