Tryptophan 32 mediates SOD1 toxicity in a in vivo motor neuron model of ALS and is a promising target for small molecule therapeutics.

SOD1 misfolding, toxic gain of function, and spread are proposed as a pathological basis of amyotrophic lateral sclerosis (ALS), but the nature of SOD1 toxicity has been difficult to elucidate. Uniquely in SOD1 proteins from humans and other primates, and rarely in other species, a tryptophan residue at position 32 (W32) is predicted to be solvent exposed and to participate in SOD1 misfolding. We hypothesized that W32 is influential in SOD1 acquiring toxicity, as it is known to be important in template-directed misfolding. We tested if W32 contributes to SOD1 cytotoxicity and if it is an appropriate drug target to ameliorate ALS-like neuromuscular deficits in a zebrafish model of motor neuron axon morphology and function (swimming). Embryos injected with human SOD1 variant with W32 substituted for a serine (SOD1W32S) had reduced motor neuron axonopathy and motor deficits compared to those injected with wildtype or disease-associated SOD1. A library of FDA-approved small molecules was ranked with virtual screening based on predicted binding to W32, and subsequently filtered for analogues using a pharmacophore model based on molecular features of the uracil moiety of a small molecule previously predicted to interact with W32 (5'-fluorouridine or 5'-FUrd). Along with testing 5'-FUrd and uridine, a lead candidate from this list was selected based on its lower toxicity and improved blood brain barrier penetrance; telbivudine significantly rescued SOD1 toxicity in a dose-dependent manner. The mechanisms whereby the small molecules ameliorated motor neuron phenotypes were specifically mediated through human SOD1 and its residue W32, because these therapeutics had no measurable impact on the effects of UBQLN4D90A, EtOH, or tryptophan-deficient human SOD1W32S. By substituting W32 for a more evolutionarily conserved residue (serine), we confirmed the significant influence of W32 on human SOD1 toxicity to motor neuron morphology and function; further, we performed pharmaceutical targeting of the W32 residue for rescuing SOD1 toxicity. This unique residue offers future novel insights into SOD1 stability and toxic gain of function, and therefore poses an potential target for drug therapy.

Radiation combined with oncolytic vaccinia virus provides pronounced antitumor efficacy and induces immune protection in an aggressive glioblastoma model.

Glioblastoma (GB) is a malignant and immune-suppressed brain cancer that remains incurable despite the current standard of care. Radiotherapy is a mainstay of GB treatment, however invasive cancer cells outside the irradiated field and radioresistance preclude complete eradication of GB cells. Oncolytic virus therapy harnesses tumor-selective viruses to spread through and destroy tumors while stimulating antitumor immune responses, and thus has potential for use following radiotherapy. We demonstrate that oncolytic ΔF4LΔJ2R vaccinia virus (VACV) replicates in and induces cytotoxicity of irradiated brain tumor initiating cells in vitro. Importantly, a single 10 Gy dose of radiation combined with ΔF4LΔJ2R VACV produced considerably superior anticancer effects relative to either monotherapy when treating immune-competent orthotopic CT2A-luc mouse models-significantly extending survival and curing the majority of mice. Mice cured by the combination displayed significantly increased survival relative to naïve age-matched controls following intracranial tumor challenge, with some complete rejections. Further, the combination therapy was associated with an increased ratio of CD8+ effector T cells to regulatory T cells compared to either monotherapy. This study validates the use of radiation with an oncolytic ΔF4LΔJ2R VACV to improve treatment of this malignant brain cancer.

Aperture Crossing in Virtual Reality: Physical Fatigue Delays Response Time.

Visual perception and cognitive (i.e., decision-making) abilities facilitate successful avoidance of obstacles in a person's environment. However, detrimental changes to cognition can occur after physical fatigue is induced by strenuous exercise. The purpose of the current study was to determine if obstacle avoidance behaviors reflect similar negative effects following physically fatiguing exercise. A virtual reality (VR) closing-gap aperture crossing task was completed by 13 recreationally active individuals to assess the effects of physical fatigue on passability judgements and response time. Participants approached closing apertures that moved at one of seven speeds while deciding to either pass through the closing aperture or stop. Participants completed four blocks of trials over a 7-day period (i.e., pre- and post-tests on the fatiguing day and control day). No significant differences for passability judgements were found across each of the blocks, but there was a significant reduction in response time on the post-test exercise day. Thus, physical fatigue increased the time required to make, and follow through on, a decision. The current findings suggest that processes requiring more cortical areas and processing (i.e., response time) may be more detrimentally affected by physically fatiguing exercise compared to dichotomous visuomotor tasks (i.e., passability judgements).

