Biomolecular simulation is increasingly central to understanding and designing biological molecules and their interactions. Detailed, physics‐based simulation methods are demonstrating rapidly ...growing impact in areas as diverse as biocatalysis, drug delivery, biomaterials, biotechnology, and drug design. Simulations offer the potential of uniquely detailed, atomic‐level insight into mechanisms, dynamics, and processes, as well as increasingly accurate predictions of molecular properties. Simulations can now be used as computational assays of biological activity, for example, in predictions of drug resistance. Methodological and algorithmic developments, combined with advances in computational hardware, are transforming the scope and range of calculations. Different types of methods are required for different types of problem. Accurate methods and extensive simulations promise quantitative comparison with experiments across biochemistry. Atomistic simulations can now access experimentally relevant timescales for large systems, leading to a fertile interplay of experiment and theory and offering unprecedented opportunities for validating and developing models. Coarse‐grained methods allow studies on larger length‐ and timescales, and theoretical developments are bringing electronic structure calculations into new regimes. Multiscale methods are another key focus for development, combining different levels of theory to increase accuracy, aiming to connect chemical and molecular changes to macroscopic observables. In this review, we outline biomolecular simulation methods and highlight examples of its application to investigate questions in biology.
This article is categorized under:
Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods
Structure and Mechanism > Computational Biochemistry and Biophysics
Molecular and Statistical Mechanics > Free Energy Methods
Biomolecular simulations reveal mechanisms, dynamics, and interactions of biological molecules. Here, molecular dynamics simulation of the enzyme MalL reveal structural and dynamical changes in the protein during its catalytic cycle; these simulations allow calculation of the activation heat capacity that explains the optimum temperature of its catalytic activity.
Background:
Sports-related concussion (SRC) assessment tools are primarily based on subjective assessments of somatic, cognitive, and psychosocial/emotional symptoms. SRC symptoms remain ...underreported, and objective measures of SRC impairments would be valuable to assist diagnosis. Measurable impairments to vestibular and oculomotor processing have been shown to occur after SRC and may provide valid objective assessments.
Purpose:
Determine the diagnostic accuracy of sideline tests of vestibular and oculomotor dysfunction to identify SRC in adults.
Study Design:
Systematic review; Level of evidence, 4.
Methods:
Electronic databases and gray literature were searched from inception until February 12, 2020. Physically active individuals (>16 years of age) who participated in sports were included. The reference standard for SRC was a combination of clinical signs and symptoms (eg, the Sport Concussion Assessment Tool SCAT), and index tests included any oculomotor assessment tool. The QUADAS tool was used to assess risk of bias, with the credibility of the evidence being rated according to GRADE.
Results:
A total of 8 studies were included in this review. All included studies used the King-Devick test, with no other measures being identified. Meta-analysis was performed on 4 studies with a summary sensitivity and specificity of 0.77 and 0.82, respectively. The overall credibility of the evidence was rated as very low.
Conclusion:
Caution must be taken when interpreting these results given the very low credibility of the evidence, and the true summary sensitivity and specificity may substantially differ from the values calculated within this systematic review. Therefore, we recommend that clinicians using the King-Devick test to diagnose SRC in adults do so in conjunction with other tools such as the SCAT.
PROSPERO Registration:
CRD42018106632.
Neurodegenerative disorders are associated with impaired cognitive function and worse physical health outcomes. This study aims to test whether polygenic risk for Alzheimer's disease, Amyotrophic ...Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) is associated with cognitive function and physical health in the UK Biobank, a cohort of healthy individuals. Group-based analyses were then performed to compare the top and bottom 10% for the three neurodegenerative polygenic risk scores; these groups were compared on the cognitive and physical health variables. Higher polygenic risk for AD, ALS, and FTD was associated with lower cognitive performance. Higher polygenic risk for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS. The results suggest some overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Life course air pollution exposure and biological ageing markers were investigated in 525 older adults.•Young-to-middle adulthood exposure was associated with higher Horvath DNAmAge.•In males, air ...pollution in middle adulthood was linked to shorter DNAm telomere length.•Air pollution around birth was associated with shorter DNAm telomere length among females.
