Group I aptazymes as genetic regulatory switches

BACKGROUND: Allosteric ribozymes (aptazymes) that have extraordinary activation parameters have been generated in vitro by design and selection. For example, hammerhead and ligase ribozymes that are activated by small organic effectors and protein effectors have been selected from random sequence pools appended to extant ribozymes. Many ribozymes, especially self-splicing introns, are known control gene regulation or viral replication in vivo. We attempted to generate Group I self-splicing introns that were activated by a small organic effector, theophylline, and to show that such Group I aptazymes could mediate theophylline-dependent splicing in vivo. RESULTS: By appending aptamers to the Group I self-splicing intron, we have generated a Group I aptazyme whose in vivo splicing is controlled by exogenously added small molecules. Substantial differences in gene regulation could be observed with compounds that differed by as little as a single methyl group. The effector-specificity of the Group I aptazyme could be rationally engineered for new effector molecules. CONCLUSION: Group I aptazymes may find applications as genetic regulatory switches for generating conditional knockouts at the level of mRNA or for developing economically viable gene therapies

Experiences of workers with post-COVID-19 symptoms can signpost suitable workplace accommodations

The prevalence and multi-system nature of post-COVID-19 symptoms warrants clearer understanding of their work ability implications within the working age population. An exploratory survey was undertaken to provide empirical evidence of the work-relevant experiences of workers recovering from COVID-19. A bespoke online survey based on a biopsychosocial framework ran between December 2020 and February 2021. It collected quantitative ratings of work ability and return-to-work status, qualitative responses about return-to-work experiences, obstacles and recommendations, along with views on employer benefits for making accommodations. A sample of 145 UK workers recovering from COVID-19 was recruited via social media, professional networks and industry contacts. Qualitative data was subject to thematic analysis. Participants were mainly from health/social care (50%) and educational settings (14%). Findings – Just over 90% indicated that they had experienced at least some post-COVID-19 symptoms, notably fatigue and cognitive effects. For 55%, symptoms lasted longer than six months. Only 15% had managed a full return-to-work. Of the 88 who provided workability ratings, just 13 and 18% respectively rated their physical and mental workability as good or very good. Difficulties in resuming work were attributed to symptom unpredictability, their interaction with job demands, managing symptoms and demands in parallel, unhelpful attitudes and expectations. Manager and peer support was reported as variable. Workplace health management characterised by flexible long-term collaborative return-to-work planning, supported bymoreCOVID-centric absence policies and organisational cultures, appear pivotal for sustaining the return-to-work of the large segments of the global workforce affected by post-COVID-19 symptoms

Enhanced flight performance by genetic manipulation of wing shape in Drosophila

Insect wing shapes are remarkably diverse and the combination of shape and kinematics determines both aerial capabilities and power requirements. However, the contribution of any specific morphological feature to performance is not known. Using targeted RNA interference to modify wing shape far beyond the natural variation found within the population of a single species, we show a direct effect on flight performance that can be explained by physical modelling of the novel wing geometry. Our data show that altering the expression of a single gene can significantly enhance aerial agility and that the Drosophila wing shape is not, therefore, optimized for certain flight performance characteristics that are known to be important. Our technique points in a new direction for experiments on the evolution of performance specialities in animals

Reflective diffractometric hydrogel sensor for biological and chemical detection

A reflective diffractometric hydrogel sensor includes an upper layer, including a microfluidic chamber formed from a substantially transparent material and configured to contain a solution, a reflective diffraction grating positioned within the microfluidic chamber, the diffraction grating including a plurality of hydrogel strips configured to change in dimension in response to a stimulus, each hydrogel strip having a top surface coated with a reflective material and a bottom surface in contact with the upper layer substrate, and a reflective surface below the reflective diffraction grating wherein when a coherent light is incident upon and reflected from the upper layer at an angle substantially normal to the upper layer an interference diffraction pattern results, including a first diffraction mode, a light intensity of which indicates the relative distance between the top surfaces of the plurality of hydrogel strips and the reflective surface.Board of Regents, University of Texas Syste

Hachimoji DNA and RNA: A genetic system with eight building blocks

Reported here are DNA and RNA-like systems built from eight (hachi-) nucleotide letters (-moji) that form four orthogonal pairs. This synthetic genetic biopolymer meets the structural requirements needed to support Darwinism, including a polyelectrolyte backbone, predictable thermodynamic stability, and stereoregular building blocks that fit a Schrödinger aperiodic crystal. Measured thermodynamic parameters predict the stability of hachimoji duplexes, allowing hachimoji DNA to double the information density of natural terran DNA. Three crystal structures show that the synthetic building blocks do not perturb the aperiodic crystal seen in the DNA double helix. Hachimoji DNA was then transcribed to give hachimoji RNA in the form of a functioning fluorescent hachimoji aptamer. These results expand the scope of molecular structures that might support life, including life throughout the cosmos

