Search

The biomedical sciences must maintain and enhance a research culture that prioritizes rigour and transparency. The US National Institute of Neurological Disorders and Stroke convened a workshop entitled Catalyzing Communities of Research Rigor Champions that brought together a diverse group of leaders in promoting research rigour and transparency (identified as rigour champions) to discuss strategies, barriers and resources for catalyzing technical, cultural and educational changes in the biomedical sciences. This article summarizes 2 days of panels and discussions and provides an overview of critical barriers to research rigour, perspectives behind reform initiatives and considerations for stakeholders across science. Additionally, we describe applications of network science to foster, maintain and expand cultural changes related to scientific rigour and opportunities to embed rigourous practices into didactic courses, training experiences and degree programme requirements. We hope this piece provides a primer for the wider research community on current discussions and actions and inspires individuals to build, join or expand collaborative networks within their own institutions that prioritize rigourous research practices.

O autor reexamina a crítica de Derrida à fenomenologia de Husserl de forma a mostrar como a sua coerência estrutural emerge não tanto de uma redução a uma doutrina particular mas antes das exigências de uma concepção unitária, especificamente impostas pelas determinações epistemológicas e metafísicas da presença

BackgroundMitochondrial DNA (mtDNA) deletion mutations lead to electron transport chain-deficient cells and age-induced cell loss in multiple tissues and mammalian species. Accurate quantitation of somatic mtDNA deletion mutations could serve as an index of age-induced cell loss. Quantitation of mtDNA deletion molecules is confounded by their low abundance in tissue homogenates, the diversity of deletion breakpoints, stochastic accumulation in single cells, and mosaic distribution between cells.AimsTranslate a pre-clinical assay to quantitate mtDNA deletions for use in human DNA samples, with technical and biological validation, and test this assay on human subjects of different ages.MethodsWe developed and validated a high-throughput droplet digital PCR assay that quantitates human mtDNA deletion frequency.ResultsAnalysis of human quadriceps muscle samples from 14 male subjects demonstrated that mtDNA deletion frequency increases exponentially with age-on average, a 98-fold increase from age 20-80. Sequence analysis of amplification products confirmed the specificity of the assay for human mtDNA deletion breakpoints. Titration of synthetic mutation mixtures found a lower limit of detection of at least 0.6 parts per million. Using muscle DNA from 6-month-old mtDNA mutator mice, we measured a 6.4-fold increase in mtDNA deletion frequency (i.e., compared to wild-type mice), biologically validating the approach.Discussion/conclusionsThe exponential increase in mtDNA deletion frequency is concomitant with the known muscle fiber loss and accelerating mortality that occurs with age. The improved assay permits the accurate and sensitive quantification of deletion mutations from DNA samples and is sufficient to measure changes in mtDNA deletion mutation frequency in healthy individuals across the lifespan and, therefore, patients with suspected mitochondrial diseases.

Mitochondrial DNA (mtDNA) quality and quantity relate to two hallmarks of aging-genomic instability and mitochondrial dysfunction. Physical performance relies on mitochondrial integrity and declines with age, yet the interactions between mtDNA quantity, quality, and physical performance are unclear. Using a validated digital PCR assay specific for mtDNA deletions, we tested the hypothesis that skeletal muscle mtDNA deletion mutation frequency (i.e., a measure of mtDNA quality) or mtDNA copy number predicts physical performance in older adults. Total DNA was isolated from vastus lateralis muscle biopsies and used to quantitate mtDNA copy number and mtDNA deletion frequency by digital PCR. The biopsies were obtained from a cross-sectional cohort of 53 adults aged 50 to 86 years. Before the biopsy procedure, physical performance measurements were collected, including VO2max, modified physical performance test score, 6-min walk distance, gait speed, grip strength, and total lean and leg mass. Linear regression models were used to evaluate the relationships between age, sex, and the outcomes. We found that mtDNA deletion mutation frequency increased exponentially with advancing age. On average from ages 50 to 86, deletion frequency increased from 0.008 to 0.15%, an 18-fold increase. Females may have lower deletion frequencies than males at older ages. We also measured declines in VO2max and mtDNA copy number with age in both sexes. The mtDNA deletion frequency measured from single skeletal muscle biopsies predicted 13.3% of the variation in VO2max. Copy number explained 22.6% of the variation in mtDNA deletion frequency and 10.4% of the lean mass variation. We found predictive relationships between age, mtDNA deletion mutation frequency, mtDNA copy number, and physical performance. These data are consistent with a role for mitochondrial function and genome integrity in maintaining physical performance with age. Analyses of mtDNA quality and quantity in larger cohorts and longitudinal studies could extend our understanding of the importance of mitochondrial DNA in human aging and longevity.

Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) 'recognizes' H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-L-lysine-binding 'cage' formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH-H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH 'reader'.

ObjectiveThis randomized trial experimentally manipulated social status to assess effects on acute eating behavior and 24-hour energy balance.MethodsParticipants (n = 133 Hispanics; age 15-21 years; 60.2% females) were randomized to low social status ("LOW") or high social status ("HIGH") conditions in a rigged game of Monopoly (Hasbro, Inc.). Acute energy intake in a lunchtime meal was measured by food scales. Twenty-four-hour energy balance was assessed via summation of resting metabolic rate (metabolic cart), physical activity energy expenditure (accelerometer), thermic effect of food, and subtraction of twenty-four-hour energy intake (food diary).ResultsIn the total sample, no significant differences were observed by study condition at lunchtime. LOW females consumed a greater percent of lunchtime daily energy needs (37.5%) relative to HIGH females (34.3%); however, this difference was not statistically significant (P = 0.291). In males, however, LOW consumed significantly less (36.5%) of their daily energy needs relative to HIGH males (45.8%; P = 0.001). For 24-hour energy balance, sex differences were nearly significant (P = 0.057; LOW females: surplus +200 kcal; HIGH males: surplus +445 kcal). Food-insecure individuals consumed a nearly significant greater lunchtime percent daily energy than those with food security (40.7% vs. 36.3%; P = 0.0797).ConclusionsThe data demonstrate differential acute and 24-hour eating behavior responses between Hispanic male and female adolescents in experimentally manipulated conditions of low social status.

The age-induced, exponential accumulation of mitochondrial DNA (mtDNA) deletion mutations contributes to muscle fiber loss. The causes of these mutations are not known. Systemic inflammation is associated with decreased muscle mass in older adults and is implicated in the formation of sporadic mtDNA deletions. Macrophage migration inhibitory factor knockout (MIF-KO) mice are long-lived with decreased inflammation. We hypothesized that aged MIF-KO mice would have lower mtDNA deletion frequencies and fewer electron transport chain (ETC) deficient fibers. We measured mtDNA copy number and mutation frequency as well as the number and length of ETC deficient fibers in 22-month old MIF-KO and F2 hybrid control mice. We also measured mtDNA copy number and deletion frequency in female UM-HET3 mice, a strain whose lifespan matches the MIF-KO mice. We did not observe a significant effect of MIF ablation on muscle mtDNA deletion frequency. There was a significantly lower mtDNA copy number in the MIF-KO mice and the lifespan-matched UM-HET3 mice compared to the F2 hybrids, suggesting the importance of genetic background in mtDNA copy number control. Our data do not support a definitive role for MIF in age-induced mtDNA deletions.

A Scientific Integrity Consortium developed a set of recommended principles and best practices that can be used broadly across scientific disciplines as a mechanism for consensus on scientific integrity standards and to better equip scientists to operate in a rapidly changing research environment. The two principles that represent the umbrella under which scientific processes should operate are as follows: (1) Foster a culture of integrity in the scientific process. (2) Evidence-based policy interests may have legitimate roles to play in influencing aspects of the research process, but those roles should not interfere with scientific integrity. The nine best practices for instilling scientific integrity in the implementation of these two overarching principles are (1) Require universal training in robust scientific methods, in the use of appropriate experimental design and statistics, and in responsible research practices for scientists at all levels, with the training content regularly updated and presented by qualified scientists. (2) Strengthen scientific integrity oversight and processes throughout the research continuum with a focus on training in ethics and conduct. (3) Encourage reproducibility of research through transparency. (4) Strive to establish open science as the standard operating procedure throughout the scientific enterprise. (5) Develop and implement educational tools to teach communication skills that uphold scientific integrity. (6) Strive to identify ways to further strengthen the peer review process. (7) Encourage scientific journals to publish unanticipated findings that meet standards of quality and scientific integrity. (8) Seek harmonization and implementation among journals of rapid, consistent, and transparent processes for correction and/or retraction of published papers. (9) Design rigorous and comprehensive evaluation criteria that recognize and reward the highest standards of integrity in scientific research.

