The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.

Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.

Cognitive and visual task effects on gaze behaviour and gait of younger and older adults.

Cognitive dual tasks alter gait of younger and older adults and recent research has demonstrated that they also influence gaze behaviour and standing postural control. These findings suggest that age-related changes in cognitive and gaze function might increase fall risk in older adults. The purpose of this study was to determine the effect cognitive and visual dual tasks on the gait and gaze behaviour of younger and older adults. Ten older and ten younger adults walked for 3 min on a treadmill at preferred walking speed under three conditions, single task, cognitive and visual dual task conditions. Gait dynamics were measured using accelerometry and gaze behaviour was measured using wearable eye-trackers. Stride time variability and centre of mass (COM) motion complexity increased in dual-task conditions in older adults but had no difference for younger adults. Dual tasks had limited effect on gaze behaviour; however, visual input duration was greater, and visual input frequency and saccade frequency were lower in older than younger adults. The gaze adaptations in older adults may be the result of slower visual processing or represent a compensatory strategy to suppress postural movement. The increase in gait COM motion complexity in older adults suggests the dual tasks led to more automatic gait control resulting from both cognitive and visual tasks.

The minimal important change for measures of balance and postural control in older adults: a systematic review.

The minimal important change and analogous terms (MIC) can provide a measure of change in health outcome variables that is associated with a level of importance for participant/patient. This review explores the availability of the MIC for different balance measures used with older adults in research and clinical settings. PubMed, ProQuest and Web of Science search engines were used and based on the inclusion and exclusion criteria, 11 studies were deemed suitable for data extraction and analysis. The results demonstrated that MIC is available for the following balance-associated tests: Berg Balance Scale, Timed Up and Go, Short Physical Performance Battery, BESTest and the Tinetti test. A range of MIC values were shown, reflective of different older adult health conditions, calculation methods and anchors used. It was also evident that the responsiveness of the test was not always available or appropriately determined, questioning the validity of the MIC value published. Greater research is needed to establish MIC for balance measurements for use with older adults with different health conditions, preferably using objective measures such as falls. The calculation of such statistics will improve the evaluation of intervention effectiveness.

Perturbations during Gait: A Systematic Review of Methodologies and Outcomes.

BACKGROUND: Despite extensive literature regarding laboratory-based balance perturbations, there is no up-to-date systematic review of methods. This systematic review aimed to assess current perturbation methods and outcome variables used to report participant biomechanical responses during walking. METHODS: Web of Science, CINAHL, and PubMed online databases were searched, for records from 2015, the last search was on 30th of May 2022. Studies were included where participants were 18+ years, with or without clinical conditions, conducted in non-hospital settings. Reviews were excluded. Participant descriptive, perturbation method, outcome variables and results were extracted and summarised. Bias was assessed using the Appraisal tool for Cross-sectional Studies risk of bias assessment tool. Qualitative analysis was performed as the review aimed to investigate methods used to apply perturbations. RESULTS: 644 records were identified and 33 studies were included, totaling 779 participants. The most frequent method of balance perturbation during gait was by means of a treadmill translation. The most frequent outcome variable collected was participant step width, closely followed by step length. Most studies reported at least one spatiotemporal outcome variable. All included studies showed some risk of bias, generally related to reporting of sampling approaches. Large variations in perturbation type, duration and intensity and outcome variables were reported. CONCLUSIONS: This review shows the wide variety of published laboratory perturbation methods. Moreover, it demonstrates the significant impact on outcome measures of a study based on the type of perturbation used. REGISTRATION: PROSPERO ID: CRD42020211876.

Stable and Unstable Load Carriage Effects on the Postural Control of Older Adults.

