Multiscale coupling and multiphysics approaches in earth sciences : applications

Geoscientists are confronted with the challenge of assessing nonlinear phenomena that result from multiphysics coupling across multiple scales from the quantum level to the scale of the earth and from femtoseconds to the 4.5 Ga of history of our planet. We neglect in this review electromagnetic modelling of the processes in the Earth’s core, and focus on four types of couplings that underpin fundamental instabilities in the Earth. These are thermal (T), hydraulic (H), mechanical (M) and chemical (C) processes which are driven and controlled by the transfer of heat to the Earth’s surface. Instabilities appear as faults, folds, compaction bands, shear/fault zones, plate boundaries and convective patterns. Convective patterns emerge from buoyancy overcoming viscous drag at a critical Rayleigh number. All other processes emerge from non-conservative thermodynamic forces with a critical critical dissipative source term, which can be characterised by the modified Gruntfest number Gr. These dissipative processes reach a quasi-steady state when, at maximum dissipation, THMC diffusion (Fourier, Darcy, Biot, Fick) balance the source term. The emerging steady state dissipative patterns are defined by the respective diffusion length scales. These length scales provide a fundamental thermodynamic yardstick for measuring instabilities in the Earth. The implementation of a fully coupled THMC multiscale theoretical framework into an applied workflow is still in its early stages. This is largely owing to the four fundamentally different lengths of the THMC diffusion yardsticks spanning micro-metre to tens of kilometres compounded by the additional necessity to consider microstructure information in the formulation of enriched continua for THMC feedback simulations (i.e., micro-structure enriched continuum formulation). Another challenge is to consider the important factor time which implies that the geomaterial often is very far away from initial yield and flowing on a time scale that cannot be accessed in the laboratory. This leads to the requirement of adopting a thermodynamic framework in conjunction with flow theories of plasticity. This framework allows, unlike consistency plasticity, the description of both solid mechanical and fluid dynamic instabilities. In the applications we show the similarity of THMC feedback patterns across scales such as brittle and ductile folds and faults. A particular interesting case is discussed in detail, where out of the fluid dynamic solution, ductile compaction bands appear which are akin and can be confused with their brittle siblings. The main difference is that they require the factor time and also a much lower driving forces to emerge. These low stress solutions cannot be obtained on short laboratory time scales and they are therefore much more likely to appear in nature than in the laboratory. We finish with a multiscale description of a seminal structure in the Swiss Alps, the Glarus thrust, which puzzled geologists for more than 100 years. Along the Glarus thrust, a km-scale package of rocks (nappe) has been pushed 40 km over its footwall as a solid rock body. The thrust itself is a m-wide ductile shear zone, while in turn the centre of the thrust shows a mm-cm wide central slip zone experiencing periodic extreme deformation akin to a stick-slip event. The m-wide creeping zone is consistent with the THM feedback length scale of solid mechanics, while the ultralocalised central slip zones is most likely a fluid dynamic instability.

Influence of different nitrogen rates and DMPP nitrification inhibitor on annual N2O emissions from a subtropical wheat–maize cropping system

