What systems biology can tell us about disease

A recent debate has touched upon the question of whether diseases can be understood as dysfunctional mechanisms or whether there are "pathological" mechanisms that deserve to be investigated and explained independently (Nervi 2010; Moghaddam-Taaheri 2011). Here I suggest that both views tell us something important about disease but that in many instances only a systemic view can shed light on the relationship between physiology and pathology. I provide examples from the literature in systems biology in support of my position. As a result of my analysis, I conclude that a perspective narrowly focusing on mechanisms is insufficient if the goal is to get a comprehensive picture of disease.     

Adaptation to the spindle checkpoint is regulated by the interplay between Cdc28/Clbs and PP2ACdc55

The spindle checkpoint arrests cells in metaphase until all chromosomes are properly attached to the chromosome segregation machinery. Thereafter, the anaphase promoting complex (APC/C) is activated and chromosome segregation can take place. Cells remain arrested in mitosis for hours in response to checkpoint activation, but not indefinitely. Eventually, they adapt to the checkpoint and proceed along the cell cycle. In yeast, adaptation requires the phosphorylation of APC/C. Here, we show that the protein phosphatase PP2A^Cdc55 dephosphorylates APC/C, thereby counteracting the activity of the mitotic kinase Cdc28. We also observe that the key regulator of Cdc28, the mitotic cyclin Clb2, increases before cells adapt and is then abruptly degraded at adaptation. Adaptation is highly asynchronous and takes place over a range of several hours. Our data suggest the presence of a double negative loop between PP2A^Cdc55 and APC/C^Cdc20 (i.e., a positive feedback loop) that controls APC/C^Cdc20 activity. The circuit could guarantee sustained APC/C^Cdc20 activity after Clb2 starts to be degraded.     

Global Material Flows and Resource Productivity: Forty Years of Evidence

The international industrial ecology (IE) research community and United Nations (UN) Environment have, for the first time, agreed on an authoritative and comprehensive data set for global material extraction and trade covering 40 years of global economic activity and natural resource use. This new data set is becoming the standard information source for decision making at the UN in the context of the post‐2015 development agenda, which acknowledges the strong links between sustainable natural resource management, economic prosperity, and human well‐being. Only if economic growth and human development can become substantially decoupled from accelerating material use, waste, and emissions can the tensions inherent in the Sustainable Development Goals be resolved and inclusive human development be achieved. In this paper, we summarize the key findings of the assessment study to make the IE research community aware of this new global research resource. The global results show a massive increase in materials extraction from 22 billion tonnes (Bt) in 1970 to 70 Bt in 2010, and an acceleration in material extraction since 2000. This acceleration has occurred at a time when global population growth has slowed and global economic growth has stalled. The global surge in material extraction has been driven by growing wealth and consumption and accelerating trade. A material footprint perspective shows that demand for materials has grown even in the wealthiest parts of the world. Low‐income countries have benefited least from growing global resource availability and have continued to deliver primary materials to high‐income countries while experiencing few improvements in their domestic material living standards. Material efficiency, the amount of primary materials required per unit of economic activity, has declined since around 2000 because of a shift of global production from very material‐efficient economies to less‐efficient ones. This global trend of recoupling economic activity with material use, driven by industrialization and urbanization in the global South, most notably Asia, has negative impacts on a suite of environmental and social issues, including natural resource depletion, climate change, loss of biodiversity, and uneven economic development. This research is a good example of the IE research community providing information for evidence‐based policy making on the global stage and testament to the growing importance of IE research in achieving global sustainable development.     

The Energetic Metabolism of the European Union and the United States: Decadal Energy Input Time-Series with an Emphasis on Biomass

This article presents an assessment of energy inputs of the European Union (the 15 countries before the 2004 enlargement, abbreviated EU‐15) for the period 1970–2001 and the United States for 1980–2000. The data are based on an energy flow analysis (EFA) that evaluates socioeconomic energy flows in a way that is conceptually consistent with current materials flow analysis (MFA) methods. EFA allows assessment of the total amount of energy required by a national economy; it yields measures of the size of economic systems in biophysical units. In contrast to conventional energy balances, which only include technically used energy, EFA also accounts for socioeconomic inputs of biomass; that is, it also considers food, feed, wood and other materials of biological origin. The energy flow accounts presented in this article do not include embodied energy. Energy flow analyses are relevant for comparisons across modes of subsistence (e.g., agrarian and industrial society) and also to detect interrelations between energy utilization and land use. In the EU‐15, domestic energy consumption (DEC = apparent consumption = domestic extraction plus import minus export) grew from 60 exajoules per year (1 EJ = 10¹⁸ J) in 1970 to 79 EJ/yr in 2001, thus exceeding its territory's net primary production (NPP, a measure of the energy throughput of ecosystems). In the United States, DEC increased from 102 EJ/yr in 1980 to 125 EJ/yr in 2000 and was thus slightly smaller than its NPP. Taken together, the EU‐15 and the United States accounted for about 38% of global technical energy use, 31% of humanity's energetic metabolism, but only 10% of global terrestrial NPP and 11% of world population in the early 1990s. Per capita DEC of the United States is more than twice that of the EU‐15. Calculated according to EFA methods, energy input in the EU and the United States was between one‐fifth and one‐third above the corresponding value reported in conventional energy balances. The article discusses implications of these results for sustainability, as well as future research needs.     

