Abstract
Traditional epitranscriptomics relies on capturing a single RNA modification by antibody or chemical treatment, combined with short-read sequencing to identify its transcriptomic location. ...This approach is labor-intensive and may introduce experimental artifacts. Direct sequencing of native RNA using Oxford Nanopore Technologies (ONT) can allow for directly detecting the RNA base modifications, although these modifications might appear as sequencing errors. The percent Error of Specific Bases (%ESB) was higher for native RNA than unmodified RNA, which enabled the detection of ribonucleotide modification sites. Based on the %ESB differences, we developed a bioinformatic tool, epitranscriptional landscape inferring from glitches of ONT signals (ELIGOS), that is based on various types of synthetic modified RNA and applied to rRNA and mRNA. ELIGOS is able to accurately predict known classes of RNA methylation sites (AUC > 0.93) in rRNAs from Escherichiacoli, yeast, and human cells, using either unmodified in vitro transcription RNA or a background error model, which mimics the systematic error of direct RNA sequencing as the reference. The well-known DRACH/RRACH motif was localized and identified, consistent with previous studies, using differential analysis of ELIGOS to study the impact of RNA m6A methyltransferase by comparing wild type and knockouts in yeast and mouse cells. Lastly, the DRACH motif could also be identified in the mRNA of three human cell lines. The mRNA modification identified by ELIGOS is at the level of individual base resolution. In summary, we have developed a bioinformatic software package to uncover native RNA modifications.
Novel findings in microbiology question the long‐standing paradigm that a healthy pregnancy implies a sterile uterus. It now seems that the placenta is frequently colonized with bacteria, and a ...placental microbiome has been identified. Recent literature findings are summarized here, and an attempt is made to separate pathological bacterial presence from a naturally occurring microbiome.
There is increasing interest in factors that may modulate white matter (WM) breakdown and, consequentially, age-related cognitive and behavioral deficits. Recent diffusion tensor imaging studies have ...examined the relationship of such factors with WM microstructure. This review summarizes the evidence regarding the relationship between WM microstructure and recognized modifiable factors, including hearing loss, hypertension, diabetes, obesity, smoking, depressive symptoms, physical (in) activity, and social isolation, as well as sleep disturbances, diet, cognitive training, and meditation. Current cross-sectional evidence suggests a clear link between loss of WM integrity (lower fractional anisotropy and higher mean diffusivity) and hypertension, obesity, diabetes, and smoking; a relationship that seems to hold for hearing loss, social isolation, depressive symptoms, and sleep disturbances. Physical activity, cognitive training, diet, and meditation, on the other hand, may protect WM with aging. Preliminary evidence from cross-sectional studies of treated risk factors suggests that modification of factors could slow down negative effects on WM microstructure. Careful intervention studies are needed for this literature to contribute to public health initiatives going forward.
•Both aging and dementia are associated with breakdown of white matter (WM) microstructure.•We review a range of modifiable factors that could prevent or slow age-related WM decline.•Risk factors are consistently related with lower fractional anisotropy and higher mean diffusivity.•Treatment of risk factors may slow WM decline.•Careful longitudinal and intervention studies are now needed.
Aims
The current Monkeypox virus (MPX) outbreak is not only the largest known outbreak to date caused by a strain belonging to the West‐African clade, but also results in remarkably different ...clinical and epidemiological features compared to previous outbreaks of this virus. Here, we consider the possibility that mutations in the viral genome may be responsible for its changed characteristics.
Methods and Results
Six genome sequences of isolates from the current outbreak were compared to five genomes of isolates from the 2017 outbreak in Nigeria and to two historic genomes, all belonging to the West‐African clade. We report differences that are consistently present in the 2022 isolates but not in the others. Although some variation in repeat units was observed, only two were consistently found in the 2022 genomes only, and these were located in intergenic regions. A total of 55 single nucleotide polymorphisms were consistently present in the 2022 isolates compared to the 2017 isolates. Of these, 25 caused an amino acid substitution in a predicted protein.
Conclusions
The nature of the substitution and the annotation of the affected protein identified potential candidates that might affect the virulence of the virus. These included the viral DNA helicase and transcription factors.
Significance
This bioinformatic analysis provides guidance for wet‐lab research to identify changed properties of the MPX.
