ABSTRACT
Indirect interactions via shared memory deposited on the field ("field memory") play an essential role in collective motions. Some motile species, such as ants and bacteria, use attractive pheromones to complete many tasks. Mimicking these kinds of collective behavior at the laboratory scale, we present a pheromone-based autonomous agent system with tunable interactions. In this system, colloidal particles leave phase-change trails reminiscent of the process of pheromone deposition by individual ants, and the trails attract other particles and themselves. To implement this, we combine two physical phenomena: the phase change of a Ge2Sb2Te5 (GST) substrate by self-propelled Janus particles (pheromone deposition) and the AC (alternating current) electroosmotic (ACEO) flow generated by this phase change (pheromone attraction). Laser irradiation causes the GST layer to crystalize locally beneath the Janus particles, owing to the lens heating effect. Under AC field application, the high conductivity of the crystalline trail causes a field concentration and generates ACEO flow, and we introduce this flow as an attractive interaction between the Janus particles and the crystalline trail. By changing the AC frequency and voltage, we can tune the attractive flow, i.e., the sensitivity of the Janus particles to the trail, and the isolated particles undergo diverse states of motion, from self-caging to directional motion. A swarm of Janus particles also shows different states of collective motion, including colony formation and line formation. This tunability enables a reconfigurable system driven by a pheromone-like memory field.
ABSTRACT
Aquaporins (AQPs) are recognized as transmembrane water channels that facilitate selective water permeation through their monomeric pores. Among the AQP family, AQP6 has an intriguing characteristic as an anion channel, which is allosterically controlled by pH conditions and is eliminated by a single amino acid mutation. However, the molecular mechanism of anion permeation through AQP6 remains unclear. Using molecular dynamics simulations in the presence of a transmembrane voltage utilizing an ion concentration gradient, we show that chloride ions permeate through the pore corresponding to the central axis of the AQP6 homotetramer. Under low pH conditions, a subtle opening of the hydrophobic selectivity filter (SF), located near the extracellular part of the central pore, becomes wetted and enables anion permeation. Our simulations also indicate that a single mutation (N63G) in human AQP6, located at the central pore, significantly reduces anion conduction, consistent with experimental data. Moreover, we demonstrate that the pH-sensing mechanism in which the protonation of H184 and H189 under low pH conditions allosterically triggers the gating of the SF region. These results suggest a unique pH-dependent allosteric anion permeation mechanism in AQP6 and could clarify the role of the central pore in some of the AQP tetramers.
Subject(s)
Aquaporin 6 , Molecular Dynamics Simulation , Hydrogen-Ion Concentration , Humans , Aquaporin 6/metabolism , Aquaporin 6/chemistry , Anions/metabolism , Permeability , Mutation , Hydrophobic and Hydrophilic Interactions , Protein Multimerization , Chlorides/metabolismABSTRACT
Improving crop yield potential through an enhanced response to rising atmospheric CO2 levels is an effective strategy for sustainable crop production in the face of climate change. Large-sized panicles (containing many spikelets per panicle) have been a recent ideal plant architecture (IPA) for high-yield rice breeding. However, few breeding programs have proposed an IPA under the projected climate change. Here, we demonstrate through the cloning of the rice (Oryza sativa) quantitative trait locus for MORE PANICLES 3 (MP3) that the improvement in panicle number increases grain yield at elevated atmospheric CO2 levels. MP3 is a natural allele of OsTB1/FC1, previously reported as a negative regulator of tiller bud outgrowth. The temperate japonica allele advanced the developmental process in axillary buds, moderately promoted tillering, and increased the panicle number without negative effects on the panicle size or culm thickness in a high-yielding indica cultivar with large-sized panicles. The MP3 allele, containing three exonic polymorphisms, was observed in most accessions in the temperate japonica subgroups but was rarely observed in the indica subgroup. No selective sweep at MP3 in either the temperate japonica or indica subgroups suggested that MP3 has not been involved and utilized in artificial selection during domestication or breeding. A free-air CO2 enrichment experiment revealed a clear increase of grain yield associated with the temperate japonica allele at elevated atmospheric CO2 levels. Our findings show that the moderately increased panicle number combined with large-sized panicles using MP3 could be a novel IPA and contribute to an increase in rice production under climate change with rising atmospheric CO2 levels.
