Independent Fragments Research Articles

Proximity-Dependent Activation of Split DNAzyme Kinase.

Binary (also known as split) nucleic acid enzymes have emerged as novel tools in biosensors. We report a new split strategy to split the DNAzyme kinase into two independent and non-functional fragments, denoted Dk1sub and Dk1enz. In the presence of the specific target, their free ends are brought sufficiently close to interact with each other without the formation of Watson-Crick base pairings between Dk1sub and Dk1enz, thus allowing the DNA phosphorylation reaction. We term this approach proximity-dependent activation of split DNAzyme kinase (ProxSDK). The utility of ProxSDK is demonstrated by engineering a biosensing system that is capable of measuring specific DNA-protein interactions. We envision that the approach described herein will find useful applications in biosensing, imaging, and clinical diagnosis.

Synthesis, characterization and reactivity of a Mn(III)–hydroxido complex as a biomimetic model for lipoxygenase

Manganese hydroxido (Mn–OH) complexes supported by a tripodal N,N′,N″-[nitrilotris(ethane-2,1-diyl)]tris(P,P-diphenylphosphinic amido) ([poat]3−) ligand have been synthesized and characterized by spectroscopic techniques including UV–vis and electron paramagnetic resonance (EPR) spectroscopies. X-ray diffraction (XRD) methods were used to confirm the solid-state molecular structures of {Na2[MnIIpoat(OH)]}2 and {Na[MnIIIpoat(OH)]}2 as clusters that are linked by the electrostatic interactions between the sodium counterions and the oxygen atom of the ligated hydroxido unit and the phosphinic (P=O) amide groups of [poat]3−. Both clusters feature two independent monoanionic fragments in which each contains a trigonal bipyramidal Mn center that is comprised of three equatorial deprotonated amide nitrogen atoms, an apical tertiary amine, and an axial hydroxido ligand. XRD analyses of {Na[MnIIIpoat(OH)]}2 also showed an intramolecular hydrogen bonding interaction between the MnIII–OH unit and P=O group of [poat]3−. Crystalline {Na[MnIIIpoat(OH)]}2 remains as clusters with Na+---O interactions in solution and is unreactive toward external substrates. However, conductivity studies indicated that [MnIIIpoat(OH)]− generated in situ is monomeric and reactivity studies found that it is capable of cleaving C-H bonds, illustrating the importance of solution-phase speciation and its direct effect on chemical reactivity.Synopsis: Manganese–hydroxido complexes were synthesized to study the influence of H-bonds in the secondary coordination sphere and their effects on the oxidative cleavage of substrates containing C-H bonds.

Structural basis for antibody recognition of the proximal MUC16 ectodomain

BackgroundMucin 16 (MUC16) overexpression is linked with cancer progression, metastasis, and therapy resistance in high grade serous ovarian cancer and other malignancies. The cleavage of MUC16 forms independent bimodular fragments, the shed tandem repeat sequence which circulates as a protein bearing the ovarian cancer biomarker (CA125) and a proximal membrane-bound component which is critical in MUC16 oncogenic behavior. A humanized, high affinity antibody targeting the proximal ectodomain represents a potential therapeutic agent against MUC16 with lower antigenic potential and restricted human tissue expression.ResultsHere, we demonstrate the potential therapeutic versatility of the humanized antibody as a monoclonal antibody, antibody drug conjugate, and chimeric antigen receptor. We report the crystal structures of 4H11-scFv, derived from an antibody specifically targeting the MUC16 C-terminal region, alone and in complex with a 26-amino acid MUC16 segment resolved at 2.36 Å and 2.47 Å resolution, respectively. The scFv forms a robust interaction with an epitope consisting of two consecutive β-turns and a β-hairpin stabilized by 2 hydrogen bonds. The VH-VL interface within the 4H11-scFv is stabilized through an intricate network of 11 hydrogen bonds and a cation-π interaction.ConclusionsTogether, our studies offer insight into antibody-MUC16 ectodomain interaction and advance our ability to design agents with potentially improved therapeutic properties over anti-CA125 moiety antibodies.

