Machine Learning Assisted Design of Experiments for Solid State Electrolyte Lithium Aluminum Titanium Phosphate

Lithium-ion batteries with solid electrolytes offer safety, higher energy density and higher long-term performance, which are promising alternatives to conventional liquid electrolyte batteries. Lithium aluminum titanium phosphate (LATP) is one potential solid electrolyte candidate due to its high Li-ion conductivity. To evaluate its performance, influences of the experimental factors on the materials design need to be investigated systematically. In this work, a materials design strategy based on machine learning (ML) is employed to design experimental conditions for the synthesis of LATP. In the variation of parameters, we focus on the tolerance against the possible deviations in the concentration of the precursors, as well as the influence of sintering temperature and holding time. Specifically, models built with different design selection strategies are compared based on the training data assembled from previous laboratory experiments. The best one is then chosen to design new experiment parameters, followed by measuring the corresponding properties of the newly synthesized samples. A previously unknown sample with ionic conductivity of 1.09 × 10$^{-3}$ S cm$^{-1}$ is discovered within several iterations. In order to further understand the mechanisms governing the high ionic conductivity of these samples, the resulting phase compositions and crystal structures are studied with X-ray diffraction, while the microstructures of sintered pellets are investigated by scanning electron microscopy. Our studies demonstrate the advantages of applying machine learning in designing experimental conditions by the synthesis of desired materials, which can effectively help researchers to reduce the number of required experiments

Large-Scale Atomistic Simulations of Environmental Effects on the Formation and Properties of Molecular Junctions

Using an updated simulation tool, we examine molecular junctions comprised of benzene-1,4-dithiolate bonded between gold nanotips, focusing on the importance of environmental factors and inter-electrode distance on the formation and structure of bridged molecules. We investigate the complex relationship between monolayer density and tip separation, finding that the formation of multi-molecule junctions is favored at low monolayer density, while single-molecule junctions are favored at high density. We demonstrate that tip geometry and monolayer interactions, two factors that are often neglected in simulation, affect the bonding geometry and tilt angle of bridged molecules. We further show that the structures of bridged molecules at 298 and 77 K are similar.Comment: To appear in ACS Nano, 30 pages, 5 figure

Measuring Dissociation Rate Constants of Protein Complexes through Subunit Exchange: Experimental Design and Theoretical Modeling

Protein complexes are dynamic macromolecules that constantly dissociate into, and simultaneously are assembled from, free subunits. Dissociation rate constants, koff, provide structural and functional information on protein complexes. However, because all existing methods for measuring koff require high-quality purification and specific modifications of protein complexes, dissociation kinetics has only been studied for a small set of model complexes. Here, we propose a new method, called Metabolically-labeled Affinity-tagged Subunit Exchange (MASE), to measure koff using metabolic stable isotope labeling, affinity purification and mass spectrometry. MASE is based on a subunit exchange process between an unlabeled affinity-tagged variant and a metabolically-labeled untagged variant of a complex. The subunit exchange process was modeled theoretically for a heterodimeric complex. The results showed that koff determines, and hence can be estimated from, the observed rate of subunit exchange. This study provided the theoretical foundation for future experiments that can validate and apply the MASE method

Assessment of the Mobilizable Vector Plasmids pSUP202 and pSUP404.2 as Genetic Tools for the Predatory Bacterium Bdellovibrio bacteriovorus

Bdellovibrio and like organisms (BALOs) form the group of predatory bacteria which require Gram-negative bacteria as prey. Genetic studies with Bdellovibrio bacteriovorus can be performed with vectors which are introduced into the predator via conjugation. The usefulness of the two vectors pSUP202 and pSUP404.2 as genetic tools were assessed. Both vectors were transferable into B. bacteriovorus by conjugative matings with an Escherichia coli K12 strain as donor. The transfer frequency was higher for vector pSUP404.2 (approx. 10−1–10−4) as for pSUP202 (approx. 10−5–10−6). Vector pSUP202 with a pMB1 origin is unstable in the predatory bacterium, whereas pSUP404.2 is stably maintained in the absence of selective antibiotics. pSUP404.2 harbors two plasmid replicons, the p15A ori and the RSF1010 replication region The copy number of pSUP404.2 was determined by quantitative PCR in B. bacteriovorus and averages seven copies per genome. pSUP404.2 harbors two resistance genes (chloramphenicol and kanamycin) which can be used for cloning either by selection for transconjugants or by insertional inactivation

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCα), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies

Design, expression and characterization of mutants of fasciculin optimized for interaction with its target, acetylcholinesterase