Wearable devices such as the ActiGraph are now commonly used in research to monitor or track physical activity. This trend corresponds with the growing need to assess the relationships between physical activity and health outcomes, such as obesity, accurately. Device‐based physical activity measures are best treated as functions when assessing their associations with scalar‐valued outcomes such as body mass index. Scalar‐on‐function regression (SoFR) is a suitable regression model in this setting. Most estimation approaches in SoFR assume that the measurement error in functional covariates is white noise. Violating this assumption can lead to underestimating model parameters. There are limited approaches to correcting measurement errors for frequentist methods and none for Bayesian methods in this area. We present a non‐parametric Bayesian measurement error‐corrected SoFR model that relaxes all the constraining assumptions often involved with these models. Our estimation relies on an instrumental variable allowing a time‐varying biasing factor, a significant departure from the current generalized method of moment (GMM) approach. Our proposed method also permits model‐based grouping of the functional covariate following measurement error correction. This grouping of the measurement error‐corrected functional covariate allows additional ease of interpretation of how the different groups differ. Our method is easy to implement, and we demonstrate its finite sample properties in extensive simulations. Finally, we applied our method to data from the National Health and Examination Survey to assess the relationship between wearable device‐based measures of physical activity and body mass index in adults in the United States. [ABSTRACT FROM AUTHOR]

In insects and other ectotherms, cold temperatures cause a coma resulting from loss of neuromuscular function, during which ionic and metabolic homeostasis are progressively lost. Cold adaptation improves homeostasis during cold exposure, but the ultimate targets of selection are still an open question. Cold acclimation and adaptation remodels mitochondrial metabolism in insects, suggesting that aerobic energy production during cold exposure could be a target of selection. Here, we test the hypothesis that cold adaptation improves the ability to maintain rates of aerobic energy production during cold exposure by using 31 P NMR on live flies. Using lines of Drosophila melanogaster artificially selected for fast and slow recovery from a cold coma, we show that cold exposure does not lower ATP levels and that cold adaptation does not alter aerobic ATP production during cold exposure. Cold-hardy and cold-susceptible lines both experienced a brief transition to anaerobic metabolism during cooling, but this was rapidly reversed during cold exposure, suggesting that oxidative phosphorylation was sufficient to meet energy demands below the critical thermal minimum, even in cold-susceptible flies. We thus reject the hypothesis that performance under mild low temperatures is set by aerobic ATP supply limitations in D. melanogaster, excluding oxygen and capacity limitation as a weak link in energy supply. This work suggests that the modulations to mitochondrial metabolism resulting from cold acclimation or adaptation may arise from selection on a biosynthetic product(s) of those pathways rather than selection on ATP supply during cold exposure.

Scientific progress depends on the quality and credibility of research methods. As discourse on rigor, transparency, and reproducibility joins the cacophony of nutrition information and misinformation in mass media, buttressing the real and perceived reliability of nutrition science is more important than ever. This broad topic was the focus of a 2016 plenary session, "Scientific Rigor and Competing Interests in the Nutrition Research Landscape." This article summarizes and expands on this session in an effort to increase understanding and dialogue with regard to factors that limit the real and perceived reliability of nutrition science and steps that can be taken to mitigate those factors. The end goal is to both earn and merit greater trust in nutrition science by both the scientific community and the general public. The authors offer suggestions in each of the domains of education and training, communications, research conduct, and procedures and policies to help achieve this goal. The authors emphasize the need for adequate funding to support these efforts toward greater rigor and transparency, which will be resource demanding and may require either increased research funding or the recognition that a greater proportion of research funding may need to be allocated to these tasks.