Retrosynthesis Zero: Self-Improving Global Synthesis Planning Using Reinforcement Learning.

The field of computer-aided synthesis planning (CASP) has witnessed significant growth in recent years. Still, many CASP programs rely on large data sets to train neural networks, resulting in limitations due to the data quality and prior knowledge from chemists. In response, we propose Retrosynthesis Zero (ReSynZ), a reaction template-based method that combines Monte Carlo Tree Search with reinforcement learning inspired by AlphaGo Zero. Unlike other single-step reaction template-based CASP methods, ReSynZ takes complete synthesis paths for complex molecules, determined by reaction rules, as input for training the neural network. ReSynZ enables neural networks trained with relatively small reaction data sets (tens of thousands of data) to generate multiple synthesis pathways for a target molecule and suggest possible reaction conditions. On multiple data sets of molecular retrosynthesis, ReSynZ demonstrates excellent predictive performance compared to existing algorithms. The advantages, such as self-improving model features, flexible reward settings, the potential to surpass human limitations in chemical synthesis route planning, and others, make ReSynZ a valuable tool in chemical synthesis design.

Interfacial Oxygen Octahedral Coupling-Driven Robust Ferroelectricity in Epitaxial Na0.5Bi0.5TiO3 Thin Films.

The oxygen octahedral rotation (OOR) forms fundamental atomic distortions and symmetries in perovskite oxides and definitely determines their properties and functionalities. Therefore, epitaxial strain and interfacial structural coupling engineering have been developed to modulate the OOR patterns and explore novel properties, but it is difficult to distinguish the 2 mechanisms. Here, different symmetries are induced in Na0.5Bi0.5TiO3 (NBT) epitaxial films by interfacial oxygen octahedral coupling rather than epitaxial strain. The NBT film grown on the Nb:SrTiO3 substrate exhibits a paraelectric tetragonal phase, while with La0.5Sr0.5MnO3 as a buffer layer, a monoclinic phase and robust ferroelectricity are obtained, with a remanent polarization of 42 µC cm-2 and a breakdown strength of 7.89 MV cm-1, which are the highest record among NBT-based films. Moreover, the interfacial oxygen octahedral coupling effect is demonstrated to propagate to the entire thickness of the film, suggesting an intriguing long-range effect. This work provides a deep insight into understanding the structure modulation in perovskite heterostructures and an important avenue for achieving unique functionalities.

A Sulfur-Controlled Approach to the Synthesis of Linerixibat.

Establishing the two stereocenters in the benzothiazepine ring of linerixibat (GSK2330672) has been a long-standing problem at GSK. Our solution rests on an episulfonium-controlled Ritter reaction followed by a sulfoxide-directed reduction. A rationale for both steps is based on a mixture of literature precedent and computational experiments. Transition state modeling suggests the sulfoxide-directed reduction proceeds through electronic repulsion between the lone pair of electrons on sulfur and the incoming borohydride anion.

Osteoblastoma of the maxilla: A case report and review of the literature.

Osteoblastoma is a benign tumour with aggressive trait usually seen in young males between 10 and 40 years of age. This condition is quite rare in children. Here, we report one such rare osteoblastoma occurring in the maxilla of a 4-year-old boy and discuss the clinical presentation, radiologic and histologic features, and treatment of this patient, and a brief review.

Anchoring Pt Single Atoms on Te Nanowires for Plasmon-Enhanced Dehydrogenation of Formic Acid at Room Temperature.

Formic acid (HCOOH), as a promising hydrogen carrier, is renewable, safe, and nontoxic. However, the catalytic dehydrogenation of HCOOH is typically conducted at elevated temperature. Here, HCOOH decomposition is successfully achieved for hydrogen production on the developed Pt single atoms modified Te nanowires with the Pt mass loading of 1.1% (1.1%Pt/Te) at room temperature via a plasmon-enhanced catalytic process. Impressively, 1.1%Pt/Te delivers 100% selectivity for hydrogen and the highest turnover frequency number of 3070 h-1 at 25 °C, which is significantly higher than that of Pt single atoms and Pt nanoclusters coloaded Te nanowires, Pt nanocrystals decorated Te nanowires, and commercial Pt/C. A plasmonic hot-electron driven mechanism rather than photothermal effect domains the enhancement of catalytic activity for 1.1%Pt/Te under light. The transformation of HCOO* to CO2 δ -* on Pt atoms is proved to be the rate-determining step by further mechanistic studies. 1.1%Pt/Te exhibits tremendous catalytic activity toward the decomposition of HCOOH owing to its plasmonic hot-electron driven mechanism, which efficiently stimulates the rate-determining step. In addition, hot electrons generated by the Te atoms nearby Pt single atoms are regarded to directly inject into the reactants adsorbed and activated on Pt single atoms.

