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BackgroundPerturbation-based training has shown to be effective in reducing fall-risk in people with chronic stroke (PwCS). However, most evidence comes from treadmill-based stance studies, with a lack of research focusing on training overground perturbed walking and exploring the relative contributions of the paretic and non-paretic limbs. This study thus examined whether PwCS could acquire motor adaptation and demonstrate immediate retention of fall-resisting skills following bilateral overground gait-slip perturbation training.Methods65 PwCS were randomly assigned to either (i) a training group, that received blocks of eight non-paretic (NP-S1 to NP-S8) and paretic (P-S1 to P-S8) overground slips during walking followed by a mixed block (seven non-paretic and paretic slips each interspersed with unperturbed walking trials) (NP-S9/P-S9 to NP-S15/P-S15) or (ii) a control group, that received a single non-paretic and paretic slip in random order. The assessor and training personnel were not blinded. Immediate retention was tested for the training group after a 30-minute rest break. Primary outcomes included laboratory-induced slip outcomes (falls and balance loss) and center of mass (CoM) state stability. Secondary outcomes to understand kinematic contributors to stability included recovery strategies, limb kinematics, slipping kinematics, and recovery stride length.ResultsPwCS within the training group showed reduced falls (p 0.01). On comparing the first and last training trial (S1 vs. S15), post-slip stability improved on both non-paretic and paretic slips, however, pre-slip stability improved only on the non-paretic slip (p

Defects in DNA repair pathways are a major cause of DNA damage accumulation leading to genomic instability and neurodegeneration. Efficient DNA damage repair is critical to maintain genomicstability and support cell function and viability. DNA damage results in the activation of cell death pathways, causing neuronal death in an expanding spectrum of neurological disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and spinal muscular atrophy (SMA). SMA is a neurodegenerative disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motor neurons due to low levels of the SMN protein. The molecular mechanism of selective motor neuron degeneration in SMA was unclear for about 20 years. However, several studies have identified biochemical and molecular mechanisms that may contribute to the predominant degeneration of motor neurons in SMA, including the RhoA/ROCK, the c-Jun NH2-terminal kinase (JNK), and p53-mediated pathways, which are involved in mediating DNA damage-dependent cell death. Recent studies provided insight into selective degeneration of motor neurons, which might be caused by accumulation of R-loop-mediated DNA damage and impaired non-homologous end joining (NHEJ) DNA repair pathway leading to genomic instability. Here, we review the latest findings involving R-loop-mediated DNA damage and defects in neuron-specific DNA repair mechanisms in SMA and discuss these findings in the context of other neurodegenerative disorders linked to DNA damage.

Background: As age progresses, decline in physical function predisposes older adults to high fall-risk, especially on exposure to environmental perturbations such as slips and trips. However, there is limited evidence of association between daily community ambulation, an easily modifiable factor of physical activity (PA), and fall-risk. Smartphones, equipped with accelerometers, can quantify, and display daily ambulation-related PA simplistically in terms of number of steps. If any association between daily steps and fall-risks is established, smartphones due to its convenience and prevalence could provide health professionals with a meaningful outcome measure, in addition to existing clinical measurements, to identify older adults at high fall-risk.Objective: This study aimed to explore whether smartphone-derived step data during older adults' community ambulation alone or together with commonly used clinical fall-risk measurements could predict falls following laboratory-induced real-life like slips and trips. Relationship between step data and PA questionnaire and clinical fall-risk assessments were examined as well.Methods: Forty-nine community-dwelling older adults (age 60–90 years) completed Berg Balance Scale (BBS), Activities-specific Balance Confidence scale (ABC), Timed Up-and-Go (TUG), and Physical Activity Scale for the Elderly (PASE). One-week and 1-month smartphone steps data were retrieved. Participants' 1-year fall history was noted. All participants' fall outcomes to laboratory-induced slip-and-trip perturbations were recorded. Logistic regression was performed to identify a model that best predicts laboratory falls. Pearson correlations examined relationships between study variables.Results: A model including age, TUG, and fall history significantly predicted laboratory falls with a sensitivity of 94.3%, specificity of 58.3%, and an overall accuracy of 85.1%. Neither 1-week nor 1-month steps data could predict laboratory falls. One-month steps data significantly positively correlated with BBS (r = 0.386, p = 0.006) and ABC (r = 0.369, p = 0.012), and negatively correlated with fall history (rp = −0.293, p = 0.041).Conclusion: Older participants with fall history and higher TUG scores were more likely to fall in the laboratory. No association between smartphone steps data and laboratory fall-risk was established in our study population of healthy community-dwelling older adults which calls for further studies on varied populations. Although modest, results do reveal a relationship between steps data and functional balance deficits and fear of falls.

