Rapid profiling of protein complex re-organization in perturbed systems

Protein complexes constitute the primary functional modules of cellular activity. To respond to perturbations, complexes undergo changes in their abundance, subunit composition or state of modification. Understanding the function of biological systems requires global strategies to capture this contextual state information on protein complexes and interaction networks. Methods based on co-fractionation paired with mass spectrometry have demonstrated the capability for deep biological insight but the scope of studies using this approach has been limited by the large measurement time per biological sample and challenges with data analysis. As such, there has been little uptake of this strategy beyond a few expert labs into the broader life science community despite rich biological information content. We present a rapid integrated experimental and computational workflow to assess the re-organization of protein complexes across multiple cellular states. It enables complex experimental designs requiring increased sample/condition numbers. The workflow combines short gradient chromatography and DIA/SWATH mass spectrometry with a data analysis toolset to quantify changes in complex organization. We applied the workflow to study the global protein complex rearrangements of THP-1 cells undergoing monocyte to macrophage differentiation and a subsequent stimulation of macrophage cells with lipopolysaccharide. We observed massive proteome organization in functions related to signaling, cell adhesion, and extracellular matrix during differentiation, and less pronounced changes in processes related to innate immune response induced by the macrophage stimulation. We therefore establish our integrated differential pipeline for rapid and state-specific profiling of protein complex organization with broad utility in complex experimental designs.

The Officials

This chapter focuses on the gymnasial officials (in particular the gymnasiarchs, kosmetai, ephebarchs, lampadarchs, and agonothetai), drawing also parallels from the situation in other Hellenistic Kingdoms. The tenure, functions, involvement, and character of the various offices of the gymnasium and the position that their holders had in local society are investigated, thus providing a picture of the complex organization of the communities of the gymnasium. It is shown how gymnasiarchs were the people chiefly in charge of the gymnasium and how prestigious their office was. A subsection on village gymnasiarchs in the Augustan period provides evidence of the last traces of survival of a Ptolemaic habit into the early years of Roman domination.

THE IMPORTANCE OF FINANCIAL MONITORING IN THE SYSTEM OF STATE FINANCIAL CONTROL

Авторами изучаются механизмы информационно-аналитического обеспечения финансового мониторинга, интегрированного в систему экономической безопасности России, на уровне научно-практической и методической основы, раскрывающей направления комплексной организации и инфраструктурных решений, учитывающих содержательные принципы государственного финансового контроля. The authors study the mechanisms of information and analytical support of financial monitoring integrated into the system of economic security of Russia, at the level of scientific, practical and methodological basis, revealing the directions of complex organization and infrastructure solutions that take into account the substantive principles of state financial control.

Graph convolutional networks: analysis, improvements and results

A graph can represent a complex organization of data in which dependencies exist between multiple entities or activities. Such complex structures create challenges for machine learning algorithms, particularly when combined with the high dimensionality of data in current applications. Graph convolutional networks were introduced to adopt concepts from deep convolutional networks (i.e. the convolutional operations/layers) that have shown good results. In this context, we propose two major enhancements to two of the existing graph convolutional network frameworks: (1) topological information enrichment through clustering coefficients; and (2) structural redesign of the network through the addition of dense layers. Furthermore, we propose minor enhancements using convex combinations of activation functions and hyper-parameter optimization. We present extensive results on four state-of-art benchmark datasets. We show that our approach achieves competitive results for three of the datasets and state-of-the-art results for the fourth dataset while having lower computational costs compared to competing methods.

Structure of the human RNA polymerase I elongation complex

Eukaryotic RNA polymerase I (Pol I) transcribes ribosomal DNA and generates RNA for ribosome synthesis. Pol I accounts for the majority of cellular transcription activity and dysregulation of Pol I transcription leads to cancers and ribosomopathies. Despite extensive structural studies of yeast Pol I, structure of human Pol I remains unsolved. Here we determined the structures of the human Pol I in the pre-translocation, post-translocation, and backtracked states at near-atomic resolution. The single-subunit peripheral stalk lacks contacts with the DNA-binding clamp and is more flexible than the two-subunit stalk in yeast Pol I. Compared to yeast Pol I, human Pol I possesses a more closed clamp, which makes more contacts with DNA. The Pol I structure in the post-cleavage backtracked state shows that the C-terminal zinc ribbon of RPA12 inserts into an open funnel and facilitates “dinucleotide cleavage” on mismatched DNA–RNA hybrid. Critical disease-associated mutations are mapped on Pol I regions that are involved in catalysis and complex organization. In summary, the structures provide new sights into human Pol I complex organization and efficient proofreading.

CGIAR

CGIAR, by far the most complex organization reviewed in this book, has had an extraordinary track record of impacts on productivity growth. CGIAR’s mission has grown over time, beginning with germplasm research and becoming more complex. Donor expectations are high, while funding has stagnated, particularly since 2014. CGIAR’s latest reorganization, known as “One CGIAR,” is a major restructuring, against the background of a history of reforms. The System Board, newly named after “unified governance” became effective on October 1, 2020, is a self-governing mechanism of the System and Centers, intended to work better under the troika of managing directors that report to the unified System Board. In addition, inter-Center research collaborations have been occurring through Center-driven efforts, with benefits of lower operational costs and better ability to improve the quality of research through skill mixes. Partnerships with advanced country institutions have strengthened, as well as those with developed countries. Partnerships with developing countries were the foundation of CGIAR’s success during the Green Revolution, but over time, they have weakened, in part due to a shortage of resources and a growing research agenda. Stronger partnerships are also needed with the private sector.

