Reduced inhibition from quadriceps onto soleus after acute quadriceps fatigue suggests Golgi tendon organ contribution to heteronymous inhibition.

Heteronymous inhibition between lower limb muscles is primarily attributed to recurrent inhibitory circuits in humans but could also arise from Golgi tendon organs (GTOs). Distinguishing between recurrent inhibition and mechanical activation of GTOs is challenging because their heteronymous effects are both elicited by stimulation of nerves or a muscle above motor threshold. Here, the unique influence of mechanically activated GTOs was examined by comparing the magnitude of heteronymous inhibition from quadriceps (Q) muscle stimulation onto ongoing soleus electromyographic at five Q stimulation intensities (1.5-2.5× motor threshold) before and after an acute bout of stimulation-induced Q fatigue. Fatigue was used to decrease Q stimulation evoked force (i.e., decreased GTO activation) despite using the same pre-fatigue stimulation currents (i.e., same antidromic recurrent inhibition input). Thus, a decrease in heteronymous inhibition after Q fatigue and a linear relation between stimulation-evoked torque and inhibition both before and after fatigue would support mechanical activation of GTOs as a source of inhibition. A reduction in evoked torque but no change in inhibition would support recurrent inhibition. After fatigue, Q stimulation-evoked knee torque, heteronymous inhibition magnitude and inhibition duration were significantly decreased for all stimulation intensities. In addition, heteronymous inhibition magnitude was linearly related to twitch-evoked knee torque before and after fatigue. These findings support mechanical activation of GTOs as a source of heteronymous inhibition along with recurrent inhibition. The unique patterns of heteronymous inhibition before and after fatigue across participants suggest the relative contribution of GTOs, and recurrent inhibition may vary across persons.

Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.

Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) ß = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW ß = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.

Distribution of the misfolded isoform of the prion protein in peripheral tissues and spinal cord of Rocky Mountain elk (Cervus elaphus nelsoni) with naturally occurring chronic wasting disease.

Chronic wasting disease (CWD) is an infectious transmissible spongiform encephalopathy of cervids associated with the presence of a misfolded prion protein (PrPCWD). Progression of PrPCWD distribution has been described using immunohistochemistry and histologic changes in a single section of brain stem at the level of the obex resulting in scores from 0 (early) to 10 (terminal) in elk with naturally occurring CWD. Here we describe the spread and distribution of PrPCWD in peripheral tissues and spinal cord in 16 wild and 17 farmed Rocky Mountain elk (Cervus elaphus nelsoni) with naturally occurring CWD and correlate these findings with obex scores. Spinal cord and approximately 110 peripheral tissues were collected, processed, stained with hematoxylin and eosin, and immunolabeled with the anti-prion protein monoclonal antibody F99/97.6.1. The medial retropharyngeal and tracheobronchial lymph nodes were the first tissues to accumulate PrPCWD, followed by other lymphoid tissues, myenteric plexus, spinal cord, and finally tissues outside of the lymphatic and neural systems. However, the only significant histological lesion observed was mild spongiform encephalopathy in the dorsal column of the lower spinal cord in elk with an obex score of ≥9. Initial exposure to CWD prions may be through the respiratory system and spread appears to occur primarily via the autonomic nervous system. Therefore, we suggest using obex scores as a proxy for stage of disease progression and verifying with key peripheral tissues.

The effect of a one-year vigorous physical activity intervention on fitness, cognitive performance and mental health in young adolescents: the Fit to Study cluster randomised controlled trial.