Collision avoidance strategies between two athlete walkers: Understanding impaired avoidance behaviours in athletes with a previous concussion.

BACKGROUND: Individuals who have sustained a concussion often display associated balance control deficits and visuomotor impairments despite being cleared by a physician to return to sport. Such visuomotor impairments can be highlighted in collision avoidance tasks that involves a mutual adaptation between two walkers. However, studies have yet to challenged athletes with a previous concussion during an everyday collision avoidance task, following return to sport. RESEARCH QUESTION: Do athletes with a previous concussion display associated behavioural changes during a 90°-collision avoidance task with an approaching pedestrian? METHODS: Thirteen athletes (ATH; 9 females, 23 ±â€¯4years) and 13 athletes with a previous concussion (CONC; 9 females, 22 ±â€¯3 years, concussion <6 months) walked at a comfortable walking speed along a 12.6 m pathway while avoiding another athlete on a 90º-collision course. Each participant randomly interacted with individuals from the same group 20 times and interacted with individuals from the opposite group 21 times. Minimum predicted distance (mpd) was used to examine collision avoidance behaviours between ATH and CONC groups. RESULTS: The overall progression of mpd(t) did not differ between groups (p > .05). During the collision avoidance task, previously concussed athletes contributed less when passing second compared to their peers(p < .001). When two previously concussed athletes were on a collision course, there was a greater amount of variability resulting in inappropriate adaptive behaviours. SIGNIFICANCE: Although successful at avoiding a collision with an approaching athlete, previously concussed athletes exhibit behavioural changes manifesting in riskier behaviours. The current findings suggest that previously concussed athletes possess behavioural changes even after being cleared to returned to sport, which may increase their risk of a subsequent injury when playing.

Occupational therapy in pulmonary rehabilitation programs: A scoping review.

Pulmonary rehabilitation (PR) is a multidisciplinary intervention forming the cornerstone of chronic respiratory disease management, improving individuals' exercise capacities and abilities to complete activities of daily living (ADLs). Although the occupational therapy (OT) scope of practice focuses on similar outcomes as PR, the tasks/roles and benefit of including OT in PR has not been reviewed. This scoping review synthesized the i) tasks/roles, ii) recommendations of guidelines, iii) prevalence and iv) effects of OT as part of PR programs. Searching of four databases (MEDLINE, EMBASE, CINAHL and Cochrane), OT association websites, and hand searching was performed, and 51 records were included. The OT tasks/roles most reported include teaching energy conservation techniques (n = 23), addressing ADLs (n = 17), and assisting with breathlessness management (n = 10). Using the Canadian Model of Occupational Performance and Engagement these tasks/roles were grouped into person (n = 16 unique tasks/roles), occupation (n = 6 tasks/roles), environment (n = 5 tasks/roles), and other (n = 3 tasks/roles) domains and were endorsed by two available practice guidelines addressing OT in PR programs. From 13 PR surveys across four continents, 17-92% of PR programs included OT. Inclusion of OT in PR resulted in positive effects on ADLs, pulmonary function, dyspnea, quality of life, and mortality. Although an increasing number of PR programs include occupational therapists in their multidisciplinary teams, there is a paucity of original studies and guidelines reporting on the tasks/roles and benefits of OT in PR. Further research is needed to clearly define the tasks/roles of OT in multidisciplinary PR teams and contributions to enhancing patient outcomes.

The Role of Occupational Therapy in Pulmonary Rehabilitation Programs: Protocol for a Scoping Review.