In2O3 Nanocrystals for CO2 Fixation: Atomic-Level Insight into the Role of Grain Boundaries.

N-functionalization of amines with CO2 and H2 is one of the most important processes to make use of CO2. Although noble metal-based catalysts with remarkable performance have been widely used in this process, developing efficient non-noble-metal-based catalysts remains a grand challenge. Herein, we report In2O3 nanocrystals with high density of grain boundaries (HGB-In2O3), which show excellent activity toward methylation of amines. Impressively, HGB-In2O3 achieved the optimal yield of 82.7% for N,N-dimethylaniline with a mass activity of 21.2 mmol·g-1h-1 in methylation of N-methylaniline, comparable to noble-metal-based catalysts. As a bonus, HGB-In2O3 held noticeable stability, remarkable selectivity, and comprehensive applicability. Further mechanistic studies revealed that the presence of high density of grain boundaries not only facilitated the adsorption and activation of CO2 to generate CH3OH as the intermediate but also enhanced the activation of N-H bond in amines, contributing to the attractive activity of HGB-In2O3 toward methylation of amines.

Identification of Preferred Healthy Weight Counseling Approaches for Children in the Dental Setting.

OBJECTIVE: There is a gap in the literature regarding optimal methods for the dental team to help address the childhood obesity epidemic; accordingly, this investigation sought to identify preferred communication approaches the dental team can rely upon to initiate dialogue with caregivers regarding the weight of their children. STUDY DESIGN: A structured interview guide containing seven potential Healthy Weight Counseling (HWC) approaches and eight follow up questions was developed, pilot-tested, revised and utilized as a structured interview guide. Interviews were conducted at the Children's Clinic at the School of Dentistry at the University of North Carolina at Chapel Hill (UNC-CH) with 50 participants who are English-speaking caregivers of children ages 4-12. RESULTS: Ninety-four percent of the participants were receptive to HWC in the dental setting. Caregivers indicated varying levels of acceptance for the seven HWC-approaches based on specific word choices in each approach. Sixty percent preferred HWC to be delivered with the child not present while 34% preferred the child's presence and 6% had no preference. CONCLUSIONS: Caregivers were open to weight-related conversations in the dental setting but to be well received, the dental team must choose their approach carefully and establish the proper doctor/patient relationship prior to HWC delivery. An individualized HWC-approach tailored to the specific needs of each family is indicated.

A novel hierarchical selective ensemble classifier with bioinformatics application.

Selective ensemble learning is a technique that selects a subset of diverse and accurate basic models in order to generate stronger generalization ability. In this paper, we proposed a novel learning algorithm that is based on parallel optimization and hierarchical selection (PTHS). Our novel feature selection method is based on maximize the sum of relevance and distance (MSRD) for solving the problem of high dimensionality. Specifically, we have a PTHS algorithm that employs parallel optimization and candidate model pruning based on k-means and a hierarchical selection framework. We combine the prediction result of each basic model by majority voting, which employs the divide-and-conquer strategy to save computing time. In addition, the PT algorithm is capable to transform a multi-class problem into a binary classification problem, and thereby allowing our ensemble model to address multi-class problems. Empirical study shows that MSRD is efficient in solving the high dimensionality problem, and PTHS exhibits better performance than the other existing classification algorithms. Most importantly, our classifier achieved high-level performance on several bioinformatics problems (e.g. tRNA identification, and protein-protein interaction prediction, etc.), demonstrating efficiency and robustness.

Pat1 protects centromere-specific histone H3 variant Cse4 from Psh1-mediated ubiquitination.