Protein Complex Organization Imposes Constraints on Proteome Dysregulation in Cancer

Protein assembly is a highly dynamic process and proteins can interact in different ways and stoichiometries within a complex. The importance of maintaining protein stoichiometry for complex function and avoiding aggregation of orphan subunits has been demonstrated. However, how exactly the organization of proteins into complexes constrains differential protein abundance in extreme cellular conditions like cancer, where a lot of protein abundance changes occur, has not been systematically investigated. To study this, we collected proteomic data made available by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) to quantify proteomic changes during carcinogenesis and systematically tested five interaction types in complexes to investigate which of these features impact on protein abundance correlation patterns in cancer. We found that higher than expected fraction of protein complex subunits does not show changes in their abundances compared to those in the normal samples. Furthermore, we found that the way proteins interact in complexes indeed constrains their co-abundance patterns. Our results highlight the role of the interactions between the proteins and the need of cancer cells to deal with aberrant changes in protein abundance.

Modelling the Spread of Covid-19 in a Typical Oil and Gas Facility Setting

The spread of infectious diseases such as COVID-19 in a typical oil and gas facility setting, the health of employees, their families and their communities, is of real concern to the industry. In this work, a suitable predictive, agent-based model is used to predict the spread of COVID-19 in different settings as well as to evaluate strategies to block the spread. The agent-based modelling work is based on the simulation platform, Complex Organization and Bifurcation Within Environmental Bounds, or COBWEB. COBWEB simulates how a system of autonomous agents adapts to variation and sudden changes in the resource base or other features of their environment. Previous COBWEB simulation results illustrate that the tool is useful for predicting the evolution of COVID-19 spread and the effectiveness of various preventive actions including self-isolation of symptomatic people, social/physical distancing, effective PPE use, and ‘shielding’ (physical isolation) of the high-risk population. We adapted model parameters to better represent uncertainty about what might be expected in such a setting, in particular by shifting the distribution of risk severity towards ineffective PPE use, self-isolation and poor social distancing, which expectedly shows upward trend of the spread of the COVID-19. Ultimately, governments and industry can apply the predicted trends, as well as apply the model to specific settings, to make more informed decisions on the additional measures and preventative strategies to curb the spread of COVID-19.

Integrin Adhesion Complex Organization in Sheep Myometrium Reflects Changing Mechanical Forces during Pregnancy and Postpartum

Cells respond to extracellular mechanical forces through the assembly of integrin adhesion complexes (IACs) that provide a scaffold through which cells sense and transduce responses to those forces. IACs are composed of transmembrane integrin receptors that bind to extracellular matrix (ECM) proteins externally and connect with the actomyosin cytoskeleton internally. Myometrial smooth muscle cells respond to forces that arise due to increases in fetal growth/weight, placental fluid volumes, and blood flow. As a result, the uterus transforms into an organ that can forcefully expel the fetus and placental membranes during parturition. While earlier studies focused on IAC expression in the myometrial compartment of rodents and humans to explore pregnancy-associated responses, the present study examines IAC assembly in ovine myometrium where mechanical forces are expected to be amplified in a manner similar to humans. Results indicate that the ITGA5 and ITGB1 heterodimers associate with the ECM protein FN1 externally, and with VCL and TLN1 internally, to form IACs in myometrial cells during the first trimester of pregnancy. These IACs become increasingly ordered until parturition. This ordered structure is lost by one day postpartum; however, the abundance of the integrin proteins remains elevated for at least two weeks postpartum. Implications of the present study are that sheep are similar to humans regarding the assembly of IACs in the pregnant myometrium and suggest that IACs may form much earlier in human gestation than was previously implied by the rat model. Results highlight the continued value of the sheep model as a flagship gynecological model for understanding parturition in humans.

MANAGEMENT OF GOVERNMENT ARCHIVES IN ITALY

The article deals with the management system of state archives in modern Italy. Research has proven the value of archives among other cultural sites, as archives are an important part of national identity. In practice, effective public administration and effective administration is the lifeblood of public authorities through the storage of relevant documents. In addition, the article covers the management functions, tasks and roles of the Italian state archives. Therefore, the final result can be assessed for the optimization of all types of public and private archival institutions. In particular, archives are analyzed not as documents, but as institutions and offices with a complex organization. An overview of Italian regulation and their characteristics in relation to territorial forms will be associated with a comparative study of the international scenario to illustrate the current bad and best practices of archival management. Archival management is an unexplored field, if not completely ignored in the Italian literature. The study allows the author to highlight best practices and develop internal management guidelines that apply to various archival institutions throughout Italy. In addition, research shows how archival institutions are able to optimize internal management through the application of project management methods, the constant growth and development of training.