Global cereal production will need to increase by 50% to 70% to feed a world population of about 9 billion by 2050. This intensification is forecast to occur mostly in subtropical regions, where warm and humid conditions can promote high N2O losses from cropped soils. To secure high crop production without exacerbating N2O emissions, new nitrogen (N) fertiliser management strategies are necessary. This one-year study evaluated the efficacy of a nitrification inhibitor (3,4-dimethylpyrazole phosphate—DMPP) and different N fertiliser rates to reduce N2O emissions in a wheat–maize rotation in subtropical Australia. Annual N2O emissions were monitored using a fully automated greenhouse gas measuring system. Four treatments were fertilized with different rates of urea, including a control (40 kg-N ha−1 year−1), a conventional N fertiliser rate adjusted on estimated residual soil N (120 kg-N ha−1 year−1), a conventional N fertiliser rate (240 kg-N ha−1 year−1) and a conventional N fertiliser rate (240 kg-N ha−1 year−1) with nitrification inhibitor (DMPP) applied at top dressing. The maize season was by far the main contributor to annual N2O emissions due to the high soil moisture and temperature conditions, as well as the elevated N rates applied. Annual N2O emissions in the four treatments amounted to 0.49, 0.84, 2.02 and 0.74 kg N2O–N ha−1 year−1, respectively, and corresponded to emission factors of 0.29%, 0.39%, 0.69% and 0.16% of total N applied. Halving the annual conventional N fertiliser rate in the adjusted N treatment led to N2O emissions comparable to the DMPP treatment but extensively penalised maize yield. The application of DMPP produced a significant reduction in N2O emissions only in the maize season. The use of DMPP with urea at the conventional N rate reduced annual N2O emissions by more than 60% but did not affect crop yields. The results of this study indicate that: (i) future strategies aimed at securing subtropical cereal production without increasing N2O emissions should focus on the fertilisation of the summer crop; (ii) adjusting conventional N fertiliser rates on estimated residual soil N is an effective practice to reduce N2O emissions but can lead to substantial yield losses if the residual soil N is not assessed correctly; (iii) the application of DMPP is a feasible strategy to reduce annual N2O emissions from sub-tropical wheat–maize rotations. However, at the N rates tested in this study DMPP urea did not increase crop yields, making it impossible to recoup extra costs associated with this fertiliser. The findings of this study will support farmers and policy makers to define effective fertilisation strategies to reduce N2O emissions from subtropical cereal cropping systems while maintaining high crop productivity. More research is needed to assess the use of DMPP urea in terms of reducing conventional N fertiliser rates and subsequently enable a decrease of fertilisation costs and a further abatement of fertiliser-induced N2O emissions.

Marine aerosol hygroscopicity and volatility, measured on the Chatham Rise (New Zealand)

The Surface Ocean Aerosol Production (SOAP) study was undertaken in February/March 2012 in the biologically active waters of the Chatham Rise, NZ. Aerosol hygroscopicity and volatility were examined with a volatility hygroscopicity tandem differential mobility analyser. These observations confirm results from other hygroscopicity-based studies that the dominant fraction of the observed remote marine particles were non-sea salt sulfates. Further observations are required to clarify the influences of seawater composition, meteorology and analysis techniques seasonally across different ocean basins.

Crunch time : how did the students perform?

Two newspaper numbers games based on simple arithmetic relationships are discussed. One is rather trivial, but very useful as an introduction to the second, whose potential to give students of elementary algebra practice in semi ad-hoc reasoning and to build general arithmetic reasoning skills was explored theoretically in an earlier paper. Preliminary results on the effectiveness of this general approach are presented, with student performance and feedback on an assignment task and formal examination included, and recommendations for future work.

Groundwater table response to sea level rise and its impact on pavement structure

It has been predicted that sea level will rise about 0.8 m by 2100. Consequently, seawater can intrude into the coastal aquifers and change the level of groundwater table. A raise in groundwater table due to seawater intrusion threats the coastal infrastructure such as road pavements. The mechanical properties of subgrade materials will change due to elevated rise of groundwater table, leading to pavement weakening and decreasing the subgrade strength and stiffness. This paper presents an assessment of the vulnerability of subgrade in coastal areas to change in groundwater table due to sea-level rise. A simple bathtub approach is applied for estimating the groundwater level changes according to sea-level rise. Then the effect of groundwater level changes on the soil water content (SWC) of a single column of fine-sand soil is simulated using MIKE SHE. The impact of an increase in moisture content on subgrade strength/stiffness is assessed for a number of scenarios.

Theory based production and project management

This paper gives an overview of an ongoing project endeavouring to advance theory-based production and project management, and the rationale for this approach is briefly justified. The status of the theoretical foundation of production management, project management and allied disciplines is discussed, with emphasis on metaphysical grounding of theories, as well as the nature of the heuristic solution method commonly used in these disciplines. Then, on-going work related to different aspects of production and project management is reviewed from both theoretical and practical orientation. Next, information systems agile project management is explored with a view to its re-use in generic project management. In production management, the consequences and implementation of a new, wider theoretical basis are analyzed. The theoretical implications and negative symptoms of the peculiarities of the construction industry for supply chains and supply chain management in construction are observed. Theoretical paths for improvements of inter-organisational relationships in construction which are fundamental for improvement of construction supply chains are described. To conclude, the observations made in this paper vis-à-vis production, project and supply chain management are related again to the theoretical basis of this paper, and finally directions for theory development and future research are given and discussed.

Molecular network analysis using reverse phase protein microarrays for patient tailored therapy.

