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1.
PLoS One ; 19(5): e0301328, 2024.
Article in English | MEDLINE | ID: mdl-38713657

ABSTRACT

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.


Subject(s)
Mice, Knockout , N-Terminal Acetyltransferase A , N-Terminal Acetyltransferase E , Animals , N-Terminal Acetyltransferase A/genetics , N-Terminal Acetyltransferase A/metabolism , N-Terminal Acetyltransferase E/genetics , N-Terminal Acetyltransferase E/metabolism , Mice , Female , Male , Phenotype , Genetic Background , Maternal Inheritance/genetics , Mice, Inbred C57BL
2.
Eur J Neurosci ; 59(12): 3184-3202, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38638001

ABSTRACT

Recent research has indicated that the relationship between age-related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self-reported frequency of falling over a 4-year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical-subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross-sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity.


Subject(s)
White Matter , Humans , White Matter/diagnostic imaging , Aged , Male , Female , Accidental Falls , Brain , Aged, 80 and over , Nerve Net/diagnostic imaging , Nerve Net/physiology , Longitudinal Studies , Inhibition, Psychological
3.
Gait Posture ; 107: 281-286, 2024 01.
Article in English | MEDLINE | ID: mdl-38349937

ABSTRACT

BACKGROUND: The present study investigated neural mechanisms for suppressing a highly automatic balance recovery step. Response inhibition has typically been researched using focal hand reaction tasks performed by seated participants, and this has revealed a neural stopping network including the Inferior Frontal Gyrus (IFG). It is unclear if the same neural networks contribute to suppressing an unwanted balance reaction. RESEARCH QUESTION: Is there greater IFG activation when suppressing an automatic balance recovery step? METHODS: Functional near-infrared spectroscopy (fNIRS) was used to measure brain activity in 21 young adults as they performed a balance recovery task that demanded rapid step suppression following postural perturbation. The hypothesis was that the IFG would show heightened activity when suppressing an automatic balance recovery step. A lean and-release system was used to impose temporally unpredictable forward perturbations by releasing participants from a supported forward lean. For most trials (80%), participants were told to recover balance by quickly stepping forward (STEP). However, on 20% of trials at random, a high-pitch tone was played immediately after postural perturbation signaling participants to suppress a step and fully relax into a catch harness (STOP). This allowed us to target the ability to cancel an already initiated step in a balance recovery context. Average oxygenated hemoglobin changes were contrasted between STEP and STOP trials, 1-6 s post perturbation. RESULTS: The results showed a greater bilateral prefrontal response during STOP trials, supporting the idea that executive brain networks are active when suppressing a balance recovery step. SIGNIFICANCE: Our study demonstrates one way in which higher brain processes may help us prevent falls in complex environments where behavioral flexibility is necessary. This study also presents a novel method for assessing response inhibition in an upright postural context where rapid stepping reactions are required.


Subject(s)
Brain , Prefrontal Cortex , Young Adult , Humans , Brain/physiology , Standing Position , Hand/physiology , Upper Extremity , Postural Balance/physiology
4.
bioRxiv ; 2024 Jan 10.
Article in English | MEDLINE | ID: mdl-37163119

ABSTRACT

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/Y male mice on the inbred genetic background in this different animal facility.

5.
Brain Sci ; 13(10)2023 Oct 21.
Article in English | MEDLINE | ID: mdl-37891855

ABSTRACT

Stepping to recover balance is an important way we avoid falling. However, when faced with obstacles in the step path, we must adapt such reactions. Physical obstructions are typically detected through vision, which then cues step modification. The present study describes a novel method to assess visually prompted step inhibition in a reactive balance context. In our task, participants recovered balance by quickly stepping after being released from a supported forward lean. On rare trials, however, an obstacle blocked the stepping path. The timing of vision relative to postural perturbation was controlled using occlusion goggles to regulate task difficulty. Furthermore, we explored step suppression in our balance task related to inhibitory capacity measured at the hand using a clinically feasible handheld device (ReacStick). Our results showed that ReacStick and step outcomes were significantly correlated in terms of successful inhibition (r = 0.57) and overall reaction accuracy (r = 0.76). This study presents a novel method for assessing rapid inhibition in a dynamic postural context, a capacity that appears to be a necessary prerequisite to a subsequent adaptive strategy. Moreover, this capacity is significantly related to ReacStick performance, suggesting a potential clinical translation.

