Analyzing the activity of large populations of neurons: how tractable is the problem?

Understanding how the brain performs computations requires understanding neuronal firing patterns at successive levels of processing-a daunting and seemingly intractable task. Two recent studies have made dramatic progress on this problem by showing how its dimensionality can be reduced. Using the retina as a model system, they demonstrated that multineuronal firing patterns can be predicted by pairwise interactions.     

Assessing the importance of genotype × environment interaction for root traits in rice using a mapping population II: conventional QTL analysis

Modifying plant root systems is considered a means of crop improvement targeted to low-resource environments, particularly low nutrient and drought-prone agriculture. The identification of quantitative trait loci (QTLs) for root traits has stimulated marker-assisted breeding to this end, but different QTLs have been detected in different populations of the same species, and importantly, in the same population when grown in different experimental environments. The presence of QTL × environment interaction is implicated, and this must be characterised if the utility of the target QTLs is to be realised. Previous attempts to do this suffer from a lack of control over replicate environments and inadequate statistical rigour. The Bala × Azucena mapping population was grown in two replicate experiments of four treatment environments, a control, a low light, a low soil nitrogen and a low soil water treatment. After a 4 weeks growth, maximum root length, maximum root thickness, root mass below 50 cm, total plant dry mass, % root mass and shoot length were measured. A summary of the overall results is presented in an accompanying paper. Here, QTL analysis by composite interval mapping is presented. A total of 145 QTLs were detected, mapping to 37 discrete loci on all chromosomes. Superficial evidence of QTL × E (great difference in LOD score) was tested by single-marker analysis which confirmed QTL × E for five loci representing only five individual trait-loci interactions. Some loci appeared to be stable across environments. Some QTLs were clearly more or less active under low light, low nitrogen or drought. A few notable loci on chromosomes 1, 2, 3, 5, 7 and 9 are briefly discussed. Also discussed are some remaining statistical shortcomings that will be addressed in another companion paper.     

Data management for large‐scale scientific computations in high performance distributed systems

With the increasing number of scientific applications manipulating huge amounts of data, effective high-level data management is an increasingly important problem. Unfortunately, so far the solutions to the high‐level data management problem either require deep understanding of specific storage architectures and file layouts (as in high-performance file storage systems) or produce unsatisfactory I/O performance in exchange for ease-of-use and portability (as in relational DBMSs). In this paper we present a novel application development environment which is built around an active meta-data management system (MDMS) to handle high-level data in an effective manner. The key components of our three-tiered architecture are user application, the MDMS, and a hierarchical storage system (HSS). Our environment overcomes the performance problems of pure database-oriented solutions, while maintaining their advantages in terms of ease-of-use and portability. The high levels of performance are achieved by the MDMS, with the aid of user-specified, performance-oriented directives. Our environment supports a simple, easy-to-use yet powerful user interface, leaving the task of choosing appropriate I/O techniques for the application at hand to the MDMS. We discuss the importance of an active MDMS and show how the three components of our environment, namely the application, the MDMS, and the HSS, fit together. We also report performance numbers from our ongoing implementation and illustrate that significant improvements are made possible without undue programming effort. This revised version was published online in July 2006 with corrections to the Cover Date.     

Robustness of life table methods in large populations—a study by computer simulation

The robustness of the product life table estimator of the survival function was studied for large populations under perturbations in the age distribution, changing levels of mortality and changing patterns of fertility. A macrosimulation system, based on a class of stochastic population models called generalised age-dependent branching processes, was used to carry out the numerical investigations. Aside from drastic perturbations in the age distribution and changes in levels of mortality, the product life table estimator of the survival function was found to be robust in large populations, under a variety of conditions.     

A segmental labeling strategy for unambiguous determination of domain–domain interactions of large multi-domain proteins

NMR structural determination of large multi-domain proteins is a challenging task due to significant spectral overlap with a particular difficulty in unambiguous identification of domain–domain interactions. Segmental labeling is a NMR strategy that allows for isotopically labeling one domain and leaves the other domain unlabeled. This significantly simplifies spectral overlaps and allows for quick identification of domain–domain interaction. Here, a novel segmental labeling strategy is presented for detection of inter-domain NOEs. To identify domain–domain interactions in human apolipoprotein E (apoE), a multi-domain, 299-residues α-helical protein, on-column expressed protein ligation was utilized to generate a segmental-labeled apoE samples in which the N-terminal (NT-) domain was ²H(99%)/¹⁵N-labeled whereas the C-terminal (CT-) domain was either ¹⁵N- or ¹⁵N/¹³C-labeled. 3-D ¹⁵N-edited NOESY spectra of these segmental-labeled apoE samples allow for direct observation of the inter-domain NOEs between the backbone amide protons of the NT-domain and the aliphatic protons of the CT-domain. This straightforward approach permits unambiguous identification of 78 inter-domain NOEs, enabling accurate definition of the relative positions of both the NT- and the CT-domains and determination of the NMR structure of apoE.     