Subject(s)
Oryza , Carbon Dioxide , Alleles , Plant Breeding , Edible Grain/geneticsABSTRACT
One of the common errors in the calculation of the population attributable fraction (PAF) is the use of an adjusted risk ratio in the Levin formula. In this article, we discuss the errors visually using wireframes by varying the standardized mortality ratio (SMR) and associational risk ratio (aRR) when the prevalence of exposure is fixed. When SMR >1 and SMR > aRR, the absolute bias is positive, and its magnitude increases as the difference between SMR and aRR increases. By contrast, when aRR > SMR > 1, the absolute bias is negative and its magnitude is relatively small. Moreover, when SMR > aRR, the relative bias is larger than one, whereas when SMR < aRR, the relative bias is smaller than one. Although the target population of the PAF is the total population, the target of causation of the PAF is not the total population but the exposed group.
Subject(s)
Bias , Humans , Mortality , Odds Ratio , Cause of DeathABSTRACT
Genome-wide association studies (GWASs) are used to detect quantitative trait loci (QTL) using genomic and phenotypic data as inputs. While genomic data are obtained with high throughput and low cost, obtaining phenotypic data requires a large amount of effort and time. In past breeding programs, researchers and breeders have conducted a large number of phenotypic surveys and accumulated results as legacy data. In this study, we conducted a GWAS using phenotypic data of temperate japonica rice (Oryza sativa) varieties from a public database. The GWAS using the legacy data detected several known agriculturally important genes, indicating reliability of the legacy data for GWAS. By comparing the GWAS using legacy data (L-GWAS) and a GWAS using phenotypic data that we measured (M-GWAS), we detected reliable QTL for agronomically important traits. These results suggest that an L-GWAS is a strong alternative to replicate tests to confirm the reproducibility of QTL detected by an M-GWAS. In addition, because legacy data have often been accumulated for many traits, it is possible to evaluate the pleiotropic effect of the QTL identified for the specific trait that we focused on with respect to various other traits. This study demonstrates the effectiveness of using legacy data for GWASs and proposes the use of legacy data to accelerate genomic breeding.
Subject(s)
Oryza , Quantitative Trait Loci , Quantitative Trait Loci/genetics , Genome-Wide Association Study/methods , Oryza/genetics , Reproducibility of Results , Plant Breeding , Phenotype , Polymorphism, Single Nucleotide/geneticsABSTRACT
In plants, the contribution of the plasmotype (mitochondria and chloroplast) in controlling the circadian clock plasticity and possible consequences on cytonuclear genetic makeup have yet to be fully elucidated. A genome-wide association study in the wild barley (Hordeum vulgare ssp. spontaneum) B1K collection identified overlap with our previously mapped DRIVERS OF CLOCKS (DOCs) loci in wild-cultivated interspecific population. Moreover, we identified non-random segregation and epistatic interactions between nuclear DOCs loci and the chloroplastic RpoC1 gene, indicating an adaptive value for specific cytonuclear gene combinations. Furthermore, we show that DOC1.1, which harbours the candidate SIGMA FACTOR-B (SIG-B) gene, is linked with the differential expression of SIG-B and CCA1 genes and contributes to the circadian gating response to heat. High-resolution temporal growth and photosynthesis measurements of B1K also link the DOCs loci to differential growth, Chl content and quantum yield. To validate the involvement of the Plastid encoded polymerase (PEP) complex, we over-expressed the two barley chloroplastic RpoC1 alleles in Arabidopsis and identified significant differential plasticity under elevated temperatures. Finally, enhanced clock plasticity of de novo ENU (N-Ethyl-N-nitrosourea) -induced barley rpoB1 mutant further implicates the PEP complex as a key player in regulating the circadian clock output. Overall, this study highlights the contribution of specific cytonuclear interaction between rpoC1 (PEP gene) and SIG-B with distinct circadian timing regulation under heat, and their pleiotropic effects on growth implicate an adaptive value.