Predicting mutations that enhance protein–protein affinity remains a challenging task, especially for high-affinity complexes. To test our capability to improve the affinity of such complexes, we studied interaction of acetylcholinesterase with the snake toxin, fasciculin. Using the program ORBIT, we redesigned fasciculin's sequence to enhance its interactions with Torpedo californica acetylcholinesterase. Mutations were predicted in 5 out of 13 interfacial residues on fasciculin, preserving most of the polar inter-molecular contacts seen in the wild-type toxin/enzyme complex. To experimentally characterize fasciculin mutants, we developed an efficient strategy to over-express the toxin in Escherichia coli, followed by refolding to the native conformation. Despite our predictions, a designed quintuple fasciculin mutant displayed reduced affinity for the enzyme. However, removal of a single mutation in the designed sequence produced a quadruple mutant with improved affinity. Moreover, one designed mutation produced 7-fold enhancement in affinity for acetylcholinesterase. This led us to reassess our criteria for enhancing affinity of the toxin for the enzyme. We observed that the change in the predicted inter-molecular energy, rather than in the total energy, correlates well with the change in the experimental free energy of binding, and hence may serve as a criterion for enhancement of affinity in protein–protein complexes

Sunda-Banda arc transition: incipient continent-island arc collision (Northwest Australia)

The eastern Sunda arc represents one of the few regions globally where the early stages of continent-arc collision can be studied. We studied along the western limit of the collision zone at the Sunda-Banda arc transition, where the Australian margin collides with the Banda island arc, causing widespread back arc thrusting. We present integrated results of a refraction/wide-angle reflection tomography, gravity modeling, and multichannel reflection seismic imaging using data acquired in 2006 southeast of Sumba Island. The composite structural model reveals the previously unresolved deep geometry of the collision zone. Changes in crustal structure encompass the 10 - 12 km thick Australian basement in the south and the 22 - 24 kmthick Sumba ridge in the north, where backthrusting of the 130 km wide accretionary prism is documented. The structural diversity along this transect could be characteristic of young collisional systems at the transition from oceanic subduction to continent-arc collision. Citation: Shulgin, A., H. Kopp, C. Mueller, E. Lueschen, L. Planert, M. Engels, E. R. Flueh, A. Krabbenhoeft, and Y. Djajadihardja (2009), Sunda-Banda arc transition: Incipient continent-island arc collision (northwest Australia), Geophys. Res. Lett., 36, L10304, doi: 10.1029/2009GL037533

Electromechanical properties of suspended Graphene Nanoribbons

Graphene nanoribbons present diverse electronic properties ranging from semiconducting to half-metallic, depending on their geometry, dimensions and chemical composition. Here we present a route to control these properties via externally applied mechanical deformations. Using state-of-the-art density functional theory calculations combined with classical elasticity theory considerations, we find a remarkable Young's modulus value of ~7 TPa for ultra-narrow graphene strips and a pronounced electromechanical response towards bending and torsional deformations. Given the current advances in the synthesis of nanoscale graphene derivatives, our predictions can be experimentally verified opening the way to the design and fabrication of miniature electromechanical sensors and devices based on ultra-narrow graphene nanoribbons.Comment: 12 pages, 6 figure

Genome-wide Copy Number Profiling on High-density Bacterial Artificial Chromosomes, Single-nucleotide Polymorphisms, and Oligonucleotide Microarrays: A Platform Comparison based on Statistical Power Analysis

Recently, comparative genomic hybridization onto bacterial artificial chromosome (BAC) arrays (array-based comparative genomic hybridization) has proved to be successful for the detection of submicroscopic DNA copy-number variations in health and disease. Technological improvements to achieve a higher resolution have resulted in the generation of additional microarray platforms encompassing larger numbers of shorter DNA targets (oligonucleotides). Here, we present a novel method to estimate the ability of a microarray to detect genomic copy-number variations of different sizes and types (i.e. deletions or duplications). We applied our method, which is based on statistical power analysis, to four widely used high-density genomic microarray platforms. By doing so, we found that the high-density oligonucleotide platforms are superior to the BAC platform for the genome-wide detection of copy-number variations smaller than 1 Mb. The capacity to reliably detect single copy-number variations below 100 kb, however, appeared to be limited for all platforms tested. In addition, our analysis revealed an unexpected platform-dependent difference in sensitivity to detect a single copy-number loss and a single copy-number gain. These analyses provide a first objective insight into the true capacities and limitations of different genomic microarrays to detect and define DNA copy-number variations

Association Rate Constants of Ras-Effector Interactions Are Evolutionarily Conserved

Evolutionary conservation of protein interaction properties has been shown to be a valuable indication for functional importance. Here we use homology interface modeling of 10 Ras-effector complexes by selecting ortholog proteins from 12 organisms representing the major eukaryotic branches, except plants. We find that with increasing divergence time the sequence similarity decreases with respect to the human protein, but the affinities and association rate constants are conserved as predicted by the protein design algorithm, FoldX. In parallel we have done computer simulations on a minimal network based on Ras-effector interactions, and our results indicate that in the absence of negative feedback, changes in kinetics that result in similar binding constants have strong consequences on network behavior. This, together with the previous results, suggests an important biological role, not only for equilibrium binding constants but also for kinetics in signaling processes involving Ras-effector interactions. Our findings are important to take into consideration in system biology approaches and simulations of biological networks