BACKGROUND: Chronic respiratory diseases are highly prevalent and compromise an individual's ability to perform activities of daily living (ADLs) and participate in meaningful life roles. Pulmonary rehabilitation (PR) is a well-established intervention aimed at restoring an individual's exercise capacity and improving their ability to complete their ADLs. Occupational therapists help individuals engage in meaningful "occupations," improving their health and well-being. Given the concordance in the aims of PR and the occupational therapy (OT) scope of practice, occupational therapists appear to be well suited as key players in PR programs. However, the benefits of adding OT to PR programs have been sparsely reported in the literature and the role of OT in PR has never been synthesized or reported in national and international guidelines. OBJECTIVE: The aim of this review is to explore the role of OT in PR programs, the current guideline recommendations for the inclusion of OT in PR programs, the estimated prevalence of OT in PR programs, and the reported or anticipated effects of OT interventions in PR programs. METHODS: The review will be conducted following the Joanna Briggs Institute (JBI) methodology for scoping reviews. A comprehensive search will be undertaken in the Cochrane Database of Systematic Reviews, EMBASE, MEDLINE, and CINAHL (EBSCO) to identify and retrieve relevant literature published in English, French, or Portuguese. Gray literature on international OT association websites will also be identified, including position statements and guidelines relevant to PR programs. All literature published since the establishment of the effectiveness of PR for chronic respiratory disease in 1994 that explores OT in PR programs for these patients will be included. Search results will be exported to Covidence for title, abstract, and full-text screening by two independent reviewers. Data will be extracted by two independent reviewers using a pilot-tested template including the following: the number of PR programs including OT (specifically from surveys), the purpose of the study, the study design, patient characteristics, respiratory conditions included, PR components, OT role, outcomes, and results. Findings will be presented using a narrative summary, supplemented by figures and/or tables. Key themes will be displayed in an infographic or schematic. RESULTS: The study was initiated in January 2021 and registered with the Open Science Framework (OSF) in February 2021, prior to title and abstract screening. Data collection and analysis and drafting of the manuscript will occur throughout 2021, with expected publication in 2022. CONCLUSIONS: The results of this scoping review will help health care professionals improve patient care by broadening their understanding and awareness of the role of OT in PR programs. This role clarification may help to inform program development and clinical decision making and will serve to optimize the delivery of multidisciplinary care for patients in PR programs, ultimately improving patient outcomes. TRIAL REGISTRATION: OSF Registries ZH63W; https://osf.io/zh63w. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30244.

Comparing Balance Control Between Soccer Players and Non-Athletes During a Dynamic Lower Limb Reaching Task.

Background: Balance control is an essential element of locomotion that enhances biomotor abilities and physical performance. Individuals with extensive soccer experience display superior static single leg balance control compared to athletes of other sports as well as non-athletes. However, during a match, players often encounter greater challenges to single leg balance that require rapid decision-making skills and dynamic stability. Purpose: The purpose of this study was to determine if individuals with extensive soccer training demonstrate superior single-leg balance control compared to non-athletes during a dynamic lower limb reaching task. Method: 22 varsity soccer players were matched with 21 non-athlete controls. Single-leg balance control was assessed during a Go/No-Go lower limb reaching task. Centre of pressure displacement (dCOP) was measured for both the dominant and non-dominant feet and compared between groups. Results: Soccer players displayed reduced dCOP during All Go trials compared to non-athletes, particularly in the medial-lateral plane. Additionally, soccer players displayed reduced anterior-posterior dCOP during Go/No-Go trials compared to non-athletes, particularly on their dominant foot. Conclusion: Athletes with soccer-specific training demonstrate improved executive control and use of proprioceptive information, which results in an improved ability to maintain single-support balance and corral COP during a dynamic visuomotor lower limb-reaching task. As such, balance training may be a useful addition to athlete training regimes to improve sport-specific performance. Future research would compare these results to athletes of other sports to explore balance control during a visuomotor reaching task and how it may differ based on sport training history.

Sensory conflict alters visual perception of action capabilities during crossing of a closing gap in virtual reality.

The somatosensory, vestibular, and visual systems contribute to multisensory integration, which facilitates locomotion around obstacles in the environment. The joystick-controlled virtual reality (VR) locomotion interface does not preserve congruent sensory input like real-walking, yet is commonly used in human behaviour research. Our purpose was to determine if collision avoidance behaviours were affected during an aperture crossing task when somatosensory and vestibular input were incongruent, and only vision was accurate. Participants included 36 young adults who completed a closing gap aperture crossing task in VR using real-walking and joystick-controlled locomotion. Participants successfully completed the task using both interfaces. Switch point between passable and impassable apertures was larger for joystick-controlled locomotion compared with real-walking, but time-to-contact (TTC) was lower for real-walking than joystick-controlled locomotion. Increased joystick-controlled locomotion switch point may be attributed to incongruency between visual and non-visual information, causing underestimation of distance travelled towards the aperture. Performance on future VR applications incorporating dynamically changing gaps can be considered successful using joystick-controlled locomotion, while taking into account a potential behaviour difference. Differences in TTC may be explained by the requirement of gait termination in real-walking but not in joystick-controlled locomotion. Future VR studies would benefit from programming acceleration and deceleration into joystick-controlled locomotion interfaces.

Minimum predicted distance: Applying a common metric to collision avoidance strategies between children and adult walkers.