The practice of medicine has always aimed at individualized treatment of disease. The relationship between patient and physician has always been a personal one, and the physician's choice of treatment has been intended to be the best fit for the patient's needs. The necessary pooling/grouping of disease families and their assignment to a number of drugs or treatment methods has, consequently, led to an increase in the number of effective therapies. However, given the heterogeneity of most human diseases, and cancer specifically, it is currently impossible for the treating clinician to effectively predict a patient's response and outcome based on current technologies, much less the idiosyncratic resistances and adverse effects associated with the limited therapeutic options.

Proteins, drug targets and the mechanisms they control : the simple truth about complex networks

Realizing the promise of molecularly targeted inhibitors for cancer therapy will require a new level of knowledge about how a drug target is wired into the control circuitry of a complex cellular network. Here we review general homeostatic principles of cellular networks that enable the cell to be resilient in the face of molecular perturbations, while at the same time being sensitive to subtle input signals. Insights into such mechanisms may facilitate the development of combination therapies that take advantage of the cellular control circuitry, with the aim of achieving higher efficacy at a lower drug dosage and with a reduced probability of drug-resistance development.

Mathematical modeling of the cancer cell’s control circuitry : paving the way to individualized therapeutic strategies

Cancer is a disease of signal transduction in which the dysregulation of the network of intracellular and extracellular signaling cascades is sufficient to thwart the cells finely-tuned biochemical control mechanisms. A keen interest in the mathematical modeling of cell signaling networks and the regulation of signal transduction has emerged in recent years, and has produced a glimmer of insight into the sophisticated feedback control and network regulation operating within cells. In this review, we present an overview of published theoretical studies on the control aspects of signal transduction, emphasizing the role and importance of mechanisms such as ‘ultrasensitivity’ and feedback loops. We emphasize that these exquisite and often subtle control strategies represent the key to orchestrating ‘simple’ signaling behaviors within the complex intracellular network, while regulating the trade-off between sensitivity and robustness to internal and external perturbations. Through a consideration of these apparent paradoxes, we explore how the basic homeostasis of the intracellular signaling network, in the face of carcinogenesis, can lead to neoplastic progression rather than cell death. A simple mathematical model is presented, furnishing a vivid illustration of how ‘control-oriented’ models of the deranged signaling networks in cancer cells may enucleate improved treatment strategies, including patient-tailored combination therapies, with the potential for reduced toxicity and more robust and potent antitumor activity.

Development of reverse phase protein microarrays for clinical applications and patient-tailored therapy

While genomics provide important information about the somatic genetic changes, and RNA transcript profiling can reveal important expression changes that correlate with outcome and response to therapy, it is the proteins that do the work in the cell. At a functional level, derangements within the proteome, driven by post-translational and epigenetic modifications, such as phosphorylation, is the cause of a vast majority of human diseases. Cancer, for instance, is a manifestation of deranged cellular protein molecular networks and cell signaling pathways that are based on genetic changes at the DNA level. Importantly, the protein pathways contain the drug targets in signaling networks that govern overall cellular survival, proliferation, invasion and cell death. Consequently, the promise of proteomics resides in the ability to extend analysis beyond correlation to causality. A critical gap in the information knowledge base of molecular profiling is an understanding of the ongoing activity of protein signaling in human tissue: what is activated and “in use” within the human body at any given point in time. To address this gap, we have invented a new technology, called reverse phase protein microarrays, that can generate a functional read-out of cell signaling networks or pathways for an individual patient obtained directly from a biopsy specimen. This “wiring diagram” can serve as the basis for both, selection of a therapy and patient stratification.

Phosphoprotein pathway mapping: Akt/Mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival

Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains ∼60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser473 (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr37/46 (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser1108 (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr389 (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.

Use of reverse phase protein microarrays and reference standard development for molecular network analysis of metastatic ovarian carcinoma

Cancer can be defined as a deregulation or hyperactivity in the ongoing network of intracellular and extracellular signaling events. Reverse phase protein microarray technology may offer a new opportunity to measure and profile these signaling pathways, providing data on post-translational phosphorylation events not obtainable by gene microarray analysis. Treatment of ovarian epithelial carcinoma almost always takes place in a metastatic setting since unfortunately the disease is often not detected until later stages. Thus, in addition to elucidation of the molecular network within a tumor specimen, critical questions are to what extent do signaling changes occur upon metastasis and are there common pathway elements that arise in the metastatic microenvironment. For individualized combinatorial therapy, ideal therapeutic selection based on proteomic mapping of phosphorylation end points may require evaluation of the patient's metastatic tissue. Extending these findings to the bedside will require the development of optimized protocols and reference standards. We have developed a reference standard based on a mixture of phosphorylated peptides to begin to address this challenge.

