205 research outputs found
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking
Simulating drug binding and unbinding is a challenge, as the rugged energy
landscapes that separate bound and unbound states require extensive sampling
that consumes significant computational resources. Here, we describe the use of
interactive molecular dynamics in virtual reality (iMD-VR) as an accurate
low-cost strategy for flexible protein-ligand docking. We outline an
experimental protocol which enables expert iMD-VR users to guide ligands into
and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease,
and recreate their respective crystallographic protein-ligand binding poses
within 5 - 10 minutes. Following a brief training phase, our studies shown that
iMD-VR novices were able to generate unbinding and rebinding pathways on
similar timescales as iMD-VR experts, with the majority able to recover binding
poses within 2.15 Angstrom RMSD of the crystallographic binding pose. These
results indicate that iMD-VR affords sufficient control for users to carry out
the detailed atomic manipulations required to dock flexible ligands into
dynamic enzyme active sites and recover crystallographic poses, offering an
interesting new approach for simulating drug docking and generating binding
hypotheses.Comment: PLOS ON
Trophic interactions modify the temperature dependence of community biomass and ecosystem function
Aquatic ecosystems worldwide continue to experience unprecedented warming and ecological change. Warming increases metabolic rates of animals, plants, and microbes, accelerating their use of energy and materials, their population growth, and interaction rates. At a much larger biological scale, warming accelerates ecosystem-level processes, elevating fluxes of carbon and oxygen between biota and the atmosphere. Although these general effects of temperature at finer and broader biological scales are widely observed, they can lead to contradictory predictions for how warming affects the structure and function of ecological communities at the intermediate scale of biological organization. We experimentally tested the hypothesis that the presence of predators and their associated species interactions modify the temperature dependence of net ecosystem oxygen production and respiration. We tracked a series of independent freshwater ecosystems (370 L) over 9 weeks, and we found that at higher temperatures, cascading effects of predators on zooplankton prey and algae were stronger than at lower temperatures. When grazing was weak or absent, standing phytoplankton biomass declined by 85%–95% (<1-fold) over the temperature gradient (19–30 °C), and by 3-fold when grazers were present and lacked predators. These temperature-dependent species interactions and consequent community biomass shifts occurred without signs of species loss or community collapse, and only modestly affected the temperature dependence of net ecosystem oxygen fluxes. The exponential increases in net ecosystem oxygen production and consumption were relatively insensitive to differences in trophic interactions among ecosystems. Furthermore, monotonic declines in phytoplankton standing stock suggested no threshold effects of warming across systems. We conclude that local changes in community structure, including temperature-dependent trophic cascades, may be compatible with prevailing and predictable effects of temperature on ecosystem functions related to fundamental effects of temperature on metabolism
ConCert: A Smart Contract Certification Framework in Coq
We present a new way of embedding functional languages into the Coq proof
assistant by using meta-programming. This allows us to develop the meta-theory
of the language using the deep embedding and provides a convenient way for
reasoning about concrete programs using the shallow embedding. We connect the
deep and the shallow embeddings by a soundness theorem. As an instance of our
approach, we develop an embedding of a core smart contract language into Coq
and verify several important properties of a crowdfunding contract based on a
previous formalisation of smart contract execution in blockchains.Comment: Extended the related work section. Significantly extended sections on
translation and semantics. Added more examples and details about the
formalisation. Commented of unquote and the trusted computing base. Commented
on adequac
A practitioner concept of contemporary creativity
This article reviews conceptualisations from three academic areas: the sociology of art, the psychology of creativity, and research on the cultural and creative industries. These are compared with findings from a critical discursive study with UK practitioners. The meanings and associations these ‘maker artists’ attach to creativity are discussed as a ‘practitioner concept’. For the practitioners, the association of creativity with art carries a promise of transcendence and escape from ordinary life, but also a potential challenge to their own entitlement and claims to a creative status. The article shows, first, that the academic areas utilise different and conflicting conceptualisations and, second, that the practitioner concept is not consistent with any one of these. The article argues that the contemporary celebration of creativity is based on different meanings and unacknowledged conflicts. The article proposes that future social psychological research on creativity requires a more critical approach to the concept
FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer
Background
ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours.
Methods
In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA).
Results
ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC.
Conclusion
FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6
Perceived and objective neighborhood support for outside of school physical activity in South African children.
The neighborhood environment has the potential to influence children's participation in physical activity. However, children's outdoor play is controlled by parents to a great extent. This study aimed to investigate whether parents' perceptions of the neighborhood environment and the objectively measured neighborhood environment were associated with children's moderate-to-vigorous intensity physical activity (MVPA) outside of school hours; and to determine if these perceptions and objective measures of the neighborhood environment differ between high and low socio-economic status (SES) groups.In total, 258 parents of 9-11 year-old children, recruited from the South African sample of the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE), completed a questionnaire concerning the family and neighborhood environment. Objective measures of the environment were also obtained using Geographic Information Systems (GIS). Children wore an Actigraph (GT3X+) accelerometer for 7 days to measure levels of MVPA. Multilevel regression models were used to determine the association between the neighborhood environment and MVPA out of school hours.Parents' perceptions of the neighborhood physical activity facilities were positively associated with children's MVPA before school (β = 1.50 ± 0.51, p = 0.003). Objective measures of neighborhood safety and traffic risk were associated with children's after-school MVPA (β = -2.72 ± 1.35, p = 0.044 and β = -2.63 ± 1.26, p = 0.038, respectively). These associations were significant in the low SES group (β = -3.38 ± 1.65, p = 0.040 and β = -3.76 ± 1.61, p = 0.020, respectively), but unrelated to MVPA in the high SES group.This study found that several of the objective measures of the neighborhood environment were significantly associated with children's outside-of-school MVPA, while most of the parents' perceptions of the neighborhood environment were unrelated
Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function
Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were s
Evidence for large-scale gene-by-smoking interaction effects on pulmonary function
Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction (beta(int) = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.Peer reviewe
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