The molecular mechanisms of toxicity of chemically modified phosphorothioate antisense oligonucleotides (PS-ASOs) are not fully understood. Here, we report that toxic gapmer PS-ASOs containing ...modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2'-O-methoxyethyl (2'-MOE) bind many cellular proteins with high avidity, altering their function, localization and stability. We show that RNase H1-dependent delocalization of paraspeckle proteins to nucleoli is an early event in PS-ASO toxicity, followed by nucleolar stress, p53 activation and apoptotic cell death. Introduction of a single 2'-O-methyl (2'-OMe) modification at gap position 2 reduced protein-binding, substantially decreasing hepatotoxicity and improving the therapeutic index with minimal impairment of antisense activity. We validated the ability of this modification to generally mitigate PS-ASO toxicity with more than 300 sequences. Our findings will guide the design of PS-ASOs with optimal therapeutic profiles.
Genomes of the Mouse Collaborative Cross Srivastava, Anuj; Morgan, Andrew P; Najarian, Maya L ...
Genetics (Austin),
06/2017, Letnik:
206, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic ...stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30× coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 ± 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (>10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources.
In the spring of 2020, US schools closed to in-person teaching and sports were cancelled to control the transmission of coronavirus disease 2019 (COVID-19). It is critical to understand the mental ...and physical health of adolescent athletes during this time.
To describe the health of athletes during COVID-19-related school closures and sport cancellations.
Cross-sectional study.
A national sample recruited via social media.
A total of 13 002 US adolescent athletes (age = 16.3 ± 1.2 years, females = 52.9%, males = 47.0%) completed an anonymous online survey.
Demographic information collected was sex, grade, sport(s) played, and zip code. Assessments used were the General Anxiety Disorder 7-Item for anxiety, Patient Health Questionnaire 9-Item for depression, the Pediatric Functional Activity Brief Scale for physical activity, and the Pediatric Quality of Life Inventory 4.0 for quality of life. Mental health, physical activity, and health-related quality-of-life variables were compared among sex, grade, sport(s) played, and poverty level using means and 95% confidence intervals (CIs) from the survey-weighted analysis of variance.
Females reported a higher prevalence of moderate to severe anxiety symptoms (females = 43.7% versus males = 28.2%). The Pediatric Functional Activity Brief Scale score was highest (best) for grade 9 (mean = 14.5, 95% CI = 14.0, 15.0) and lowest for grade 11 (mean = 10.9, 95% CI = 10.5, 11.3). The prevalence of depression symptoms was highest in team sport (74.1%) and lowest in individual sport (64.9%) participants. The total Pediatric Quality of Life Inventory score was lowest (worst) for athletes from counties with the highest poverty levels (high: mean = 74.5, 95% CI = 73.7, 75.3; middle: mean = 78.9, 95% CI = 78.0, 79.8; and low: mean = 78.3, 95% CI = 77.4, 79.1).
The health of US adolescents during the COVID-19-related school closures and sport cancellations varied to differing degrees depending on sex, grade level, type of sport participation, and level of poverty. Health policy experts should consider these findings in the future when creating and implementing policies to improve the health of adolescents in the United States.
We measure the mass function for a sample of 840 young star clusters with ages between 10 and 300 Myr observed by the Panchromatic Hubble Andromeda Treasury (PHAT) survey in M31. The data show clear ...evidence of a high-mass truncation: only 15 clusters more massive than are observed, compared to the ∼100 expected for a canonical pure power-law mass function with the same total number of clusters above the catalog completeness limit. Adopting a Schechter function parameterization, we fit a characteristic truncation mass of M☉. Although previous studies have measured cluster mass function truncations, the characteristic truncation mass we measure is the lowest ever reported. Combining this M31 measurement with previous results, we find that the cluster mass function truncation correlates strongly with the characteristic star formation rate surface density of the host galaxy, where . We also find evidence that suggests the observed Mc- relation also applies to globular clusters, linking the two populations via a common formation pathway. If so, globular cluster mass functions could be useful tools for constraining the star formation properties of their progenitor host galaxies in the early universe.
Background:
Recommendations exist to encourage safe youth participation in sport. These recommendations include not specializing in 1 sport, limiting participation to less than 8 months per year, and ...limiting participation to fewer hours per week than a child’s age. However, limited evidence exists to support or refute these recommendations.
Hypothesis:
High levels of specialization will be associated with a history of injuries and especially overuse injuries, independent of age, sex, or weekly sport training hours. Athletes who exceed current sport volume recommendations will be more likely to have a history of injuries and overuse injuries.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
Youth athletes (n = 2011; 989 female and 1022 male; 12-18 years of age) completed a questionnaire regarding their specialization status, yearly and weekly sport participation volume, and injury history. Specialization was classified as low, moderate, or high using a previously utilized 3-point scale. Athletes were classified into groups based on either meeting or exceeding current volume recommendations (months per year and hours per week). Odds ratios (ORs) and 95% CIs were calculated to investigate associations of specialization and volume of participation with a history of sport-related injuries in the past year (P ≤ .05).