6.
Nat Commun ; 14(1): 3859, 2023 Jun 29.
Article in English | MEDLINE | ID: mdl-37386022

ABSTRACT

Understanding the connection between seismic activity and the earthquake nucleation process is a fundamental goal in earthquake seismology with important implications for earthquake early warning systems and forecasting. We use high-resolution acoustic emission (AE) waveform measurements from laboratory stick-slip experiments that span a spectrum of slow to fast slip rates to probe spatiotemporal properties of laboratory foreshocks and nucleation processes. We measure waveform similarity and pairwise differential travel-times (DTT) between AEs throughout the seismic cycle. AEs broadcasted prior to slow labquakes have small DTT and high waveform similarity relative to fast labquakes. We show that during slow stick-slip, the fault never fully locks, and waveform similarity and pairwise differential travel times do not evolve throughout the seismic cycle. In contrast, fast laboratory earthquakes are preceded by a rapid increase in waveform similarity late in the seismic cycle and a reduction in differential travel times, indicating that AEs begin to coalesce as the fault slip velocity increases leading up to failure. These observations point to key differences in the nucleation process of slow and fast labquakes and suggest that the spatiotemporal evolution of laboratory foreshocks is linked to fault slip velocity.


Subject(s)
Earthquakes , Plastic Surgery Procedures , Laboratories , Travel
7.
Brain Behav ; 13(2): e2895, 2023 02.
Article in English | MEDLINE | ID: mdl-36706040

ABSTRACT

INTRODUCTION: Children with developmental language disorder (DLD) exhibit cognitive deficits that interfere with their ability to learn language. Little is known about the functional neuroanatomical differences between children developing typically (TD) and children with DLD. METHODS: Using functional near-infrared spectroscopy, we recorded oxygenated hemoglobin (O2 hb) concentration values associated with neural activity in children with and without DLD during an auditory N-back task that included 0-back, 1-back, and 2-back conditions. Analyses focused on the left dorsolateral prefrontal cortex (DLPFC) and left inferior parietal lobule (IPL). Multilevel models were constructed with accuracy, response time, and O2 hb as outcome measures, with 0-back outcomes as fixed effects to control for sustained attention. RESULTS: Children with DLD were significantly less accurate than their TD peers at both the 1-back and 2-back tasks, and they demonstrated slower response times during 2-back. In addition, children in the TD group demonstrated significantly greater sensitivity to increased task difficulty, showing increased O2 hb to the IPL during 1-back and to the DLPFC during the 2-back, whereas the DLD group did not. A secondary analysis revealed that higher O2 hb in the DLPFC predicted better task accuracy across groups. CONCLUSION: When task difficulty increased, children with DLD failed to recruit the DLPFC for monitoring information and the IPL for processing information. Reduced memory capacity and reduced engagement likely contribute to the language learning difficulties of children with DLD.


Subject(s)
Language Development Disorders , Memory, Short-Term , Humans , Child , Memory, Short-Term/physiology , Spectroscopy, Near-Infrared , Language Development Disorders/diagnostic imaging , Language Development Disorders/psychology , Learning , Language
8.
PLoS One ; 17(10): e0275733, 2022.
Article in English | MEDLINE | ID: mdl-36223397

ABSTRACT

Reactive balance, a critical automatic movement pattern in response to a perturbation, is directly linked to fall prevention in older adults. Various exercise interventions have been broadly performed to improve reactive balance and thus prevent falls. Curiously, aquatic exercises have been suggested as an effective balance intervention and a safer alternative to exercises on dry land yet the efficacy of aquatic exercises on reactive balance has not been formally investigated. The present clinical trial aims to identify if skills acquired during aquatic exercise are more effectively transferred to a reactive balance task than land exercise. This study is designed as a double-blinded, randomized controlled clinical trial. Forty-four older adults aged 65 years or above who meet the eligibility criteria will be recruited and randomized into an aquatic exercise group or land exercise group. Each group will participate in the same single bout intervention that includes a ball throwing and catching task. A modified lean-and-release test will be implemented on land immediately before, after, and one week after the single bout intervention. The outcomes will include reaction time, rapid response accuracy, and mini-BESTest scores obtained from stepping and grasping reactions. All statistical analyses will be conducted using an intention-to-treat approach. Our conceptual hypothesis is that participants in the aquatic exercise group will demonstrate more improved outcome scores in the lean-and-release test when compared to those in the land exercise group. The results of the present study are expected to provide evidence to support the benefits of aquatic exercises for improving reactive balance in older adults. Further, participants may find aquatic exercises safer and more motivating, thus encouraging them to participate in further aquatic exercise programs.


Subject(s)
Exercise Therapy , Postural Balance , Aged , Exercise/physiology , Exercise Therapy/methods , Humans , Physical Therapy Modalities , Postural Balance/physiology , Randomized Controlled Trials as Topic
9.
J Geophys Res Solid Earth ; 127(6): e2022JB024170, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35864884

ABSTRACT

Tectonic faults fail through a spectrum of slip modes, ranging from slow aseismic creep to rapid slip during earthquakes. Understanding the seismic radiation emitted during these slip modes is key for advancing earthquake science and earthquake hazard assessment. In this work, we use laboratory friction experiments instrumented with ultrasonic sensors to document the seismic radiation properties of slow and fast laboratory earthquakes. Stick-slip experiments were conducted at a constant loading rate of 8 µm/s and the normal stress was systematically increased from 7 to 15 MPa. We produced a full spectrum of slip modes by modulating the loading stiffness in tandem with the fault zone normal stress. Acoustic emission data were recorded continuously at 5 MHz. We demonstrate that the full continuum of slip modes radiate measurable high-frequency energy between 100 and 500 kHz, including the slowest events that have peak fault slip rates <100 µm/s. The peak amplitude of the high-frequency time-domain signals scales systematically with fault slip velocity. Stable sliding experiments further support the connection between fault slip rate and high-frequency radiation. Experiments demonstrate that the origin of the high-frequency energy is fundamentally linked to changes in fault slip rate, shear strain, and breaking of contact junctions within the fault gouge. Our results suggest that having measurements close to the fault zone may be key for documenting seismic radiation properties and fully understanding the connection between different slip modes.

11.
Gait Posture ; 95: 56-62, 2022 06.
Article in English | MEDLINE | ID: mdl-35453084

ABSTRACT

BACKGROUND: Correlations between falls and individual differences in inhibitory control, suggest the ability to suppress automatic, but unwanted, action is important in fall prevention. Response inhibition has been a topic of considerable interest in the cognitive neuroscience community for many decades, bringing a wealth of techniques that could potentially inform assessment of reactive balance. For example, the stop signal task is a popular method to quantify inhibitory control ability. RESEARCH QUESTION: Can we apply the stop signal task to measure response inhibition in a balance recovery task? METHODS: Twenty healthy, young adults completed a novel reactive balance test that required occasional suppression of a balance recovery step. Participants were released from a supported lean ('Go' cue) requiring them to quickly step forward to regain balance. On some trials, a tone ('Stop' cue) instructed participants to suppress a step and relax into a harness. Step trials were more frequent (80%) than stop trials (20%) to bias a rapid stepping response. The stop tone was presented at various delays following cable release, to manipulate task difficulty (i.e., longer delays make step suppression difficult). Individual differences in inhibitory control were determined using lift off times from force plates, and by contrasting muscle activation in failed compared to successful stop trials. RESULTS: Most participants were able to successfully suppress a balance recovery step on occasion, allowing for accurate estimation of individual differences in inhibitory control. The successful suppression of a balance recovery step was more likely in the group (n = 10) where shorter stop signal delays were used (i.e., the task was easier). SIGNIFICANCE: While balance assessments often stress reflexive action, there is a need for methods that evaluate response inhibition. The present study leveraged a well-established cognitive test of inhibitory control to develop a method to quantify stopping ability in a reactive balance context.


Subject(s)
Postural Balance , Humans , Postural Balance/physiology , Reaction Time/physiology , Young Adult
12.
Elife ; 102021 08 06.
Article in English | MEDLINE | ID: mdl-34355692

ABSTRACT

Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking Naa10 show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather Naa10 nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. Naa12 is a previously unannotated Naa10-like paralog with NAT activity that genetically compensates for Naa10. Mice deficient for Naa12 have no apparent phenotype, whereas mice deficient for Naa10 and Naa12 display embryonic lethality. The discovery of Naa12 adds to the currently known machinery involved in amino-terminal acetylation in mice.


