C8-Arylguanine Modified Hairpin Oligonucleotides: Synthesis, Conformational Analysis, and Tools for the Investigation of Z-DNA Formation

Z-DNA is the only DNA conformation that has a left-handed helical twist. Z-DNA has been implicated in carcinogenesis from its role in gene expression. Z-DNA formation has been linked to mutagenesis since it may play a role in genetic instability and can induce gene deletions. However, the specific biological role for Z-DNA in vivo remains uncertain. Arylhydrazines are carcinogenic compounds that are known to form DNA adducts, although it is unknown how DNA adduct formation is related to their carcinogenicity. Previous work in our lab has demonstrated that the formation of C8-arylguanine DNA adducts, derived from arylhydrazines, shifts the B /Z DNA equilibrium toward the Z-DNA conformation in d(CG)5 sequences. However, our previous work examined the effect of two adducts in the duplex and it was unclear whether the two base modifications were working together to cause the equilibrium shift toward the Z-DNA conformation. Here we sought to determine the conformational effects of a hairpin oligonucleotide sequence (d(CG) 5T4(CG)5) containing only one C8-arylguanine modified base to compare with our previous results.;Synthesis of C8-arylguanine modified hairpin oligonucleotides began at the nucleoside level and then the C8-aryl-2\u27-deoxyguanosine phosphoramidite was incorporated into a hairpin sequence (d(5\u27CGCGCG*CGCGTTTTCGCGCGCGCG3\u27) where G*= C8-arylguanine). The conformational effects of a single C8-arylguanine modification on the hairpin oligonucleotide were determined and quantitated by a combination of NMR, CD and molecular modeling. The unmodified hairpin and the previously studied unmodified double-stranded oligonucleotide were conformationally similar and each required ∼3 M NaCl to yield a B-/Z-DNA ratio of 1:1. The introduction of a single C8-arylguanine modification significantly reduced the NaCl concentration needed to produce a 1:1 B-/Z-DNA ratio in the hairpin. Further, the addition of MgCl2 and spermine to the C8-arylguanine modified hairpin shifts the B-/Z-DNA equilibrium such that the Z form predominated under physiological conditions. NMR and molecular modeling indicated the conformational effects produced by the C8-arylguanine modification occurred locally at the site of modification while CD data demonstrated that the C8-arylguanine modified base destabilized the B form. Additionally, the data show that adopting the Z-DNA conformation is preferred over denaturation to the single-stranded form. Finally, the conformational effects of the C8-arylguanine modifications were not additive and the introduction of any such modifications drive Z-DNA formation under physiological conditions, which may provide a novel carcinogenesis mechanism where DNA adducts confer their carcinogenicity through a Z-DNA mediated mechanism

Matreex: Compact and Interactive Visualization for Scalable Studies of Large Gene Families.

Studying gene family evolution strongly benefits from insightful visualizations. However, the ever-growing number of sequenced genomes is leading to increasingly larger gene families, which challenges existing gene tree visualizations. Indeed, most of them present users with a dilemma: display complete but intractable gene trees, or collapse subtrees, thereby hiding their children's information. Here, we introduce Matreex, a new dynamic tool to scale up the visualization of gene families. Matreex's key idea is to use "phylogenetic" profiles, which are dense representations of gene repertoires, to minimize the information loss when collapsing subtrees. We illustrate Matreex's usefulness with three biological applications. First, we demonstrate on the MutS family the power of combining gene trees and phylogenetic profiles to delve into precise evolutionary analyses of large multicopy gene families. Second, by displaying 22 intraflagellar transport gene families across 622 species cumulating 5,500 representatives, we show how Matreex can be used to automate large-scale analyses of gene presence-absence. Notably, we report for the first time the complete loss of intraflagellar transport in the myxozoan Thelohanellus kitauei. Finally, using the textbook example of visual opsins, we show Matreex's potential to create easily interpretable figures for teaching and outreach. Matreex is available from the Python Package Index (pip install Matreex) with the source code and documentation available at https://github.com/DessimozLab/matreex

Microscopic origins of the ferromagnetic exchange coupling in oxoverdazyl-based Cu(II) complex