Human-Induced Forest Fragmentation in Trabzon, Eastern Black Sea Region, Türkiye: A Case Study

Due to the geographical structure of the Eastern Black Sea Region, agricultural activities are carried out in high-sloped areas that should ideally be used solely for forestry purposes. The region is characterized by an intricate intertwining of forested areas, agricultural fields, pasture lands, and residential areas, giving rise to a distinct and unique way of life. Within this framework, forest resources have been constantly under pressure and fragmented. This study, therefore, aims to determine the fragmentation status of forests, particularly due to various anthropogenic activities, such as agricultural activities, using the example of Trabzon Province in the Eastern Black Sea Region of Türkiye. Utilizing Geographic Information Systems (GIS), a comprehensive “forest fragmentation map” was meticulously crafted, drawing upon the land-use plans and cadastral maps specific to the study area. Spatial land metrics were calculated using patch analysis. In the study area, there is a total of 31,153.2 hectares of registered state forests. These forests consist of 423 separate and independent fragments. The average forest fragment size in the area is 73.6 hectares. The smallest fragment measures 0.01 hectares (100 square meters), while the largest one covers an area of 18,002 hectares. The area-weighted average figure index of the forest fragments is 9.4. This study quantified fragmented forests, providing evidence of forest fragmentation due to various anthropogenic activities, primarily agricultural activities. This study also proposed an integrated planning approach for the management of fragmented forests.

RNA independent fragment partition method based on deep learning for RNA secondary structure prediction

The non-coding RNA secondary structure largely determines its function. Hence, accuracy in structure acquisition is of great importance. Currently, this acquisition primarily relies on various computational methods. The prediction of the structures of long RNA sequences with high precision and reasonable computational cost remains challenging. Here, we propose a deep learning model, RNA-par, which could partition an RNA sequence into several independent fragments (i-fragments) based on its exterior loops. Each i-fragment secondary structure predicted individually could be further assembled to acquire the complete RNA secondary structure. In the examination of our independent test set, the average length of the predicted i-fragments was 453 nt, which was considerably shorter than that of complete RNA sequences (848 nt). The accuracy of the assembled structures was higher than that of the structures predicted directly using the state-of-the-art RNA secondary structure prediction methods. This proposed model could serve as a preprocessing step for RNA secondary structure prediction for enhancing the predictive performance (especially for long RNA sequences) and reducing the computational cost. In the future, predicting the secondary structure of long-sequence RNA with high accuracy can be enabled by developing a framework combining RNA-par with various existing RNA secondary structure prediction algorithms. Our models, test codes and test data are provided at https://github.com/mianfei71/RNAPar.

Increasing the Scalability of Toxin-Intein Orthogonal Combinations.

Inteins are proteins embedded into host proteins from which they are excised in an autocatalytic reaction. Specifically, split inteins are separated into two independent fragments that reconstitute the host protein during the catalytic process. We recently developed a novel strategy for the specific killing of pathogenic and antibiotic resistant bacteria based on toxin-intein combinations. Bacterial type II toxin-antitoxin systems are protein modules in which the toxin can provoke cell death whereas the antitoxin inhibits toxin activity. Although our previous system was based on a split intein (iDnaE) and the CcdB toxin, we demonstrated that iDnaE is able to reconstitute four different toxins. To expand the applicability of our system by widening the repertoire of toxin-intein combinations for complex set-ups, we introduced a second intein, iDnaX, which was artificially split. We demonstrate that iDnaX is able to reconstitute the four toxins, and we manage to reduce its scar size to facilitate their use. In addition, we prove the orthogonality of both inteins (iDnaE and iDnaX) through a toxin reconstitution assay, thus opening the possibility for complex set-ups based on these toxin-intein modules. This could be used to develop specific antimicrobial and other biotechnological applications.

