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Purpose: The purpose of this study was to evaluate a weekly school-based fruit and vegetable delivery via a mobile market on urban middle schoolers' nutrition behaviors., Design: One-group, pretest-posttest design, quasi-experimental intervention in middle schoolers (6th-8th graders, N = 158) in Kansas City, MO., Intervention: Weekly delivery of free produce via a mobile market over 12 weeks., Measures: A self-administered survey to assess self-report consumption of fruits, vegetables, soda, and sports drinks., Analysis: Univariate and bivariate analyses were used. Proportions were compared and chi-square tests were conducted to compare youth at baseline and 12 weeks., Results: More youth reported consuming fresh fruit (73.8% to 83.3%; χ 2 = 7.76, P = .005) and vegetables (66.4% to 71.3%; χ 2 = 13.55, P = <.001) from baseline to follow-up. Less youth reported soda (49.0% to 52.8%; χ 2 = 6.33, P = .012) and sports drinks (41.8% to 38.2%; χ 2 = 12.32, P < .001) from baseline to follow-up., Conclusions: A mobile produce delivery intervention, like the Healthy Harvest Mobile Market, may be an effective strategy to increase fruit and vegetable consumption for adolescents.

Falls are a critical public health issue among older adults. One notable factor contributing to falls in older adults is a deterioration of the structures supporting balance and overall balance control. Preliminary evidence suggests older adults who ride a bicycle have better balance than those who do not. Cycling may be an effective intervention to prevent falls among older adults. This study aims to objectively measure the relationship between bicycling, physical activity, and balance for older adults. Older adult cyclists (n = 19) and non-cyclists (n = 27) were recruited to (1) complete a survey that assessed demographics; (2) wear an accelerometer for 3 weeks to objectively assess physical activity; and (3) complete balance-related tasks on force platforms. Mann-Whitney U-tests were performed to detect differences in balance and physical activity metrics between cyclists and non-cyclists. Cyclists were significantly more physically active than non-cyclists. Cyclists, compared to non-cyclists, exhibited differences in balance-related temporospatial metrics and long-range temporal correlations that suggest a more tightly regulated postural control strategy that may relate to higher stability. Cycling was observed to correlate more strongly with balance outcomes than other physical activity. Taken together, these results demonstrate the possible implications for cycling as an effective intervention to improve balance and reduce fall risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Baughn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The purpose of this study is to qualitatively explore the impact of the COVID-19 pandemic on older adults' PA nearly 6 months into the pandemic. Approximately 230 interviews were conducted with a diverse sample of participants (22.1% Black and 10.8% Hispanic). Data were transcribed in fall 2020 and analyzed using NVivo 12. Overall, most older adults (54.6%) interviewed reported no change in their PA, often reporting that their work kept them active. Decreases in PA for older adults (42.7%) were attributed to little social connectedness and stay-at-home restrictions. The few reporting an increase in PA (2.6%) had more time available to be active, including setting goals while staying home. This data provides an insight on how COVID-19 impacted PA levels for older adults. These findings can inform tailored interventions to promote PA during the pandemic., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Physical activity and nutrition behaviors are important to reducing the prevalence of childhood obesity. Previous research has identified school-based interventions as effective strategies to improve physical activity and nutrition. However, the results are often mixed, and middle schoolers are an under-studied population., Objective: Our study aims to fill this gap by developing an after-school intervention to increase physical activity and fruit and vegetable consumption that is influenced by national guidelines and formative research., Methods: This study was an after-school, quasi-experimental study spanning 9 months. Enrollment began in September 2021 and continued on a rolling basis through February 2022. Weekly, middle schoolers were offered 2-3 physical activity sessions and 1 produce kit. Physical activity was measured using accelerometers and questionnaires. Nutrition behaviors were assessed using questionnaires, and physical literacy was assessed using researcher observations. Follow-up data collection occurred in December 2021 and in April 2022. Difference scores will be calculated and analyzed for each outcome variable., Results: The intervention started in September 2021 and will conclude in May 2022. Published study results are expected in late 2022., Conclusions: An increase in physical literacy, physical activity, and fruit and vegetable consumption is expected. If successful, future studies will focus on reach and sustainability. Lastly, this study may serve as a model for improving health outcomes in middle schools., International Registered Report Identifier (irrid): DERR1-10.2196/37126., (©Amanda Grimes, Joseph S Lightner, Katlyn Eighmy, Bridget D Wray, Ella Valleroy, Maya Baughn. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 04.05.2022.)

Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore proteins and C9orf72 protein in clinically related and clinically unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Of the five DPRs, only poly-GR was significantly abundant in clinically related areas compared to unrelated areas (p < 0.001), and formed dendritic-like aggregates in the motor cortex that co-localized with pTDP-43 (p < 0.0001). While most poly-GR dendritic inclusions were pTDP-43 positive, only 4% of pTDP-43 dendritic inclusions were poly-GR positive. Staining for arginine-containing poly-GR and poly-PR in nuclei of neurons produced signals that were not specific to C9 ALS. We could not detect significant differences of nuclear markers RanGap, Lamin B1, and Importin β1 in C9 ALS, although we observed subtle nuclear changes in ALS, both C9 and non-C9, compared to control. The C9orf72 protein itself was diffusely expressed in cytoplasm of large neurons and glia, and nearly 50% reduced, in both clinically related frontal cortex and unrelated occipital cortex, but not in cerebellum. In summary, sense-encoded poly-GR DPR was unique, and localized to dendrites and pTDP43 in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites.

Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat-containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-α, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.

Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue., (Copyright © 2013 Elsevier Inc. All rights reserved.)

FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive weakness from loss of motor neurons. The fundamental pathogenic mechanisms are unknown and recent evidence is implicating a significant role for abnormal exon splicing and RNA processing. Using new comprehensive genomic technologies, we studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords acquired by a rapid autopsy system that processed nervous systems specifically for genomic studies. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. We created two RNA pools, one from motor neurons collected by laser capture microdissection and one from the surrounding anterior horns. From each, we isolated RNA, amplified mRNA, profiled whole-genome exon splicing, and applied advanced bioinformatics. We employed rigorous quality control measures at all steps and validated findings by qPCR. In the motor neuron enriched mRNA pool, we found two distinct cohorts of mRNA signals, most of which were up-regulated: 148 differentially expressed genes (P