Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer's Disease in Rat and Dog.

PURPOSE: We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer's disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs. METHOD: Beagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aß levels were quantified using multiplexed selected reaction monitoring mass spectrometry. RESULTS: After systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement. CONCLUSION: This study demonstrates translational attributes of BBB-crossing Aß-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Phylogenomics of Ichneumonoidea (Hymenoptera) and implications for evolution of mode of parasitism and viral endogenization.

Ichneumonoidea is one of the most diverse lineages of animals on the planet with >48,000 described species and many more undescribed. Parasitoid wasps of this superfamily are mostly beneficial insects that attack and kill other arthropods and are important for understanding diversification and the evolution of life history strategies related to parasitoidism. Further, some lineages of parasitoids within Ichneumonoidea have acquired endogenous virus elements (EVEs) that are permanently a part of the wasp's genome and benefit the wasp through host immune disruption and behavioral control. Unfortunately, understanding the evolution of viral acquisition, parasitism strategies, diversification, and host immune disruption mechanisms, is deeply limited by the lack of a robust phylogenetic framework for Ichneumonoidea. Here we design probes targeting 541 genes across 91 taxa to test phylogenetic relationships, the evolution of parasitoid strategies, and the utility of probes to capture polydnavirus genes across a diverse array of taxa. Phylogenetic relationships among Ichneumonoidea were largely well resolved with most higher-level relationships maximally supported. We noted codon use biases between the outgroups, Braconidae, and Ichneumonidae and within Pimplinae, which were largely solved through analyses of amino acids rather than nucleotide data. These biases may impact phylogenetic reconstruction and caution for outgroup selection is recommended. Ancestral state reconstructions were variable for Braconidae across analyses, but consistent for reconstruction of idiobiosis/koinobiosis in Ichneumonidae. The data suggest many transitions between parasitoid life history traits across the whole superfamily. The two subfamilies within Ichneumonidae that have polydnaviruses are supported as distantly related, providing strong evidence for two independent acquisitions of ichnoviruses. Polydnavirus capture using our designed probes was only partially successful and suggests that more targeted approaches would be needed for this strategy to be effective for surveying taxa for these viral genes. In total, these data provide a robust framework for the evolution of Ichneumonoidea.

Limitations of Hartree-Fock with quantum resources.

The Hartree-Fock problem provides the conceptual and mathematical underpinning of a large portion of quantum chemistry. As efforts in quantum technology aim to enhance computational chemistry algorithms, the Hartree-Fock method, central to many other numerical approaches, is a natural target for quantum enhanced algorithms. While quantum computers and quantum simulation offer many prospects for the future of modern chemistry, the non-deterministic polynomial-complete Hartree-Fock problem is not a likely candidate. We highlight this fact from a number of perspectives including computational complexity, practical examples, and the full characterization of energy landscapes for simple systems.

Recent developments in the PySCF program package.

PySCF is a Python-based general-purpose electronic structure platform that supports first-principles simulations of molecules and solids as well as accelerates the development of new methodology and complex computational workflows. This paper explains the design and philosophy behind PySCF that enables it to meet these twin objectives. With several case studies, we show how users can easily implement their own methods using PySCF as a development environment. We then summarize the capabilities of PySCF for molecular and solid-state simulations. Finally, we describe the growing ecosystem of projects that use PySCF across the domains of quantum chemistry, materials science, machine learning, and quantum information science.

Systematics, Biology, and Evolution of Microgastrine Parasitoid Wasps.

The braconid parasitoid wasp subfamily Microgastrinae is perhaps the most species-rich subfamily of animals on Earth. Despite their small size, they are familiar to agriculturalists and field ecologists alike as one of the principal groups of natural enemies of caterpillars feeding on plants. Their abundance and nearly ubiquitous terrestrial distribution, their intricate interactions with host insects, and their historical association with mutualistic polydnaviruses have all contributed to Microgastrinae becoming a key group of organisms for studying parasitism, parasitoid genomics, and mating biology. However, these rich sources of data have not yet led to a robust genus-level classification of the group, and some taxonomic confusion persists as a result. We present the current status of understanding of the general biology, taxonomic history, diversity, geographical patterns, host relationships, and phylogeny of Microgastrinae as a stimulus and foundation for further study. Current progress in elucidating the biology and taxonomy of this important group is rapid and promises a revolution in the classification of these wasps in the near future.

Fragmentary Gene Sequences Negatively Impact Gene Tree and Species Tree Reconstruction.

