RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Invited Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art

Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and noncoding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may coexist within a single neuronal cell, including RNA/protein toxic gain-of-function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins – and how these lead to neurodegeneration – remain unknown. The field of RNA biology research faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterization of pathological mechanisms that trigger disease onset and progression

Investigating Symptoms of Concussion and Depression in Adolescent Athletes Devoid of a Recent Concussion Injury

Sport-related concussion is a concern for all athletes involved in sport and recreational activity. At this time, few investigations have sought to examine the relationship between concussion-like and depressive symptoms in an adolescent athlete population prior to the occurrence of a concussion; examining these two symptom categories among a group of healthy individuals is necessary to understand the relationship that exists between concussion and depressive symptoms. This study aimed to investigate the prevalence and relationship between concussion and depressive symptoms, and various demographic and medical history variables. Healthy uninjured adolescent athletes (aged 13 to 18 years old) completed validated symptom scales assessing perceived current concussion-like and depressive symptoms. Findings indicate that many athletes experience concussion-like and depressive symptoms in the absence of a recent injury. Therefore it may be unrealistic for an adolescent athlete to reach asymptomatic status prior to their return-to-play following an actual concussion. Results highlight large differences in the reporting of both concussion-like and depressive symptoms between males and females. Implications for practice and future research are discussed.M.Sc

Investigating Correlates of Athletic Identity, Coping with Concussion, and Return-To-Play Behavioural Intentions Among Healthy Young Athletes

Participation in sport is associated with several positive outcomes including improved physical fitness and mental wellbeing. Irrespective of these benefits, sport participation imparts an inherent risk for injury upon all athletes. Although defined as a mild traumatic brain injury, concussions are a cause for concern in sport considering the myriad of symptoms associated with the injury (e.g., cognitive, emotional, physical, and sleep-related) and the negative repercussions they can have on an individual’s psychosocial functioning. In the case of a suspected concussion, an athlete is expected to remove themselves from play. However, evidence suggests that for various reasons many athletes choose not to do so. To date, little research has examined the role of athletic identity and how this construct is related to how athletes think, feel and act in the context of a sport-related injury. This thesis is comprised of one scoping review and two original research studies that seek to better understand the relationship athletic identity has with respect to athlete cognitions, emotions, and behaviours following a sport-related injury. The first manuscript provides a comprehensive summary of known demographic, behavioural, psychosocial, functional, and pain-related correlates associated athletic identity following sport injury. The second study assesses healthy young athletes’ cognitive coping appraisals in response to a hypothetical concussion, and how these appraisals relate to both their return-to-play behavioural intentions and athletic identity. The third study assesses concussion knowledge accuracy among healthy young athletes and how their knowledge relates to concussion reporting behaviours, return-to-play behavioural intentions (in the context of a hypothetical concussion) and athletic identity. Research pertaining to athletic identity as a predictor of sport injury outcomes is still in its infancy. Therefore, the primary goal of this thesis is to determine if athletic identity is harmful or helpful to an athlete’s recovery following an actual or hypothetical injury. Findings from this program of research can be useful for guiding subsequent hypothesis generation, can serve as the impetus for future behavioural interventions, and may inform clinical practice(s). Most importantly, findings are useful for informing our understanding of athletes’ psychosocial response to concussion.Ph.D

Depression & Concussion-Like Symptoms in Adolescent Athletes in the Absence of Recent Injury

This data set contains normative (healthy control) data for Canadian adolescent athletes aged 13 to 18 years old. All participants were involved in recreational sport at time of participation in this investigation. Each participant provided data on: 1)basic demographics 2)basic medical history (including concussion history, history of depression and/or anxiety) 3)Post-Concussion Symptom Scale (PCSS) 4)The Mood & Feelings Questionnaire (MFQ

Investigating correlates of athletic identity and sport-related injury outcomes: a scoping review

Objectives To conduct a scoping review that (1) describes what is known about the relationship between athletic identity and sport-related injury outcomes and (2) describes the relationship that an injury (as an exposure) has on athletic identity (as an outcome) in athletes.Design Scoping review.Participants A total of n=1852 athletes from various sport backgrounds and levels of competition.Primary and secondary outcome measures The primary measure used within the studies identified was the Athletic Identity Measurement Scale. Secondary outcome measures assessed demographic, psychosocial, behavioural, physical function and pain-related constructs.Results Twenty-two studies were identified for inclusion. Samples were dominated by male, Caucasian athletes. The majority of studies captured musculoskeletal injuries, while only three studies included sport-related concussion. Athletic identity was significantly and positively associated with depressive symptom severity, sport performance traits (eg, ego-orientation and mastery-orientation), social network size, physical self-worth, motivation, rehabilitation overadherence, mental toughness and playing through pain, as well as injury severity and functional recovery outcomes. Findings pertaining to the association that an injury (as an exposure) had on athletic identity (as an outcome) were inconsistent and limited.Conclusions Athletic identity was most frequently associated with psychosocial, behavioural and injury-specific outcomes. Future research should seek to include diverse athlete samples (eg, women, athletes of different races, para-athletes) and should continue to reference theoretical injury models to inform study methodologies and to specify variables of interest for further exploration

Neurofeedback as a form of cognitive rehabilitation therapy following stroke: A systematic review

<div><p>Neurofeedback therapy (NFT) has been used within a number of populations however it has not been applied or thoroughly examined as a form of cognitive rehabilitation within a stroke population. Objectives for this systematic review included: i) identifying how NFT is utilized to treat cognitive deficits following stroke, ii) examining the strength and quality of evidence to support the use of NFT as a form of cognitive rehabilitation therapy (CRT) and iii) providing recommendations for future investigations. Searches were conducted using OVID (Medline, Health Star, Embase + Embase Classic) and PubMed databases. Additional searches were completed using the Cochrane Reviews library database, Google Scholar, the University of Toronto online library catalogue, ClinicalTrials.gov website and select journals. Searches were completed Feb/March 2015 and updated in June/July/Aug 2015. Eight studies were eligible for inclusion in this review. Studies were eligible for inclusion if they: i) were specific to a stroke population, ii) delivered CRT via a NFT protocol, iii) included participants who were affected by a cognitive deficit(s) following stroke (i.e. memory loss, loss of executive function, speech impairment etc.). NFT protocols were highly specific and varied within each study. The majority of studies identified improvements in participant cognitive deficits following the initiation of therapy. Reviewers assessed study quality using the Downs and Black <i>Checklist for Measuring Study Quality</i> tool; limited study quality and strength of evidence restricted generalizability of conclusions regarding the use of this therapy to the greater stroke population. Progression in this field requires further inquiry to strengthen methodology quality and study design. Future investigations should aim to standardize NFT protocols in an effort to understand the dose-response relationship between NFT and improvements in functional outcome. Future investigations should also place a large emphasis on long-term participant follow-up.</p></div

Study design & participants.

<p>Study design & participants.</p

Downs & Black Critical Appraisal Score & Oxford Level of Evidence.

<p>Downs & Black Critical Appraisal Score & Oxford Level of Evidence.</p