Chemical Degradation-Inspired Total Synthesis of the Antibiotic Macrodiolide, Luminamicin.

This article describes the first total synthesis of luminamicin using a strategy combining chemical degradation with synthesis. Chemical degradation studies provided a sense of the inherent reactivity of the natural product, and deconstruction of the molecule gave rise to a key intermediate, which became the target for chemical synthesis. The core structure of the southern part of luminamicin was constructed by a 1,6-oxa-Michael reaction to form an oxa-bridged ring, followed by coupling with a functionalized organolithium species. Modified Shiina macrolactonization conditions forged the strained 10-membered lactone containing a tri-substituted olefin. Diastereoselective α-oxidation of the 10-membered lactone completed the center part to provide the key intermediate. Inspired by the degradation study, an unprecedented enol ether/maleic anhydride moiety was constructed with a one-pot chlorosulfide coupling and thiol ß-elimination sequence. Finally, macrolactonization to the 14-membered ring in the presence of the highly electrophilic maleic anhydride moiety was accomplished using modified Mukaiyama reagents to complete the synthesis of luminamicin.

Consensus-based distribution of power packets and decentralized control for routing.

A power packet distribution network is expected to be one of the advanced power distribution systems, providing high controllability in both energy management and failure management. Regarding network operations, the power packet transmission is governed by switching operation within each of the routers. Here, the power distribution through power packets exhibits consensus-like dynamical behaviors. These features lead to the question of a consensus dynamics on switching topology and routing controls for appropriate power flows. Our approach to the above subjects is based on the dynamical modeling and the emulation of dynamics through the decentralized control of routers. The simulations on a ring-structure network, of the power distribution, reveal that the dynamical solution of the unbiased distribution is feasible via the decentralized control, while in the biased case, the result shows two behavioral fragments, which is quite different from the dynamical solution. In this discussion, we propose a decentralized algorithm that contains only fundamental functions for the packet transmission and is able to be redesigned or extended for further applications.

Computation harvesting from nature dynamics for predicting wind speed and direction.

Natural phenomena generate complex dynamics because of nonlinear interactions among their components. The dynamics can be exploited as a kind of computational resource. For example, in the framework of natural computation, various natural phenomena such as quantum mechanics and cellular dynamics are used to realize general purpose calculations or logical operations. In recent years, simple collection of such nature dynamics has become possible in a sensor-rich society. For example, images of plant movement that have been captured indirectly by a surveillance camera can be regarded as sensor outputs reflecting the state of the wind striking the plant. Herein, based on ideas of physical reservoir computing, we present a methodology for wind speed and direction estimation from naturally occurring sensors in movies. Then we demonstrate its effectiveness through experimentation. Specifically using the proposed methodology, we investigate the computational capability of the nature dynamics, revealing its high robustness and generalization performance for computation.

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir.

We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta-cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route at the early research and development stage, the overall yield of the longest linear sequence (6 steps) was improved by approximately 7-fold. Furthermore, 9 out of the 12 isolated intermediates were crystallized directly from each reaction mixture without any extractive workup (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19.

A concise synthesis of tetrodotoxin.

Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its α-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives.

Nucleosynthetic signatures of the first stars.

The chemically most primitive stars provide constraints on the nature of the first stellar objects that formed in the Universe; elements other than hydrogen, helium and traces of lithium present within these objects were generated by nucleosynthesis in the very first stars. The relative abundances of elements in the surviving primitive stars reflect the masses of the first stars, because the pathways of nucleosynthesis are quite sensitive to stellar masses. Several models have been suggested to explain the origin of the abundance pattern of the giant star HE0107-5240, which hitherto exhibited the highest deficiency of heavy elements known. Here we report the discovery of HE1327-2326, a subgiant or main-sequence star with an iron abundance about a factor of two lower than that of HE0107-5240. Both stars show extreme overabundances of carbon and nitrogen with respect to iron, suggesting a similar origin of the abundance patterns. The unexpectedly low Li and high Sr abundances of HE1327-2326, however, challenge existing theoretical understanding: no model predicts the high Sr abundance or provides a Li depletion mechanism consistent with data available for the most metal-poor stars.

Mathematical analysis of the effect of portal vein cells on biliary epithelial cell differentiation through the Delta-Notch signaling pathway.