International and national committees have started to evaluate the evidence for the effects of physical activity on neurocognitive health in childhood and adolescence to inform policy. Despite an ...increasing body of evidence, such reports have shown mixed conclusions. We aimed to critically evaluate and synthesise the evidence for the effects of chronic physical activity on academic achievement, cognitive performance and the brain in children and adolescents in order to guide future research and inform policy. MedLine, Embase, PsycINFO, Cochrane Library, Web of Science, and ERIC electronic databases were searched from inception to February 6th, 2019. Articles were considered eligible for inclusion if they were systematic reviews with or without meta-analysis, published in peer-reviewed (English) journals. Reviews had to be on school-aged children and/or adolescents that reported on the effects of chronic physical activity or exercise interventions, with cognitive markers, academic achievement or brain markers as outcomes. Reviews were selected independently by two authors and data were extracted using a pre-designed data extraction template. The quality of reviews was assessed using AMSTAR-2 criteria. Of 908 retrieved, non-duplicated articles, 19 systematic reviews met inclusion criteria. One high-quality review reported inconsistent evidence for physical activity-related effects on cognitive- and academic performance in obese or overweight children and adolescents. Eighteen (critically) low-quality reviews presented mixed favourable and null effects, with meta-analyses showing small effect sizes (0.1-0.3) and high heterogeneity. Low-quality reviews suggested physical activity-related brain changes, but lacked an interpretation of these findings. Systematic reviews varied widely in their evidence synthesis, rarely took intervention characteristics (e.g. dose), intervention fidelity or study quality into account and suspected publication bias. Reviews consistently reported that there is a lack of high-quality studies, of studies that include brain imaging outcomes, and of studies that include adolescents or are conducted in South American and African countries. Inconsistent evidence exists for chronic physical activity-related effects on cognitive-, academic-, and brain outcomes. The field needs to refocus its efforts towards improving study quality, transparency of reporting and dissemination, and is urged to differentiate between intervention characteristics for its findings to have a meaningful impact on policy.
To establish the prevalence of osteoporosis, vertebral fractures (VFs), and non-VFs in acromegaly patients with long-term controlled disease and factors potentially influencing fracture risk.
...Case-control study. Patients and measurements Eighty-nine patients (46% male, mean age: 58 years) were included. We studied VFs and non-VFs, bone mineral density (BMD), and markers of bone turnover. In 48 patients, BMD assessment was also obtained 7 years prior to the current study. To compare VF prevalence, data from a sample of the Dutch population (n=3469) were used.
VF prevalence was 59% (men 64% and women 54%), significantly increased when compared with controls (odds ratio up to 6.5), and independent of the duration of disease control, BMD, markers of bone turnover, and acromegalic disease characteristics. Mean number of VFs per patient was 3.4±0.3 (range 1-8). There was no relationship between the number and severity of fractures, parameters of bone turnover, and follow-up BMD measurements. BMD did not change during prolongation of follow-up by 7 years of controlled acromegaly.
There is a very high prevalence of VFs in acromegaly patients with long-term controlled disease, independently of BMD. In view of the significant morbidity and mortality associated with VFs in general and the inability of BMD to predict fracture risk in acromegalic patients, we propose to include VF assessment, for example by lateral conventional radiographs of the spine in the screening of patients with acromegaly, both at diagnosis and during follow-up after establishment of disease control.
The reported numbers of Covid‐19 cases and deaths were compared for 18 countries (14 in Western Europe, plus Australia, Brazil, Israel and the USA) to assess the effect of historic and current ...national BCG immunizations. In view of the high death rate for Covid‐19 patients over 70 years of age, and given the fact that BCG vaccination is typically given early in life, we compared countries that had introduced BCG in the 1950s with those that had not. No effect on Covid‐19 case fatality rate (CFR) or number of deaths per population could be demonstrated. Since some countries test for Covid‐19 more than others, the effect of tests performed per million population on reported deaths per million was also assessed, but again did not demonstrate an effect of BCG vaccination in the 1950s. Whether countries had never used the vaccine, had historically used it but since ceased to do so, or were presently vaccinating with BCG did not correlate with national total number of deaths or CFR. We conclude that there is currently no evidence for a beneficial effect of BCG vaccination on Covid‐19 reported cases or fatalities.
Significance and Impact of the Study: It has been suggested in the recent literature that some countries have lower case rates or death rates of Covid‐19 as a result of large‐scale BCG vaccination programs. This has resulted in the initiation of clinical trials to assess if the vaccine can act as a prophylactic or ameliorate the disease. However, by comparing countries that are well into the epidemic and have different (current or past) BCG vaccination practices, we conclude that there is currently no compelling evidence of any such protective effect.