Species tree reconstruction from genome-wide data is increasingly being attempted, in most cases using a two-step approach of first estimating individual gene trees and then summarizing them to obtain a species tree. The accuracy of this approach, which promises to account for gene tree discordance, depends on the quality of the inferred gene trees. At the same time, phylogenomic and phylotranscriptomic analyses typically use involved bioinformatics pipelines for data preparation. Errors and shortcomings resulting from these preprocessing steps may impact the species tree analyses at the other end of the pipeline. In this article, we first show that the presence of fragmentary data for some species in a gene alignment, as often seen on real data, can result in substantial deterioration of gene trees, and as a result, the species tree. We then investigate a simple filtering strategy where individual fragmentary sequences are removed from individual genes but the rest of the gene is retained. Both in simulations and by reanalyzing a large insect phylotranscriptomic data set, we show the effectiveness of this simple filtering strategy.

DiscoVista: Interpretable visualizations of gene tree discordance.

Phylogenomics has ushered in an age of discordance. Analyses often reveal abundant discordances among phylogenies of different parts of genomes, as well as incongruences between species trees obtained using different methods or data partitions. Researchers are often left trying to make sense of such incongruences. Interpretive ways of measuring and visualizing discordance are needed, both among alternative species trees and gene trees, especially for specific focal branches of a tree. Here, we introduce DiscoVista, a publicly available tool that creates a suite of simple but interpretable visualizations. DiscoVista helps quantify the amount of discordance and some of its potential causes.

Bravyi-Kitaev Superfast simulation of electronic structure on a quantum computer.

Present quantum computers often work with distinguishable qubits as their computational units. In order to simulate indistinguishable fermionic particles, it is first required to map the fermionic state to the state of the qubits. The Bravyi-Kitaev Superfast (BKSF) algorithm can be used to accomplish this mapping. The BKSF mapping has connections to quantum error correction and opens the door to new ways of understanding fermionic simulation in a topological context. Here, we present the first detailed exposition of the BKSF algorithm for molecular simulation. We provide the BKSF transformed qubit operators and report on our implementation of the BKSF fermion-to-qubits transform in OpenFermion. In this initial study of a hydrogen molecule we have compared BKSF, Jordan-Wigner, and Bravyi-Kitaev transforms under the Trotter approximation. The gate count to implement BKSF is lower than Jordan-Wigner but higher than Bravyi-Kitaev. We considered different orderings of the exponentiated terms and found lower Trotter errors than the previously reported for Jordan-Wigner and Bravyi-Kitaev algorithms. These results open the door to the further study of the BKSF algorithm for quantum simulation.

Widespread genome reorganization of an obligate virus mutualist.

The family Polydnaviridae is of interest because it provides the best example of viruses that have evolved a mutualistic association with their animal hosts. Polydnaviruses in the genus Bracovirus are strictly associated with parasitoid wasps in the family Braconidae, and evolved ∼100 million years ago from a nudivirus. Each wasp species relies on its associated bracovirus to parasitize hosts, while each bracovirus relies on its wasp for vertical transmission. Prior studies establish that bracovirus genomes consist of proviral segments and nudivirus-like replication genes, but how these components are organized in the genomes of wasps is unknown. Here, we sequenced the genome of the wasp Microplitis demolitor to characterize the proviral genome of M. demolitor bracovirus (MdBV). Unlike nudiviruses, bracoviruses produce virions that package multiple circular, double-stranded DNAs. DNA segments packaged into MdBV virions resided in eight dispersed loci in the M. demolitor genome. Each proviral segment was bounded by homologous motifs that guide processing to form mature viral DNAs. Rapid evolution of proviral segments obscured homology between other bracovirus-carrying wasps and MdBV. However, some domains flanking MdBV proviral loci were shared with other species. All MdBV genes previously identified to encode proteins required for replication were identified. Some of these genes resided in a multigene cluster but others, including subunits of the RNA polymerase that transcribes structural genes and integrases that process proviral segments, were widely dispersed in the M. demolitor genome. Overall, our results indicate that genome dispersal is a key feature in the evolution of bracoviruses into mutualists.

Networks: expanding evolutionary thinking.

Networks allow the investigation of evolutionary relationships that do not fit a tree model. They are becoming a leading tool for describing the evolutionary relationships between organisms, given the comparative complexities among genomes.

Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aß42 prompted by exogenous fibrillary or soluble Aß25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer's disease.