OBJECTIVE: The Delta-Notch signaling pathway induces fine-grained patterns of differentiation from initially homogeneous progenitor cells in many biological contexts, including Drosophila bristle formation, where mathematical modeling reportedly suggests the importance of production rate of the components of this signaling pathway. In contrast, the epithelial differentiation of bile ducts in the developing liver is unique in that it occurs around the portal vein cells, which express extremely high amounts of Delta ligands and act as a disturbance for the amount of Delta ligands in the field by affecting the expression levels of downstream target genes in the cells nearby. In the present study, we mathematically examined the dynamics of the Delta-Notch signaling pathway components in disturbance-driven biliary differentiation, using the model for fine-grained patterns of differentiation. RESULTS: A portal vein cell induced a high Notch signal in its neighboring cells, which corresponded to epithelial differentiation, depending on the production rates of Delta ligands and Notch receptors. In addition, this epithelial differentiation tended to occur in conditions where fine-grained patterning was reported to be lacking. These results highlighted the potential importance of the stability towards homogeneity determined by the production rates in Delta ligands and Notch receptors, in a disturbance-dependent epithelial differentiation.

Toward the total synthesis of luminamicin; an anaerobic antibiotic: construction of highly functionalized cis-decalin containing a bridged ether moiety.

Synthesis of a cis-decalin moiety, containing an oxa-bridged cis-decalin ring system (11-oxatricyclo(5.3.1.1,703,8)undecane), as a key intermediate of the total synthesis of luminamicin (1) was accomplished. One of the essential steps in our synthetic route is construction of a cis-decaline framework using a one-pot Michael addition-aldol reaction. Additionally, the bridged ether moiety was obtained by an intramolecular 1,6-oxa-Michael reaction of a conjugated aldehyde.

Automatic control and tracking of periodic orbits in chaotic systems.

Based on an automatic feedback adjustment of an additional parameter of a dynamical system, we propose a strategy for controlling periodic orbits of desired periods in chaotic dynamics and tracking them toward the set of unstable periodic orbits embedded within the original chaotic attractor. The method does not require information on the system to be controlled, nor on any reference states for the targets, and it overcomes some of the difficulties encountered by other techniques. Assessments of the method's effectiveness and robustness are given by means of the application of the technique to the stabilization of unstable periodic orbits in both discrete- and continuous-time systems.

Time-delayed feedback control of diffusion in random walkers.

Time delay in general leads to instability in some systems, while specific feedback with delay can control fluctuated motion in nonlinear deterministic systems to a stable state. In this paper, we consider a stochastic process, i.e., a random walk, and observe its diffusion phenomenon with time-delayed feedback. As a result, the diffusion coefficient decreases with increasing delay time. We analytically illustrate this suppression of diffusion by using stochastic delay differential equations and justify the feasibility of this suppression by applying time-delayed feedback to a molecular dynamics model.

Adaptation to the edge of chaos in one-dimensional chaotic maps.

We present a method that enables chaotic systems to change its dynamics to stable periodic dynamics by a feedback adjustment. The proposed method uses feedback of a largest value obtained from observations of a fixed interval of time series of the system variable and therefore does not require any a priori detailed information. We apply this method to several chaotic systems and confirm numerically that chaotic states are stabilized to stable periodic ones. Since the stabilized states in the system are formed around a boundary between regular states and chaotic ones, the method provides a kind of adaptation to the edge of chaos.

High-Contrast Imaging of Intermediate-Mass Giants with Long-Term Radial Velocity Trends.

A radial velocity (RV) survey for intermediate-mass giants has been operated for over a decade at Okayama Astrophysical Observatory (OAO). The OAO survey has revealed that some giants show long-term linear RV accelerations (RV trends), indicating the presence of outer companions. Direct imaging observations can help clarify what objects generate these RV trends. We present the results of high-contrast imaging observations of six intermediate-mass giants with long-term RV trends using the Subaru Telescope and HiCIAO camera. We detected co-moving companions to γ Hya B ( 0.61 - 0.14 + 0.12 M ⊙ ) , HD 5608 B (0.10 ± 0.01M ⊙), and HD 109272 B (0.28 ± 0.06M ⊙). For the remaining targets(ι Dra, 18 Del, and HD 14067) we exclude companions more massive than 30-60 M Jup at projected separations of 1''-7''. We examine whether these directly imaged companions or unidentified long-period companions can account for the RV trends observed around the six giants. We find that the Kozai mechanism can explain the high eccentricity of the inner planets ι Dra b, HD 5608 b, and HD 14067 b.

Communicability angles reveal critical edges for network consensus dynamics.