A toxin-deformation dependent inhibition mechanism in the T7SS toxin-antitoxin system of Gram-positive bacteria

Toxin EsaD secreted by some S. aureus strains through the type VII secretion system (T7SS) specifically kills those strains lacking the antitoxin EsaG. Here we report the structures of EsaG, the nuclease domain of EsaD and their complex, which together reveal an inhibition mechanism that relies on significant conformational change of the toxin. To inhibit EsaD, EsaG breaks the nuclease domain of EsaD protein into two independent fragments that, in turn, sandwich EsaG. The originally well-folded ββα-metal finger connecting the two fragments is stretched to become a disordered loop, leading to disruption of the catalytic site of EsaD and loss of nuclease activity. This mechanism is distinct from that of the other Type II toxin-antitoxin systems, which utilize an intrinsically disordered region on the antitoxins to cover the active site of the toxins. This study paves the way for developing therapeutic approaches targeting this antagonism.

Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.

Down syndrome (DS) is caused by human chromosome 21 (HSA21) trisomy. It is characterized by a poorly understood intellectual disability (ID). We studied two mouse models of DS, one with an extra copy of the <i>Dyrk1A</i> gene (189N3) and the other with an extra copy of the mouse Chr16 syntenic region (Dp(16)1Yey). RNA-seq analysis of the transcripts deregulated in the embryonic hippocampus revealed an enrichment in genes associated with chromatin for the 189N3 model, and synapses for the Dp(16)1Yey model. A large-scale yeast two-hybrid screen (82 different screens, including 72 HSA21 baits and 10 rebounds) of a human brain library containing at least 10<sup>7</sup> independent fragments identified 1,949 novel protein-protein interactions. The direct interactors of HSA21 baits and rebounds were significantly enriched in ID-related genes (<i>P</i>-value < 2.29 × 10<sup>-8</sup>). Proximity ligation assays showed that some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic density, in a protein network at the dendritic spine postsynapse. We located HSA21 DYRK1A and DSCAM, mutations of which increase the risk of autism spectrum disorder (ASD) 20-fold, in this postsynaptic network. We found that an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds comprising receptors, ion channels and associated signaling proteins, or DYRK1A. The DYRK1A-DSCAM interaction domain is conserved in <i>Drosophila</i> and humans. The postsynaptic network was found to be enriched in proteins associated with ARC-related synaptic plasticity, ASD, and late-onset Alzheimer's disease. These results highlight links between DS and brain diseases with a complex genetic basis.

Dynamical Synthesis of ^{4}He in the Scission Phase of Nuclear Fission.

In the exothermic process of fission decay, an atomic nucleus splits into two or more independent fragments. Several aspects of nuclear fission are not properly understood, in particular the formation of the neck between the nascent fragments, and the subsequent mechanism of scission into two or more independent fragments. Using an implementation of time-dependent density functional theory, based on a relativistic energy density functional and including pairing correlations, we analyze the final phase of the process of induced fission of ^{240}Pu, and show that the timescale of neck formation coincides with the assembly of two α-like clusters. Because of its much larger binding energy, the dynamical synthesis of ^{4}He in the neck predominates over other light clusters, e.g., ^{3}H and ^{6}He. At the instant of scission the neck ruptures exactly between the two α-like clusters, which separate because of the Coulomb repulsion and are eventually absorbed by the two emerging fragments. The mechanism of light charged clusters formation at scission could also be linked to ternary fission.

Abstract 1836: Structural basis for recognition of MUC16 expressed in various cancers