Effects of unexpected chords and of performer's expression on brain responses and electrodermal activity

Background

There is lack of neuroscientific studies investigating music processing with naturalistic stimuli, and brain responses to real music are, thus, largely unknown.

Methodology/Principal Findings

This study investigates event-related brain potentials (ERPs), skin conductance responses (SCRs) and heart rate (HR) elicited by unexpected chords of piano sonatas as they were originally arranged by composers, and as they were played by professional pianists. From the musical excerpts played by the pianists (with emotional expression), we also created versions without variations in tempo and loudness (without musical expression) to investigate effects of musical expression on ERPs and SCRs. Compared to expected chords, unexpected chords elicited an early right anterior negativity (ERAN, reflecting music-syntactic processing) and an N5 (reflecting processing of meaning information) in the ERPs, as well as clear changes in the SCRs (reflecting that unexpected chords also elicited emotional responses). The ERAN was not influenced by emotional expression, whereas N5 potentials elicited by chords in general (regardless of their chord function) differed between the expressive and the non-expressive condition.

Conclusions/Significance

These results show that the neural mechanisms of music-syntactic processing operate independently of the emotional qualities of a stimulus, justifying the use of stimuli without emotional expression to investigate the cognitive processing of musical structure. Moreover, the data indicate that musical expression affects the neural mechanisms underlying the processing of musical meaning. Our data are the first to reveal influences of musical performance on ERPs and SCRs, and to show physiological responses to unexpected chords in naturalistic music.     

Comparing the processing of music and language meaning using EEG and FMRI provides evidence for similar and distinct neural representations

Recent demonstrations that music is capable of conveying semantically meaningful information has raised several questions as to what the underlying mechanisms of establishing meaning in music are, and if the meaning of music is represented in comparable fashion to language meaning. This paper presents evidence showing that expressed affect is a primary pathway to music meaning and that meaning in music is represented in a very similar fashion to language meaning. In two experiments using EEG and fMRI, it was shown that single chords varying in harmonic roughness (consonance/dissonance) and thus perceived affect could prime the processing of subsequently presented affective target words, as indicated by an increased N400 and activation of the right middle temporal gyrus (MTG). Most importantly, however, when primed by affective words, single chords incongruous to the preceding affect also elicited an N400 and activated the right posterior STS, an area implicated in processing meaning of a variety of signals (e.g. prosody, voices, motion). This provides an important piece of evidence in support of music meaning being represented in a very similar but also distinct fashion to language meaning: Both elicit an N400, but activate different portions of the right temporal lobe.     

Consumption‐based Material Flow Accounting

In 2007, imports accounted for approximately 34% of the material input (domestic extraction and imports) into the Austrian economy and almost 60% of the GDP stemmed from exports. Upstream material inputs into the production of traded goods, however, are not yet included in the standard framework of material flow accounting (MFA). We have reviewed different approaches accounting for these upstream material inputs, or raw material equivalents (RME), positioning them in a wider debate about consumption‐based perspectives in environmental accounting. For the period 1995–2007, we calculated annual RME of Austria's trade and consumption applying a hybrid approach. For exports and competitive imports, we used an environmentally extended input‐output model of the Austrian economy, based on annual supply and use tables and MFA data. For noncompetitive imports, coefficients for upstream material inputs were extracted from life cycle inventories. The RME of Austria's imports and exports were approximately three times larger than the trade flows themselves. In 2007, Austria's raw material consumption was 30 million tonnes or 15% higher than its domestic material consumption. We discuss the material composition of these flows and their temporal dynamics. Our results demonstrate the need for a consumption‐based perspective in MFA to provide robust indicators for dematerialization and resource efficiency analysis of open economies.     

Accounting for the Material Stock of Nations

National material stock (MS) accounts have been a neglected field of analysis in industrial ecology, possibly because of the difficulty in establishing such accounts. In this research, we propose a novel method to model national MS based on historical material flow data. This enables us to avoid the laborious data work involved with bottom‐up accounts for stocks and to arrive at plausible levels of stock accumulation for nations. We apply the method for the United States and Japan to establish a proof of concept for two very different cases of industrial development. Looking at a period of 75 years (1930–2005), we find that per capita MS has been much higher in the United States for the entire period, but that Japan has experienced much higher growth rates throughout, in line with Japan's late industrial development. By 2005, however, both Japan and the United States arrive at a very similar level of national MS of 310 to 375 tonnes per capita, respectively. This research provides new insight into the relationship between MS and flows in national economies and enables us to extend the debate about material efficiency from a narrow perspective of throughput to a broader perspective of stocks.