BACKGROUND: Physical activity (PA) may positively stimulate the brain, cognition and mental health during adolescence, a period of dynamic neurobiological development. High-intensity interval training (HIIT) or vigorous PA interventions are time-efficient, scalable and can be easily implemented in existing school curricula, yet their effects on cognitive, academic and mental health outcomes are unclear. The primary aim of the Fit to Study trial was to investigate whether a pragmatic and scalable HIIT-style VPA intervention delivered during school physical education (PE) could improve attainment in maths. The primary outcome has previously been reported and was null. Here, we report the effect of the intervention on prespecified secondary outcomes, including cardiorespiratory fitness, cognitive performance, and mental health in young adolescents. METHODS: The Fit to Study cluster randomised controlled trial included Year 8 pupils (n = 18,261, aged 12-13) from 104 secondary state schools in South/Mid-England. Schools were randomised into an intervention condition (n = 52), in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year (2017-2018), or into a "PE as usual" control condition. Secondary outcomes included assessments of cardiorespiratory fitness (20-m shuttle run), cognitive performance (executive functions, relational memory and processing speed) and mental health (Strength and Difficulties Questionnaire and self-esteem measures). The primary intention-to-treat (ITT) analysis used linear models and structural equation models with cluster-robust standard errors to test for intervention effects. A complier-average causal effect (CACE) was estimated using a two-stage least squares procedure. RESULTS: The HIIT-style VPA intervention did not significantly improve cardiorespiratory fitness, cognitive performance (executive functions, relational memory or processed speed), or mental health (all p > 0.05). Subgroup analyses showed no significant moderation of intervention effects by sex, socioeconomic status or baseline fitness levels. Changes in cardiorespiratory fitness were not significantly related to changes in cognitive or mental health outcomes. The trial was marked by high drop-out and low intervention compliance. Findings from the CACE analysis were in line with those from the ITT analysis. CONCLUSION: The one-academic year HIIT-style VPA intervention delivered during regular school PE did not significantly improve fitness, cognitive performance or mental health, but these findings should be interpreted with caution given low implementation fidelity and high drop-out. Well-controlled, large-scale, school-based trials that examine the effectiveness of HIIT-style interventions to enhance cognitive and mental health outcomes are warranted. TRIAL REGISTRATION: ISRCTN registry, 15,730,512 . Trial protocol and analysis plan for primary outcome prospectively registered on 30th March 2017. ClinicalTrials.gov , NCT03286725 . Secondary measures (focus of current manuscript) retrospectively registered on 18 September 2017.

Non-uniform upregulation of the autogenic stretch reflex among hindlimb extensors following lateral spinal lesion in the cat.

Successful propagation throughout the step cycle is contingent on adequate regulation of whole-limb stiffness by proprioceptive feedback. Following spinal cord injury (SCI), there are changes in the strength and organization of proprioceptive feedback that can result in altered joint stiffness. In this study, we measured changes in autogenic feedback of five hindlimb extensor muscles following chronic low thoracic lateral hemisection (LSH) in decerebrate cats. We present three features of the autogenic stretch reflex obtained using a mechanographic method. Stiffness was a measure of the resistance to stretch during the length change. The dynamic index documented the extent of adaptation or increase of the force response during the hold phase, and the impulse measured the integral of the response from initiation of a stretch to the return to the initial length. The changes took the form of variable and transient increases in the stiffness of vastus (VASTI) group, soleus (SOL), and flexor hallucis longus (FHL), and either increased (VASTI) or decreased adaptation (GAS and PLANT). The stiffness of the gastrocnemius group (GAS) was also variable over time but remained elevated at the final time point. An unexpected finding was that these effects were observed bilaterally. Potential reasons for this finding and possible sources of increased excitability to this muscle group are discussed.

Adaptation to slope in locomotor-trained spinal cats with intact and self-reinnervated lateral gastrocnemius and soleus muscles.