Abstract Background: Overexpressed Mucin 16 (MUC16) is highly related with cancer progression, metastasis, and therapy resistance in multiple malignancies. The proteolytic cleavages of MUC16 form independent bimodular fragments, a circulating shed form known as an ovarian cancer biomarker (CA 125) and a C-terminal tail-connected juxtamembrane region as an unshed form which is critical in determining the unique mechanistic roles of MUC16 and therapeutic interventions. Effective neutralizing antibody for MUC16-positive solid cancers is urgently needed for earlier diagnosis and immunotherapeutic approaches. Methods: The novel 4H11-scFv (single chain antibody) targeting MUC16-juxtamembrane was optimized for mammalian cell usage and Liter-scale cultures of HEK293T were infected with high-titer lentiviral stocks expressing the 4H11-scFv and the recombinant proteins were purified by a series of purification process and prepared for further characterization and crystallization. The sequence corresponding to human MUC16-juxtamembrane was cloned with maltose binding protein (MBP) and expressed by the bacterial system. The purified MBP-fused-MUC16 was prepared for co-crystallization with 4H11-scFv. A series of biochemical studies are performed: Thermal stability measurement of 4H11-scFv, MBP-pull down, Isothermal titration calorimetry (ITC) for interaction analysis, bioactivity of Alexa-labeled 4H11-scFv, analytical size-exclusion chromatography, multi-mutagenesis studies at the interface of 4H11-scFv-MUC16 complex. Crystallizations were performed using high-throughput crystallization screen kits, followed by extensive manual optimization. X-ray diffraction data were collected at the Advanced Photon Source (APS) and processed with HKL2000, PHENIX, CCP4 suite package and COOT. Results: We determined the crystal structures of 4H11-scFv at 2.36 Å and 4H11-scFv-MUC16 at 2.47 Å resolutions, respectively. Structural analysis of a 4H11-scFv demonstrated that all six complementarity-determining regions (CDRs) are composed of 5 loop-like coiled coil regions and 1 short-helix in VH (Heavy chain), while juxtamembrane portion showing flexible loop regions with β-Turns. The complex was stabilized through extensive hydrogen bond-mediated interaction, salt bridge, and cation-π interaction. We identified some specific residues of MUC16, critical to form the complex, from mutagenesis studies. Biochemical analysis demonstrated the 4H11-scFv potently neutralizes MUC16 and stable at the cancer microenvironmental and endosomal pH with a possibility of pre-clinical diagnosis/treatment in various cancers. Conclusion: We investigate the structures and the neutralizing mechanisms for 4H11-scFv targeting the MUC16. Our study offer insight into antibody to neutralize the non-cleaved cell surface retained portion of MUC16 and advance our ability to design anti-MUC16 antibody with improved therapeutic properties. Citation Format: Kwangkook Lee, Kay Perry, Oladapo O. Yeku, David R. Spriggs. Structural basis for recognition of MUC16 expressed in various cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1836.

Until death do us part: abundance and survival of necrophagous beetle species associated with fox scats in fragmented landscapes

Forestry companies have replaced and fragmented the native landscapes, generating a large number of unpaved roads, which can have a negative effect on non-flying invertebrates. Polynoncus bullatus is a common necrophagous beetle species depend on fox scats present on unpaved roads in fragmented landscapes in central Chile. Here, the effect of different habitat types (native forest, clear-cuts and unpaved roads) on the abundance of Lycalopex culpaeus scats as well as abundance and survival of P. bullatus in the fragmented landscape was evaluated. Scats and beetles were counted in seven independent fragments during 6 months and through sampling transects. Both responses and factors were associated with GLM, whereas survival was evaluated with a Kaplan-Meier test. Higher scats abundance was found on unpaved roads than other habitat types. Higher P. bullatus abundance was also significantly associated with unpaved roads than clear-cuts and native forest fragments. An additive model between habitat type and scat abundance was correlated with beetle abundance. Survival was significantly lower in unpaved roads, generating up to 42 % of beetles road-killed. Lycalopex culpaeus response positively to fragmentation defecating more on unpaved roads because foxes use it to move through the landscape. This fact attracts more P. bullatus individuals, being run-over by cars and trucks, representing an ecological trap for beetles. This interaction can be predictable and modeled for any period, length or road type avoiding potential massive road-kill events. Implications for insect conservation. Common and threatened invertebrate species are run-over when minor roads cross valuable natural or protected areas, evidencing the need of advance in road designs compatible with their conservation and mitigating negative impacts of forestry.

A multi-criteria approach to time cheating in the divisible load scheduling

The divisible load scheduling (DLS) can be considered as a special class of scheduling model in the area of distributed and parallel systems. According to the DLS, the computations and communications can be divided into some arbitrarily independent fragments in which each fragment can be computed independently by a processor. The basic assumptions of the traditional DLS models are $$w_j\le w_{j+1}$$ and $$z_j\le z_{j+1}$$ for all $$j\le m$$ ( $$z_j$$ and $$w_j$$ are the rates of communication and computation of the jth processor, respectively). These presumptions are not acceptable if the processors do not report their real rates of communication or computation. The problem that a processor may not report its real rates of communication or computation is called cheating problem. This paper has a multi-criteria approach to the time cheating problem in the area of the DLS. The multi-criteria DLS model is a new paradigm in the area of DLS and its applications. The main contribution of this paper is to reduce the effects of time cheating in a DLS scheduling model.