BACKGROUND: Collision avoidance between two walkers involves a mutual adaptation to speed and orientation in order to successfully avoid a collision. Minimum Predicted Distance (MPD) is the distance at which two walkers would collide if their speed and path trajectory were maintained at first sight of one another. MPD has been used to describe the risk of collision and its evolution over time between two adult walkers when on a collision course. Middle-aged children have been shown to have poor perception-action coupling during static and dynamic collision avoidance tasks. Research has yet to examine whether perception-action coupling deficits persist in a dynamic collision avoidance task involving a child and another walker. RESEARCH QUESTION: Can the metric MPD(t) be used to examine collision avoidance strategies between children and adults? METHODS: Eighteen children (age: 10 ±â€¯1.5 years) and eighteen adults (34 ±â€¯9.6 years) walked along a 12.6 m pathway while avoiding another participant (child or adult). Groups of three children and three adults were recruited per session. Trials were randomized equally such that each adult interacted with another adult 20 times, each child interacted with another child 20 times, and each adult interacted with a child 21 times, for a total of 141 trials. 3D kinematic data of each participant's head was recorded using the Vicon system. RESULTS: The results demonstrated: (1) MPD(t) can be used to predict future collisions in children, (2) MPD(t) is an absolute measure that is consistently lower when a child is involved compared to two adult walkers, (3) the individual passing second, even when it is a child, contributes more to MPD(t) than the walker passing first. SIGNIFICANCE: It appears children have developed adult-like strategies during a collision avoidance task involving two walkers. Body anthropometrics should be considered when determining collision avoidance strategies between children and adults.

Comparison of the temporal programs regulating tyrosine hydroxylase and enkephalin expressions in TIDA neurons of lactating rats following pup removal and then pup return.

Dopamine (DA) and enkephalin (ENK) release from the tuberoinfundibular dopaminergic neurons (TIDA) into the hypophysial portal circulation is fundamentally different under non-lactating and lactating conditions. The aim of this experiment was to compare the effect of a brief interruption then resumption of suckling on the temporal program of tyrosine hydroxylase (TH; rate-limiting enzyme of dopamine synthesis) and ENK regulation in dams. On post partum day 10, pups were removed for a 4-h period from a group of the dams then returned for 4- and 24-h periods. It was examined whether such a brief interruption of suckling provokes full up-regulation of TH and down-regulation of ENK, and whether reinitiation of suckling limits the extent to which TH up- and ENK down-regulate. At the end of experiment, the animals were decapitated. In situ hybridization was used to examine the expression of TH and ENK mRNA in the arcuate nucleus where TIDA neurons reside. The results showed that, on one hand, the removal of pups induced TH up-regulation, on the other hand, ENK expression also increased 8 h after removal of pups and then started to slowly decline. In dams whose sucklings were reinitiated both TH and ENK mRNAs were up-regulated at least for a day. ENK expression responded more slowly to the removal of pups than expression of TH, and after reinitiation of suckling, the temporal program of regulation of both TH and ENK expressions ran parallel in the first 24 h.

A direct neuronal connection between the subparafascicular and ventrolateral arcuate nuclei in non-lactating female rats. Could this pathway play a role in the suckling-induced prolactin release?

The neuronal pathways, through which prolactin secretion is regulated during lactation, have still not been fully explored. Studies indicate that the suckling stimulus travels through the spinal cord, the brain stem, and then reaches the hypothalamus. The focus of this present experiment is to further explore the neuronal connections between the brain stem and the arcuate nucleus that may be involved in suckling-induced prolactin release. Ante- and retrograde tracing techniques were used. To chemically characterize the explored neurons neuropeptide immunohistochemistry was applied. Previous studies have indicated that the peripeduncular nucleus is a relay of the suckling stimulus in the midbrain, conveying the information to the hypothalamus. In our experiments, we have found an additional cell group in the subparafascicular parvocellular nucleus located just behind the posterior thalamus that projects to the arcuate neurons. The injection of the retrograde tracer into the ventrolateral part of the arcuate nucleus labeled cells in the lateral subdivision of the subparafascicular parvocellular nucleus. Anterograde tracing from the subparafascicular parvocellular nucleus resulted in fiber labeling in the arcuate nucleus in close apposition with dynorphin immunopositive neurons. Double labeling revealed that a subpopulations of the subparafascicular parvocellular neurons projecting to the arcuate nucleus contained tuberoinfundibular peptide of 39 residues or calcitonin gene-related peptide. The presented findings suggest that the ascending fibers from the subparafascicular parvocellular nucleus might be in the pathway involved in the suckling-induced prolactin release.