Physical activity (PA) may positively stimulate the brain, cognition and mental health during adolescence, a period of dynamic neurobiological development. High-intensity interval training (HIIT) or ...vigorous PA interventions are time-efficient, scalable and can be easily implemented in existing school curricula, yet their effects on cognitive, academic and mental health outcomes are unclear. The primary aim of the Fit to Study trial was to investigate whether a pragmatic and scalable HIIT-style VPA intervention delivered during school physical education (PE) could improve attainment in maths. The primary outcome has previously been reported and was null. Here, we report the effect of the intervention on prespecified secondary outcomes, including cardiorespiratory fitness, cognitive performance, and mental health in young adolescents.
The Fit to Study cluster randomised controlled trial included Year 8 pupils (n = 18,261, aged 12-13) from 104 secondary state schools in South/Mid-England. Schools were randomised into an intervention condition (n = 52), in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year (2017-2018), or into a "PE as usual" control condition. Secondary outcomes included assessments of cardiorespiratory fitness (20-m shuttle run), cognitive performance (executive functions, relational memory and processing speed) and mental health (Strength and Difficulties Questionnaire and self-esteem measures). The primary intention-to-treat (ITT) analysis used linear models and structural equation models with cluster-robust standard errors to test for intervention effects. A complier-average causal effect (CACE) was estimated using a two-stage least squares procedure.
The HIIT-style VPA intervention did not significantly improve cardiorespiratory fitness, cognitive performance (executive functions, relational memory or processed speed), or mental health (all p > 0.05). Subgroup analyses showed no significant moderation of intervention effects by sex, socioeconomic status or baseline fitness levels. Changes in cardiorespiratory fitness were not significantly related to changes in cognitive or mental health outcomes. The trial was marked by high drop-out and low intervention compliance. Findings from the CACE analysis were in line with those from the ITT analysis.
The one-academic year HIIT-style VPA intervention delivered during regular school PE did not significantly improve fitness, cognitive performance or mental health, but these findings should be interpreted with caution given low implementation fidelity and high drop-out. Well-controlled, large-scale, school-based trials that examine the effectiveness of HIIT-style interventions to enhance cognitive and mental health outcomes are warranted.
ISRCTN registry, 15,730,512 . Trial protocol and analysis plan for primary outcome prospectively registered on 30th March 2017. ClinicalTrials.gov , NCT03286725 . Secondary measures (focus of current manuscript) retrospectively registered on 18 September 2017.
Early adolescence is a period of dynamic neurobiological change. Converging lines of research suggest that regular physical activity (PA) and improved aerobic fitness have the potential to stimulate ...positive brain changes, improve cognitive function and boost academic attainment in this age group, but high-quality studies are needed to substantiate these findings. The primary aim of the Fit to Study trial is to investigate whether short infusions of vigorous PA (VPA) delivered during secondary school physical education (PE) can improve attainment in maths, as described in a protocol published by NatCen Social Research. The present protocol concerns the trial's secondary outcome measures, which are variables thought to moderate or mediate the relationship between PA and attainment, including the effect of the intervention on cardiorespiratory fitness, cognitive performance, mental health and brain structure and function.
The Fit to Study project is a cluster-randomised controlled trial that includes Year 8 pupils (aged 12-13) from secondary state schools in South/Mid-England. Schools were randomised into an intervention condition in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year, or a 'PE as usual' control condition. Intervention and control groups were stratified according to whether schools were single-sex or co-educational. Assessments take place at baseline (end of Year 7, aged 11-12) and after 12 months (Year 8). Secondary outcomes are cardiorespiratory fitness, objective PA during PE, cognitive performance and mental health. The study also includes exploratory measures of daytime sleepiness, attitudes towards daily PA and PE enjoyment. A sub-set of pupils from a sub-set of schools will also take part in a brain imaging sub-study, which is embedded in the trial.
The Fit to Study trial could advance our understanding of the complex relationships between PA and aerobic fitness, the brain, cognitive performance, mental health and academic attainment during adolescence. Further, it will add to our understanding of whether school PE is an effective setting to increase VPA and fitness, which could inform future PA interventions and education policy.
ClinicalTrials.gov, NCT03286725 . Retrospectively registered on 18 September 2017. ClinicalTrials.gov, NCT03593863 . Retrospectively registered on 19 July 2018.
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