Thematic organization of instructional texts as a linguistic basis for the acquisition of knowledge by an intelligent agent

The article examines the thematic organization of instructional texts in the aspect of problems relevant to work on the creation of a cognitive assistant. The purpose of the assistant is to provide a user with the necessary information to follow the rules of a particular scenario to successfully achieve a goal according to the search query. The query containing certain keywords, further specified as the task being solved, is focused on a detailed set of topics which mark the subject areas reflected in the scenario. The authors of the article provide a review of some linguistic works devoted to the issues of theme-rhematic structuring of a produced text and its compression within the limits of keywords. The importance of the description of the text’s thematic chains, to obtain the detailed objective information on its thematic structure, is emphasized. When comparing the list of keywords identified by the automatic system TextApplianсe in a collection of Internet-extracted instructional texts retrieved from the Internet with the results of hand-held analysis of these texts, to determine the place of various nominative units in the text’s thematic organization, the authors consider the most significant characteristics of a keyword shown in different nominative units to varying degrees. This is a high indicator of a text identifier, content capacity, and communicative significance of a word or a substantive phrase as a marker of important information for a recipient. Defining keywords in whole instructional texts and in relatively independent text fragments (subtexts) that describe individual stages of the user’s goal achievement (for example, the stages of selecting a car, its inspection, making a transaction, car registration) makes it possible to improve the quality of scenario identification in the Network. Extracting keywords along with their context allows for the creation of a recommendations’ database for users automatically. The significance of the theme-rhematic text structure analysis, as a sign for its modeling in the sign picture of the world, is revealed.

Splitting aptamers and nucleic acid enzymes for the development of advanced biosensors.

In analogy to split-protein systems, which rely on the appropriate fragmentation of protein domains, split aptamers made of two or more short nucleic acid strands have emerged as novel tools in biosensor set-ups. The concept relies on dissecting an aptamer into a series of two or more independent fragments, able to assemble in the presence of a specific target. The stability of the assembled structure can further be enhanced by functionalities that upon folding would lead to covalent end-joining of the fragments. To date, only a few aptamers have been split successfully, and application of split aptamers in biosensing approaches remains as promising as it is challenging. Further improving the stability of split aptamer target complexes and with that the sensitivity as well as efficient working modes are important tasks. Here we review functional nucleic acid assemblies that are derived from aptamers and ribozymes/DNAzymes. We focus on the thrombin, the adenosine/ATP and the cocaine split aptamers as the three most studied DNA split systems and on split DNAzyme assemblies. Furthermore, we extend the subject into split light up RNA aptamers used as mimics of the green fluorescent protein (GFP), and split ribozymes.

P-Stereogenic Amino-Phosphines as Chiral Ligands: From Privileged Intermediates to Asymmetric Catalysis.

