Rate-independent constructs for chemical computation.
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ABSTRACT:
SUBMITTER: Senum P
PROVIDER: S-EPMC3127954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Expectation of reward can be shaped by the observation of actions and expressions of other people in one's environment. A person's apparent confidence in the likely reward of an action, for instance, makes qualities of their evidence, not observed directly, socially accessible. This strategy is computationally distinguished from associative learning methods that rely on direct observation, by its use of inference from indirect evidence. In twenty-three healthy human subjects, we isolated effects of first-hand experience, other people's choices, and the mediating effect of their confidence, on decision-making and neural correlates of value within ventromedial prefrontal cortex (vmPFC). Value derived from first-hand experience and other people's choices (regardless of confidence) were indiscriminately represented across vmPFC. However, value computed from agent choices weighted by their associated confidence was represented with specificity for ventromedial area 10. This pattern corresponds to shifts of connectivity and overlapping cognitive processes along a posterior-anterior vmPFC axis. Task behavior and self-reported self-reliance for decision-making in other social contexts correlated. The tendency to conform in other social contexts corresponded to increased activation in cortical regions previously shown to respond to social conflict in proportion to subsequent conformity (Campbell-Meiklejohn et al., 2010). The tendency to self-monitor predicted a selectively enhanced response to accordance with others in the right temporoparietal junction (rTPJ). The findings anatomically decompose vmPFC value representations according to computational requirements and provide biological insight into the social transmission of preference and reassurance gained from the confidence of others.Significance statementDecades of research have provided evidence that the ventromedial prefrontal cortex (vmPFC) signals the satisfaction we expect from imminent actions. However, we have a surprisingly modest understanding of the organization of value across this substantial and varied region. This study finds that using cues of the reliability of other peoples' knowledge to enhance expectation of personal success generates value correlates that are anatomically distinct from those concurrently computed from direct, personal experience. This suggests that representation of decision values in vmPFC is suborganized according to the underlying computation, consistent with what we know about the anatomical heterogeneity of the region. These results also provide insight into the observational learning process by which someone else's confidence can sway and reassure our choices.
| S-EPMC6596755 | biostudies-literature
Project description:Background:Exposure to mercury (Hg) is associated with adverse developmental effects. However, Hg occurs with a multitude of chemicals. We assessed the associations of developmental exposure to multiple pollutants with children's neurodevelopment using a novel approach. Methods:Hg, polychlorinated biphenyls (PCBs), and perfluoroalkyl substances were measured in maternal and children's blood at 5-years (n=449 and 419). At 7-years, children were administered Boston Naming Test (BNT) and the Strengths and Difficulties Questionnaire (SDQ). We used the G-formula combined with SuperLearner to estimate independent and joint effects of chemicals at both ages. We constructed flexible exposure-response relationships and assessed interactions. Results:Most chemicals showed negative relationships with BNT scores. An inter-quartile range (IQR) increase in maternal Hg and perfluorooctanoic acid (PFOA) was associated with 0.15 standard deviation [SD] (95% Confidence Interval [CI]: -0.29,-0.03) and 0.14 SD (95%CI: -0.26,-0.05) lower scores in BNT, whereas a joint IQR increase in the mixture of chemicals was associated with 0.48 SD (95%CI: -0.69,-0.25) lower scores in BNT. An IQR increase in PFOA was associated with 0.11 SD (95%CI: 0.02,0.26) higher total SDQ difficulties scores. Maternal ?PCBs concentrations were associated with lower SDQ scores (?=-0.09 SD; 95%CI: -0.19,0), whereas 5-years ?PCBs showed a negative association (?=-0.09 SD; 95%CI: -0.21,0). Finally, a joint IQR increase in the mixture was associated with 0.22 SD (95%CI: 0.04,0.4) higher SDQ scores. Conclusions:Using a novel statistical approach, we confirmed associations between prenatal mercury exposure and lower cognitive function. The potential developmental effects of PFASs need additional attention.
| S-EPMC7015154 | biostudies-literature
Project description:Recently, progress in IR sources has led to the discovery that humans can detect infrared (IR) light. This is hypothesized to be due to the two-photon absorption (TPA) events promoting the retina dim-light rod photoreceptor rhodopsin to the same excited state populated via one-photon absorption (OPA). Here, we combine quantum mechanics/molecular mechanics and extended multiconfiguration quasi-degenerate perturbation theory calculations to simulate the TPA spectrum of bovine rhodopsin (Rh) as a model for the human photoreceptor. The results show that the TPA spectrum of Rh has an intense S0 ? S1 band but shows also S0 ? S2 and S0 ? S3 transitions whose intensities, relative to the S0 ? S1 band, are significantly increased when compared to the corresponding bands of the OPA spectrum. In conclusion, we show that IR light in the 950 nm region can be perceived by rod photoreceptors, thus supporting the two-photon origin of the IR perception. We also found that the same photoreceptor can perceive red (i.e., close to 680 nm) light provided that TPA induces population of S2.