Sensorimotor training providing motion-dependent somatosensory feedback to spinal locomotor networks restores treadmill weight-bearing stepping on flat surfaces in spinal cats. In this study, we examined if locomotor ability on flat surfaces transfers to sloped surfaces and the contribution of length-dependent sensory feedback from lateral gastrocnemius (LG) and soleus (Sol) to locomotor recovery after spinal transection and locomotor training. We compared kinematics and muscle activity at different slopes (±10° and ±25°) in spinalized cats (n = 8) trained to walk on a flat treadmill. Half of those animals had their right hindlimb LG/Sol nerve cut and reattached before spinal transection and locomotor training, a procedure called muscle self-reinnervation that leads to elimination of autogenic monosynaptic length feedback in spinally intact animals. All spinal animals trained on a flat surface were able to walk on slopes with minimal differences in walking kinematics and muscle activity between animals with/without LG/Sol self-reinnervation. We found minimal changes in kinematics and muscle activity at lower slopes (±10°), indicating that walking patterns obtained on flat surfaces are robust enough to accommodate low slopes. Contrary to results in spinal intact animals, force responses to muscle stretch largely returned in both SELF-REINNERVATED muscles for the trained spinalized animals. Overall, our results indicate that the locomotor patterns acquired with training on a level surface transfer to walking on low slopes and that spinalization may allow the recovery of autogenic monosynaptic length feedback following muscle self-reinnervation.NEW & NOTEWORTHY Spinal locomotor networks locomotor trained on a flat surface can adapt the locomotor output to slope walking, up to ±25° of slope, even with total absence of supraspinal CONTROL. Autogenic length feedback (stretch reflex) shows signs of recovery in spinalized animals, contrary to results in spinally intact animals.

Redistribution of inhibitory force feedback between a long toe flexor and the major ankle extensor muscles following spinal cord injury.

Inhibitory pathways from Golgi tendon organs project widely between muscles crossing different joints and axes of rotation. Evidence suggests that the strength and distribution of this intermuscular inhibition is dependent on motor task and corresponding signals from the brainstem. The purpose of the present study was to investigate whether this sensory network is altered after spinal cord hemisection as a potential explanation for motor deficits observed after spinal cord injury (SCI). Force feedback was assessed between the long toe flexor and ankle plantarflexor (flexor hallucis longus), and the three major ankle extensors, (combined gastrocnemius, soleus, and plantaris muscles) in the hind limbs of unanesthetized, decerebrate, female cats. Data were collected from animals with intact spinal cords (control) and lateral spinal hemisections (LSHs) including chronic LSH (4-20 weeks), subchronic LSH (2 weeks), and acute LSH. Muscles were stretched individually and in pairwise combinations to measure intermuscular feedback between the toe flexor and each of the ankle extensors. In control animals, three patterns were observed (balanced inhibition between toe flexor and ankle extensors, stronger inhibition from toe flexor to ankle extensor, and vice versa). Following spinal hemisection, only strong inhibition from toe flexors onto ankle extensors was observed independent of survival time. The results suggest immediate and permanent reorganization of force feedback in the injured spinal cord. The altered strength and distribution of force feedback after SCI may be an important future target for rehabilitation.

Evaluating intermuscular Golgi tendon organ feedback with twitch contractions.

KEY POINTS: Golgi tendon organ feedback has been evaluated most frequently using electrical stimulation of peripheral nerves, which is not a physiological or selective stimulus for Golgi tendon organs. Golgi tendon organs are most responsive to active muscle contractions. This study provides evidence that muscle stimulation evoked twitches - a physiological stimulus for Golgi tendon organs - induces intermuscular effects most likely due to mechanical activation of Golgi tendon organ feedback and not direct activation of sensory axons. The results demonstrate that twitch contractions are a feasible non-invasive approach that can be used to advance understanding of the functional role of Golgi tendon organ feedback. ABSTRACT: Force feedback from Golgi tendon organs (GTOs) has widespread intermuscular projections mediated by interneurons that share inputs from muscle spindles, among others. Because current methods to study GTO circuitry (nerve stimulation or muscle stretch) also activate muscle spindle afferents, the selective role of GTOs remains uncertain. Here, we tested the hypothesis that intramuscular stimulation evoked twitch contractions could be used to naturally bias activation of GTOs and thus evaluate their intermuscular effects in decerebrate cats. This was achieved by comparing the effects of twitch contractions and stretches as donor inputs onto the motor output of recipient muscles. Donor-recipient pairs evaluated included those already known in the cat to receive donor excitatory muscle spindle feedback only, inhibitory GTO feedback only, and both excitatory spindle and inhibitory GTO effects. Muscle stretch, but not twitch contractions, evoked excitation onto recipient muscles with muscle spindle afferent inputs only. Both donor muscle stretch and twitch contractions inhibited a recipient muscle with GTO projections only. In a recipient muscle that receives both muscle spindle and GTO projections, donor muscle stretch evoked both excitatory and inhibitory effects, whereas twitch contractions evoked inhibitory effects only. These data support the hypothesis that muscle stimulation evoked contractions can induce intermuscular effects most consistent with mechanical GTO receptor activation and not direct activation of sensory axons. We propose this approach can be used to evaluate GTO circuitry more selectively than muscle stretch or nerve stimulation and can be adapted to study GTO feedback non-invasively in freely moving cats and humans.