Exposure to air pollution is associated with a range of diseases. Biomarkers derived from DNA methylation (DNAm) offer potential mechanistic insights into human health differences, connecting disease pathogenesis and biological ageing. However, little is known about sensitive periods during the life course where air pollution might have a stronger impact on DNAm, or whether effects accumulate over time. We examined associations between air pollution exposure across the life course and DNAm-based markers of biological ageing.
Data were derived from the Scotland-based Lothian Birth Cohort 1936. Participants’ residential history was linked to annual levels of fine particle (PM2.5), sulphur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) around 1935, 1950, 1970, 1980, 1990, and 2001; pollutant concentrations were estimated using the EMEP4UK atmospheric chemistry transport model. Blood samples were obtained between ages of 70 and 80 years, and Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, DNAmGrimAge, and DNAm telomere length (DNAmTL) were computed. We applied the structured life-course modelling approach: least angle regression identified best-fit life-course models for a composite measure of air pollution (air quality index AQI), and mixed-effects regression estimated selected models for AQI and single pollutants.
We included 525 individuals with 1782 observations. In the total sample, increased air pollution around 1970 was associated with higher epigenetic age (AQI: b = 0.322 year, 95 %CI: 0.088, 0.555) measured with Horvath DNAmAge in late adulthood. We found shorter DNAmTL among males with higher air pollution around 1980 (AQI: b = −0.015 kilobase, 95 %CI: −0.027, −0.004) and among females with higher exposure around 1935 (AQI: b = −0.017 kilobase, 95 %CI: −0.028, −0.006). Findings were more consistent for the pollutants PM2.5, SO2 and NO2.
We tested the life-course relationship between air pollution and DNAm-based biomarkers. Air pollution around birth and in young-to-middle adulthood is linked to accelerated epigenetic ageing and telomere-associated ageing in later life.
The overuse of disposable plastic bags is a major environmental problem across the globe. In recent years, numerous jurisdictions have sought to curb disposable bag use by implementing a levy or fee ...at the point of purchase. These levies are typically small and symbolic (around $0.05 per bag), but serve as a highly-visible and continuous reminder to consumers. As such, they are consistent with nudging policies that seek to encourage broad changes in behaviour through small, non-coercive measures that influence people's thinking about an issue. While existing empirical evidence suggests that nudges are highly effective in reducing disposable bag use, we argue that many of these studies are flawed because they lack adequate temporal and geographic controls. We use longitudinal data from four waves of a major Canadian survey to analyze the effect of a disposable bag levy in the City of Toronto. Controlling for demographics and changes in social norms over time, we find that the levy increased the use of reusable shopping bags by 3.4 percentage points. Moreover, we find that the impact of the policy was highly variable across behavioural and demographic groups. The levy was highly effective in encouraging people who already used reusable bags to use them more frequently, while having no effect on infrequent users. We also find that the effects are limited to households with high socio-economic status (as measured by income, educational attainment, and housing situation). This suggests important limitations for nudging policy more generally, as people with lower socio-economic status appear to have been unaffected by this behavioural prompt.
•Nudging policy has become popular as a non-coercive way to promote change.•We investigate the effects of an economic nudge on reusable shopping bag use.•The difference-in-difference analysis yields a smaller effect than other studies.•The effects of nudging are highly unequal, particularly across social classes.•This suggests limitations for nudging policy more generally.
The mechanical failure of mature amyloid fibers produces fragments that act as seeds for the growth of new fibrils. Fragmentation may also be correlated with cytotoxicity. We have used steered ...atomistic molecular dynamics simulations to study the mechanical failure of fibrils formed by the amyloidogenic fragment of human amylin hIAPP20-29 subjected to force applied in a variety of directions. By introducing systematic variations to this peptide sequence in silico, we have also investigated the role of the amino-acid sequence in determining the mechanical stability of amyloid fibrils. Our calculations show that the force required to induce mechanical failure depends on the direction of the applied stress and upon the degree of structural order present in the β-sheet assemblies, which in turn depends on the peptide sequence. The results have implications for the importance of sequence-dependent mechanical properties on seeding the growth of new fibrils and the role of breakage events in cytotoxicity.