| S-EPMC7141604 | biostudies-literature
Project description:Glycosaminoglycans (GAGs) have therapeutic potential in areas ranging from angiogenesis, inflammation, hemostasis and cancer. GAG bioactivity is conferred by intrinsic structural features, such as disaccharide composition, glycosidic linkages and sulfation pattern. Unfortunately, the in vitro enzymatic synthesis of defined GAGs is quite restricted by a limited understanding of current GAG synthases and modifying enzymes. Our work provides insights into GAG-active enzymes through the creation of sulfated oligosaccharides, a new polysaccharide and chimeric polymers. We show that a C6-sulfonated uridine diphospho (UDP)-glucose (Glc) derivative, sulfoquinovose, can be used as an uronic acid donor, but not as a hexosamine donor, to cap hyaluronan (HA) chains by the HA synthase from the microbe Pasteurella multocida. However, the two heparosan (HEP) synthases from the same species, PmHS1 and PmHS2, could not employ the UDP-sulfoquinovose under similar conditions. Serendipitously, we found that PmHS2 co-polymerized Glc with glucuronic acid (GlcA), creating a novel HEP-like polymer we named hepbiuronic acid [-4-GlcA?1-4-Glc?1-]n. In addition, we created chimeric block polymers composed of both HA and HEP segments; in these reactions GlcA-, but not N-acetylglucosamine-(GlcNAc), terminated GAG acceptors were recognized by their noncognate synthase for further extension, likely due to the common ?-linkage connecting GlcA to GlcNAc in both of these GAGs. Overall, these GAG constructs provide new tools for studying biology and offer potential for future sugar-based therapeutics.
| S-EPMC5458544 | biostudies-literature
Project description:Despite the growing application of gas-phase measurements in structural biology and drug discovery, the factors that govern protein stabilities and structures in a solvent-free environment are still poorly understood. Here, we examine the solvent-free unfolding pathway for a group of homologous serum albumins. Utilizing a combination of chemical probes and noncovalent reconstructions, we draw new specific conclusions regarding the unfolding of albumins in the gas phase, as well as more general inferences regarding the sensitivity of collision induced unfolding to changes in protein primary and tertiary structure. Our findings suggest that the general unfolding pathway of low charge state albumin ions is largely unaffected by changes in primary structure; however, the stabilities of intermediates along these pathways vary widely as sequences diverge. Additionally, we find that human albumin follows a domain associated unfolding pathway, and we are able to assign each unfolded form observed in our gas-phase data set to the disruption of specific domains within the protein. The totality of our data informs the first detailed mechanism for multidomain protein unfolding in the gas phase, and highlights key similarities and differences from the known solution-phase pathway.
| S-EPMC5724362 | biostudies-literature
Project description:Characterizing the sensitivity to infinitesimally small perturbations in parameters is a powerful tool for the analysis, modeling, and design of chemical reaction networks. Sensitivity analysis of networks modeled using stochastic chemical kinetics, in which a probabilistic description is used to characterize the inherent randomness of the system, is commonly performed using Monte Carlo methods. Monte Carlo methods require large numbers of stochastic simulations in order to generate accurate statistics, which is usually computationally demanding or in some cases altogether impractical due to the overwhelming computational cost. In this work, we address this problem by presenting the regularized pathwise derivative method for efficient sensitivity analysis. By considering a regularized sensitivity problem and using the random time change description for Markov processes, we are able to construct a sensitivity estimator based on pathwise differentiation (also known as infinitesimal perturbation analysis) that is valid for many problems in stochastic chemical kinetics. The theoretical justification for the method is discussed, and a numerical algorithm is provided to permit straightforward implementation of the method. We show using numerical examples that the new regularized pathwise derivative method (1) is able to accurately estimate the sensitivities for many realistic problems and path functionals, and (2) in many cases outperforms alternative sensitivity methods, including the Girsanov likelihood ratio estimator and common reaction path finite difference method. In fact, we observe that the variance reduction using the regularized pathwise derivative method can be as large as ten orders of magnitude in certain cases, permitting much more efficient sensitivity analysis than is possible using other methods.
| S-EPMC3272067 | biostudies-other
Project description:PURPOSE:There is an increased interest to determine the exchange rate using CEST to provide pH information. However, current CEST quantification methods require lengthy scan times and do not address magnetization transfer effects. The purpose of this work was to apply the magnetic resonance fingerprinting (MRF) concept to CEST to achieve more efficient and accurate exchange rate quantification. METHODS:The proposed CEST fingerprinting method used varying saturation powers and saturation times to create unique signal evolutions for different exchange rates. The acquired signal was matched to a predefined dictionary to determine the exchange rate. The magnetization transfer effects were also addressed in the framework of CEST fingerprinting: The simulated dictionary could predict the signal curves without magnetization transfer effects, and comparing the dictionary to the acquired signals allowed the correction of the magnetization transfer effects. The CEST fingerprinting method was compared with the conventional pulsed quantitative CEST method using omega plots in the creatine phantom study. RESULTS:The CEST fingerprinting method has a significantly reduced scan time (10 minutes versus 50 minutes) while providing more accurate exchange rate quantification using literature values as the reference. CONCLUSION:In this study, we demonstrate that CEST fingerprinting is more efficient (5 times faster) compared with pulsed quantitative CEST. It is also shown that the results of the proposed CEST fingerprinting technique are much closer to the literature values than pulsed quantitative CEST at 3?T.