Distributed force feedback in the spinal cord and the regulation of limb mechanics.

This review is an update on the role of force feedback from Golgi tendon organs in the regulation of limb mechanics during voluntary movement. Current ideas about the role of force feedback are based on modular circuits linking idealized systems of agonists, synergists, and antagonistic muscles. In contrast, force feedback is widely distributed across the muscles of a limb and cannot be understood based on these circuit motifs. Similarly, muscle architecture cannot be understood in terms of idealized systems, since muscles cross multiple joints and axes of rotation and further influence remote joints through inertial coupling. It is hypothesized that distributed force feedback better represents the complex mechanical interactions of muscles, including the stresses in the musculoskeletal network born by muscle articulations, myofascial force transmission, and inertial coupling. Together with the strains of muscle fascicles measured by length feedback from muscle spindle receptors, this integrated proprioceptive feedback represents the mechanical state of the musculoskeletal system. Within the spinal cord, force feedback has excitatory and inhibitory components that coexist in various combinations based on motor task and integrated with length feedback at the premotoneuronal and motoneuronal levels. It is concluded that, in agreement with other investigators, autogenic, excitatory force feedback contributes to propulsion and weight support. It is further concluded that coexistent inhibitory force feedback, together with length feedback, functions to manage interjoint coordination and the mechanical properties of the limb in the face of destabilizing inertial forces and positive force feedback, as required by the accelerations and changing directions of both predator and prey.

Patterns of intermuscular inhibitory force feedback across cat hindlimbs suggest a flexible system for regulating whole limb mechanics.

Prior work has suggested that Golgi tendon organ feedback, via its distributed network linking muscles spanning all joints, could be used by the nervous system to help regulate whole limb mechanics if appropriately organized. We tested this hypothesis by characterizing the patterns of intermuscular force-dependent feedback between the primary extensor muscles spanning the knee, ankle, and toes in decerebrate cat hindlimbs. Intermuscular force feedback was evaluated by stretching tendons of selected muscles in isolation and in pairwise combinations and then measuring the resulting force-dependent intermuscular interactions. The relative inhibitory feedback between extensor muscles was examined, as well as symmetry of the interactions across limbs. Differences in the directional biases of inhibitory feedback were observed across cats, with three patterns identified as points on a spectrum: pattern 1, directional bias of inhibitory feedback onto the ankle extensors and toe flexors; pattern 2, convergence of inhibitory feedback onto ankle extensors and mostly balanced inhibitory feedback between vastus muscle group and flexor hallucis longus, and pattern 3, directional bias of inhibitory feedback onto ankle and knee extensors. The patterns of inhibitory feedback, while different across cats, were symmetric across limbs of individual cats. The variable but structured distribution of force feedback across cat hindlimbs provides preliminary evidence that inhibitory force feedback could be a regulated neural control variable. We propose the directional biases of inhibitory feedback observed experimentally could provide important task-dependent benefits, such as directionally appropriate joint compliance, joint coupling, and compensation for nonuniform inertia. NEW & NOTEWORTHY Feedback from Golgi tendon organs project widely among extensor motor nuclei in the spinal cord. The distributed nature of force feedback suggests these pathways contribute to the global regulation of limb mechanics. Analysis of this network in individual animals indicates that the strengths of these pathways can be reorganized appropriately for a variety of motor tasks, including level walking, slope walking, and landing.

Self-reinnervated muscles lose autogenic length feedback, but intermuscular feedback can recover functional connectivity.

