Neuronal Function and Dysfunction of Drosophila dTDP

Background: TDP-43 is an RNA- and DNA-binding protein well conserved in animals including the mammals, Drosophila, and C. elegans. In mammals, the multi-function TDP-43 encoded by the TARDBP gene is a signature protein of the ubiquitinpositive inclusions (UBIs) in the diseased neuronal/glial cells of a range of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). Methodology/Principal Findings: We have studied the function and dysfunction of the Drosophila ortholog of the mammalian TARDBP gene, dTDP, by genetic, behavioral, molecular, and cytological analyses. It was found that depletion of dTDP expression caused locomotion defect accompanied with an increase of the number of boutons at the neuromuscular junctions (NMJ). These phenotypes could be rescued by overexpression of Drosophila dTDP in the motor neurons. In contrast, overexpression of dTDP in the motor neurons also resulted in reduced larval and adult locomotor activities, but this was accompanied by a decrease of the number of boutons and axon branches at NMJ. Significantly, constitutive overexpression of dTDP in the mushroom bodies caused smaller axonal lobes as well as severe learning deficiency. On the other hand, constitutive mushroom body-specific knockdown of dTDP expression did not affect the structure of the mushroom bodies, but it impaired the learning ability of the flies, albeit moderately. Overexpression of dTDP also led to the formation of cytosolic dTDP (+) aggregates

Gene and genon concept: coding versus regulation: A conceptual and information-theoretic analysis of genetic storage and expression in the light of modern molecular biology

We analyse here the definition of the gene in order to distinguish, on the basis of modern insight in molecular biology, what the gene is coding for, namely a specific polypeptide, and how its expression is realized and controlled. Before the coding role of the DNA was discovered, a gene was identified with a specific phenotypic trait, from Mendel through Morgan up to Benzer. Subsequently, however, molecular biologists ventured to define a gene at the level of the DNA sequence in terms of coding. As is becoming ever more evident, the relations between information stored at DNA level and functional products are very intricate, and the regulatory aspects are as important and essential as the information coding for products. This approach led, thus, to a conceptual hybrid that confused coding, regulation and functional aspects. In this essay, we develop a definition of the gene that once again starts from the functional aspect. A cellular function can be represented by a polypeptide or an RNA. In the case of the polypeptide, its biochemical identity is determined by the mRNA prior to translation, and that is where we locate the gene. The steps from specific, but possibly separated sequence fragments at DNA level to that final mRNA then can be analysed in terms of regulation. For that purpose, we coin the new term “genon”. In that manner, we can clearly separate product and regulative information while keeping the fundamental relation between coding and function without the need to introduce a conceptual hybrid. In mRNA, the program regulating the expression of a gene is superimposed onto and added to the coding sequence in cis - we call it the genon. The complementary external control of a given mRNA by trans-acting factors is incorporated in its transgenon. A consequence of this definition is that, in eukaryotes, the gene is, in most cases, not yet present at DNA level. Rather, it is assembled by RNA processing, including differential splicing, from various pieces, as steered by the genon. It emerges finally as an uninterrupted nucleic acid sequence at mRNA level just prior to translation, in faithful correspondence with the amino acid sequence to be produced as a polypeptide. After translation, the genon has fulfilled its role and expires. The distinction between the protein coding information as materialised in the final polypeptide and the processing information represented by the genon allows us to set up a new information theoretic scheme. The standard sequence information determined by the genetic code expresses the relation between coding sequence and product. Backward analysis asks from which coding region in the DNA a given polypeptide originates. The (more interesting) forward analysis asks in how many polypeptides of how many different types a given DNA segment is expressed. This concerns the control of the expression process for which we have introduced the genon concept. Thus, the information theoretic analysis can capture the complementary aspects of coding and regulation, of gene and genon

Improving health care quality and safety: the role of collective learning

Sara J Singer,1–4 Justin K Benzer,4–6 Sami U Hamdan4,6 1Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 2Department of Medicine, Harvard Medical School, Boston, MA, USA; 3Mongan Institute for Health Policy, Massachusetts General Hospital, Boston, MA, USA; 4Center for Healthcare Organization and Implementation Research, VA Boston Healthcare System, Boston, MA, USA; 5VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, USA; 6Department of Health Policy and Management, Boston University School of Public Health, Boston, MA, USA Abstract: Despite decades of effort to improve quality and safety in health care, this goal feels increasingly elusive. Successful examples of improvement are infrequently replicated. This scoping review synthesizes 76 empirical or conceptual studies (out of 1208 originally screened) addressing learning in quality or safety improvement, that were published in selected health care and management journals between January 2000 and December 2014 to deepen understanding of the role that collective learning plays in quality and safety improvement. We categorize learning activities using a theoretical model that shows how leadership and environmental factors support collective learning processes and practices, and in turn team and organizational improvement outcomes. By focusing on quality and safety improvement, our review elaborates the premise of learning theory that leadership, environment, and processes combine to create conditions that promote learning. Specifically, we found that learning for quality and safety improvement includes experimentation (including deliberate experimentation, improvisation, learning from failures, exploration, and exploitation), internal and external knowledge acquisition, performance monitoring and comparison, and training. Supportive learning environments are characterized by team characteristics like psychological safety, appreciation of differences, openness to new ideas social motivation, and team autonomy; team contextual factors including learning resources like time for reflection, access to knowledge, organizational capabilities; incentives; and organizational culture, strategy, and structure; and external environmental factors including institutional pressures, environmental dynamism and competitiveness and learning collaboratives. Lastly learning in the context of quality and safety improvement requires leadership that reinforces learning through actions and behaviors that affect people, such as coaching and trust building, and through influencing contextual factors, including providing resources, developing culture, and taking strategic actions that support improvement. Our review highlights the importance of leadership in both promoting a supportive learning environment and implementing learning processes. Keyword: collective learning, systematic review, scoping review, health care quality, patient safety, quality improvemen