The aim of this study was to investigate the effects of backpack load carriage on quiet standing postural control and limits of stability (LOS) of older adults. Fourteen older adults (65 [6] y) performed quiet standing and a forward, right, and left LOS test in 3 conditions, unloaded, stable, and unstable backpack loads while activity of 4 leg muscles was recorded. Stable and unstable loads decreased postural sway (main effect ηp2=.84, stable P < .001, unstable P < .001), mediolateral (main effect ηp2=.49, stable P = .002, unstable P = .018) and anterior-posterior (main effect ηp2=.64, stable P < .001, unstable P = .001) fractal dimension, and LOS distance (main effect ηp2=.18, stable P = .011, unstable P = .046) compared with unloaded. Rectus femoris (main effect ηp2=.39, stable P = .001, unstable P = .010) and gastrocnemius (main effect ηp2=.30, unstable P = .027) activity increased in loaded conditions during LOS and quiet standing. Gastrocnemius-tibialis anterior coactivation was greater in unstable load than stable loaded quiet standing (main effect ηp2=.24, P = .040). These findings suggest older adults adopt conservative postural control strategies minimizing the need for postural corrections in loaded conditions. Reduced LOS may also increase fall risk when carrying a load. However, there was no difference between unstable and stable loads for postural control variables.

Calcium signals act through histone deacetylase to mediate pronephric kidney morphogenesis.

BACKGROUND: Autosomal dominant polycystic kidney disease is the most common monogenetic kidney disorder and is linked to mutations in PKD1 and PKD2. PKD2, a Ca2+ -conducting TRP channel enriched in ciliated cells and gated by extracellular signals, is necessary to activate the multifunctional Ca2+/ calmodulin-dependent protein kinase type 2 (CaMK-II), enabling kidney morphogenesis and cilia stability. RESULTS: In this study, antisense morpholino oligonucleotides and pharmacological compounds were employed to investigate the roles of class II HDAC family members (HDAC 4, 5, and 6) in Zebrafish kidney development. While all three class II HDAC genes were expressed throughout the embryo during early development, HDAC5-morphant embryos exhibited anterior cysts and destabilized cloacal cilia, similar to PKD2 and CaMK-II morphants. In contrast, HDAC4-morphant embryos exhibited elongated cloacal cilia and lacked anterior kidney defects. Suppression of HDAC4 partially reversed the cilia shortening and anterior convolution defects caused by CaMK-II deficiency, whereas HDAC5 loss exacerbated these defects. EGFP-HDAC4, but not EGFP-HDAC5, translocated into the nucleus upon CaMK-II suppression in pronephric kidney cells. CONCLUSIONS: These results support a model by which activated CaMK-II sequesters HDAC4 in the cytosol to enable primary cilia formation and kidney morphogenesis. Developmental Dynamics 247:807-817, 2018. © 2018 Wiley Periodicals, Inc.

Planar cell polarity genes Frizzled3a, Vangl2, and Scribble are required for spinal commissural axon guidance.

BACKGROUND: A fundamental feature of early nervous system development is the guidance of axonal projections to their targets in order to assemble neural circuits that control behavior. Spinal commissural neurons are an attractive model to investigate the multiple guidance cues that control growth cone navigation both pre- and post-midline crossing, as well as along both the dorsal-ventral (D-V) and anterior-posterior (A-P) axes. Accumulating evidence suggests that guidance of spinal commissural axons along the A-P axis is dependent on components of the planar cell polarity (PCP) signaling pathway. In the zebrafish, the earliest born spinal commissural neuron to navigate the midline and turn rostrally is termed commissural primary ascending (CoPA). Unlike mammalian systems, CoPA axons cross the midline as a single axon and allow an analysis of the role of PCP components in anterior pathfinding in single pioneering axons. RESULTS: Here, we establish CoPA cells in the zebrafish spinal cord as a model system for investigating the molecular function of planar cell polarity signaling in axon guidance. Using mutant analysis, we show that the functions of Fzd3a and Vangl2 in the anterior turning of commissural axons are evolutionarily conserved in teleosts. We extend our findings to reveal a role for the PCP gene scribble in the anterior guidance of CoPA axons. Analysis of single CoPA axons reveals that these commissural axons become responsive to PCP-dependent anterior guidance cues even prior to midline crossing. When midline crossing is prevented by dcc gene knockdown, ipsilateral CoPA axons still extend axons anteriorly in response to A-P guidance cues. We show that this ipsilateral anterior pathfinding that occurs in the absence of midline crossing is dependent on PCP signaling. CONCLUSION: Our results demonstrate that anterior guidance decisions by CoPA axons are dependent on the function of planar cell polarity genes both prior to and after midline crossing.

Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration.

Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons.

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity.

The facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration.

The comparative effect of exercise interventions on balance in perimenopausal and early postmenopausal women: A systematic review and network meta-analysis of randomised, controlled trials.

In addition to a range of physiological and psychological symptoms, menopause causes a decrement to balance performance and risk of falls. This review aimed to determine the effects of exercise interventions on balance in perimenopausal and early postmenopausal women. Web of Science, PubMed, CINAHL, SPORTDiscus and Cochrane Central Register of Controlled Trials databases were searched. Randomised, controlled trials of exercise interventions in perimenopausal or early postmenopausal populations with an average age of 65 years or younger reporting balance measures were included. Risk of bias was assessed using Cochrane RoB 2. A random effects model network meta-analysis was performed to assess the effect of exercise on balance. Standardised mean differences with 95 % confidence intervals were used as the measure of effect. Twenty-six studies were included after screening. Network meta-analyses were conducted for 5 balance variables. Whole-body vibration (standardised mean difference: 2.25, confidence interval: 0.08; 4.43), balance (standardised mean difference: 1.84, confidence interval: 0.15; 3.53), balance + nutrition (standardised mean difference: 3.81, confidence interval: 1.57; 6.05) and resistance (standardised mean difference: 1.43, confidence interval: 0.41; 2.46) exercise improved Berg balance scale performance. Resistance + aerobic + balance exercise improved one-leg stance (standardised mean difference: 0.80, confidence interval: 0.39; 1.22) and whole-body vibration improved anterior-posterior (standardised mean difference: -0.89, confidence interval: -1.48; -0.31), medio-lateral (standardised mean difference: -0.58, confidence interval: -1.15; -0.01) postural sway and falls indices (standardised mean difference: -0.75, confidence interval: -1.45; -0.04). Exercise improved all balance measures and should be considered as an adjunct therapy in perimenopausal and postmenopausal women. Whole-body vibration was most frequently the highest ranked intervention; resistance and balance training also improved balance.

The impact of anxiety on postural control: CO2 challenge model.

Anxiety and balance and postural control are linked via common neural pathways, such as the parabrachial nucleus network. A laboratory-based model of general anxiety disorder (GAD) using the CO2 challenge, has potential to be used to observe this relationship, potentially mimicking subjective, autonomic, and neuropsychological features of GAD. The current feasibility study used the CO2 challenge to explore postural control changes in healthy adults. It was predicted that during the CO2 condition, participants would show increased postural sway path length and decreased sway stability, compared with a normal air breathing condition. To assess this, heart and breathing rate, quiet standing postural sway path length, sway dynamic stability, and subjective measures of emotion were measured either before and after or during and after the inhalation conditions. Results demonstrated that CO2 inhalation led to both an increase in sway path length and reduced sway stability compared to the air breathing conditions; the effect on sway path lasted after the inhalation of CO2 had ceased. Additionally, replication of HR and subjective measures of emotion were observed when comparing air and CO2 conditions. This provides experimental evidence that CO2 inhalation can affect balance, suggestive of shared mechanisms between anxiety and balance performance, as well as indicating that the CO2 model of GAD is suitable to look at changes in balance performance in healthy adults. Future use of this model to explore factors that can reduce the influence of GAD on balance would be beneficial as would a more detailed exploration of the neural pathways associated with the associated comorbidity.

Gait and neuromuscular dynamics during level and uphill walking carrying military loads.