Subject(s)
Circadian Clocks , Hordeum , Hordeum/metabolism , Genome-Wide Association Study , Circadian Clocks/genetics , Photosynthesis/geneticsABSTRACT
This study aims to quantify the relationship between the arbitrary thermal environment of houses in winter and their occupants' health through a comprehensive questionnaire survey, involving approximately 24,000 individuals who moved into insulated dwellings in Japan. A relationship between the degree of the thermal insulation of these houses and corresponding rates of improvement in the following 10 diseases were formulated: heart disease, cerebrovascular disease, hypertension, diabetes mellitus, asthma, dermatitis and eczema, pneumonia, inflammatory polyarthropathies, allergic rhinitis, and conjunctivitis. Following the statistical analysis of these outcomes, significant differences in improvement rates were identified among the levels of the thermal insulation of houses for the following five diseases: cerebrovascular diseases, asthma, dermatitis and eczema, allergic rhinitis, and conjunctivitis. In addition, the thermal environments of houses corresponding to each thermal insulation level were estimated by numerical simulations. Using these results, we organized the relationships between the thermal environment conditions of houses and observed prevalence rate for the following four diseases for which the improvement rates increased with increasing insulation levels and significant differences were identified: asthma, dermatitis and eczema, allergic rhinitis, and conjunctivitis. Consequently, we formulated equations to predict the prevalence rates of these diseases using the "mean operative temperature of rooms occupied by each family member from January 1 to February 28."
Subject(s)
Housing , Seasons , Humans , Japan/epidemiology , Adult , Female , Male , Middle Aged , Aged , Surveys and Questionnaires , Young Adult , Adolescent , Child , Prevalence , Health Status , TemperatureABSTRACT
Carbon nanotubes (CNTs) have potential applications in separation membranes and nanofluidic devices. It is well known that the behavior of water molecules confined in CNTs is affected by surface functional groups and external electric fields, leading to structural changes. The understanding of these structural changes of water within various CNTs is crucial, particularly in the context of material separation. While there have been many investigations into the effects of individual specific functional groups, a comprehensive understanding of the effect of these functional groups and the electric fields they generate on water molecules remains elusive. In this study, we investigate the properties of water molecules in tip-charged CNTs of (8,8), (10,10), and (12,12) chiral vectors with positive charges at one tip and negative charges at the other tip. Abstraction of ionized functional groups as tip charges enables a comprehensive understanding that is independent of individual functional groups. The symmetrically arranged tip-charges spontaneously generate a strong and symmetric electric field in the CNTs. However, the strength and directionality of the electric field are non-uniform and complex. In the interiors of (8,8) and (10,10) tip-charged CNTs, helical and square structures, which have disturbances caused by the non-uniformity of the electric field, are observed. The properties of the water molecules differed significantly in the center of the CNTs and near positive and negative charges, despite the electric field symmetry. In (12,12) tip-charged CNTs with 12 charges, a local ring structure is observed in the vicinity of negative charges but not in the vicinity of positive charges. It is concluded that the water structures in tip-charged CNTs have different characteristics from those in plain CNTs under a uniform electric field.