| S-EPMC6592698 | biostudies-literature
Project description:PurposeTo investigate the variation in computed dose-volume (DV) indices for high-dose-rate (HDR) prostate brachytherapy that can result from typical differences in computation settings in treatment planning systems (TPSs).MethodsFive factors were taken into account: number of dose-calculation points, radioactive source description, interpolation between delineated contours, intersections between delineated organ contours, and organ shape at the top and bottom contour using either full or partial slice thickness. Using in-house developed software, the DV indices of the treatment plans of 26 patients were calculated with different settings, and compared to a baseline setting that closely followed the default settings of the TPS used in our medical center. Studied organs were prostate and seminal vesicles, denoted as targets, and bladder, rectum, and urethra, denoted as organs at risk (OARs), which were delineated on MRI scans with a 3.3 mm slice thickness.ResultsWhen sampling a fixed number of points in each organ, in order to achieve a width of the 95% confidence interval over all patients of the DV indices of 1% or less, only 32,000 points had to be sampled per target, but 256,000 points had to be sampled per OAR. For the remaining factors, DV indices changed up to 0.4% for rectum, 1.3% for urethra, and 2.6% for prostate. DV indices of the bladder changed especially if the high-dose-region was (partly) located at the most caudal contour, up to 8.5%, and DV indices of the vesicles changed especially if there were few delineated contours, up to 9.8%, both due to the use of full slice thickness for the top and bottom contour.ConclusionsThe values of DV indices used in prostate HDR brachytherapy treatment planning are influenced by the computation settings in a TPS, especially at the most caudal part of the bladder, as well as in the seminal vesicles.
| S-EPMC6448172 | biostudies-literature
Project description:Computing with molecules is at the center of complex natural phenomena, where the information contained in ordered sequences of molecules is used to implement functionalities of synthesized materials or to interpret the environment, as in Biology. This uses large macromolecules and the hindsight of billions of years of natural evolution. But, can one implement computation with small molecules? If so, at what levels in the hierarchy of computing complexity? We review here recent work in this area establishing that all physically realizable computing automata, from Finite Automata (FA) (such as logic gates) to the Linearly Bound Automaton (LBA, a Turing Machine with a finite tape) can be represented/assembled/built in the laboratory using oscillatory chemical reactions. We examine and discuss in depth the fundamental issues involved in this form of computation exclusively done by molecules. We illustrate their implementation with the example of a programmable finite tape Turing machine which using the Belousov-Zhabotinsky oscillatory chemistry is capable of recognizing words in a Context Sensitive Language and rejecting words outside the language. We offer a new interpretation of the recognition of a sequence of chemicals representing words in the machine's language as an illustration of the "Maximum Entropy Production Principle" and concluding that word recognition by the Belousov-Zhabotinsky Turing machine is equivalent to extremal entropy production by the automaton. We end by offering some suggestions to apply the above to problems in computing, polymerization chemistry, and other fields of science.
| S-EPMC8144498 | biostudies-literature
Project description:BackgroundMolecular mechanisms generating genetic variation provide the basis for evolution and long-term survival of a population in a changing environment. In stable, laboratory conditions, the variation-generating mechanisms are dispensable, as there is limited need for the cell to adapt to adverse conditions. In fact, newly emerging, evolved features might be undesirable when working on highly refined, precise molecular and synthetic biological tasks.ResultsBy constructing low-mutation-rate variants, we reduced the evolutionary capacity of MDS42, a reduced-genome E. coli strain engineered to lack most genes irrelevant for laboratory/industrial applications. Elimination of diversity-generating, error-prone DNA polymerase enzymes involved in induced mutagenesis achieved a significant stabilization of the genome. The resulting strain, while retaining normal growth, showed a significant decrease in overall mutation rates, most notably under various stress conditions. Moreover, the error-prone polymerase-free host allowed relatively stable maintenance of a toxic methyltransferase-expressing clone. In contrast, the parental strain produced mutant clones, unable to produce functional methyltransferase, which quickly overgrew the culture to a high ratio (50% of clones in a 24-h induction period lacked functional methyltransferase activity). The surprisingly large stability-difference observed between the strains was due to the combined effects of high stress-induced mutagenesis in the parental strain, growth inhibition by expression of the toxic protein, and selection/outgrowth of mutants no longer producing an active, toxic enzyme.ConclusionsBy eliminating stress-inducible error-prone DNA-polymerases, the genome of the mobile genetic element-free E. coli strain MDS42 was further stabilized. The resulting strain represents an improved host in various synthetic and molecular biological applications, allowing more stable production of growth-inhibiting biomolecules.
| S-EPMC3280934 | biostudies-literature