Critical Self-Organized Self-Sustained Oscillations in Large Regulatory Networks: Towards Understanding the Gene Expression Initiation

In this paper, a new model of self-organized criticality is introduced. This model, called the gene expression paradigm, is motivated by the problem of gene expression initiation in the newly-born daughter cells after mitosis. The model is fundamentally different in dynamics and properties from the well known sand-pile paradigm. Simulation experiments demonstrate that a critical total number of proteins exists below which transcription is impossible. Above this critical threshold, the system enters the regime of self-sustained oscillations with standard deviations and periods proportional to the genes’ complexities with probability one. The borderline between these two regimes is very sharp. Importantly, such a self-organization emerges without any deterministic feedback loops or external supervision, and is a result of completely random redistribution of proteins between inactive genes. Given the size of the genome, the domain of self-organized oscillatory motion is also limited by the genes’ maximal complexities. Below the critical complexity, all the regimes of self-organized oscillations are self-similar and largely independent of the genes’ complexities. Above the level of critical complexity, the whole-genome transcription is impossible. Again, the borderline between the domains of oscillations and quiescence is very sharp. The gene expression paradigm is an example of cellular automata with the domain of application potentially far beyond its biological context. The model seems to be simple enough for staging an experiment for verification of its remarkable properties

GATA2 deficiency syndrome: a decade of discovery

Accepted: 8 August 2021GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome (MDS) is the first diagnosis in 75% of these cases with acute myeloid leukemia (AML) in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing and expression. In this review, we provide the first expert-curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings. This article is protected by copyright. All rights reserved.Claire C. Homan, Parvathy Venugopal, Peer Arts, Nur H. Shahrin, Simone Feurstein, Lesley Rawlings, David M. Lawrence, James Andrews, Sarah L. King, Smith, Natasha L. Harvey, Anna L. Brown, Hamish S. Scott, Christopher N. Hah

El Apego Va a Juicio: Problemas de Custodia y Protección Infantil1

Attachment theory and research are drawn upon in many applied settings, including family courts, but misunderstandings are widespread and sometimes result in misapplications. The aim of this consensus statement is, therefore, to enhance understanding, counter misinformation, and steer family-court utilisation of attachment theory in a supportive, evidence-based direction, especially with regard to child protection and child custody decision-making. This article is divided into two parts. In the first part, we address problems related to the use of attachment theory and research in family courts, and discuss reasons for these problems. To this end, we examine family court applications of attachment theory in the current context of the best-interest-of-the-child standard, discuss misunderstandings regarding attachment theory, and identify factors that have hindered accurate implementation. In the second part, we provide recommendations for the application of attachment theory and research. To this end, we set out three attachment principles: the child’s need for familiar, non-abusive caregivers; the value of continuity of good-enough care; and the benefits of networks of attachment relationships. We also discuss the suitability of assessments of attachment quality and caregiving behaviour to inform family court decision-making. We conclude that assessments of caregiver behaviour should take center stage. Although there is dissensus among us regarding the use of assessments of attachment quality to inform child custody and child-protection decisions, such assessments are currently most suitable for targeting and directing supportive interventions. Finally, we provide directions to guide future interdisciplinary research collaboration

A connectome of the adult drosophila central brain

The neural circuits responsible for behavior remain largely unknown. Previous efforts have reconstructed the complete circuits of small animals, with hundreds of neurons, and selected circuits for larger animals. Here we (the FlyEM project at Janelia and collaborators at Google) summarize new methods and present the complete circuitry of a large fraction of the brain of a much more complex animal, the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses, and proofread such large data sets; new methods that define cell types based on connectivity in addition to morphology; and new methods to simplify access to a large and evolving data set. From the resulting data we derive a better definition of computational compartments and their connections; an exhaustive atlas of cell examples and types, many of them novel; detailed circuits for most of the central brain; and exploration of the statistics and structure of different brain compartments, and the brain as a whole. We make the data public, with a web site and resources specifically designed to make it easy to explore, for all levels of expertise from the expert to the merely curious. The public availability of these data, and the simplified means to access it, dramatically reduces the effort needed to answer typical circuit questions, such as the identity of upstream and downstream neural partners, the circuitry of brain regions, and to link the neurons defined by our analysis with genetic reagents that can be used to study their functions. Note: In the next few weeks, we will release a series of papers with more involved discussions. One paper will detail the hemibrain reconstruction with more extensive analysis and interpretation made possible by this dense connectome. Another paper will explore the central complex, a brain region involved in navigation, motor control, and sleep. A final paper will present insights from the mushroom body, a center of multimodal associative learning in the fly brain

A connectome and analysis of the adult Drosophila central brain

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain

The non-adoption of supply chain management

This is an Accepted Manuscript of an article published by Taylor & Francis in Construction Management and Economics on 10th October 2013, available online: http://wwww.tandfonline.com/10.1080/01446193.2013.830186.Largely taken for granted within the UK construction sector has been a view that supply chain management theory is robust, relevant and reliable. As such it has formed a substantial aspect of previous and contemporary policy and government funded research. Despite this, the general view of its development and diffusion over the last 15 years within the construction industry has been problematic. Coincidentally, prevailing debates within the supply chain management academic community point to the lack of unified theory, models of diffusion and strong connections to organization theory. Using Straussian grounded theory, iterations between data and organization theory provided a fresh perspective on the development and diffusion of supply chain management in construction. This inductive research provided contextually rich explanations for development and diffusion that explicitly connected with and drew upon robust, relevant and reliable theories of institutions, innovation diffusion, triads, quasifirms and mechanisms of organizational governance. These explanations challenge the simplistic assumption that chains and networks of organizations are holistically managed and controlled by any single organization or institution in the construction industry. The debate therefore shifts away from proselytizing supply chain management towards research that explores the rigour, relevance and reliability of supply chain management assumptions in construction. The gap between industry practice and policy is exposed and the question is posed: to what extent policy and practice do, or should, constitute a recursive relationship.© 2013 Taylor & Francis