ABSTRACT
Dimensions and molecular structures play pivotal roles in the principle of heat conduction. The dimensional characteristics of a solution within nanoscale systems depend on the degrees of confinement. However, the influence of such variations on heat transfer remains inadequately understood. Here, we perform quasi-one-dimensional non-equilibrium molecular dynamics simulations to calculate the thermal conductivity of water molecules confined in carbon nanotubes. The structure of water molecules is determined depending on the nanotube radius, forming a single-file, a single-layer, and a double-layer structure, corresponding to an increasing radius order. We reveal that the thermal conductivity of liquid water has a sublinear dependency on nanotube length exclusively when water molecules form a single file. A stronger confinement leads to behavioral and structural characteristics closely resembling a one-dimensional nature. Moreover, single-layer-structured water molecules exhibit enhanced thermal conductivity. We elucidate that this is due to the increase in the local water density and the absence of transitions to another layer, which typically occurs in systems with double-layer water structures within relatively large radius nanotubes.
ABSTRACT
Heterogeneous noble metal catalysts exhibit various functions. Although their redox functions have been extensively studied, we focused on their soft Lewis acid functions. Supported Au, Pt, and Pd catalysts electrophilically attack the π-electrons of soft bases such as alkynes, alkenes, and aromatic compounds to perform addition and substitution reactions. Hydroamination, intramolecular cyclization of alkynyl carboxylic acids, isomerization of allylic esters, vinyl exchange reactions, Wacker oxidation, and oxidative homocoupling of aromatics are introduced based on a discussion of the active species and reaction mechanisms. Furthermore, the adsorption of sulfur compounds, which are soft bases, onto the supported AuNPs is discussed. The adsorption and removal of 1,3-dimethyltrisulfane (DMTS), which is the compound responsible for the stale odor of "hine-ka" in alcoholic beverages, particularly Japanese sake, is described.
ABSTRACT
A detailed theoretical mechanistic investigation on the dynamic kinetic resolution of N-protected amino acid esters using phase-transfer catalysts is described. Semiautomatic exhaustive conformation search of transition state (TS)-like structures were carried out using the ConFinder program and the pseudo-TS conformational search (PTSCS) method. This conformational search method successfully provided reasonable TS structures for determining the stereoselectivity in the asymmetric base hydrolysis of hexafluoroisopropyl (HFIP) esters as well as the racemization mechanism. Furthermore, the independent gradient model (IGM) analysis of the TS structures suggested that the H-bonding interactions with the oxyanion hole and π-stacking interactions are the common important features of the proposed TS structures that determine the stereoselectivity.
Subject(s)
Amino Acids , Esters , Esters/chemistry , Amino Acids/chemistry , Molecular Conformation , Hydrolysis , CatalysisABSTRACT
BACKGROUND: The counterfactual definition of confounding is often explained in the context of exchangeability between the exposed and unexposed groups. One recent approach is to examine whether the measures of association (eg, associational risk difference) are exchangeable when exposure status is flipped in the population of interest. We discuss the meaning and utility of this approach, showing their relationships with the concept of confounding in the counterfactual framework. METHODS: Three hypothetical cohort studies are used, in which the target population is the total population. After providing an overview of the notions of confounding in distribution and in measure, we discuss the approach from the perspective of exchangeability of measures of association (eg, factual associational risk difference vs counterfactual associational risk difference). RESULTS: In general, if the measures of association are non-exchangeable when exposure status is flipped, confounding in distribution is always present, although confounding in measure may or may not be present. Even if the measures of association are exchangeable when exposure status is flipped, there could be confounding both in distribution and in measure. When we use risk difference or risk ratio as a measure of interest and the exposure prevalence in the population is 0.5, testing the exchangeability of measures of association is equivalent to testing the absence of confounding in the corresponding measures. CONCLUSION: The approach based on exchangeability of measures of association essentially does not provide a definition of confounding in the counterfactual framework. Subtly differing notions of confounding should be distinguished carefully.