In this study, we sought to identify sensory circuitry responsible for motor deficits or compensatory adaptations after peripheral nerve cut and repair. Self-reinnervation of the ankle extensor muscles abolishes the stretch reflex and increases ankle yielding during downslope walking, but it remains unknown whether this finding generalizes to other muscle groups and whether muscles become completely deafferented. In decerebrate cats at least 19 wk after nerve cut and repair, we examined the influence of quadriceps (Q) muscles' self-reinnervation on autogenic length feedback, as well as intermuscular length and force feedback, among the primary extensor muscles in the cat hindlimb. Effects of gastrocnemius and soleus self-reinnervation on intermuscular circuitry were also evaluated. We found that autogenic length feedback was lost after Q self-reinnervation, indicating that loss of the stretch reflex appears to be a generalizable consequence of muscle self-reinnervation. However, intermuscular force and length feedback, evoked from self-reinnervated muscles, was preserved in most of the interactions evaluated with similar relative inhibitory or excitatory magnitudes. These data indicate that intermuscular spinal reflex circuitry has the ability to regain functional connectivity, but the restoration is not absolute. Explanations for the recovery of intermuscular feedback are discussed, based on identified mechanisms responsible for lost autogenic length feedback. Functional implications, due to permanent loss of autogenic length feedback and potential for compensatory adaptations from preserved intermuscular feedback, are discussed.

Analysis of waste management issues arising from a field study evaluating decontamination of a biological agent from a building.

UNLABELLED: The Bio-response Operational Testing and Evaluation (BOTE) Project was a cross-government effort designed to operationally test and evaluate a response to a biological incident (release of Bacillus anthracis [Ba] spores, the causative agent for anthrax) from initial public health and law enforcement response through environmental remediation. The BOTE Project was designed to address site remediation after the release of a Ba simulant, Bacillus atrophaeus spp. globigii (Bg), within a facility, drawing upon recent advances in the biological sampling and decontamination areas. A key component of response to a biological contamination incident is the proper management of wastes and residues, which is woven throughout all response activities. Waste is generated throughout the response and includes items like sampling media packaging materials, discarded personal protective equipment, items removed from the facility either prior to or following decontamination, aqueous waste streams, and materials generated through the application of decontamination technologies. The amount of residual contaminating agent will impact the available disposal pathways and waste management costs. Waste management is an integral part of the decontamination process and should be included through "Pre-Incident" response planning. Overall, the pH-adjusted bleach decontamination process generated the most waste from the decontamination efforts, and fumigation with chlorine dioxide generated the least waste. A majority of the solid waste generated during pH-adjusted bleach decontamination was the nonporous surfaces that were removed, bagged, decontaminated ex situ, and treated as waste. The waste during the two fumigation rounds of the BOTE Project was associated mainly with sampling activities. Waste management activities may represent a significant contribution to the overall cost of the response/recovery operation. This paper addresses the waste management activities for the BOTE field test. IMPLICATIONS: Management of waste is a critical element of activities dealing with remediation of buildings and outdoor areas following a biological contamination incident. Waste management must be integrated into the overall remediation process, along with sampling, decontamination, resource management, and other important response elements, rather than being a stand-alone activity. The results presented in this paper will provide decision makers and emergency planners at the federal/state/tribal/local level information that can be used to integrate waste management into an overall systems approach to planning and response activities.

Toward a multisubject analysis of neural connectivity.

Directed acyclic graphs (DAGs) and associated probability models are widely used to model neural connectivity and communication channels. In many experiments, data are collected from multiple subjects whose connectivities may differ but are likely to share many features. In such circumstances, it is natural to leverage similarity among subjects to improve statistical efficiency. The first exact algorithm for estimation of multiple related DAGs was recently proposed by Oates, Smith, Mukherjee, and Cussens ( 2014 ). In this letter we present examples and discuss implications of the methodology as applied to the analysis of fMRI data from a multisubject experiment. Elicitation of tuning parameters requires care, and we illustrate how this may proceed retrospectively based on technical replicate data. In addition to joint learning of subject-specific connectivity, we allow for heterogeneous collections of subjects and simultaneously estimate relationships between the subjects themselves. This letter aims to highlight the potential for exact estimation in the multisubject setting.

The mechanical actions of muscles predict the direction of muscle activation during postural perturbations in the cat hindlimb.

Humans and cats respond to balance challenges, delivered via horizontal support surface perturbations, with directionally selective muscle recruitment and constrained ground reaction forces. It has been suggested that this postural strategy arises from an interaction of limb biomechanics and proprioceptive networks in the spinal cord. A critical experimental validation of this hypothesis is to test the prediction that the principal directions of muscular activation oppose the directions responding muscles exert their forces on the environment. Therefore, our objective was to quantify the endpoint forces of a diverse set of cat hindlimb muscles and compare them with the directionally sensitive muscle activation patterns generated in the intact and decerebrate cat. We hypothesized that muscles are activated based on their mechanical advantage. Our primary expectation was that the principal direction of muscle activation during postural perturbations will be directed oppositely (180°) from the muscle endpoint ground reaction force. We found that muscle activation during postural perturbations was indeed directed oppositely to the endpoint reaction forces of that muscle. These observations indicate that muscle recruitment during balance challenges is driven, at least in part, by limb architecture. This suggests that sensory sources that provide feedback about the mechanical environment of the limb are likely important to appropriate and effective responses during balance challenges. Finally, we extended the analysis to three dimensions and different stance widths, laying the groundwork for a more comprehensive study of postural regulation than was possible with measurements confined to the horizontal plane and a single stance configuration.

Effects of reinnervation of the biarticular shoulder-elbow muscles on joint kinematics and electromyographic patterns of the feline forelimb during downslope walking.

Full recovery of the forelimb kinematics during level and upslope walking following reinnervation of the biarticular elbow extensor suggests that the proprioceptive loss is compensated by other sensory sources or altered central drive, yet these findings have not been explored in downslope walking. Kinematics and muscle activity of the shoulder and elbow during downslope locomotion following reinnervation of the feline long head of the triceps brachii (TLo) and biceps brachii (Bi) were evaluated (1) during paralysis and (2) after the motor function was recovered but the proprioceptive feedback was permanently disrupted. The step cycle was examined in three walking conditions: level (0%), -25% grade (-14° downslope) and -50% grade (-26.6° downslope). Measurements were taken prior to and at three time points (2 weeks, and 1 and 12+ months) after transecting and suturing the radial and musculocutaneous nerves. There was an increase in the yield (increased flexion) at the elbow and less extensor activity duration of flexion during stance as the downslope grade increased. There were two notable periods of eccentric contractions (active lengthening) providing an apparent 'braking' action. Paralysis of the TLo and the Bi resulted in uncompensated alterations in shoulder-elbow kinematics and motor activity during the stance phase. However, unlike the case for the level and upslope conditions, during both paralysis and reinnervation, changes in interjoint coordination persisted for the downslope condition. The lack of complete recovery in the long term suggests that the autogenic reflexes contribute importantly to muscle and joint stiffness during active lengthening.

Effects of reinnervation of the triceps brachii on joint kinematics and electromyographic patterns of the feline forelimb during level and upslope walking.

Nerve injury in the hindlimb of the cat results in locomotor changes, yet these findings have not been explored in a more multifunctional forelimb. Kinematics and muscle activity of the shoulder and elbow during level and upslope locomotion following reinnervation of the feline long head of the triceps brachii (TLo) were evaluated (1) during paralysis [none to minimum motor activity (short-term effects)] and (2) after the motor function was recovered but the proprioceptive feedback was permanently disrupted (long-term effects). The step cycle was examined in three walking conditions: level (0%), 25% grade (14° upslope) and 50% grade (26.6° upslope). Measurements were taken prior to and at three time points (2 weeks, 1 month and 12+ months) after transecting and suturing the radial nerve of TLo. There was less of a yield (increased flexion) at the elbow joint and more extensor activity during elbow flexion during stance (E2) as the grade of walking increased. Substantial short-term effects were observed at the elbow joint (increased flexion during E2) as well as increased motor activity by the synergistic elbow extensors, and greater shoulder extension at paw contact, leading to altered interjoint coordination during stance. Forelimb shoulder and elbow kinematics during level and upslope locomotion progressed back to baseline at 12 months. The short-term effects can be explained by both mechanical and neural factors that are altered by the functional elimination of the TLo. Full recovery of the forelimb kinematics during level and upslope walking suggests that the proprioceptive length feedback loss is compensated by other sensory sources or altered central drive.

