System-wide Function Research Articles

Integrating the analysis of human biopsies using post-translational modifications proteomics.

Proteome diversities and their biological functions are significantly amplified by post-translational modifications (PTMs) of proteins. Shotgun proteomics, which does not typically survey PTMs, provides an incomplete picture of the complexity of human biopsies in health and disease. Recent advances in mass spectrometry-based proteomic techniques that enrich and study PTMs are helping to uncover molecular detail from the cellular level to system-wide functions, including how the microbiome impacts human diseases. Protein heterogeneity and disease complexity are challenging factors that make it difficult to characterize and treat disease. The search for clinical biomarkers to characterize disease mechanisms and complexity related to patient diagnoses and treatment has proven challenging. Knowledge of PTMs is fundamentally lacking. Characterization of complex human samples that clarify the role of PTMs and the microbiome in human diseases will result in new discoveries. This review highlights the key role of proteomic techniques used to characterize unknown biological functions of PTMs derived from complex human biopsies. Through the integration of diverse methods used to profile PTMs, this review explores the genetic regulation of proteoforms, cells of origin expressing specific proteins, and several bioactive PTMs and their subsequent analyses by liquid chromatography and tandem mass spectrometry.

A guide to complement biology, pathology and therapeutic opportunity.

Complement has long been considered a key innate immune effector system that mediates host defence and tissue homeostasis. Yet, growing evidence has illuminated a broader involvement of complement in fundamental biological processes extending far beyond its traditional realm in innate immunity. Complement engages in intricate crosstalk with multiple pattern-recognition and signalling pathways both in the extracellular and intracellular space. Besides modulating host-pathogen interactions, this crosstalk guides early developmental processes and distinct cell trajectories, shaping tissue immunometabolic and regenerative programmes in different physiological systems. This Review provides a guide to the system-wide functions of complement. It highlights illustrative paradigm shifts that have reshaped our understanding of complement pathobiology, drawing examples from evolution, development of the central nervous system, tissue regeneration and cancer immunity. Despite its tight spatiotemporal regulation, complement activation can be derailed, fuelling inflammatory tissue pathology. The pervasive contribution of complement to disease pathophysiology has inspired a resurgence of complement therapeutics with major clinical developments, some of which have challenged long-held dogmas. We thus highlight major therapeutic concepts and milestones in clinical complement intervention.

System-Wide Analysis of Protein Acetylation and Ubiquitination Reveals a Diversified Regulation in Human Cancer Cells.

Post-translational modifications are known to be widely involved in the regulation of various biological processes, through the extensive diversification of each protein function at the cellular network level. In order to unveil the system-wide function of the protein lysine modification in cancer cell signaling, we performed global acetylation and ubiquitination proteome analyses of human cancer cells, based on high-resolution nanoflow liquid chromatography–tandem mass spectrometry, in combination with the efficient biochemical enrichment of target modified peptides. Our large-scale proteomic analysis enabled us to identify more than 5000 kinds of ubiquitinated sites and 1600 kinds of acetylated sites, from representative human cancer cell lines, leading to the identification of approximately 900 novel lysine modification sites in total. Very interestingly, 236 lysine residues derived from 141 proteins were found to be modified with both ubiquitination and acetylation. As a consequence of the subsequent motif extraction analyses, glutamic acid (E) was found to be highly enriched at the position (−1) for the lysine acetylation sites, whereas the same amino acid was relatively dispersed along the neighboring residues of the lysine ubiquitination sites. Our pathway analysis also indicated that the protein translational control pathways, such as the eukaryotic initiation factor 2 (EIF2) and the ubiquitin signaling pathways, were highly enriched in both of the acetylation and ubiquitination proteome data at the network level. This report provides the first integrative description of the protein acetylation and ubiquitination-oriented systematic regulation in human cancer cells.

Функції державного регулювання сталого розвитку в сучасних умовах

The article clarifies the functions of state regulation of sustainable development in modern conditions. The following functions of state regulation of sustainable development, which are presented in scientific publications target, stimulating, normative, corrective, social, control, are singled out. The main functions of state regulation of sustainable development are illustrated, among them: the target; stimulating; normative (regulatory); corrective; social direct management of the nonmarket sector of the economy; controlling, as well as the exclusive functions of the state in the economic, environmental and social spheres. The system-wide functions of state regulation of sustainable development are also singled out, among them: the whole lay-out, regulation, stimulation, motivation, coordination, monitoring and control.

Anti-aging dilemma: to restore the hardware or to reinstall the software?