Subject(s)
Causality , Humans , Confounding Factors, Epidemiologic , JapanABSTRACT
BACKGROUND: After reviewing selected scientific evidence, Schüz et al. made two recommendations in the 2018 International Agency for Research on Cancer (IARC) Technical Publication No. 46. Their first recommendation was against population thyroid screening after a nuclear accident, and the second was that consideration be given to offering a long-term thyroid monitoring program for higher-risk individuals (100-500 mGy or more radiation) after a nuclear accident. However, their review of the scientific evidence was inadequate and misrepresented the information from both Chernobyl and Fukushima. We wrote a review article published in Environmental Health in 2022 using the "Toolkit for detecting misused epidemiological methods." Schüz et al. critiqued our 2022 review article in 2023; their critique, based also on their 2018 IARC Technical Publication No. 46, was so fraught with problems that we developed this response. MAIN BODY: Schüz et al. suggest that hundreds of thyroid cancer cases in children and adolescents, detected through population thyroid examinations using ultrasound echo and conducted since October 2011 in Fukushima, were not caused by the 2011 Fukushima Daiichi Nuclear Power Plant accident. Schüz et al. compared thyroid cancers in Fukushima directly with those in Chernobyl after April 1986 and listed up to five reasons to deny a causal relationship between radiation and thyroid cancers in Fukushima; however, those reasons we dismiss based on available evidence. No new scientific evidence was presented in their response to our commentary in which we pointed out that misinformation and biased scientific evidence had formed the basis of their arguments. Their published article provided erroneous information on Fukushima. The article implied overdiagnosis in adults and suggested that overdiagnosis would apply to current Fukushima cases. The IARC report did not validate the secondary confirmatory examination in the program which obscures the fact that overdiagnosis may not have occurred as much in Fukushima. The report consequently precluded the provision of important information and measures. CONCLUSION: Information provided in the IARC Technical Publication No. 46 was based on selected scientific evidence resulting in both public and policy-maker confusion regarding past and present nuclear accidents, especially in Japan. It should be withdrawn.
Subject(s)
Lead , Thyroid Neoplasms , Adolescent , Adult , Child , Humans , Policy , Thyroid Neoplasms/epidemiology , Environmental Health , JapanABSTRACT
Many agronomic traits that are important in rice breeding are controlled by multiple genes. The extensive time and effort devoted so far to identifying and selecting such genes are still not enough to target multiple agronomic traits in practical breeding in Japan because of a lack of suitable plant materials in which to efficiently detect and validate beneficial alleles from diverse genetic resources. To facilitate the comprehensive analysis of genetic variation in agronomic traits among Asian cultivated rice, we developed 12 sets of chromosome segment substitution lines (CSSLs) with the japonica background, 11 of them in the same genetic background, using donors representing the genetic diversity of Asian cultivated rice. Using these materials, we overviewed the chromosomal locations of 1079 putative QTLs for seven agronomic traits and their allelic distribution in Asian cultivated rice through multiple linear regression analysis. The CSSLs will allow the effects of putative QTLs in the highly homogeneous japonica background to be validated.
ABSTRACT
It is well known that science can be misused to hinder the resolution (i.e., the elimination and/or control) of a health problem. To recognize distorted and misapplied epidemiological science, a 33-item "Toolkit for detecting misused epidemiological methods" (hereinafter, the Toolkit) was published in 2021. Applying the Toolkit, we critically evaluated a review paper entitled, "Lessons learned from Chernobyl and Fukushima on thyroid cancer screening and recommendations in the case of a future nuclear accident" in Environment International in 2021, published by the SHAMISEN (Nuclear Emergency Situations - Improvement of Medical and Health Surveillance) international expert consortium. The article highlighted the claim that overdiagnosis of childhood thyroid cancers greatly increased the number of cases detected in ultrasound thyroid screening following the 2011 Fukushima nuclear accident. However, the reasons cited in the SHAMISEN review paper for overdiagnosis in mass screening lacked important information about the high incidence of thyroid cancers after the accident. The SHAMISEN review paper ignored published studies of screening results in unexposed areas, and included an invalid comparison of screenings among children with screenings among adults. The review omitted the actual state of screening in Fukushima after the nuclear accident, in which only nodules > 5 mm in diameter were examined. The growth rate of thyroid cancers was not slow, as emphasized in the SHAMISEN review paper; evidence shows that cancers detected in second-round screening grew to more than 5 mm in diameter over a 2-year period. The SHAMISEN consortium used an unfounded overdiagnosis hypothesis and misguided evidence to refute that the excess incidence of thyroid cancer was attributable to the nuclear accident, despite the findings of ongoing ultrasound screening for thyroid cancer in Fukushima and around Chernobyl. By our evaluation, the SHAMISEN review paper includes 20 of the 33 items in the Toolkit that demonstrate the misuse of epidemiology. The International Agency for Research on Cancer meeting in 2017 and its publication cited in the SHAMISEN review paper includes 12 of the 33 items in the Toolkit. Finally, we recommend a few enhancements to the Toolkit to increase its utility.
