Features of 80S mammalian ribosome and its subunits

It is generally believed that basic features of ribosomal functions are universally valid, but a systematic test still stands out for higher eukaryotic 80S ribosomes. Here we report: (i) differences in tRNA and mRNA binding capabilities of eukaryotic and bacterial ribosomes and their subunits. Eukaryotic 40S subunits bind mRNA exclusively in the presence of cognate tRNA, whereas bacterial 30S do bind mRNA already in the absence of tRNA. 80S ribosomes bind mRNA efficiently in the absence of tRNA. In contrast, bacterial 70S interact with mRNA more productively in the presence rather than in the absence of tRNA. (ii) States of initiation (Pi), pre-translocation (PRE) and post-translocation (POST) of the ribosome were checked and no significant functional differences to the prokaryotic counterpart were observed including the reciprocal linkage between A and E sites. (iii) Eukaryotic ribosomes bind tetracycline with an affinity 15 times lower than that of bacterial ribosomes (Kd 30 μM and 1–2 μM, respectively). The drug does not effect enzymatic A-site occupation of 80S ribosomes in contrast to non-enzymatic tRNA binding to the A-site. Both observations explain the relative resistance of eukaryotic ribosomes to this antibiotic

Understanding the role of objects in cross-disciplinary collaboration

In this paper we make a case for the use of multiple theoretical perspectives – theory on boundary objects, epistemic objects, cultural historical activity theory and objects as infrastructure - to understand the role of objects in cross-disciplinary collaboration. A pluralist approach highlights that objects perform at least three types of work in this context: they motivate collaboration; they allow participants to work across different types of boundaries; and they constitute the fundamental infrastructure of the activity. Building on the results of an empirical study we illustrate the insights that each theoretical lens affords into practices of collaboration and develop a novel analytical framework that organizes objects according to the active work they perform. Our framework can help shed new light on the phenomenon, especially with regards the shifting status of objects and sources of conflict (and change) in collaboration. After discussing these novel insights, we outline directions for future research stemming from a pluralist approach. We conclude by noting the managerial implications of our finding

Phronesis and Automated Science: The Case of Machine Learning and Biology

The applications of machine learning (ML) and deep learning to the natural sciences has fostered the idea that the automated nature of algorithmic analysis will gradually dispense human beings from scientific work. In this paper, I will show that this view is problematic, at least when ML is applied to biology. In particular, I will claim that ML is not independent of human beings and cannot form the basis of automated science. Computer scientists conceive their work as being a case of Aristotle’s poiesis perfected by techne, which can be reduced to a number of straightforward rules and technical knowledge. I will show a number of concrete cases where at each level of computational analysis, more is required to ML than just poiesis and techne, and that the work of ML practitioners in biology needs also the cultivation of something analogous to phronesis, which cannot be automated. But even if we knew how to frame phronesis into rules (which is inconsistent with its own definition), still this virtue is deeply entrenched in our biological constitution, which computers lack. Whether computers can fully perform scientific practice (which is the result of the way we are cognitively and biologically) independently of humans (and their cognitive and biological specificities) is an ill-posed question

Technoscientia est Potentia?: Contemplative, interventionist, constructionist and creationist idea(l)s in (techno)science

Within the realm of nano-, bio-, info- and cogno- (or NBIC) technosciences, the ‘power to change the world’ is often invoked. One could dismiss such formulations as ‘purely rhetorical’, interpret them as rhetorical and self-fulfilling or view them as an adequate depiction of one of the fundamental characteristics of technoscience. In the latter case, a very specific nexus between science and technology, or, the epistemic and the constructionist realm is envisioned. The following paper focuses on this nexus drawing on theoretical conceptions as well as empirical material. It presents an overview of different technoscientific ways to ‘change the world’—via contemplation and representation, intervention and control, engineering, construction and creation. It further argues that the hybrid character of technoscience makes it difficult (if not impossible) to separate knowledge production from real world interventions and challenges current science and technology policy approaches in fundamental ways

A Computational Study of Elongation Factor G (EFG) Duplicated Genes: Diverged Nature Underlying the Innovation on the Same Structural Template

BACKGROUND: Elongation factor G (EFG) is a core translational protein that catalyzes the elongation and recycling phases of translation. A more complex picture of EFG's evolution and function than previously accepted is emerging from analyzes of heterogeneous EFG family members. Whereas the gene duplication is postulated to be a prominent factor creating functional novelty, the striking divergence between EFG paralogs can be interpreted in terms of innovation in gene function. METHODOLOGY/PRINCIPAL FINDINGS: We present a computational study of the EFG protein family to cover the role of gene duplication in the evolution of protein function. Using phylogenetic methods, genome context conservation and insertion/deletion (indel) analysis we demonstrate that the EFG gene copies form four subfamilies: EFG I, spdEFG1, spdEFG2, and EFG II. These ancient gene families differ by their indispensability, degree of divergence and number of indels. We show the distribution of EFG subfamilies and describe evidences for lateral gene transfer and recent duplications. Extended studies of the EFG II subfamily concern its diverged nature. Remarkably, EFG II appears to be a widely distributed and a much-diversified subfamily whose subdivisions correlate with phylum or class borders. The EFG II subfamily specific characteristics are low conservation of the GTPase domain, domains II and III; absence of the trGTPase specific G2 consensus motif "RGITI"; and twelve conserved positions common to the whole subfamily. The EFG II specific functional changes could be related to changes in the properties of nucleotide binding and hydrolysis and strengthened ionic interactions between EFG II and the ribosome, particularly between parts of the decoding site and loop I of domain IV. CONCLUSIONS/SIGNIFICANCE: Our work, for the first time, comprehensively identifies and describes EFG subfamilies and improves our understanding of the function and evolution of EFG duplicated genes

The life of the cortical column: opening the domain of functional architecture of the cortex

The concept of the cortical column refers to vertical cell bands with similar response properties, which were initially observed by Vernon Mountcastle’s mapping of single cell recordings in the cat somatic cortex. It has subsequently guided over 50 years of neuroscientific research, in which fundamental questions about the modularity of the cortex and basic principles of sensory information processing were empirically investigated. Nevertheless, the status of the column remains controversial today, as skeptical commentators proclaim that the vertical cell bands are a functionally insignificant by-product of ontogenetic development. This paper inquires how the column came to be viewed as an elementary unit of the cortex from Mountcastle’s discovery in 1955 until David Hubel and Torsten Wiesel’s reception of the Nobel Prize in 1981. I first argue that Mountcastle’s vertical electrode recordings served as criteria for applying the column concept to electrophysiological data. In contrast to previous authors, I claim that this move from electrophysiological data to the phenomenon of columnar responses was concept-laden, but not theory-laden. In the second part of the paper, I argue that Mountcastle’s criteria provided Hubel Wiesel with a conceptual outlook, i.e. it allowed them to anticipate columnar patterns in the cat and macaque visual cortex. I argue that in the late 1970s, this outlook only briefly took a form that one could call a ‘theory’ of the cerebral cortex, before new experimental techniques started to diversify column research. I end by showing how this account of early column research fits into a larger project that follows the conceptual development of the column into the present

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Abstract: Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer