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Biological systems have been shown to have quantum-like behaviors by applying the adaptive dynamics view on their interaction networks. In particular, in the process of lactose–glucose metabolism, cells generate probabilistic interference patterns similarly to photons in the two-slit experiment. Such quantum-like interference patterns can be found in biological data, on all scales, from proteins to cognitive, ecological, and social systems. The adaptive dynamics approach covers both biological and physical phenomena, including the ones which are typically associated with quantum physics. We guess that the adaptive dynamics can be used for the clarification of quantum foundations, and the present paper is the first step in this direction. We suggest the use of an algorithm for the numerical simulation of the behavior of a billiard ball-like particle passing through two slits by explicitly considering the influence of the two-slit environment (experimental context). Our simulation successfully mimics the interference pattern obtained experimentally in quantum physics. The interference of photons or electrons by two slits is known as a typical quantum mechanical effect. We do not claim that the adaptive dynamics can reproduce the whole body of quantum mechanics, but we hope that this numerical simulation example will stimulate further extensive studies in this direction—the representation of quantum physical phenomena in an adaptive dynamical framework.

The class I ligase ribozyme consists of 121 nucleotides and shows a high catalytic rate comparable to that found in natural proteinaceous polymerases. In this study, we aimed to identify the smaller active unit of the class I ligase ribozyme comprising ~50 nucleotides, comparable to the estimated length of prebiotically synthesized RNA. Based on the three-dimensional structure of the class I ligase ribozyme, mutants were prepared and their ligation activities were analyzed. Sufficient ligation activity was maintained even when shortening to 94 nucleotides. However, because it would be difficult to approach the target of ~50 nucleotides by removing only the partial structure, the class I ligase ribozyme was then split into two molecules. The ligation activity was maintained even when splitting into two molecules of 55 and 39 nucleotides. Using a system with similar split ribozymes, we analyzed the ligation activity of mutants C30, C47, and A71, which have been previously identified as the positions that contribute to catalytic activity, and discussed the structural basis of the activity of these bases. Our findings suggest the rationale for the class I ligase ribozyme’s assembling from multiple fragments that would be achievable with prebiotic synthesis.

Aminoacylation of a primordial RNA minihelix composed of D-ribose shows L-amino acid preference over D-amino acid without any ribozymes or enzymes. This preference in the amino acylation reaction likely plays an important role in the establishment of homochirality in L-amino acid in modern proteins. However, molecular mechanisms of the chiral selective reaction remain unsolved mainly because of difficulty in direct observation of the reaction at the molecular scale by experiments. For seeking a possible mechanism of the chiral selectivity, quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations of the aminoacylation reactions in a modeled RNA were performed to investigate differences in their free-energy profiles along the reactions for L- and D-alanine and its physicochemical origin. The reaction is initiated by approaching a 3′-oxygen of the RNA minihelix to the carbonyl carbon of an aminoacyl phosphate oligonucleotide. The QM/MM umbrella sampling MD calculations showed that the height of the free-energy barrier for L-alanine aminoacylation reaction was 17 kcal/mol, which was 9 kcal/mol lower than that for the D-alanine system. At the transition state, the distance between the negatively charged 3′-oxygen and the positively charged amino group of L-alanine was shorter than that of D-alanine, which was caused by the chirality difference of the amino acid. These results indicate that the transition state for L-alanine is more electrostatically stabilized than that for D-alanine, which would be a plausible mechanism previously unexplained for chiral selectivity in the RNA minihelix aminoacylation.

In this study, we performed molecular dynamics (MD) simulations of the filling process of few-nanometer-wide trenches with various resist materials in ultraviolet nanoimprint lithography (UV-NIL) to identify the main molecular features necessary for a successful filling process. The 2- and 3-nm wide trenches were successfully filled with the resist materials that had (experimentally determined) viscosities less than 10 mPa·s. The resist composed of a three-armed bulky and highly viscous molecule could not fill the trenches. The radius of gyration of this molecule was smaller than half of the distance in which the first peak of its radial distribution function occurred. The available shapes of 1,6-hexanediol diacrylate (HDDA) and tri(propylene glycol) diacrylate (TPGDA), which are linear photopolymers, were compared to reveal that TPGDA is more flexible and adopts more conformations than HDDA. The terminal functional groups of TPGDA can be close due to its flexibility, which would increase the probability of intramolecular crosslinking of the molecule. This simulation result could explain the difference in hardness between the UV-cured HDDA and TPGDA based materials observed by experiments. The findings revealed by our MD simulations provide useful information for selecting and designing resists for fine patterning by UV-NIL.

The peptidyl transferase center (PTC) in the ribosome is composed of two symmetrically arranged tRNA-like units that contribute to peptide bond formation. We prepared units of the PTC components with putative tRNA-like structure and attempted to obtain peptide bond formation between aminoacyl-minihelices (primordial tRNAs, the structures composed of a coaxial stack of the acceptor stem on the T-stem of tRNA). One of the components of the PTC, P1c2UGGU (74-mer), formed a dimer and a peptide bond was formed between two aminoacyl-minihelices tethered by the dimeric P1c2UGGU. Peptide synthesis depended on both the existence of the dimeric P1c2UGGU and the sequence complementarity between the ACCA-3′ sequence of the minihelix. Thus, the tRNA-like structures derived from the PTC could have originated as a scaffold of aminoacyl-minihelices for peptide bond formation through an interaction of the CCA sequence of minihelices. Moreover, with the same origin, some would have evolved to constitute the present PTC of the ribosome, and others to function as present tRNAs.

We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed.

In the present in vitro selection study, we isolated and characterized RNA aptamers for a tRNA-binding protein (Trbp) from an extremophile archaeon Aeropyrum pernix. Trbp-like structures are frequently found not only in aminoacyl-tRNA synthetases but also in diverse types of proteins from different organisms. They likely arose early in evolution and have played important roles in evolution through interactions with key RNA structures. RNA aptamers specific for A. pernix Trbp were successfully selected from a pool of RNAs composed of 60 nucleotides, including a random 30-nucleotide region. From the secondary structures, we obtained a shortened sequence composed of 21 nucleotides, of which the 3′-terminal single stranded CA nucleotides are essential for binding. This may be related to the initial evolutionary role of the universal CCA-3′ terminus of tRNA in the interaction with Trbp-like structures.

Biological macromolecules function in highly crowded cellular environments. The structure and dynamics of proteins and nucleic acids are well characterized in vitro, but in vivo crowding effects remain unclear. Using molecular dynamics simulations of a comprehensive atomistic model cytoplasm we found that protein-protein interactions may destabilize native protein structures, whereas metabolite interactions may induce more compact states due to electrostatic screening. Protein-protein interactions also resulted in significant variations in reduced macromolecular diffusion under crowded conditions, while metabolites exhibited significant two-dimensional surface diffusion and altered protein-ligand binding that may reduce the effective concentration of metabolites and ligands in vivo. Metabolic enzymes showed weak non-specific association in cellular environments attributed to solvation and entropic effects. These effects are expected to have broad implications for the in vivo functioning of biomolecules. This work is a first step towards physically realistic in silico whole-cell models that connect molecular with cellular biology.

DNA binding proteins efficiently search for their cognitive sites on long genomic DNA by combining 3D diffusion and 1D diffusion (sliding) along the DNA. Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch. Here, we performed Brownian dynamics simulations using newly developed coarse-grained protein and DNA models for evaluating how hydrodynamic interactions between the protein and DNA molecules, binding affinity of the protein to DNA, and DNA fluctuations affect the one dimensional diffusion of the protein on the DNA. Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%. On the other hand, structural fluctuations of DNA give rise to steric collisions between the CG-proteins and DNA, resulting in faster 1D sliding of the protein. Proteins with low binding affinities consistent with experimental estimates of non-specific DNA binding show hopping along the CG-DNA. This hopping significantly increases sliding speed. These simulation studies provide additional insights into the mechanism of how DNA binding proteins find their target sites on the genome.