Subject(s)
Chernobyl Nuclear Accident , Fukushima Nuclear Accident , Neoplasms, Radiation-Induced , Thyroid Neoplasms , Adult , Child , Health Policy , Humans , Incidence , Japan/epidemiology , Neoplasms, Radiation-Induced/epidemiology , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/epidemiology , Thyroid Neoplasms/etiologyABSTRACT
Nanoparticles exhibit diverse self-assembly attributes and are expected to be applicable under unique settings. For instance, biomolecules can be sandwiched between dimer nanoparticles and detected by surface-enhanced Raman scattering. Controlling the gap between extremely close dimers and stably capturing the target molecule in the gap are crucial aspects of this strategy. Therefore, polymer-tethered nanoparticles (PTNPs), which show promise as high-performance materials that exhibit the attractive features of both NPs and polymers, were targeted in this study to achieve stable biomolecule sensing. Using coarse-grained molecular dynamics simulations, the dependence of the PTNP interactions on the length of the grafted polymer, graft density, and coverage ratio of a hydrophobic tether were examined. The results indicated that the smaller the tether length and graft density, the smaller was the distance between the PTNP surfaces (Rsurf). In contrast, Rsurf decreased as the coverage ratio of the hydrophobic surface (Ï) increased. The sandwiching probability of the sensing target increased in proportion to the coverage ratio. At high Ï values, the PTNPs aggregated into three or more particles, which hindered their sensing attributes. These results provide fundamental insight into the sensing applications of NPs and demonstrate the usefulness of PTNPs in sensing biomolecules.
Subject(s)
Nanoparticles , Nucleic Acids , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Nanoparticles/chemistry , Polymers/chemistryABSTRACT
Bacterial canker of tomato (Solanum lycopersicon) caused by the Gram-positive bacterium Clavibacter michiganensis subsp. michiganensis (Cmm) is an economically important disease. To understand the host defense response to Cmm infection, transcriptome sequences in tomato cotyledons were analyzed by RNA-seq. Overall, 1788 and 540 genes were upregulated and downregulated upon infection, respectively. Gene Ontology enrichment analysis revealed that genes involved in the defense response, phosphorylation, and hormone signaling were over-represented by the infection. Induced expression of defense-associated genes suggested that the tomato response to Cmm showed similarities to common plant disease responses. After infection, many resistance gene analogs (RGAs) were transcriptionally upregulated, including the expressions of some receptor-like kinases (RLKs) involved in pattern-triggered immunity. The expressions of WRKYs, NACs, HSFs, and CBP60s encoding transcription factors (TFs) reported to regulate defense-associated genes were induced after infection with Cmm. Tomato genes orthologous to Arabidopsis EDS1, EDS5/SID1, and PAD4/EDS9, which are causal genes of salicylic acid (SA)-deficient mutants, were upregulated after infection with Cmm. Furthermore, Cmm infection drastically stimulated SA accumulation in tomato cotyledons. Genes involved in the phenylalanine ammonia lyase pathway were upregulated, whereas metabolic enzyme gene expression in the isochorismate synthase pathway remained unchanged. Exogenously applied SA suppressed bacterial growth and induced the expression of WRKYs, suggesting that some Cmm-responsive genes are regulated by SA signaling, and SA signaling activation should improve tomato immunity against Cmm.