Subject(s)
N-Terminal Acetyltransferase A/genetics , N-Terminal Acetyltransferase E/genetics , Acetylation , Animals , Female , Male , Mice , Mice, Knockout , N-Terminal Acetyltransferase A/deficiency , N-Terminal Acetyltransferase A/metabolism , N-Terminal Acetyltransferase E/deficiency , N-Terminal Acetyltransferase E/metabolism
13.
Article in English | MEDLINE | ID: mdl-34444124

ABSTRACT

Many diseases, disabilities, and mental health conditions associated with aging can be delayed or prevented through regular exercise. Several barriers to exercise, many of which are exacerbated in rural communities, prevent mid-life and older adults from accessing its benefits. However, recently, a racquet sport named pickleball has become popular among older adults, and it appears to overcome some of these barriers. We conducted a feasibility study to evaluate the impact of a six-week pickleball intervention on measures of muscle function, cognitive function, perceived pain, and cardio-metabolic risk, as well as several psychosocial factors contributing to adherence in sedentary rural participants. Participants improved their vertical jump, cognitive performance, and reported a decrease in self-reported pain, suggesting improved physical and cognitive health across the sample. Participants also reported high levels of satisfaction and demonstrated good adherence over the duration of the study. Perhaps of greatest value was the overwhelmingly positive response from participants to the intervention and follow-up interviews reporting a desire to continue pickleball play beyond the study period. Overall, pickleball appears to be a promising intervention to, (1) elicit functional- and cognitive-related improvements, and (2) motivate mid-life and older adults to adhere to exercise sufficiently long to benefit their health.


Subject(s)
Rural Population , Sedentary Behavior , Aged , Exercise , Feasibility Studies , Humans , Utah
14.
Front Neurosci ; 15: 699428, 2021.
Article in English | MEDLINE | ID: mdl-34276299

ABSTRACT

Brain-computer interfaces (BCIs) provide a unique technological solution to circumvent the damaged motor system. For neurorehabilitation, the BCI can be used to translate neural signals associated with movement intentions into tangible feedback for the patient, when they are unable to generate functional movement themselves. Clinical interest in BCI is growing rapidly, as it would facilitate rehabilitation to commence earlier following brain damage and provides options for patients who are unable to partake in traditional physical therapy. However, substantial challenges with existing BCI implementations have prevented its widespread adoption. Recent advances in knowledge and technology provide opportunities to facilitate a change, provided that researchers and clinicians using BCI agree on standardisation of guidelines for protocols and shared efforts to uncover mechanisms. We propose that addressing the speed and effectiveness of learning BCI control are priorities for the field, which may be improved by multimodal or multi-stage approaches harnessing more sensitive neuroimaging technologies in the early learning stages, before transitioning to more practical, mobile implementations. Clarification of the neural mechanisms that give rise to improvement in motor function is an essential next step towards justifying clinical use of BCI. In particular, quantifying the unknown contribution of non-motor mechanisms to motor recovery calls for more stringent control conditions in experimental work. Here we provide a contemporary viewpoint on the factors impeding the scalability of BCI. Further, we provide a future outlook for optimal design of the technology to best exploit its unique potential, and best practices for research and reporting of findings.