Conspectus Magnetic resonance imaging (MRI) has emerged over the years as one of the preferred modalities for medical diagnostic and biomedical research. It has the advantage over other imaging ...modalities such as positron emission tomography and X-ray of affording high resolution three-dimensional images of the body without using harmful radiation. The use of contrast agents has further expanded this technique by increasing the contrast between regions where they accumulate and background tissues. As MRI most often measures the relaxation rate of water throughout the body, contrast agents function by modulating the intensity of the water signal either via improved relaxation or via saturation transfer to selected exchangeable proton. Among the growing class of MRI contrast agents, a subset of them called “smart” contrast agents function as responsive probes. Their ability to increase or decrease their signal intensity is modulated by the presence of an analyte. These probes offer the unique ability to image the distribution of an analyte in vivo, thereby opening new possibilities for diagnostics and for elucidating the role of specific analytes in various pathologies or biological processes. A number of different strategies can be exploited to design responsive MRI contrast agents. The majority of contrast agents are based on GdIII complexes. These complexes can be rendered responsive in either of two ways: either by modulating the number of inner-sphere water molecules, q, or via modulating the rotational correlation time, τR, of the contrast agent upon substrate binding. The longitudinal relaxivity increases with the number of inner-sphere water molecules. GdIII complexes can be rendered responsive if they contain a recognition moiety that can bind to both the open coordination site of GdIII and to the analyte. When the recognition moiety leaves the lanthanide ion to bind to the analyte, q increases and therefore so does the relaxivity. The dependence of relaxivity on rotational correlation time is more complex and more pronounced at lower magnetic fields. In general, slower tumbling macromolecules have longer rotational correlation times and higher relaxivities. Analyte-triggered formation of macromolecules thus also increases relaxivity. Such macromolecules can either be analyte-templated supramolecular assemblies, or analyte-enhanced protein-contrast agent complexes. Chemical Exchange Saturation Transfer (CEST) agents are a newer class of contrast agents that offer the possibility of multifrequency and thus ratiometric imaging, which in turn enables quantitative mapping of the concentration of an analyte in vivo under conditions where the concentration of the contrast agent is not known. Such agents can be rendered responsive if the analyte changes the number of exchangeable proton(s), its exchange rate, or its chemical shift. All of these approaches have been successfully employed for detecting and imaging both copper and zinc, including in vivo. Magnetic Iron Oxide Nanoparticles (MIONs) are powerful MRI transverse relaxation agents. They can also be rendered responsive to an analyte if the latter can control the aggregation of the nanoparticles. For metal ions, this can be achieved via chemical functionalities that only react to form conjugates in the presence of the metal ion analyte.
Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire ...age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (
-0.75 for DNAmTL versus
-0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL
. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.
The current economic climate demands more innovative approaches to increasing labor market participation for people with disabilities. Social entrepreneurship (SE) offers one alternative employment ...pathway. However, little is known about the broader factors influencing SE for people with disabilities. Using empirical data from focus groups comprised of social entrepreneurs with disabilities and interviews with key stakeholders working in the fields of policy, disability, and business, this research frames its analysis in the intersection of disability studies and entrepreneurship to explore which factors influence the potential for SE to provide equal participation opportunities for people with disabilities in the labor market. Findings suggest that further consideration of political-economic and socio-cultural factors is needed if we are to better understand the potential of SE for people with disabilities.
To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive ...outcomes.
At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation-serum C-reactive protein (CRP)-and an epigenetic measure (DNA methylation DNAm signature of CRP). Linear models were used to examine the inflammation-brain health associations; mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning.
We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = -0.197, 95% confidence interval CI -0.28 to -0.12,
= 8.42 × 10
), gray matter volume (β = -0.200, 95% CI -0.28 to -0.12,
= 1.66 × 10
), and white matter volume (β = -0.150, 95% CI -0.23 to -0.07,
= 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP-cognitive association (up to 29.7%), dependent on lifestyle and health factors.
These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status.
This study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.
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