Computationally driven discovery of SARS-CoV-2 M pro inhibitors: From design to experimental validation

We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (

Parental views on informed consent for expanded newborn screening

Background  An increasing array of rare inherited conditions can be detected as part of the universal newborn screening programme. The introduction and evaluation of these service developments require consideration of the ethical issues involved and appropriate mechanisms for informing parents and gaining consent if required. Exploration of parental views is needed to inform the debate and specifically consider whether more flexible protocols are needed to fit with the public perception of new developments in this context. Objective  This study has been undertaken to explore perceptions and attitudes of parents and future parents to an expanded newborn screening programme in the United Kingdom and the necessary information provision and consent processes. Design and participants  A mixed methods study involving focus groups (n = 29) and a web‐survey (n = 142) undertaken with parents and future parents. Results and conclusions  Parents want guaranteed information provision with clear decision‐making powers and an awareness of the choices available to them. The difference between existing screening provision and expanded screening was not considered to be significant enough by participants to warrant formal written, informed consent for expanded screening. It is argued that the ethical review processes need to be more flexible towards the provision of information and consent processes for service developments in newborn screening

An Electroactive Oligo-EDOT Platform for Neural Tissue Engineering

The unique electrochemical properties of the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) make it an attractive material for use in neural tissue engineering applications. However, inadequate mechanical properties, and difficulties in processing and lack of biodegradability have hindered progress in this field. Here, the functionality of PEDOT:PSS for neural tissue engineering is improved by incorporating 3,4-ethylenedioxythiophene (EDOT) oligomers, synthesized using a novel end-capping strategy, into block co-polymers. By exploiting end-functionalized oligoEDOT constructs as macroinitiators for the polymerization of poly(caprolactone), a block co-polymer is produced that is electroactive, processable, and bio-compatible. By combining these properties, electroactive fibrous mats are produced for neuronal culture via solution electrospinning and melt electrospinning writing. Importantly, it is also shown that neurite length and branching of neural stem cells can be enhanced on the materials under electrical stimulation, demonstrating the promise of these scaffolds for neural tissue engineering

SUMOylation of Paraflagellar Rod Protein, PFR1, and Its Stage-Specific Localization in Trypanosoma cruzi

BACKGROUND: The flagellate protozoan parasite, Trypanosoma cruzi, is a causative agent of Chagas disease that is transmitted by reduviid bugs to humans. The parasite exists in multiple morphological forms in both vector and host, and cell differentiation in T. cruzi is tightly associated with stage-specific protein synthesis and degradation. However, the specific molecular mechanisms responsible for this coordinated cell differentiation are unclear. METHODOLOGY/PRINCIPAL FINDINGS: The SUMO conjugation system plays an important role in specific protein expression. In T. cruzi, a subset of SUMOlylated protein candidates and the nuclear localization of SUMO have been shown. Here, we examined the biological roles of SUMO in T. cruzi. Site-directed mutagenesis analysis of SUMO consensus motifs within T. cruzi SUMO using a bacterial SUMOylation system revealed that T. cruzi SUMO can polymerize. Indirect fluorescence analysis using T. cruzi SUMO-specific antibody showed the extra-nuclear localization of SUMO on the flagellum of epimastigote and metacyclic and bloodstream trypomastigote stages. In the short-flagellate intracellular amastigote, an extra-nuclear distribution of SUMO is associated with basement of the flagellum and becomes distributed along the flagellum as amastigote transforms into trypomastigote. We examined the flagellar target protein of SUMO and show that a paraflagellar rod protein, PFR1, is SUMOylated. CONCLUSIONS: These findings indicate that SUMOylation is associated with flagellar homeostasis throughout the parasite life cycle, which may play an important role in differentiation of T. cruzi

Catastrophic Floods May Pave the Way for Increased Genetic Diversity in Endemic Artesian Spring Snail Populations

The role of disturbance in the promotion of biological heterogeneity is widely recognised and occurs at a variety of ecological and evolutionary scales. However, within species, the impact of disturbances that decimate populations are neither predicted nor known to result in conditions that promote genetic diversity. Directly examining the population genetic consequences of catastrophic disturbances however, is rarely possible, as it requires both longitudinal genetic data sets and serendipitous timing. Our long-term study of the endemic aquatic invertebrates of the artesian spring ecosystem of arid central Australia has presented such an opportunity. Here we show a catastrophic flood event, which caused a near total population crash in an aquatic snail species (Fonscochlea accepta) endemic to this ecosystem, may have led to enhanced levels of within species genetic diversity. Analyses of individuals sampled and genotyped from the same springs sampled both pre (1988–1990) and post (1995, 2002–2006) a devastating flood event in 1992, revealed significantly higher allelic richness, reduced temporal population structuring and greater effective population sizes in nearly all post flood populations. Our results suggest that the response of individual species to disturbance and severe population bottlenecks is likely to be highly idiosyncratic and may depend on both their ecology (whether they are resilient or resistant to disturbance) and the stability of the environmental conditions (i.e. frequency and intensity of disturbances) in which they have evolved

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research

Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Introduction Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk. Methods We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene. Results No significant breast cancer associations were detected with any individual or combination of tag SNPs. Conclusion It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population

Complementary regulation of four Eucalyptus CBF genes under various cold conditions

CBF transcription factors play central roles in the control of freezing tolerance in plants. The isolation of two additional CBF genes, EguCBF1c and EguCBF1d, from E. gunnii, one of the cold-hardiest Eucalyptus species, is described. While the EguCBF1D protein sequence is very similar to the previously characterized EguCBF1A and EguCBF1B sequences, EguCBF1C is more distinctive, in particular in the AP2-DBD (AP2-DNA binding domain). The expression analysis of the four genes by RT-qPCR reveals that none of them is specific to one stress but they are all preferentially induced by cold, except for the EguCBF1c gene which is more responsive to salt. The calculation of the transcript copy number enables the quantification of constitutive CBF gene expression. This basal level, significant for the four genes, greatly influences the final EguCBF1 transcript level in the cold. A cold shock at 4 °C, as well as a progressive freezing which mimics a natural frost episode, trigger a fast and strong response of the EguCBF1 genes, while growth at acclimating temperatures results in a lower but more durable induction. The differential expression of the four EguCBF1 genes under these cold regimes suggests that there is a complementary regulation. The high accumulation of the CBF transcript, observed in response to the different types of cold conditions, might be a key for the winter survival of this evergreen broad-leaved tree

Monte Carlo Techniques for Drug Design: The Success Case of PELE

This chapter summarizes the most representative software packages that readily allow running Monte Carlo (MC) simulations in relevant scenarios for drug design. It explores in detail the Protein Energy Landscape Exploration (PELE) program, providing first the main characteristics of the technique, followed by an analysis of the different application studies in mapping protein‐ligand interactions. The ligand, formed by a rigid core and a set of rotatable side chains, is perturbed by translating and rotating it. PELE creates a list of perturbation poses, and then chooses the one with the lowest system energy. PELE was originally designed to map ligand migration pathways: its first applications aimed at finding exit pathways starting from ligand‐bound crystallographic structures. Additional applied studies have centered on modeling enzymatic mechanisms and engineering; the same techniques applied in mapping protein‐drug interactions can be used in the study of substrate recognition by enzymes.Along the development of PELE in the last years, we gratefully acknowledge financial support from the European Union (in particular from the ERC program) and from the Catalan and Spanish Governments. In addition we want to thank all present and past members from the EAPM lab. at BSC for their dedication and work.Peer ReviewedPostprint (author's final draft