We consider the question of determining how the topological structure influences a consensus dynamical processes taking place on a network. By considering a large data set of real-world networks we first determine that the removal of edges according to their communicability angle, an angle between position vectors of the nodes in an Euclidean communicability space, increases the average time of consensus by a factor of 5.68 in real-world networks. The edge betweenness centrality also identifies, in a smaller proportion, those critical edges for the consensus dynamics; i.e., its removal increases the time of consensus by a factor of 3.70. We justify theoretically these findings on the basis of the role played by the algebraic connectivity and the isoperimetric number of networks on the dynamical process studied and their connections with the properties mentioned before. Finally, we study the role played by global topological parameters of networks on the consensus dynamics. We determine that the network density and the average distance-sum, which is analogous of the node degree for shortest-path distances, account for more than 80% of the variance of the average time of consensus in the real-world networks studied.

State concentration exponent as a measure of quickness in Kauffman-type networks.

We study the dynamics of randomly connected networks composed of binary Boolean elements and those composed of binary majority vote elements. We elucidate their differences in both sparsely and densely connected cases. The quickness of large network dynamics is usually quantified by the length of transient paths, an analytically intractable measure. For discrete-time dynamics of networks of binary elements, we address this dilemma with an alternative unified framework by using a concept termed state concentration, defined as the exponent of the average number of t-step ancestors in state transition graphs. The state transition graph is defined by nodes corresponding to network states and directed links corresponding to transitions. Using this exponent, we interrogate the dynamics of random Boolean and majority vote networks. We find that extremely sparse Boolean networks and majority vote networks with arbitrary density achieve quickness, owing in part to long-tailed in-degree distributions. As a corollary, only relatively dense majority vote networks can achieve both quickness and robustness.

Chaotic phase synchronization in bursting-neuron models driven by a weak periodic force.

We investigate the entrainment of a neuron model exhibiting a chaotic spiking-bursting behavior in response to a weak periodic force. This model exhibits two types of oscillations with different characteristic time scales, namely, long and short time scales. Several types of phase synchronization are observed, such as 1:1 phase locking between a single spike and one period of the force and 1:l phase locking between the period of slow oscillation underlying bursts and l periods of the force. Moreover, spiking-bursting oscillations with chaotic firing patterns can be synchronized with the periodic force. Such a type of phase synchronization is detected from the position of a set of points on a unit circle, which is determined by the phase of the periodic force at each spiking time. We show that this detection method is effective for a system with multiple time scales. Owing to the existence of both the short and the long time scales, two characteristic phenomena are found around the transition point to chaotic phase synchronization. One phenomenon shows that the average time interval between successive phase slips exhibits a power-law scaling against the driving force strength and that the scaling exponent has an unsmooth dependence on the changes in the driving force strength. The other phenomenon shows that Kuramoto's order parameter before the transition exhibits stepwise behavior as a function of the driving force strength, contrary to the smooth transition in a model with a single time scale.

Pulmonary Artery Calcification in Contact with a Left Coronary Artery Bypass Graft: An X-ray Computed Tomographic Study.

Calcification in the pulmonary artery (PA) occurs in rare cases. There have been no studies of calcification in the PA at the site of its contact with a left coronary artery bypass graft (CABG). In the present study, X-ray computed tomography (CT) was employed for examination of such calcification. The subjects were 53 patients (49 male and 4 female, mean age of 56.7 years) who underwent 74 left CABGs (69 saphenous veins and five internal thoracic arteries). Following surgery, non-contrasted CT was performed from the lower level of the aortic arch to the lower boundary of the left ventricle at 5-mm horizontal intervals, and contrasted CT was performed at the level of the PA; this procedure was repeated at approximately six-month intervals after the operation. In addition, aortography and selective graft angiography were carried out at 7.6 months postoperatively. The inner diameter of the grafts and the levels of serum cholesterol were also examined. Calcification in the PA was detected in 24 cases (all of them saphenous vein grafts), but graft angiography found no stenosis in those sites. Calcification size varied from 1 mm to 14 mm, with 10 of the cases at or exceeding 10 mm and showing high density. Only three of the cases enlarged with time. Calcification appeared at 2.9 to 54.3 months postoperatively and the mean time of onset was 10.0 +/- 15.7 months. The mean age of the patients with PA calcification was 58.7 +/- 5.9 years while that of the patients without calcification was 57.3 +/- 10.0 years. Graft diameter was 5.9 +/- 1.9 mm in the former group and 5.6 +/- 1.7 mm in the latter. Serum cholesterol level was 235 +/- 32 mg/dl in the former group and 243 +/- 42 mg/dl in the latter. There were three cases of occlusion in the calcification group, and four in the other. There were no significant intergroup differences in these four parameters. The incidence of CT-detected calcification in the PA was found to be high at its point of contact with saphenous vein grafts.