Affinity chromatography in dynamic combinatorial libraries: one-pot amplification and isolation of a strongly binding receptor

We report the one-pot amplification and isolation of a nanomolar receptor in a multibuilding block aqueous dynamic combinatorial library using a polymer-bound template. By appropriate choice of a poly(N,N-dimethylacrylamide)-based support, unselective ion-exchange type behaviour between the oppositely charged cationic guest and polyanionic hosts was overcome, such that the selective molecular recognition arising in aqueous solution reactions is manifest also in the analogous templated solid phase DCL syntheses. The ability of a polymer bound template to identify and isolate a synthetic receptor via dynamic combinatorial chemistry was not compromised by the large size of the library, consisting of well over 140 theoretical members, demonstrating the practical advantages of a polymer-supported DCL methodology

Probing the limits of selectivity in a recognition-mediated reaction network embedded within a dynamic covalent library

This work was supported by the award of a Postgraduate Studentship from EPSRC (EP/K503162/1) to TK.Two recognition-mediated reaction processes operating through a reactive binary complex drive resolution of a 24-component dynamic covalent library, assembled from individual aldehydes and nucleophiles. The effectiveness of the library resolution and selective amplification of one recognition-enabled species over another is limited by the difference in the rates of the recognition-mediated reactive processes and strength of the recognition processes employed in the dynamic system.PostprintPeer reviewe

Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use.

Genetic decoding is not 'frozen' as was earlier thought, but dynamic. One facet of this is frameshifting that often results in synthesis of a C-terminal region encoded by a new frame. Ribosomal frameshifting is utilized for the synthesis of additional products, for regulatory purposes and for translational 'correction' of problem or 'savior' indels. Utilization for synthesis of additional products occurs prominently in the decoding of mobile chromosomal element and viral genomes. One class of regulatory frameshifting of stable chromosomal genes governs cellular polyamine levels from yeasts to humans. In many cases of productively utilized frameshifting, the proportion of ribosomes that frameshift at a shift-prone site is enhanced by specific nascent peptide or mRNA context features. Such mRNA signals, which can be 5' or 3' of the shift site or both, can act by pairing with ribosomal RNA or as stem loops or pseudoknots even with one component being 4 kb 3' from the shift site. Transcriptional realignment at slippage-prone sequences also generates productively utilized products encoded trans-frame with respect to the genomic sequence. This too can be enhanced by nucleic acid structure. Together with dynamic codon redefinition, frameshifting is one of the forms of recoding that enriches gene expression.This work was supported by grants from Science Foundation Ireland [12/IP/1492 and 13/1A/1853 to J.F.A; 12/IA/1335 to P.V.B.], US. National Institutes of Health [RO3 MH098688 to J.F.A.], the Wellcome Trust [106207 to A.E.F and 094423 to P.V.B.] and the European Research Council (ERC) grant No. 646891 to A.E.F.]This is the final version of the article. It first appeared from Oxford University Press via https://doi.org/10.1093/nar/gkw53

Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target

This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the context of the physiological and pathogenic roles played in human cells. First, we discuss the occurrence and frequency of various trinucleotide repeats in transcripts and classify them according to the propensity to form RNA structures of different architectures and stabilities. We show that repeats capable of forming hairpin structures are overrepresented in exons, which implies that they may have important functions. We further describe long triplet repeat RNA as a pathogenic agent by presenting human neurological diseases caused by triplet repeat expansions in which mutant RNA gains a toxic function. Prominent examples of these diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, which are triggered by mutant CUG and CGG repeats, respectively. In addition, we discuss RNA-mediated pathogenesis in polyglutamine disorders such as Huntington's disease and spinocerebellar ataxia type 3, in which expanded CAG repeats may act as an auxiliary toxic agent. Finally, triplet repeat RNA is presented as a therapeutic target. We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases

Bulgarian relative and factive clauses with an invariant complementizer

The paper offers an analysis of Bulgarian relative clauses introduced by the invariant complementizer deto ‘that’, whose distribution also extends to factive contexts. Using reconstruction as primary evidence for movement, I review the basic facts for its presence (amount readings, idiom interpretation, binding and scope) and absence (Principle C) and argue that both a raising and a matching analysis must be available for the derivation of deto-relatives. I also discuss the distribution and structural properties of resumptive clitics which are shown to block reconstruction in all types of contexts and hence to be compatible with a matching derivation only. Given the structural ambiguity in the derivation of Bulgarian complementizer relatives and in search of a unified treatment of their potentially ambivalent behavior, the paper applies Cinque’s (2003, 2008) analysis of relative clauses, which postulates two identical copies of the relativized Head (internal and external) and exploits different movement options to account for the raising and the matching derivations. It is then argued that such a proposal, which also exploits distinct CP positions, can successfully accommodate all of the observed reconstruction effects (or lack thereof), including the option of resumption. The paper also offers a discussion of factive clauses introduced by the same complementizer and proposes that they are best treated as hidden relatives embedded under a more complex structure involving a PP projection and a silent D head

IndigiQueer the Space: An Interview with Ty Defoe

Ty Defoe is an Oneida and Ojibwe interdisciplinary artist. This contribution includes a video entitled “Circle” and an interview with Nic Gareiss, in which Defoe discusses the ways in which he has worked to Indigenize, decolonize, and queer a variety of spaces, including online digital spaces, during the pandemic

Imagining Outside of a Pandemic: A Response from a Queer Improvising Percussive Dancer

I'm a dancer who engages improvisation every time I put on my shoes to brush, step, click, and knock the floor. Not surprisingly, my work until March 2020 was primarily with fellow sound-makers, usually folk musicians from Ireland, Scotland, what's now called Canada, and what's now called Appalachia. COVID-19 has forced me to listen to the extemporaneous music I make anew, in the absence of collaborators, within a soundscape of profound uncertainty. In this contribution, I offer a voice from the floor, enunciated by my lowest limbs contacting the surface upon which I stand. This is where my work as an LGBTQ2IA+ improvising step dancer finds its meaning. In this essay, I respond to the incisive queer horizon Thomas F. DeFrantz casts, as "imagining outside of what came before." I share ways I have been thinking about improvisation and offer thoughts on how we might learn from DeFrantz to imagine and improvise “outside of” critically, queerly, and generatively

Bemerkungen über die Verwitterung des Serpentin und seine Entstehung

von A. Garreis

IndigiQueer the Space

Ty Defoe is an Oneida and Ojibwe interdisciplinary artist. This contribution includes a video entitled “Circle” and an interview with Nic Gareiss, in which Defoe discusses the ways in which he has worked to Indigenize, decolonize, and queer a variety of spaces, including online digital spaces, during the pandemic.&nbsp