The neuromuscular system responds to perturbation and increasing locomotor task difficulty by altering the stability of neuromuscular output signals. The purpose of this study was to determine the effects of two different military load carriage systems on the dynamic stability of gait and muscle activation signals. 14 army office cadets (20 ± 1 years) performed 4-minute treadmill walking trials on level (0%) and uphill (10%) gradients while unloaded, and with 11 kg backpack and 11 kg webbing loads while the activity of 6 leg and trunk muscles and the motion of the centre of mass (COM) were recorded. Loaded and uphill walking decreased stability and increased magnitude of muscle activations compared to loaded and level gradient walking. Backpack loads increased the medio-lateral stability of COM and uphill walking decreased stability of vertical COM motion and increased stride time variability. However, there was no difference between the two load carriage systems for any variable. The reduced stability of muscle activations in loaded and uphill conditions indicates an impaired ability of the neuromuscular control systems to accommodate perturbations in these conditions which may have implications on the operational performance of military personnel. However, improved medio-lateral stability in backpack conditions may indicate that participants were able to compensate for the loads used in this study, despite the decreased vertical stability and increased stride time variability evident in uphill walking. This study did not find differences between load carriage systems however, specific load carriage system effects may be elicited by greater load carriage masses.

The Relationship between Postural Control and Muscle Quality in Older Adults.

This study aimed to determine relationships between muscle quality, the ratio of muscle strength to muscle mass, and postural control and compare postural control of older adults with higher and lower muscle quality. Twenty-five older adults had leg muscle quality and postural control with eyes open and closed measured. Linear and non-linear postural control variables were calculated from center of pressure movements. There was a significant canonical correlation between muscle quality and sway complexity, but no relationship between muscle quality and sway magnitude. Higher muscle quality older adults had greater medio-lateral sway complexity than lower muscle quality older adults. These findings suggest that higher muscle quality relates to greater sway complexity in older adults, suggesting maintenance of muscle quality should be considered important to attenuate postural control declines.

Dynamics of Modular Neuromotor Control of Walking and Running during Single and Dual Task Conditions.

The aim of the study was to determine the stability and complexity of muscle synergies to provide insight to the neural control of gait stability in walking and running and when performing a concurrent cognitive dual task. Eighteen healthy young adults performed walking and running at preferred speeds and 120% of preferred speeds in single and dual task conditions. Muscle synergies were determined from the activity of 9 trunk and leg muscles and centre of mass (COM) motion was recorded with an inertial measurement unit. Local dynamic stability, complexity and width of synergies, and stability and complexity of COM motion were determined, in addition to the cross sample entropy to determine the coupling between COM motion and muscle synergies. Increasing locomotion speed increased complexity and decreased stability of COM motion with a concurrent decrease in synergy complexity and stability but with no change in synergy width. The coupling of COM motion and muscle synergies also increased with increasing speed. Vertical COM motion was more complex and less stable but with no change in anterior-posterior or medio-lateral directions in dual task locomotion. Muscle synergies were also more stable in dual task conditions. These findings indicate that changes in neuromotor dynamics may underpin reported changes in COM local stability during gait as the neural commands responsible for generating the movement are altered in response to increasing task demands. Increased cognitive demands lead to more stable neuromotor commands possibly to maintain local stability of COM motion in the anterior-posterior and medio-lateral directions.

Visuomotor control dynamics of quiet standing under single and dual task conditions in younger and older adults.