15.
Brain Sci ; 11(5)2021 May 15.
Article in English | MEDLINE | ID: mdl-34063458

ABSTRACT

In young adults, performance on a test of response inhibition was recently found to be correlated with performance on a reactive balance test where automated stepping responses must occasionally be inhibited. The present study aimed to determine whether this relationship holds true in older adults, wherein response inhibition is typically deficient and the control of postural equilibrium presents a greater challenge. Ten participants (50+ years of age) completed a seated cognitive test (stop signal task) followed by a reactive balance test. Reactive balance was assessed using a modified lean-and-release system where participants were required to step to regain balance following perturbation, or suppress a step if an obstacle was present. The stop signal task is a standardized cognitive test that provides a measure of the speed of response inhibition called the Stop Signal Reaction Time (SSRT). Muscle responses in the legs were compared between conditions where a step was allowed or blocked to quantify response inhibition of the step. The SSRT was significantly related to leg muscle suppression during balance recovery in the stance leg. Thus, participants that were better at inhibiting their responses in the stop signal task were also better at inhibiting an unwanted leg response in favor of grasping a supportive handle. The relationship between a seated cognitive test using finger responses and leg muscle suppression when a step was blocked indicates a context-independent, generalized capacity for response inhibition. This suggests that a simple cognitive test such as the stop signal task could be used clinically to predict an individual's capacity for adapting balance reactions and fall risk. The present results provide support for future studies, with larger samples, to verify this relationship between stop signal reaction time and leg response during balance recovery.

16.
Brain Sci ; 11(3)2021 Mar 22.
Article in English | MEDLINE | ID: mdl-33810159

ABSTRACT

Recent studies have shown balance recovery can be enhanced via task-specific training, referred to as perturbation-based balance training (PBT). These interventions rely on principles of motor learning where repeated exposure to task-relevant postural perturbations results in more effective compensatory balance responses. Evidence indicates that compensatory responses trained using PBT can be retained for many months and can lead to a reduction in falls in community-dwelling older adults. A notable shortcoming with PBT is that it does not transfer well to similar but contextually different scenarios (e.g., falling sideways versus a forward trip). Given that it is not feasible to train all conditions in which someone could fall, this limited transfer presents a conundrum; namely, how do we best use PBT to appropriately equip people to deal with the enormous variety of fall-inducing scenarios encountered in daily life? In this perspective article, we draw from fields of research that explore how general learning can be promoted. From this, we propose a series of methods, gleaned from parallel streams of research, to inform and hopefully optimize this emerging field where people receive training to specifically improve their balance reactions.

17.
J Geophys Res Solid Earth ; 126(11): e2021JB022175, 2021 Nov.
Article in English | MEDLINE | ID: mdl-35865108

ABSTRACT

Understanding the temporal evolution of foreshocks and their relation to earthquake nucleation is important for earthquake early warning systems, earthquake hazard assessment, and earthquake physics. Laboratory experiments on intact rock and rough fractures have demonstrated that the number and size of acoustic emission (AE) events increase and that the Gutenberg-Richter b-value decreases prior to coseismic failure. However, for lab fault zones of finite width, where shear occurs within gouge, the physical processes that dictate temporal variations in frequency-magnitude (F/M) statistics of lab foreshocks are unclear. Here, we report on a series of laboratory experiments to illuminate the physical processes that govern temporal variations in b-value and AE size. We record AE data continuously for hundreds of lab seismic cycles and report F/M statistics. Our foreshock catalogs include cases where F/M data are not exponentially distributed, but we retain the concept of b-value for comparison with other works. We find that b-value decreases as the fault approaches failure, consistent with previous works. We also find that b-value scales inversely with shear velocity and fault slip rate, suggesting that fault slip acceleration during earthquake nucleation could impact foreshock F/M statistics. We propose that fault zone dilation and grain mobilization have a strong influence on foreshock magnitude. Fault dilation at higher shearing rates increases porosity and results in larger foreshocks and smaller b-values. Our observations suggest that lab earthquakes are preceded by a preparatory nucleation phase with systematic variations in AE and fault zone properties.

18.
J Geophys Res Solid Earth ; 126(7): e2020JB021588, 2021 Jul.
Article in English | MEDLINE | ID: mdl-35865235

ABSTRACT

Machine learning (ML) techniques have become increasingly important in seismology and earthquake science. Lab-based studies have used acoustic emission data to predict time-to-failure and stress state, and in a few cases, the same approach has been used for field data. However, the underlying physical mechanisms that allow lab earthquake prediction and seismic forecasting remain poorly resolved. Here, we address this knowledge gap by coupling active-source seismic data, which probe asperity-scale processes, with ML methods. We show that elastic waves passing through the lab fault zone contain information that can predict the full spectrum of labquakes from slow slip instabilities to highly aperiodic events. The ML methods utilize systematic changes in P-wave amplitude and velocity to accurately predict the timing and shear stress during labquakes. The ML predictions improve in accuracy closer to fault failure, demonstrating that the predictive power of the ultrasonic signals improves as the fault approaches failure. Our results demonstrate that the relationship between the ultrasonic parameters and fault slip rate, and in turn, the systematically evolving real area of contact and asperity stiffness allow the gradient boosting algorithm to "learn" about the state of the fault and its proximity to failure. Broadly, our results demonstrate the utility of physics-informed ML in forecasting the imminence of fault slip at the laboratory scale, which may have important implications for earthquake mechanics in nature.