The exchange channels governing the experimentally reported coupling constant Jexpt=6 cm−1 value in the verdazyl-ligand based Cu II complex Cu hfac 2 imvdz are inspected using wave function-based difference dedicated configuration interaction calculations. The interaction between the two spin 1/2 holders is summed up in a unique coupling constant J. Nevertheless, by gradually increasing the level of calculation, different mechanisms of interaction are turned on step by step. In the present system, the calculated exchange interaction then appears alternatively ferromagnetic/ antiferromagnetic/ferromagnetic. Our analysis demonstrates the tremendously importance of some specific exchange mechanisms. It is actually shown that both parts of the imvdz ligand simultaneously influence the ferromagnetic behavior which ultimately reaches Jcalc=6.3 cm−1, in very good agreement with the experimental value. In accordance with the alternation of J, it is shown that the nature of the magnetic behavior results from competing channels. First, an antiferromagnetic contribution can be essentially attributed to single excitations involving the network localized on the verdazyl part. In contrast, the ligand-to-metal charge transfer LMCT involving the imidazole moiety affords a ferromagnetic contribution. The distinct nature / of the mechanisms is responsible for the net ferromagnetic behavior. The intuitively innocent part of the verdazyl-based ligands is deeply reconsidered and opens new routes into the rational design of magnetic object

Key issues in innovation and knowledge management in the finance and construction sectors

In today's dynamic global trading environment it is vital that firms develop dynamic capabilities allowing them to stay ahead of the competition. It is generally accepted that innovation can provide a firm with sustainable competitive advantage. Tacit knowledge, the type which resides in humans and organisational routines, has also been identified as a means of sustainable competitive advantage. An examination of how teams, units and organisations build dynamic capabilities from innovations through harnessing and exploiting knowledge for organisational benefits will be made. A comparison will be made between the UK construction and finance industries. The UK construction industry is often seen as underachieving in terms of meeting its own needs and those of its client. In contrast, the finance sector is perceived as being highly innovative one of the UK's most profitable industries. Current innovation and knowledge management practices in both industries will be examined, plus the relationships between Innovation and Knowledge Management in each sector will be analysed using a new conceptual framework. The key challenges likely to be faced by the researcher as well as proposed research methodology are also documented. Evidence from the literature points to innovation as a complex social process. Similarly, it is suggested that a robust research methodology for uncovering complex social processes in innovation and knowledge management will benefit from the employment of qualitative research approaches

Closed-Form Bayesian Inferences for the Logit Model via Polynomial Expansions

Articles in Marketing and choice literatures have demonstrated the need for incorporating person-level heterogeneity into behavioral models (e.g., logit models for multiple binary outcomes as studied here). However, the logit likelihood extended with a population distribution of heterogeneity doesn't yield closed-form inferences, and therefore numerical integration techniques are relied upon (e.g., MCMC methods). We present here an alternative, closed-form Bayesian inferences for the logit model, which we obtain by approximating the logit likelihood via a polynomial expansion, and then positing a distribution of heterogeneity from a flexible family that is now conjugate and integrable. For problems where the response coefficients are independent, choosing the Gamma distribution leads to rapidly convergent closed-form expansions; if there are correlations among the coefficients one can still obtain rapidly convergent closed-form expansions by positing a distribution of heterogeneity from a Multivariate Gamma distribution. The solution then comes from the moment generating function of the Multivariate Gamma distribution or in general from the multivariate heterogeneity distribution assumed. Closed-form Bayesian inferences, derivatives (useful for elasticity calculations), population distribution parameter estimates (useful for summarization) and starting values (useful for complicated algorithms) are hence directly available. Two simulation studies demonstrate the efficacy of our approach.Comment: 30 pages, 2 figures, corrected some typos. Appears in Quantitative Marketing and Economics vol 4 (2006), no. 2, 173--20

Phylogenetic approaches to identifying fragments of the same gene, with application to the wheat genome.