Sinceitsearlydays,thevalueofdecipheringthehumanDNAhasbeenseenprimarilyinextractingthe set of messages that run the cells that constitute the body. In common understanding, thesemessages are encoded in DNA and transcribed as cell-specific sets of RNAs, some of which aretranslatedtoproteins,thenmodifiedwithvariouspost-translationaladd-onsmadeofsugars,lipidsand other moieties. This complex chain of events is further complicated by multi-layered possi-bilities for the modifications allowed at every step–epigenetics for DNA, editing for RNAs andtherecentlydiscoveredphenomenonofnon-templatepolypeptideextensionallowedbyribosomes(Shen et al., 2015). It seems that when looked at as a whole, the DNA, and all the messages associ-ated with DNA, do not look like a blueprint, or even a clear set of instructions, but rather a messydraft or a stack of notes that are scribbled all over and full of ambiguities.However, let us hack through the majority of the “omics” and look upon the set of smallmolecules known as metabolites, and the budding discipline of Metabolomics that researches thetrueunderpinningsoftheabundantlycomplexmechanicsofthelivingcell.Itisworthwhiletonotethat,toasomewhatdefineddegree,thecellwilltoleratethelossofageneorchangesinthelevelsofRNAs or even the most important of proteins, while even slight deregulation of the levels of someof the smallest metabolites leads to immediate and catastrophic consequences. The potassium ionandATPmaybeusedastheprimaryexamplesofsmallestmoleculescapableofelicitingasystemicresponse.Accordingtoourcalculation,amere0.5%increaseinthetotalcontentofpotassiumchlo-ride, one of the most common electrolytes in the human body, leads to immediate cardiac arrest.TheconsequencesofthedepletionofATPmaymanifestasavarietyofailments,withtheirdurationinversely proportional to the severity of the defect. Aging, in particular, is associated with a declinein the efficiency of oxidative phosphorylation and an increase in the risk of resulting pathologies.Of course, there are other small molecules, possibly not as well-known as ATP, but still indispens-able and irreplaceable. In particular, the metabolites derived from the amino acid tryptophan havethe capacity for similar dramatic alteration of system-wide function. Most pertinent to the topicof this discussion, the changes in metabolic profiles are considered as drivers for the pathogene-sis of age-associated disorders, including Alzheimer’s disease (Tacutu et al., 2010; Demetrius andDriver, 2013; Jia et al., 2014; Obre and Rossignol, 2015). It also is of note that metabolites are notasabundantascommonlystudiedspeciesofproteinsandRNAs.Hence,theworldofmetabolitesisimmensely easier to comprehend than the overly complicated world of other famous “omics.” Thelatter point is extremely important, as it provides a possibility for the use of a powerful reduction-ist approach without falling into ill-fitting or over-fitting of the underlying model, a well-knownperpetual source of entrapment.Letuscomparetheliving(andaging)cell,withitsendless“omics”-scalelayersofinterconnectedcomponents, to modern computers. Computer hardware is a collection of interconnected physicaldevices used in or with your machine. One of these parts may wear itself out and die; however,

A Nonhierarchical Formulation of Analytical Target Cascading

Analytical target cascading (ATC) is a method developed originally for translating system-level design targets to design specifications for the components that comprise the system. ATC has been shown to be useful for coordinating decomposition-based optimal system design. The traditional ATC formulation uses hierarchical problem decompositions, in which coordination is performed by communicating target and response values between parents and children. The hierarchical formulation may not be suitable for general multidisciplinary design optimization (MDO) problems. This paper presents a new ATC formulation that allows nonhierarchical target-response coupling between subproblems and introduces system-wide functions that depend on variables of two or more subproblems. Options to parallelize the subproblem optimizations are also provided, including a new bilevel coordination strategy that uses a master problem formulation. The new formulation increases the applicability of the ATC to both decomposition-based optimal system design and MDO. Moreover, it belongs to the class of augmented Lagrangian coordination methods, having thus convergence properties under standard convexity and continuity assumptions. A supersonic business jet design problem is used to demonstrate the flexibility and effectiveness of the presented formulation.

Simulation Of The Operation Of Personal Rapid Transit Systems

This paper describes a computer simulation program developed by the author to study the operation of personal rapid transit (PRT) systems of any size and configuration. The control scheme is asynchronous with maneuvers commanded by wayside zone controllers. The simulation runs on a PC, is accurate in every detail, and can be used to run an operational system, which would have dualredundant computers on the vehicles, at wayside to manage specific zones, and in a central location to manage the flow of empty vehicles and to perform other system-wide functions. Some results are given.

On the mechanism of transient instability of power systems

In recent studies, it has been verifiedheuristically andexperimentally (via simulations) that instability in power systems due to a fault occurs when one machine or a group of machines, called thecritical group, loses synchronism with the remaining machines. Using energy functions associated with a critical group (rather than system-wide functions), transient stability results which are less conservative than other existing results, have been obtained. The existence and identity of a critical group is ascertained in these studies byoff-line simulations.

Neighborhood Influences on Travel Behavior and Availability Constraints

Traditionally, transportation demand studies have, for the most part, viewed modal choice in terms of an aggregate system-wide function. However, it seems reasonable to expect that the travel decision may be influenced by a composite of factors that include not only availability conditions, but determinants relating to neighborhood characteristics and peer-group pressures. In this paper, supply-side constraints on availability were used to segment the market and logit probabilistic choice models were fitted to each segment. It was found that inducements to individuals to alter their modal choice must consider not only cost factors and standard demographics, but also peer-group (class) constraints. System-wide approaches will fail to consider these important demand considerations.