Results:
Highly specialized athletes were more likely to report a previous injury of any kind (P < .001; OR, 1.59; 95% CI, 1.26-2.02) or an overuse injury (P = .011; OR, 1.45; 95% CI, 1.07-1.99) in the previous year compared with athletes in the low specialization group. Athletes who played their primary sport more than 8 months of the year were more likely to report an upper extremity overuse injury (P = .04; OR, 1.68; 95% CI, 1.06-2.80) or a lower extremity overuse injury (P = .001; OR, 1.66; 95% CI, 1.22-2.30). Athletes who participated in their primary sport for more hours per week than their age (ie, a 16-year-old athlete who participated in his or her primary sport for more than 16 h/wk) were more likely to report an injury of any type (P = .001; OR, 1.34; 95% CI, 1.12-1.61) in the previous year.
Conclusion:
High levels of specialization were associated with a history of injuries, independent of age, sex, and weekly organized sport volume. Athletes who exceeded volume recommendations were more likely to have a history of overuse injuries.
Clinical Relevance:
Parents and youth athletes should be aware of the risks of specialization and excessive sport volume to maximize safe sport participation.
In spring 2020, schools closed to in-person teaching and sports were cancelled to control the transmission of COVID-19. The changes that affected the physical and mental health among young athletes ...during this time remain unknown.
To identify changes in the health (mental health, physical activity, and quality of life) of athletes that occurred during the COVID-19 pandemic.
Cross-sectional study.
Sample recruited via social media.
A total of 3243 Wisconsin adolescent athletes (age = 16.2 ± 1.2 years, 58% female) were surveyed in May 2020 (During COVID-19). Measures for this cohort were compared with previously reported data for Wisconsin adolescent athletes (n = 5231; age = 15.7 ± 1.2 years, 47% female) collected in 2016 to 2018 (PreCOVID-19).
Demographic information included sex, grade, and sport(s) played. Health assessments included the Patient Health Questionnaire-9 Item to identify depression symptoms, the Pediatric Functional Activity Brief Scale to gauge physical activity, and the Pediatric Quality of Life Inventory 4.0 to evaluate health-related quality of life. Univariable comparisons of these variables between groups were conducted via t or χ2 tests. Means and 95% CIs for each group were estimated using survey-weighted analysis-of-variance models.
Compared with preCOVID-19 participants, a larger proportion of During COVID-19 participants reported moderate to severe levels of depression (9.7% versus 32.9%, P < .001). Scores of the During COVID-19 participants were 50% lower (worse) on the Pediatric Functional Activity Brief Scale (mean 95% CI = 12.2 11.9, 12.5 versus 24.7 24.5, 24.9, P < .001) and the Pediatric Quality of Life Inventory 4.0 compared with the PreCOVID-19 participants (78.4 78.0, 78.8 versus 90.9 90.5, 91.3, P < .001).
During the COVID-19 pandemic, adolescent athletes described increased symptoms of depression, decreased physical activity, and decreased quality of life compared with adolescent athletes in previous years.
Background:
Sport specialization is associated with an increased risk of musculoskeletal lower extremity injuries (LEIs) in adolescent athletes presenting in clinical settings. However, sport ...specialization and the incidence of LEIs have not been investigated prospectively in a large population of adolescent athletes.
Purpose:
To determine if sport specialization was associated with an increased risk of LEIs in high school athletes.
Study Design:
Cohort study; Level of evidence, 2.
Methods:
Participants (interscholastic athletes in grades 9-12) were recruited from 29 Wisconsin high schools during the 2015-2016 school year. Participants completed a questionnaire identifying their sport participation and history of LEIs. Sport specialization of low, moderate, or high was determined using a previously published 3-point scale. Athletic trainers reported all LEIs that occurred during the school year. Analyses included group proportions, odds ratios (ORs) and 95% CIs, and days lost due to injury (median and interquartile range IQR). Multivariate Cox proportional hazard ratios (HRs) with 95% CIs were calculated to investigate the association between the incidence of LEIs and sport specialization level.
Results:
A total of 1544 participants (50.5% female; mean age, 16.1 ± 1.1 years) enrolled in the study, competed in 2843 athletic seasons, and participated in 167,349 athlete-exposures. Sport specialization was classified as low (59.5%), moderate (27.1%), or high (13.4%). Two hundred thirty-five participants (15.2%) sustained a total of 276 LEIs that caused them to miss a median of 7.0 days (IQR, 2.0-22.8). Injuries occurred most often to the ankle (34.4%), knee (25.0%), and upper leg (12.7%) and included ligament sprains (40.9%), muscle/tendon strains (25.4%), and tendinitis/tenosynovitis (19.6%). The incidence of LEIs for moderate participants was higher than for low participants (HR, 1.51 95% CI, 1.04-2.20; P = .03). The incidence of LEIs for high participants was higher than for low participants (HR, 1.85 95% CI, 1.12-3.06; P = .02).