As the time and cost of sequencing decrease, the number of available genomes and transcriptomes rapidly increases. Yet the quality of the assemblies and the gene annotations varies considerably and often remains poor, affecting downstream analyses. This is particularly true when fragments of the same gene are annotated as distinct genes, which may cause them to be mistaken as paralogs. In this study, we introduce two novel phylogenetic tests to infer non-overlapping or partially overlapping genes that are in fact parts of the same gene. One approach collapses branches with low bootstrap support and the other computes a likelihood ratio test. We extensively validated these methods by (i) introducing and recovering fragmentation on the bread wheat, Triticum aestivum cv. Chinese Spring, chromosome 3B; (ii) by applying the methods to the low-quality 3B assembly and validating predictions against the high-quality 3B assembly; and (iii) by comparing the performance of the proposed methods to the performance of existing methods, namely Ensembl Compara and ESPRIT. Application of this combination to a draft shotgun assembly of the entire bread wheat genome revealed 1221 pairs of genes that are highly likely to be fragments of the same gene. Our approach demonstrates the power of fine-grained evolutionary inferences across multiple species to improving genome assemblies and annotations. An open source software tool is available at https://github.com/DessimozLab/esprit2. Supplementary data are available at Bioinformatics online

Commonwealth of Massachusetts Mill Building Repurposing Pilot Project (Twist Mill - Athol, MA)

The purpose of the UMass Amherst Department of Landscape Architecture and Regional Planning’s participation in this project is to establish a redevelopment action plan that incorporates the ownership’s clear vision for reuse of the site, proposes solutions to various obstacles that have hindered progress, and serves as a guiding model in terms of improving the feasibility of similar projects throughout the state. The project team gathered information from a variety of resources, and conducted three distinct phases of analysis in order to complete this redevelopment action plan. The Phase I: Inventory examines the physical, regulatory, and financial context surrounding the current site in order to gauge its condition as a viable location to foster desired economic development for the region. The Phase II: Assessment utilizes these inventory findings to identify clear challenges that impact the redevelopment potential of the site in an effort to reduce overall project roadblocks. The Phase III: Implementation provides strategies to alleviate these challenges moving forward, in the form of clear recommendations for local, regional, and state level regulatory improvements. Phases I and II were conducted in the fall of 2013, and Phase III was conducted in the spring of 2014. Particular thanks for guidance on this project are extended to L.P. Athol Corporation ownership, Dr. John Mullin of the UMass Amherst Center for Economic Development, State Representative Denise Andrews of the Franklin County Second District, State Senator Stephen Brewer, State Senator Stanley Rosenberg, Congressman James McGovern, and the Town of Athol

OMA orthology in 2021: website overhaul, conserved isoforms, ancestral gene order and more

OMA is an established resource to elucidate evolutionary relationships among genes from currently 2326 genomes covering all domains of life. OMA provides pairwise and groupwise orthologs, functional annotations, local and global gene order conservation (synteny) information, among many other functions. This update paper describes the reorganisation of the database into gene-, group- and genome-centric pages. Other new and improved features are detailed, such as reporting of the evolutionarily best conserved isoforms of alternatively spliced genes, the inferred local order of ancestral genes, phylogenetic profiling, better cross-references, fast genome mapping, semantic data sharing via RDF, as well as a special coronavirus OMA with 119 viruses from the Nidovirales order, including SARS-CoV-2, the agent of the COVID-19 pandemic. We conclude with improvements to the documentation of the resource through primers, tutorials and short videos. OMA is accessible at https://omabrowser.org

High-Speed Rail Versus Air Transportation: Case Study of Madrid–Barcelona, Spain.

Travel time savings, better quality of the supplied services, greater comfort for the users, and improved accessibility are the main factors of success of High Speed Rail(HSR)links. This paper presents the results from a revealed and stated preference survey conducted to both HSR and air transport users in the Madrid Barcelona corridor. The data gathered from the stated preference survey was used to calibrate a modal choice model aiming at explaining competition between HSR and air transportation in the corridor. From the model, the authors obtain that prices and service frequency are the most important variables to compete with the other mode. In addition, they found that check-in and security controls at the airport are a crucial variable for the users in their modal choice. Other policies, such as the improvement of parking facilities at the train stations, play a secondary role

Practical solutions for sampling alternatives in large-scale models

Many large-scale real-world transport applications have choice sets that are so large as to make model estimation and application computationally impractical. The ability to estimate models on subsets of the alternatives is thus of great appeal, and correction approaches have existed since the late 1970s for the simple multinomial logit (MNL) model. However, many of these models in practice rely on nested logit specifications, for example, in the context of the joint choice of mode and destination. Recent research has put forward solutions for such generalized extreme value (GEV) structures, but these structures remain difficult to apply in practice. This paper puts forward a simplification of the GEV method for use in computationally efficient implementations of nested logit. The good performance of this approach is illustrated with simulated data, and additional insights into sampling error are also provided with different sampling strategies for MNL