19.
FEBS J ; 288(5): 1648-1663, 2021 03.
Article in English | MEDLINE | ID: mdl-32814359

ABSTRACT

The N-terminal segment of the chemokine receptor Human CC chemokine receptor 5 (CCR5), Nt-CCR5, contains four tyrosine residues, Y3, Y10, Y14, and Y15. Sulfation of at least two of these tyrosine residues was found to be essential for high-affinity binding of CCR5 to its chemokine ligands. Here, we show that among the monosulfated Nt-CCR5(8-20) peptide surrogates (sNt-CCR5) those sulfated at Y15 and Y14 have the highest affinity for the CC chemokine ligand 5 (CCL5) chemokine in comparison with monosulfation at position Y10. Sulfation at Y3 was not investigated. A peptide sulfated at both Y14 and Y15 has the highest affinity for CCL5 by up to a factor of 3, in comparison with the other disulfated (sNt-CCR5) peptides. Chemical shift perturbation analysis and transferred nuclear Overhauser effect measurements indicate that the sulfated tyrosine residues interact with the same CCL5-binding pocket and that each of the sulfated tyrosines at positions 10, 14, and 15 can occupy individually the binding site on CCL5 in a similar manner, although with somewhat different affinity, suggesting the possibility of allovalency in sulfated Nt-CCR5 peptides. The affinity of the disulfated peptides to CCL5 could be increased by this allovalency and by stronger electrostatic interactions.


Subject(s)
Chemokine CCL5/chemistry , Protein Processing, Post-Translational , Receptors, CCR5/chemistry , Sulfates/chemistry , Tyrosine/chemistry , Amino Acid Sequence , Binding Sites , Chemokine CCL5/genetics , Chemokine CCL5/metabolism , Gene Expression , Humans , Ligands , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Static Electricity , Sulfates/metabolism , Tyrosine/metabolism
20.
Front Aging Neurosci ; 13: 764826, 2021.
Article in English | MEDLINE | ID: mdl-35115917

ABSTRACT

BACKGROUND: Reactive balance is the last line of defense to prevent a fall when the body loses stability, and beneficial effects of various exercise-based interventions on reactive balance in older adults have been reported. However, their pooled evidence on the relative effects has yet to be described. OBJECTIVE: To review and evaluate the comparative effectiveness of various exercise-based interventions on reactive balance in older adults. METHODS: Nine electronic databases and reference lists were searched from inception to August 2021. Eligibility criteria according to PICOS criteria were as follows: (1) population: older adults with the mean age of 65 years or above; (2) intervention and comparison: at least two distinct exercise interventions or one exercise intervention with a no-exercise controlled intervention (NE) compared in each trial; (3) outcome: at least one measure of reactive balance; (4) study: randomized controlled trial. The main network meta-analysis was performed on data from the entire older adult population, involving all clinical conditions as well as healthy older adults. Subgroup analyses stratified by characteristics of participants (healthy only) and reactive balance outcomes (simulated slip or trip while walking, simulated forward falls, being pushed or pulled, and movable platform) were also conducted. RESULTS: Thirty-nine RCTs (n = 1388) investigating 17 different types of exercise interventions were included in the network meta-analysis. Reactive balance training as a single intervention presented the highest probability (surface under the cumulative ranking (SUCRA) score) of being the best intervention for improving reactive balance and the greatest relative effects vs. NE in the entire sample involving all clinical conditions [SUCRA = 0.9; mean difference (95% Credible Interval): 2.7 (1.0 to 4.3)]. The results were not affected by characteristics of participants (i.e., healthy older adults only) or reactive balance outcomes. SUMMARY/CONCLUSION: The findings from the NMA suggest that a task-specific reactive balance exercise could be the optimal intervention for improving reactive balance in older adults, and power training can be considered as a secondary training exercise.

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