Analysis of albumin-associated peptides and proteins from ovarian cancer patients

Albumin binds low–molecular-weight molecules, including proteins and peptides, which then acquire its longer half-life, thereby protecting the bound species from kidney clearance. We developed an experimental method to isolate albumin in its native state and to then identify [mass spectrometry (MS) sequencing] the corresponding bound low–molecular-weight molecules. We used this method to analyze pooled sera from a human disease study set (high-risk persons without cancer, n= 40; stage I ovarian cancer, n = 30; stage III ovarian cancer, n = 40) to demonstrate the feasibility of this approach as a discovery method. Methods Albumin was isolated by solid-phase affinity capture under native binding and washing conditions. Captured albumin-associated proteins and peptides were separated by gel electrophoresis and subjected to iterative MS sequencing by microcapillary reversed-phase tandem MS. Selected albumin-bound protein fragments were confirmed in human sera by Western blotting and immunocompetition. Results In total, 1208 individual protein sequences were predicted from all 3 pools. The predicted sequences were largely fragments derived from proteins with diverse biological functions. More than one third of these fragments were identified by multiple peptide sequences, and more than one half of the identified species were in vivo cleavage products of parent proteins. An estimated 700 serum peptides or proteins were predicted that had not been reported in previous serum databases. Several proteolytic fragments of larger molecules that may be cancer-related were confirmed immunologically in blood by Western blotting and peptide immunocompetition. BRCA2, a 390-kDa low-abundance nuclear protein linked to cancer susceptibility, was represented in sera as a series of specific fragments bound to albumin. Conclusion Carrier-protein harvesting provides a rich source of candidate peptides and proteins with potential diverse tissue and cellular origins that may reflect important disease-related information.

The amplified peptidome : the new treasure chest of candidate biomarkers

Mass spectrometric analysis of the low-molecular weight (LMW) range of the serum/plasma proteome is revealing the existence of large numbers of previously unknown peptides and protein fragments predicted to be derived from low- abundance proteins. This raises the question of why such low abundance molecules would be retained at detectable levels in the circulation, instead of being rapidly cleared and excreted. Theoretical models of biomarker production and association with serum carrier proteins have been developed to elucidate the mechanisms governing biomarker half-life in the bloodstream. These models predict that the vast majority of LMW biomarkers exist in association with circulating high molecular mass carrier proteins. Moreover, the total serum/ plasma concentration of the biomarker is largely determined by the clearance rate of the carrier protein, not the free-phase biomarker clearance itself. These predictions have been verified experimentally using molecular mass fractionation of human serum before mass spectrometry sequence analysis. These principles have profound implications for biomarker discovery and measurement.

Modeling of protein signaling networks in clinical proteomics

Molecular interactions that underlie pathophysiological states are being elucidated using techniques that profile proteomicend points in cellular systems. Within the field of cancer research, protein interaction networks play pivotal roles in the establishment and maintenance of the hallmarks of malignancy, including cell division, invasion, and migration. Multiple complementary tools enable a multifaceted view of how signal protein pathway alterations contribute to pathophysiological states.One pivotal technique is signal pathway profiling of patient tissue specimens. This microanalysis technology provides a proteomic snapshot at one point in time of cells directly procured from the native context of a tumor micro environment. To study the adaptive patterns of signal pathway events over time, before and after experimental therapy, it is necessary to obtain biopsies from patients before, during, and after therapy. A complementary approach is the profiling of cultured cell lines with and without treatment. Cultured cell models provide the opportunity to study short-term signal changes occurring over minutes to hours. Through this type of system, the effects of particular pharmacological agents may be used to test the effects of signal pathway inhibition or activation on multiple endpoints within a pathway. The complexity of the data generated has necessitated the development of mathematical models for optimal interpretation of interrelated signaling pathways. In combination,clinical proteomic biopsy profiling, tissue culture proteomic profiling, and mathematical modeling synergistically enable a deeper understanding of how protein associations lead to disease states and present new insights into the design of therapeutic regimens.