Evolutionarily conserved histone H3 variant Cse4 and its homologues are essential components of specialized centromere (CEN)-specific nucleosomes and serve as an epigenetic mark for CEN identity and propagation. Cse4 is a critical determinant for the structure and function of the kinetochore and is required to ensure faithful chromosome segregation. The kinetochore protein Pat1 regulates the levels and spatial distribution of Cse4 at centromeres. Deletion of PAT1 results in altered structure of CEN chromatin and chromosome segregation errors. In this study, we show that Pat1 protects CEN-associated Cse4 from ubiquitination in order to maintain proper structure and function of the kinetochore in budding yeast. PAT1-deletion strains exhibit increased ubiquitination of Cse4 and faster turnover of Cse4 at kinetochores. Psh1, a Cse4-specific E3-ubiquitin ligase, interacts with Pat1 in vivo and contributes to the increased ubiquitination of Cse4 in pat1∆ strains. Consistent with a role of Psh1 in ubiquitination of Cse4, transient induction of PSH1 in a wild-type strain resulted in phenotypes similar to a pat1∆ strain, including a reduction in CEN-associated Cse4, increased Cse4 ubiquitination, defects in spatial distribution of Cse4 at kinetochores, and altered structure of CEN chromatin. Pat1 interacts with Scm3 and is required for its maintenance at kinetochores. In conclusion, our studies provide novel insights into mechanisms by which Pat1 affects the structure of CEN chromatin and protects Cse4 from Psh1-mediated ubiquitination for faithful chromosome segregation.

Improving tRNAscan-SE Annotation Results via Ensemble Classifiers.

tRNAScan-SE is a tRNA detection program that is widely used for tRNA annotation; however, the false positive rate of tRNAScan-SE is unacceptable for large sequences. Here, we used a machine learning method to try to improve the tRNAScan-SE results. A new predictor, tRNA-Predict, was designed. We obtained real and pseudo-tRNA sequences as training data sets using tRNAScan-SE and constructed three different tRNA feature sets. We then set up an ensemble classifier, LibMutil, to predict tRNAs from the training data. The positive data set of 623 tRNA sequences was obtained from tRNAdb 2009 and the negative data set was the false positive tRNAs predicted by tRNAscan-SE. Our in silico experiments revealed a prediction accuracy rate of 95.1 % for tRNA-Predict using 10-fold cross-validation. tRNA-Predict was developed to distinguish functional tRNAs from pseudo-tRNAs rather than to predict tRNAs from a genome-wide scan. However, tRNA-Predict can work with the output of tRNAscan-SE, which is a genome-wide scanning method, to improve the tRNAscan-SE annotation results. The tRNA-Predict web server is accessible at http://datamining.xmu.edu.cn/∼gjs/tRNA-Predict.

An efficient synthesis of a potent PPARpan agonist.

An efficient synthesis of 2-{4-[({4-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)thio]phenoxy}-2-methylpropanoic acid (1), a potent PPARpan agonist, is described. The seven-step synthesis, which afforded 1 in 30% overall yield, includes a highly regioselective carbon-sulfur bond formation via coupling of a bishydroxymethylthiazole (3) with 4-hydroxythiophenol, displacement of the remaining alcohol through a three-step telescoped sequence involving an efficient cleavage of an aryl mesylate, and an efficient and practical method of introducing an isobutyric acid fragment.

Synthetic Studies in Phytochrome Chemistry.

An account is given of the author's several approaches to the synthesis of the parent chromophore of phytochrome (1), a protein-bound linear tetrapyrrole derivative that controls photomorphogenesis in higher plants. These studies culminated in enantioselective syntheses of both 2R- and 2S-phytochromobilin (4), as well as several (13)C-labeled derivatives designed to probe the site of Z,E-isomerization during photoexcitation. When reacted in vitro, synthetic 2R-4 and recombinant-derived phytochrome apoprotein N-C produced a protein-bound chromophore with identical difference spectra to naturally occurring 1.

Dihydropyrromethenones by Pd(0)-Mediated Coupling of Iodopyrroles and Acetylenic Amides. Synthesis of the A,B-Ring Segment of Phytochrome.

Dihydropyrromethenone derivative 32b, which constitutes the A,B-ring segment of phytochrome (6), has been prepared in enantiomerically pure form beginning with acetylenic amide 47b and iodopyrrole 27. The key steps involved the TBAF-catalyzed 5-exo-dig cyclization of the acetylenic pyrrole 48b, followed by thia-Mitsunobu inversion of the resulting alcohol derivative 31b.