Conclusion:
Athletes with moderate or high sport specialization were more likely to sustain an LEI than athletes with low specialization. Sports medicine providers need to educate coaches, parents, and interscholastic athletes regarding the increased risk of LEIs for athletes who specialize in a single sport.
New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the ...Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
The prevalence of sport specialization in high school athletes is unknown. This information is needed to determine the scope of this issue in an active population.
Purpose:
To determine ...the prevalence of sport specialization in high school athletes and to determine if specialization is influenced by classification method, year in school, sex, and school size. A secondary purpose was to determine if highly specialized athletes would be more likely to report a history of lower extremity injuries.
Study Design:
Cross-sectional study; Level of evidence, 3.
Methods:
High school athletes between the ages of 13 and 18 years from 2 local high schools completed both a sport specialization survey and an injury history survey. Athletes were classified into low, moderate, or high specialization groups using a recently developed 3-point system and were also classified using a self-classification method.
Results:
A total of 302 athletes completed the surveys and were classified as low specialization (n = 105, 34.8%), moderate specialization (n = 87, 28.8%), or high specialization (n = 110, 36.4%). Athletes from the small school were more likely to be classified in the low specialization group (low, 43%; moderate, 32%; high, 25%) compared with those from the large school (low, 26%; moderate, 26%; high, 48%) (P < .001). Athletes in the high specialization group were more likely to report a history of overuse knee injuries (n = 18) compared with moderate (n = 8) or low specialization (n = 7) athletes (P = .048). Athletes who trained in one sport for more than 8 months out of the year were more likely to report a history of knee injuries (odds ratio OR, 2.32; 95% CI, 1.22-4.44; P = .009), overuse knee injuries (OR, 2.93; 95% CI, 1.16-7.36; P = .018), and hip injuries (OR, 2.74; 95% CI, 1.09-6.86; P = .026). Using the self-classification method, more participants self-classified as multisport (n = 213, 70.5%) than single sport (n = 89, 29.5%). Athletes from the small school were more likely to classify themselves as multisport (n = 128, 86%) (P < .001) than those from the large school (n = 85, 56%). There were no differences in the history of hip, knee, or ankle injuries between athletes who self-classified as single sport (hip: n = 10, 3%; knee: n = 19, 6%; ankle: n = 35, 12%) versus those who self-classified as multisport (hip: n = 45, 8%; knee: n = 23, 15%; ankle: n = 98, 33%) (P > .370).
Conclusion:
Classification method and school size influenced the prevalence of specialization in high school athletes. Highly specialized athletes were more likely to report a history of overuse knee or hip injuries. Participating in a single sport for more than 8 months per year appeared to be an important factor in the increased injury risk observed in highly specialized athletes.
During the fall of 2020, some high schools across the United States allowed their students to participate in interscholastic sports while others cancelled or postponed their sport programs due to ...concerns regarding COVID-19 transmission. What effect this has had on the physical and mental health of adolescents is unknown.
To identify the effect of playing a sport during the COVID-19 pandemic on the health of student-athletes.
Cross-sectional study.
Sample recruited via email.
A total of 559 Wisconsin high school athletes (age = 15.7 ± 1.2 years, female = 43.6%, male = 56.4%) from 44 high schools completed an online survey in October 2020. A total of 171 (30.6%) athletes played (PLY) a fall sport, while 388 (69.4%) did not play (DNP).
Demographic data included sex, grade, and sport(s) played. Assessments were the General Anxiety Disorder-7 Item for anxiety, Patient Health Questionnaire-9 Item for depression, the Hospital for Special Surgery Pediatric Functional Activity Brief Scale for physical activity, and the Pediatric Quality of Life Inventory 4.0 for quality of life. Univariable comparisons between the 2 groups were made via t tests or χ2 tests. Means for each continuous outcome measure were compared between groups using analysis-of-variance models that controlled for age, sex, teaching method (virtual, hybrid, or in person), and the percentage of students eligible for free or reduced-price lunch.
The PLY group participants were less likely to report moderate to severe symptoms of anxiety (PLY = 6.6%, DNP = 44.1%, P < .001) and depression (PLY = 18.2%, DNP = 40.4%, P < .001). They also demonstrated higher (better) Pediatric Functional Activity Brief Scale scores (PLY = 23.2 95% CI = 22.0, 24.5, DNP = 16.4 95% CI = 15.0, 17.8, P < .001) and higher (better) Pediatric Quality of Life Inventory total scores (PLY = 88.4 95% CI = 85.9, 90.9, DNP = 79.6 95% CI = 76.8, 82.4, P < .001).
Adolescents who played a sport during the COVID-19 pandemic described fewer symptoms of anxiety and depression and had better physical activity and quality-of-life scores compared with adolescent athletes who did not play a sport.
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