Among chiral phosphines, P-stereogenic phosphines provide unparalleled activity and selectivity and have thus emerged as "state-of-the-art" ligands for asymmetric hydrogenation and other industrially relevant processes. However, the synthesis of this type of ligand implies lengthy multistep sequences, which are a hurdle for many laboratories. There is a lack of methods for the rapid construction of P-stereogenic phosphine ligands. In this respect, P-stereogenic synthons that can be rapidly incorporated into a given ligand scaffold are highly desirable. Over the last 10 years, our group has unveiled that P-stereogenic aminophosphines can be rapidly assembled in a convenient fashion from the corresponding primary aminophosphine and/or the corresponding phosphinous acid.Using cis-1-amino-2-indanol as chiral auxiliary, we devised a multigram synthesis of tert-butylmethylaminophosphine borane and tert-butylmethylphosphinous acid borane, which are key intermediate synthons. Primary aminophosphine works as nucleophilic intermediates at nitrogen. From this synthon, aminodiphosphine (MaxPHOS) and secondary imino phosphoranes (SIP) ligands were synthesized. These ligands exhibit a tautomeric equilibrium between the PH and NH forms, and because of that, they do not undergo oxidation in air. NH/PH tautomerism does not jeopardize their configurational stability, and most importantly, in the presence of a metal source, the equilibrium is shifted toward the NH form, thus allowing coordination through phosphorus. Rh-MaxPHOS and Rh-SIP complexes have been used in asymmetric hydrogenation and [2 + 2 + 2] cycloaddition reactions with outstanding results. On the other hand, P-stereogenic phosphinous acid, upon activation, serves as an electrophilic reagent with amine nucleophiles, allowing SN2 reactions at phosphorus with complete inversion of configuration. This coupling technology exhibits a great potential because it allows the incorporation of the P*-phosphine fragment in numerous ligand structures, provided there is an amino group with which to react. In a mild and efficient process, phosphinous acid has been coupled to hydrazine to yield C2 diphosphines and to chiral benzoimidazole-amines to yield P-stereogenic benzoimidazole-phosphine ligands. The most powerful ligand system, however, arises from the condensation of three independent fragments: our phosphinous acid borane, an amino acid, and an amino alcohol, which yields a library of phosphino-oxazoline ligands named MaxPHOX. The corresponding Ir-MaxPHOX catalyst library was applied with excellent results in the asymmetric hydrogenation of α,β-unsaturated esters, 2-aryl allyl phthalimides, unfunctionalized tetrasubstituted alkenes, cyclic enamides, and N-aryl and N-methyl imines. It also has found application in asymmetric isomerization of alkenes.Overall, we developed key P-stereogenic building blocks that can be incorporated stereospecifically to ligand scaffolds and demonstrated that integration of the P*-aminophosphine fragment in a given catalytic system provides structural diversity that can be a critical contribution to obtaining optimal results and selectivity.

Global seismic horizon interpretation based on data mining — A new tool for seismic geomorphologic study

Accurate and efficient seismic horizon interpretation is important for seismic geomorphology study. By integrating the improved density-based clustering method to generate horizon patches and a heuristic combining strategy to merge horizon patches, we have developed a novel data mining approach to automatically extract globally optimal horizons for detailed geomorphologic interpretation. First, the application of improved density-based clustering method has distinct merits in calculation speed and avoiding the phenomenon of mis-ties. We design a heuristic combining strategy to effectively combine the horizon patches. It is also able to ameliorate the problem of mis-ties that frequently occurs in horizon picking. Second, the proposed algorithm can identify abnormal unit in terms of independent horizon fragments. Furthermore, the introduced method is capable of detecting small-scale seismic geomorphologic features. The applications indicate good real-time performance of our new global interpretation algorithm in automated-tracking speed and quality. Our method can resolve the problem of mis-ties in cases of complex seismic reflection to a certain extent. Besides, not only are a series of channels separately recognized, but also small-scale meandering rivers are clearly mapped. Our algorithm is capable of adding more geologic information and realizing a better showcase of geomorphologic features.

Refining the high-fidelity archaeointensity curve for western Europe over the past millennium: analysis of Tuscan architectural bricks (Italy)

Abstract New archaeointensity results were obtained from 14 groups of baked-brick fragments collected in and around Pisa (Tuscany, Italy). The fragments were assembled from civil and religious buildings whose dating of construction or renovation, over the past millennium, was constrained by documentary sources. This collection, analysed using the Triaxe protocol, was found particularly suitable for intensity experiments, with a success rate of c. 84% corresponding to 276 fruitful specimens associated with 125 independent brick fragments. The Tuscan data clearly show a peak in intensity at the transition between the sixteenth and seventeenth centuries. They are also in very good agreement with, and complementary to, a dense dataset previously obtained in France. Considering the results available within a 700 km radius of Beaune (between Paris and Pisa), all satisfying a set of quality criteria, a mean geomagnetic field intensity variation curve was constructed for the past millennium using a newly developed transdimensional Bayesian technique. This curve, which thus incorporates the new Tuscan results, allows a better recognition of three intensity peaks (during the twelfth century, the fourteenth century and around AD 1600) in western Europe. The detail of this curve is a clear illustration of the centennial-scale resolution that can be achieved using accurate archaeointensity data.