Glioblastoma Multiforme (GBM) is the most common form of malignant brain tumor with poor prognosis. Amplification of Epidermal Growth Factor Receptor (EGFR), and mutations leading to activation of Phosphatidyl-Inositol-3 Kinase (PI3K) pathway are commonly associated with GBM. Using a previously published Drosophila glioma model generated by coactivation of PI3K and EGFR pathways [by downregulation of Pten and overexpression of oncogenic Ras] in glial cells, we showed that the Drosophila Tep1 gene (ortholog of human CD109) regulates Yki (the Drosophila ortholog of human YAP/TAZ) via an evolutionarily conserved mechanism. Oncogenic signaling by the YAP/TAZ pathway occurs in cells that acquire CD109 expression in response to the inflammatory environment induced by radiation in clinically relevant models. Further, downregulation of Tep1 caused a reduction in Yki activity and reduced glioma growth. A key function of Yki in larval CNS is stem cell renewal and formation of neuroblasts. Other reports suggest different upstream regulators of Yki activity in the optic lobe versus the central brain regions of the larval CNS. We hypothesized that Tep1 interacts with the Hippo pathway effector Yki to regulate neuroblast numbers. We tested if Tep1 acts through Yki to affect glioma growth, and if in normal cells Tep1 affects neuroblast number and proliferation. Our data suggests that Tep1 affects Yki mediated stem cell renewal in glioma, as reduction of Tep significantly decreases the number of neuroblasts in glioma. Thus, we identify Tep1-Yki interaction in the larval CNS that plays a key role in glioma growth and progression.

Hippo pathway was initially identified through genetic screens for genes regulating organ size in fruitflies. Recent studies have highlighted the role of Hippo signaling as a key regulator of homeostasis, and in tumorigenesis. Hippo pathway is comprised of genes that act as tumor suppressor genes like hippo (hpo) and warts (wts), and oncogenes like yorkie (yki). YAP and TAZ are two related mammalian homologs of Drosophila Yki that act as effectors of the Hippo pathway. Hippo signaling deficiency can cause YAP- or TAZ-dependent oncogene addiction for cancer cells. YAP and TAZ are often activated in human malignant cancers. These transcriptional regulators may initiate tumorigenic changes in solid tumors by inducing cancer stem cells and proliferation, culminating in metastasis and chemo-resistance. Given the complex mechanisms (e.g., of the cancer microenvironment, and the extrinsic and intrinsic cues) that overpower YAP/TAZ inhibition, the molecular roles of the Hippo pathway in tumor growth and progression remain poorly defined. Here we review recent findings from studies in whole animal model organism like Drosophila on the role of Hippo signaling regarding its connection to inflammation, tumor microenvironment, and other oncogenic signaling in cancer growth and progression.

The International Classification of Functioning, Disability and Health framework recognizes that an individual's functioning post-stroke reflects an interaction between their health condition and contextual factors encompassing personal and environmental factors. Personal factors significantly impact rehabilitation outcomes as they determine how an individual evaluates their situation and copes with their condition in daily life. A key personal factor is self-efficacy—an individual's belief in their capacity to achieve certain outcomes. Self-efficacy influences an individual's motivational state to execute behaviors necessary for achieving desired rehabilitation outcomes. Stroke rehabilitation practice and research now acknowledge self-efficacy and motivation as critical elements in post-stroke recovery, and increasing evidence highlights their contributions to motor (re)learning. Given the informative value of neuroimaging-based biomarkers in stroke, elucidating the neurological underpinnings of self-efficacy and motivation may optimize post-stroke recovery. In this review, we examine the role of self-efficacy and motivation in stroke rehabilitation and recovery, identify potential neural substrates underlying these factors from current neuroimaging literature, and discuss how leveraging these factors and their associated neural substrates has the potential to advance the field of stroke rehabilitation.