“I’m a Red River local”: rock climbing mobilities and community hospitalities

With individuals continually on the move, mobility fosters constellations of places at which individuals collectively moor and perform community. By focusing on one climbing destination – the Red River Gorge – this paper works across scales to highlight the spatial politics of mobilizing hospitality. In so doing, it summarizes the ways hosting/guesting thresholds dissolve with the growth of particular rock climbing associated infrastructures and moves to examine the ways climbers performances of community result in the (semi-)privatization of public space and attempts at localization. Further, the paper highlights the ways mobility is employed to maintain a political voice from afar, as well as to forge “local” identities with The Red as place with distinct subcultural (in)hospitality practices. Hospitality practices affirm power relations, they communicate who is at “home” and who has the power in a particular space to extend hospitality. The decision to extend hospitality is not simply the difference between an ethical encounter and a conditional one; it takes place in the very performance of identity. Thus, integrating a mobilities perspective into hospitality studies further illuminates the spatial politics that are at play in an ethics of hospitality

Modelling amorphous computations with transcription networks

The power of electronic computation is due in part to the development of modular gate structures that can be coupled to carry out sophisticated logical operations and whose performance can be readily modelled. However, the equivalences between electronic and biochemical operations are far from obvious. In order to help cross between these disciplines, we develop an analogy between complementary metal oxide semiconductor and transcriptional logic gates. We surmise that these transcriptional logic gates might prove to be useful in amorphous computations and model the abilities of immobilized gates to form patterns. Finally, to begin to implement these computations, we design unique hairpin transcriptional gates and then characterize these gates in a binary latch similar to that already demonstrated by Kim et al. (Kim, White & Winfree 2006 Mol. Syst. Biol. 2, 68 (doi:10.1038/msb4100099)). The hairpin transcriptional gates are uniquely suited to the design of a complementary NAND gate that can serve as an underlying basis of molecular computing that can output matter rather than electronic information

Propagating the fear of witchcraft: Pentecostal prophecies in the new prophetic churches in South Africa

Pentecostal prophecy is one of the major themes of the theology and practice of religion among the prophets of New Prophetic Churches in South Africa and a major factor to the growth and expansion of Pentecostalism in Southern Africa. This paper offers a reflection on the role of prophecy in relation to the fear of witchcraft in the region. The contribution is that Pentecostal prophecy is not always in confrontation but sometime propels the fear of witchcraft. Through media analysis, the paper illustrates with some examples of Pentecostal prophecies on witchcraft how Pentecostal prophecy can aid rather than dispel fear of witchcraft. These prophecies raise several challenges to the discernment of Pentecostal prophetic ministry.Christian Spirituality, Church History and Missiolog

A Synthetic Genetic Edge Detection Program

SummaryEdge detection is a signal processing algorithm common in artificial intelligence and image recognition programs. We have constructed a genetically encoded edge detection algorithm that programs an isogenic community of E. coli to sense an image of light, communicate to identify the light-dark edges, and visually present the result of the computation. The algorithm is implemented using multiple genetic circuits. An engineered light sensor enables cells to distinguish between light and dark regions. In the dark, cells produce a diffusible chemical signal that diffuses into light regions. Genetic logic gates are used so that only cells that sense light and the diffusible signal produce a positive output. A mathematical model constructed from first principles and parameterized with experimental measurements of the component circuits predicts the performance of the complete program. Quantitatively accurate models will facilitate the engineering of more complex biological behaviors and inform bottom-up studies of natural genetic regulatory networks

Combined bezafibrate, medroxyprogesterone acetate and valproic acid treatment inhibits osteosarcoma cell growth without adversely affecting normal mesenchymal stem cells.

This document is the Accepted Manuscript version of a published work that appeared in final form in Bioscience Reports. To access the final edited and published work see http://dx.doi.org/10.1042/BSR20202505Drug repurposing is a cost effective means of targeting new therapies for cancer. We have examined the effects of the repurposed drugs, bezafibrate, medroxyprogesterone acetate and valproic acid on human osteosarcoma cells, i.e., SAOS2 and MG63 compared with their normal cell counterparts, i.e. mesenchymal stem/stromal cells (MSCs). Cell growth, viability and migration were measured by biochemical assay and live cell imaging, whilst levels of lipid-synthesising enzymes were measured by immunoblotting cell extracts. These drug treatments inhibited the growth and survival of SAOS2 and MG63 cells most effectively when used in combination (termed V-BAP). In contrast, V-BAP treated MSCs remained viable with only moderately reduced cell proliferation. V-BAP treatment also inhibited migratory cell phenotypes. MG63 and SAOS2 cells expressed much greater levels of fatty acid synthase and stearoyl CoA desaturase 1 than MSCs, but these elevated enzyme levels significantly decreased in the V-BAP treated osteosarcoma cells prior to cell death. Hence, we have identified a repurposed drug combination that selectively inhibits the growth and survival of human osteosarcoma cells in association with altered lipid metabolism without adversely affecting their non-transformed cell counterparts