The "amyloid-ß (Aß) hypothesis" posits that accumulating Aß peptides (Aßs) produced by neurons cause Alzheimer's disease (AD). However, the Aßs contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)Aß25-35, an Aß42 proxy, evokes a surplus endogenous Aß42 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fAß25-35 and soluble (s)Aß25-35 on Aß42 and Aß40 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds Aßs, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAß25-35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of Aß42, while Aß40 also accrued but its secretion was unchanged. Accordingly, secreted Aß42/Aß40 ratio values rose for astrocytes and neurons. While slightly enhancing Aß40 secretion by fAß25-35-treated astrocytes, NPS 2143 specifically suppressed the fAß25-35-elicited surges of endogenous Aß42 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept Aß42/Aß40 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/ß-secretase and γ-secretase activity in fAß25-35-treated astrocytes. Compared to fAß25-35, sAß25-35 also stimulated Aß42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any Aß/CaSR-induced surplus secretion of endogenous Aß42 and hence further vicious cycles of Aß self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD.

Evidence that a synthetic amyloid-ß oligomer-binding peptide (ABP) targets amyloid-ß deposits in transgenic mouse brain and human Alzheimer's disease brain.

The synthetic ~5 kDa ABP (amyloid-ß binding peptide) consists of a region of the 228 kDa human pericentrioloar material-1 (PCM-1) protein that selectively and avidly binds in vitro Aß1-42 oligomers, believed to be key co-drivers of Alzheimer's disease (AD), but not monomers (Chakravarthy et al., (2013) [3]). ABP also prevents Aß1-42 from triggering the apoptotic death of cultured human SHSY5Y neuroblasts, likely by sequestering Aß oligomers, suggesting that it might be a potential AD therapeutic. Here we support this possibility by showing that ABP also recognizes and binds Aß1-42 aggregates in sections of cortices and hippocampi from brains of AD transgenic mice and human AD patients. More importantly, ABP targets Aß1-42 aggregates when microinjected into the hippocampi of the brains of live AD transgenic mice.

On the NP-completeness of the Hartree-Fock method for translationally invariant systems.

The self-consistent field method utilized for solving the Hartree-Fock (HF) problem and the closely related Kohn-Sham problem is typically thought of as one of the cheapest methods available to quantum chemists. This intuition has been developed from the numerous applications of the self-consistent field method to a large variety of molecular systems. However, as characterized by its worst-case behavior, the HF problem is NP-complete. In this work, we map out boundaries of the NP-completeness by investigating restricted instances of HF. We have constructed two new NP-complete variants of the problem. The first is a set of Hamiltonians whose translationally invariant Hartree-Fock solutions are trivial, but whose broken symmetry solutions are NP-complete. Second, we demonstrate how to embed instances of spin glasses into translationally invariant Hartree-Fock instances and provide a numerical example. These findings are the first steps towards understanding in which cases the self-consistent field method is computationally feasible and when it is not.

Pierid Butterflies, Legume Hostplants, and Parasitoids in Urban Areas of Southern Florida.

Are parasitoids less likely to find their Lepidoptera hosts on non-native hostplants than native hostplants? We predicted that with longer periods of coevolution between herbivores and the plants they consume, the parasitoids that provide top-down control would be more attuned to finding their hosts on native plants. To test this hypothesis, we collected immature stages of sulfur butterflies (the cloudless sulfur (Phoebis sennae) and the orange-barred sulfur (Phoebis agarithe) over a three-year period (2008-2011) from native and ornamental hostplants in the genus Senna in three different parts of the urban landscape of Miami, Florida, USA. We reared the immature specimens to pupation and either eclosion of adults or emergence of parasitoids and compared the levels of parasitization among the three areas, and among native vs. exotic hostplants. We found, contrary to our prediction, that caterpillars feeding on non-native leguminous hostplant species were more likely to be parasitized than those feeding on native hostplants. We discuss this surprising finding in the light of recent findings in other plant/herbivore/parasitoid systems.

A synthetic peptide corresponding to a region of the human pericentriolar material 1 (PCM-1) protein binds ß-amyloid (Aß1-42 ) oligomers.

We have recently reported that a ~19-kDa polypeptide, rPK-4, is a protein kinase Cs inhibitor that is 89% homologous to the 1171-1323 amino acid region of the 228-kDa human pericentriolar material-1 (PCM-1) protein (Chakravarthy et al. 2012). We have now discovered that rPK-4 binds oligomeric amyloid-ß peptide (Aß)1-42 with high affinity. Most importantly, a PCM-1-selective antibody co-precipitated Aß and amyloid ß precursor protein (AßPP) from cerebral cortices and hippocampi from AD (Alzheimer's disease) transgenic mice that produce human AßPP and Aß1-42 , suggesting that PCM-1 may interact with amyloid precursor protein/Aß in vivo. We have identified rPK-4's Aß-binding domain using a set of overlapping synthetic peptides. We have found with ELISA, dot-blot, and polyacrylamide gel electrophoresis techniques that a ~ 5 kDa synthetic peptide, amyloid binding peptide (ABP)-p4-5 binds Aß1-42 at nM levels. Most importantly, ABP-p4-5, like rPK-4, appears to preferentially bind Aß1-42 oligomers, believed to be the toxic AD-drivers. As expected from these observations, ABP-p4-5 prevented Aß1-42 from killing human SH-SY5Y neuroblastoma cells via apoptosis. These findings indicate that ABP-p4-5 is a possible candidate therapeutic for AD.