Subject(s)
Host-Pathogen Interactions , Plant Diseases/immunology , Salicylic Acid/metabolism , Solanum lycopersicum/genetics , Transcriptome , Clavibacter/growth & development , Clavibacter/physiology , Cotyledon/genetics , Cotyledon/microbiology , Cotyledon/physiology , Gene Expression Profiling , Solanum lycopersicum/microbiology , Solanum lycopersicum/physiology , Plant Diseases/microbiology , Plant Immunity , Up-RegulationABSTRACT
Circadian clock rhythms are shown to be intertwined with crop adaptation. To realize the adaptive value of changes in these rhythms under crop domestication and improvement, there is a need to compare the genetics of clock and yield traits. We compared circadian clock rhythmicity based on Chl leaf fluorescence and transcriptomics among wild ancestors, landraces, and breeding lines of barley under optimal and high temperatures. We conducted a genome scan to identify pleiotropic loci regulating the clock and field phenotypes. We also compared the allelic diversity in wild and cultivated barley to test for selective sweeps. We found significant loss of thermal plasticity in circadian rhythms under domestication. However, transcriptome analysis indicated that this loss was only for output genes and that temperature compensation in the core clock machinery was maintained. Drivers of the circadian clock (DOC) loci were identified via genome-wide association study. Notably, these loci also modified growth and reproductive outputs in the field. Diversity analysis indicated selective sweep in these pleiotropic DOC loci. These results indicate a selection against thermal clock plasticity under barley domestication and improvement and highlight the importance of identifying genes underlying for understanding the biochemical basis of crop adaptation to changing environments.
Subject(s)
Circadian Clocks , Hordeum , Circadian Clocks/genetics , Circadian Rhythm/genetics , Domestication , Genome-Wide Association Study , Hordeum/genetics , Plant BreedingABSTRACT
For decades, the sufficient cause model and the counterfactual model have shaped our understanding of causation in biomedical science, and the link between these two models has enabled us to obtain a deeper understanding of causality. Recently, a new causal model-the marginal sufficient component cause model-was proposed and applied in the context of interaction or mediation. The proponents of this model have emphasized its utility in visualizing the presence of "agonism" (a subtype of mechanistic interaction) in the counterfactual framework, claiming that the concept of agonism has not been clearly defined in causal inference and that agonistic interaction cannot be visualized by the conventional sufficient cause model. In this article, we illustrate that careful scrutiny based on the conventional sufficient cause model yields further insights into the concept of agonism in a more biologic sense. We primarily focus on the following three points: (1) "agonism" defined in the counterfactual model can be visualized as sets of sufficient causes in the conventional sufficient cause model; (2) although the so-called independent competing assumption or no redundancy assumption may seem irrelevant in the marginal sufficient component cause model, researchers do need to assume that potential completion times of relevant marginal sufficient causes differ; and (3) possibly differing potential completion times of marginal sufficient causes cannot be discerned until their hidden mechanistic paths are considered in the conventional sufficient cause model. In this rapidly progressing field of research, decades after its introduction, the sufficient cause model retains its worth.
Subject(s)
Models, Theoretical , Causality , HumansABSTRACT
Protein conformational fluctuations are highly complex and exhibit long-term correlations. Here, molecular dynamics simulations of small proteins demonstrate that these conformational fluctuations directly affect the protein's instantaneous diffusivity D_{I}. We find that the radius of gyration R_{g} of the proteins exhibits 1/f fluctuations that are synchronous with the fluctuations of D_{I}. Our analysis demonstrates the validity of the local Stokes-Einstein-type relation D_{I}â1/(R_{g}+R_{0}), where R_{0}â¼0.3 nm is assumed to be a hydration layer around the protein. From the analysis of different protein types with both strong and weak conformational fluctuations, the validity of the Stokes-Einstein-type relation appears to be a general property.