USE OF GENERALIZED SCHEMES IN TEACHING PROGRAMMING

The article discusses the use of generalized schemes as language independent fragments of algorithmic problem solving in the design of training materials, the generation of sets of multilevel test tasks. The use of schemes in teaching programming develops in schoolchildren the ability to formalize a problem, to correlate its solution with the basic algorithm, and to establish block-modular programming skills.

Multilayer Divide-Expand-Consolidate Coupled-Cluster Method: Demonstrative Calculations of the Adsorption Energy of Carbon Dioxide in the Mg-MOF-74 Metal-Organic Framework.

The implementation and evaluation of a multilayer extension of the divide-expand-consolidate (DEC) scheme within the LSDalton program is presented. The DEC scheme is a linear-scaling, fragmentation-based local coupled-cluster (CC) method that provides a means of overcoming the scaling wall associated with canonical CC electronic structure calculations on large molecular systems. Taking advantage of the local nature of correlation effects, the correlation energy for the full molecule is calculated from a set of independent fragments using localized molecular orbitals. However, when only a small subsystem of a larger system is of interest, for example, adsorption sites or catalytically active sites, the majority of the computational time may be spent evaluating the correlation energy of fragments which have little effect on the properties in the area of interest (AOI). The multilayer DEC (ML-DEC) scheme addresses this by taking advantage of the independent nature of the fragments in order to evaluate the correlation energy of various regions of the system at different levels of theory. Regions far from the AOI are evaluated at lower (cheaper) levels of theory such as Hartree-Fock (HF) or Møller-Plesset second-order perturbation theory (MP2), while the area immediately surrounding the AOI is treated with a higher level CC model. Through the ML-DEC scheme, the computational cost of CC calculations on these types of systems can be significantly reduced while maintaining the accuracy of higher-level calculations. Results from HF/RI-MP2 and RI-MP2/CCSD ML-DEC calculations of the binding energy of a fatty acid dimer are presented. We find that the ML-DEC scheme is capable of reproducing DEC energy differences at a target level of theory, provided that the region treated at the target level of theory is chosen to be sufficiently large. Time-to-solution is found to be significantly reduced, particularly in the RI-MP2/CCSD calculations. Finally, the ML-DEC scheme is applied to the calculation of CO2 adsorption in a Mg-MOF-74 channel.

Significance testing and genomic inflation factor using high‐density genotypes or whole‐genome sequence data

Significance testing for genome‐wide association study (GWAS) with increasing SNP density up to whole‐genome sequence data (WGS) is not straightforward, because of strong LD between SNP and population stratification. Therefore, the objective of this study was to investigate genomic control and different significance testing procedures using data from a commercial pig breeding scheme. A GWAS was performed in GCTA with data of 4,964 Large White pigs using medium density, high density or imputed whole‐genome sequence data, fitting a genomic relationship matrix based on a leave‐one–chromosome‐out approach to account for population structure. Subsequently, genomic inflation factors were assessed on whole‐genome level and the chromosome level. To establish a significance threshold, permutation testing, Bonferroni corrections using either the total number of SNPs or the number of independent chromosome fragments, and false discovery rates (FDR) using either the Benjamini–Hochberg procedure or the Benjamini and Yekutieli procedure were evaluated. We found that genomic inflation factors did not differ between different density genotypes but do differ between chromosomes. Also, the leave‐one‐chromosome‐out approach for GWAS or using the pedigree relationships did not account appropriately for population stratification and gave strong genomic inflation. Regarding different procedures for significance testing, when the aim is to find QTL regions that are associated with a trait of interest, we recommend applying the FDR following the Benjamini and Yekutieli approach to establish a significance threshold that is adjusted for multiple testing. When the aim is to pinpoint a specific mutation, the more conservative Bonferroni correction based on the total number of SNPs is more appropriate, till an appropriate method is established to adjust for the number of independent tests.