The cytoplasm of a cell is crowded with many different kinds of macromolecules. The macromolecular crowding affects the thermodynamics and kinetics of biological reactions in a living cell, such as protein folding, association, and diffusion. Theoretical and simulation studies using simplified models focus on the essential features of the crowding effects and provide a basis for analyzing experimental data. In most of the previous studies on the crowding effects, a uniform crowder size is assumed, which is in contrast to the inhomogeneous size distribution of macromolecules in a living cell. Here, we evaluate the free energy changes upon macromolecular association in a cell-like inhomogeneous crowding system via a theory of hard-sphere fluids and free energy calculations using Brownian dynamics trajectories. The inhomogeneous crowding model based on 41 different types of macromolecules represented by spheres with different radii mimics the physiological concentrations of macromolecules in the cytoplasm of Mycoplasma genitalium. The free energy changes of macromolecular association evaluated by the theory and simulations were in good agreement with each other. The crowder size distribution affects both specific and nonspecific molecular associations, suggesting that not only the volume fraction but also the size distribution of macromolecules are important factors for evaluating in vivo crowding effects. This study relates in vitro experiments on macromolecular crowding to in vivo crowding effects by using the theory of hard-sphere fluids with crowder-size heterogeneity. [ABSTRACT FROM AUTHOR]

Decadal variability of subsurface temperature in the North Pacific has been investigated. Two dominant regions were found; the central subarctic region (CSa) and the north-eastern subtropical region (NESt). In CSa, cooling (warming) of wintertime subsurface temperature corresponds to the large (small) temperature gradient and southward (northward) shift of subsurface temperature front, associated with the increase (decrease) of positive wind stress curl and the southward (northward) shift of curl τ zero line with 2 years delay. It is suggested that the relocation of subtropical-subarctic boundary plays an important role. In NESt, importance of heat flux through the sea surface and heat divergence in the Ekman layer is also discussed. [ABSTRACT FROM AUTHOR]

We retrospectively investigated the effects of subthalamic nucleus stimulation (STN-DBS) on new postoperative onset of cognitive decline and prognostic factors for advanced Parkinson's disease (PD). We studied 39 PD patients who had received bilateral STN-DBS. Clinical symptoms, cognitive function, psychiatric function, and health-related quality of life (HRQOL) were assessed before and six months after surgery. Based on the results of neuropsychological examinations six months after the surgery, the subjects were divided into those with and those without cognitive decline. We compared pre- and post-operative assessments between the two groups. Prognostic factors were investigated using multiple logistic regression analyses. Seven patients had cognitive decline six months after the operation (17.9%); they were significantly older than those without cognitive decline. Preoperative neuropsychological examinations revealed impairments in language and executive function. No differences were found in clinical symptoms. Patients with cognitive decline had significantly worse apathy scale scores. The HRQOL revealed significant declines in the Mental Component Summary (MCS), vitality, and mental health (MH) domains. Postoperative comparisons revealed novel significant differences in activities of daily living in the "on" and "off" states and in daytime drowsiness. Preoperative differences seen in the MCS and vitality indices were no longer present. Word fluency, and apathy scale and MH scores were independent preoperative prognostic factors for cognitive decline. New postoperative onset of cognitive decline due to STN-DBS affected activities of daily living and psychiatric function. Preoperative non-motor symptoms may be prognostic factors for new onset of cognitive decline. [ABSTRACT FROM AUTHOR]

Dynamic actin filaments are required for the formation and internalization of endocytic vesicles. Yeast actin cables serve as a track for the translocation of endocytic vesicles to early endosomes, but the molecular mechanisms regulating the interaction between vesicles and the actin cables remain ambiguous. Previous studies have demonstrated that the yeast Eps15-like protein Pan1p plays an important role in this interaction, and that interaction is not completely lost even after deletion of the Pan1p actin-binding domain, suggesting that additional proteins mediate association of the vesicle with the actin cable. Other candidates for mediating the interaction are endocytic coat proteins Sla2p (yeast Hip1R) and Ent1p/2p (yeast epsins), as these proteins can bind to both the plasma membrane and the actin filament. Here, we investigated the degree of redundancy in the actin-binding activities of Pan1p, Sla2p, and Ent1p/2p involved in the internalization and transport of endocytic vesicles. Expression of the nonphosphorylatable form of Pan1p, Pan1-18TA, caused abnormal accumulation of both actin cables and endocytic vesicles, and this accumulation was additively suppressed by deletion of the actin-binding domains of both Pan1p and Ent1p. Interestingly, deletion of the actin-binding domains of Pan1p and Ent1p in cells lacking the ENT2 gene resulted in severely defective internalization of endocytic vesicles and recruitment of actin cables to the site of endocytosis. These results suggest that Pan1p and Ent1p/2p cooperatively regulate the interaction between the endocytic vesicle and the actin cable. [ABSTRACT FROM AUTHOR]