Visual input facilitates stable postural control; however, ageing alters visual gaze strategies and visual input processing times. Understanding the complex interaction between visual gaze behaviour and the effects of age may inform future interventions to improve postural control in older adults. The purpose of this study was to determine effects of age and dual task on gaze and postural sway dynamics, and the sway-gaze complexity coupling to explore the coupling between sensory input and motor output. Ten older and 10 younger adults performed single and dual task quiet standing while gaze behaviour and centre of mass motion were recorded. The complexity and stability of postural sway, saccade characteristics, visual input duration and complexity of gaze were calculated in addition to sway-gaze coupling quantified by cross-sample entropy. Dual tasking increased complexity and decreased stability of sway with increased gaze complexity and visual input duration, suggesting greater automaticity of sway with greater exploration of the visual field but with longer visual inputs to maintain postural stability in dual task conditions. In addition, older adults had lower complexity and stability of sway than younger adults indicating less automated and stable postural control. Older adults also demonstrated lower gaze complexity, longer visual input durations and greater sway-gaze coupling. These findings suggest older adults adopted a strategy to increase the capacity for visual information input, whilst exploring less of the visual field than younger adults.

Military load carriage effects on the gait of military personnel: A systematic review.

Carrying heavy loads results in biomechanical changes to gait and to an increased risk of injury in soldiers. The aim of this review is to examine the effects of military specific load carriage on the gait of soldiers. The Web of Science, PubMed and CINAHL databases were searched, a total of 1239 records were screened and 20 papers were included in the review. Participant, load and task characteristics and a summary of key findings were extracted. Due to heterogeneity in the reviewed studies, analysis was restricted to qualitative synthesis. There were limited effects on spatio-temporal variables but consistently reported increased trunk, hip and knee flexion and increased hip and knee extension moments. Muscle activation of lower limb and trunk muscles were also increased with loads. However, there were some conflicting findings for most parameters reviewed and apart from spatio-temporal parameters the findings of this review were in line with previous reviews of combined military and civilian populations.

Cadherins regulate nuclear topography and function of developing ocular motor circuitry.

In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.

SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase.

Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity.

Complexity, symmetry and variability of forward and backward walking at different speeds and transfer effects on forward walking: Implications for neural control.

This study aimed to investigate effects of walking direction and speed on gait complexity, symmetry and variability as indicators of neural control mechanisms, and if a period of backward walking has acute effects on forward walking. Twenty-two young adults attended 2 visits. In each visit participants walked forwards at preferred walking speed (PWS) for 3-minutes (pre) followed by 5-minutes walking each at 80%, 100% and 120% of PWS of either forward or backward walking then a further 3-minutes walking forward at PWS (post). The order of walking speed in each visit was randomised and walking direction of each visit was randomised. An inertial measurement unit was placed over L5 vertebra to record tri-axial accelerations. From the trunk accelerations multiscale entropy, harmonic ratio and stride time variability were calculated to measure complexity, symmetry and variability for each walk. Complexity increased with increasing walking speed for all axes in forward and backward walking, and backward walking was less complex than forward walking. Stride time variability was also greater in backward than forward walking. Anterio-posterior and medio-lateral complexity increased following forward and backward walking but there was no difference between forward and backward walking post effects. No effects were found for harmonic ratio. These results suggest during backward walking trunk motion is rigidly controlled but central pattern generators responsible for temporal gait patterns are less refined for backward walking. However, in both directions complexity increased as speed increased suggesting additional constraint of trunk motion, normally characterised by reduced complexity, is not applied as speed increases.

Signaling mechanisms underlying reversible, activity-dependent dendrite formation.

Neuronal activity and neurotrophins play a central role in the formation, maintenance, and plasticity of dendritic arbors. Here, we show that neuronal activity, mediated by electrical stimulation, KCl depolarization, or cholinergic receptor activation, promotes reversible dendrite formation in sympathetic neurons and that this effect is enhanced by NGF. Activity-dependent dendrite formation is accompanied by increased association of HMW MAP2 with microtubules and increased microtubule stability. Inhibition of either CaMKII or the MEK-ERK pathway, both of which phosphorylate MAP2, inhibits dendrite formation, but inhibition of both pathways simultaneously is required for dendrites to retract. These data indicate that neuronal activity signals via CamKII and the ERKs to regulate MAP2:microtubule interactions and hence reversible dendrite stability, and to provide a mechanism whereby activity and neurotrophins converge intracellularly to dynamically regulate dendritic morphology.