Parasitism rate, parasitoid community composition and host specificity on exposed and semi-concealed caterpillars from a tropical rainforest.

The processes maintaining the enormous diversity of herbivore-parasitoid food webs depend on parasitism rate and parasitoid host specificity. The two parameters have to be evaluated in concert to make conclusions about the importance of parasitoids as natural enemies and guide biological control. We document parasitism rate and host specificity in a highly diverse caterpillar-parasitoid food web encompassing 266 species of lepidopteran hosts and 172 species of hymenopteran or dipteran parasitoids from a lowland tropical forest in Papua New Guinea. We found that semi-concealed hosts (leaf rollers and leaf tiers) represented 84% of all caterpillars, suffered a higher parasitism rate than exposed caterpillars (12 vs. 5%) and their parasitoids were also more host specific. Semi-concealed hosts may therefore be generally more amenable to biological control by parasitoids than exposed ones. Parasitoid host specificity was highest in Braconidae, lower in Diptera: Tachinidae, and, unexpectedly, the lowest in Ichneumonidae. This result challenges the long-standing view of low host specificity in caterpillar-attacking Tachinidae and suggests higher suitability of Braconidae and lower suitability of Ichneumonidae for biological control of caterpillars. Semi-concealed hosts and their parasitoids are the largest, yet understudied component of caterpillar-parasitoid food webs. However, they still remain much closer in parasitism patterns to exposed hosts than to what literature reports on fully concealed leaf miners. Specifically, semi-concealed hosts keep an equally low share of idiobionts (2%) as exposed caterpillars.

Computational complexity in electronic structure.

In quantum chemistry, the price paid by all known efficient model chemistries is either the truncation of the Hilbert space or uncontrolled approximations. Theoretical computer science suggests that these restrictions are not mere shortcomings of the algorithm designers and programmers but could stem from the inherent difficulty of simulating quantum systems. Extensions of computer science and information processing exploiting quantum mechanics has led to new ways of understanding the ultimate limitations of computational power. Interestingly, this perspective helps us understand widely used model chemistries in a new light. In this article, the fundamentals of computational complexity will be reviewed and motivated from the vantage point of chemistry. Then recent results from the computational complexity literature regarding common model chemistries including Hartree-Fock and density functional theory are discussed.

Communication: Spin-free quantum computational simulations and symmetry adapted states.

The ideas of digital simulation of quantum systems using a quantum computer parallel the original ideas of numerical simulation using a classical computer. In order for quantum computational simulations to advance to a competitive point, many techniques from classical simulations must be imported into the quantum domain. In this article, we consider the applications of symmetry in the context of quantum simulation. Building upon well established machinery, we propose a form of first quantized simulation that only requires the spatial part of the wave function, thereby allowing spin-free quantum computational simulations. We go further and discuss the preparation of N-body states with specified symmetries based on projection techniques. We consider two simple examples, molecular hydrogen and cyclopropenyl cation, to illustrate the ideas. The methods here are the first to explicitly deal with preparing N-body symmetry-adapted states and open the door for future investigations into group theory, chemistry, and quantum simulation.

Basis Set Generation and Optimization in the NISQ Era with Quiqbox.jl.

In the noisy intermediate-scale quantum era, ab initio computation of electronic structure problems has become one of the major benchmarks for identifying the boundary between classical and quantum computational power. Basis sets play a key role in the electronic structure methods implemented on both classical and quantum devices. To investigate the consequences of single-particle basis sets, we propose a framework for more customizable basis set generation and optimization. This framework allows composite basis sets to go beyond typical basis set frameworks, such as atomic basis sets, by introducing the concept of mixed-contracted Gaussian-type orbitals. These basis set generations set the stage for more flexible variational optimization of basis set parameters. To realize this framework, we have developed an open-source software package named "Quiqbox" in the Julia programming language. We demonstrate various examples of using Quiqbox for basis set optimization and generation, ranging from optimizing atomic basis sets on the Hartree-Fock level, preparing the initial state for variational quantum eigensolver computation, and constructing basis sets with completely delocalized orbitals. We also include various benchmarks of Quiqbox for basis set optimization and ab initial electronic structure computation.