ROLE OF FORELIMB MORPHOLOGY IN MUSCLE SENSORIMOTOR FUNCTIONS DURING LOCOMOTION IN THE CAT.

Previous studies established strong links between morphological characteristics of mammalian hindlimb muscles and their sensorimotor functions during locomotion. Less is known about the role of forelimb morphology in motor outputs and generation of sensory signals. Here, we measured morphological characteristics of 46 forelimb muscles from 6 cats. These characteristics included muscle attachments, physiological cross-sectional area (PCSA), fascicle length, etc. We also recorded full-body mechanics and EMG activity of forelimb muscles during level overground and treadmill locomotion in 7 and 16 adult cats of either sex, respectively. We computed forelimb muscle forces along with force- and length-dependent sensory signals mapped onto corresponding cervical spinal segments. We found that patterns of computed muscle forces and afferent activities were strongly affected by the muscle's moment arm, PCSA, and fascicle length. Morphology of the shoulder muscles suggests distinct roles of the forelimbs in lateral force production and movements. Patterns of length-dependent sensory activity of muscles with long fibers (brachioradialis, extensor carpi radialis) closely matched patterns of overall forelimb length, whereas the activity pattern of biceps brachii matched forelimb orientation. We conclude that cat forelimb muscle morphology contributes substantially to locomotor function, particularly to control lateral stability and turning, rather than propulsion.

Transcriptomics of cortical gray matter thickness decline during normal aging.

INTRODUCTION: We performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging. METHODS: Transcriptome and GMT data were available for 379 individuals (age range=28-85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800 µm) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability. RESULTS: Transcripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10(-6)) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT. CONCLUSION: Expression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.

Detection of multiple waterborne pathogens using microsequencing arrays.

AIMS: A microarray was developed to simultaneously detect Cryptosporidium parvum, Cryptosporidium hominis, Enterococcus faecium, Bacillus anthracis and Francisella tularensis in water. METHODS AND RESULTS: A DNA microarray was designed to contain probes that specifically detected C. parvum, C. hominis, Ent. faecium, B. anthracis and F. tularensis. The microarray was then evaluated with samples containing target and nontarget DNA from near-neighbour micro-organisms, and tap water spiked with multiple organisms. Results demonstrated that the microarray consistently detected Ent. faecium, B. anthracis, F. tularensis and C. parvum when present in samples. Cryptosporidium hominis was only consistently detected through the use of shared probes between C. hominis and C. parvum. CONCLUSIONS: This study successfully developed and tested a microarray-based assay that can specifically detect faecal indicator bacteria and human pathogens in tap water. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of indicator organisms has become a practical solution for monitoring for water quality. However, they do not always correlate well with the presence of many microbial pathogens, thus necessitating direct monitoring for most pathogens. This microarray can be used to simultaneously detect multiple organisms in a single sample. More importantly, it can provide occurrence information that may be used in assessing potential exposure risks to waterborne pathogens.

The danger of systematic bias in group-level FMRI-lag-based causality estimation.

Schippers, Renken and Keysers (NeuroImage, 2011) present a simulation of multi-subject lag-based causality estimation. We fully agree that single-subject evaluations (e.g., Smith et al., 2011) need to be revisited in the context of multi-subject studies, and Schippers' paper is a good example, including detailed multi-level simulation and cross-subject statistical modelling. The authors conclude that "the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics" and that "when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases". Unfortunately, we believe that the general meaning that may be taken from these statements is not supported by the paper's results, as there may in reality be a systematic (group-average) difference in haemodynamic delay between two brain areas. While many statements in the paper (e.g., the final two sentences) do refer to this problem, we fear that the overriding message that many readers may take from the paper could cause misunderstanding.