The Role of Cohesiveness in the Permeability of the Spatial Assemblies of FG Nucleoporins

Nuclear pore complexes (NPCs) conduct selective, bidirectional transport across the nuclear envelope. The NPC passageway is lined by intrinsically disordered proteins that contain hydrophobic phenylalanine-glycine (FG) motifs, known as FG nucleoporins (FG nups), that play the key role in the NPC transport mechanism. Cohesive interactions among the FG nups, which arise from the combination of hydrophobic, electrostatic, and other forces, have been hypothesized to control the morphology of the assemblies of FG nups in the NPC, as well as their permeability with respect to the transport proteins. However, the role of FG nup cohesiveness is still vigorously debated. Using coarse-grained polymer theory and numerical simulations, we study the effects of cohesiveness on the selective permeability of in vitro FG nup assemblies in different geometries that have served as proxies for the morphological and transport properties of the NPC. We show that in high-density FG nup assemblies, increase in cohesiveness leads to the decrease in their permeability, in accordance with the accepted view. On the other hand, the permeability of low-density assemblies is a nonmonotonic function of the cohesiveness, and a moderate increase in cohesiveness can enhance permeability. The density- and cohesiveness-dependent effects on permeability are explained by considering the free-energy cost associated with penetrating the FG nup assemblies. We discuss the implications of these findings for the organization and function of the NPC.     

Generation of retroviruses for the overexpression of cytosolic and mitochondrial glutathione reductase in macrophages in vivo

Retroviral gene transfer and bone marrow transplantation has been used by many investigators to study the role of macrophage proteins in different mouse models of human disease. While this approach is faster and less expensive than generating transgenic mice with macrophage-specific promoters and applicable to a wider array of mouse models, it has been hampered by two major drawbacks: labor-intensive cloning procedures involved in generating retroviral vectors for each gene of interest and low viral titers. Here we describe the construction of a MSCV-based retroviral vector that can serve as an acceptor vector for commercially available Cre-lox-compatible donor vectors. Using this new retroviral vector in combination with a FACS approach to enhance viral titers, we generated high-titer retroviruses carrying either EGFP-tagged cytosolic or EGFP-tagged mitochondria-targeted glutathione reductase. We show that the introduction of these constructs via retroviral gene transfer and bone marrow transplantation into atherosclerosis-prone LDL receptor-null mice results in the long-term increase in macrophage glutathione reductase activity.     

Variations in the microbial community of biofilms under different near-wall hydraulic shear stresses in agricultural irrigation systems

Abstract

The hydraulic characteristics along agricultural irrigation pipelines directly affect the local near-wall hydraulic shear stress and biofilm accumulation. However, the variations in the microbial community during the process remain unknown. Based on the Couette-Taylor reactor, a device was developed to accurately control the hydraulic shear stress. The results indicated that the near-wall hydraulic shear stresses showed quadratic correlations with microbial contents (represented by phospholipid fatty acids r?>?0.77, p?<?0.05), and the maximum values were obtained under the shear stresses of 0.20-0.35?Pa. For two types of treated wastewater, the mutual operational taxonomic units among different shear stress treatments showed good consistency (>185). Their corresponding response in the microbial community was represented by the quantitative correlations between the near-wall hydraulic shear stresses and the polymorphism indices (r?>?0.82, p?<?0.05). Among the microorganisms, Firmicutes at the phylum level were significantly affected by the shear stress and significantly influenced the biofilm accumulation process.     

The importance of willow thickets for ptarmigan and hares in shrub tundra: the more the better?

In patchy habitats, the relationship between animal abundance and cover of a preferred habitat may change with the availability of that habitat, resulting in a functional response in habitat use. Here, we investigate the relationship of two specialized herbivores, willow ptarmigan (Lagopus lagopus) and mountain hare (Lepus timidus), to willows (Salix spp.) in three regions of the shrub tundra zone-northern Norway, northern European Russia and western Siberia. Shrub tundra is a naturally patchy habitat where willow thickets represent a major structural element and are important for herbivores both as food and shelter. Habitat use was quantified using feces counts in a hierarchical spatial design and related to several measures of willow thicket configuration. We document a functional response in the use of willow thickets by ptarmigan, but not by hares. For hares, whose range extends into forested regions, occurrence increased overall with willow cover. The occurrence of willow ptarmigan showed a strong positive relationship to willow cover and a negative relationship to thicket fragmentation in the region with lowest willow cover at landscape scale, where willow growth may be limited by reindeer browsing. In regions with higher cover, in contrast, such relationships were not observed. Differences in predator communities among the regions may contribute to the observed pattern, enhancing the need for cover where willow thickets are scarce. Such region-specific relationships reflecting regional characteristics of the ecosystem highlight the importance of large-scale investigations to understand the relationships of habitat availability and use, which is a critical issue considering that habitat availability changes quickly with climate change and human impact.     

Network genomics – A novel approach for the analysis of biological systems in the post-genomic era

Network Genomics studies genomics and proteomics foundations of cellular networks in biological systems. It complements systems biology in providing information on elements, their interaction and their functional interplay in cellular networks. The relationship between genomic and proteomic high-throughput technologies and computational methods are described, as well as several examples of specific network genomic application are presented.     

A model for the rate of enzymatic hydrolysis of cellulose in heterogeneous solid–liquid systems

Hydrolysis of cellulose by cellulase enzymes has been studied in a stirred batch reactor at 50°C. A kinetic model has been devised by which the behaviour of such a reaction could be described. The model has been developed on the basis of shrinking particle theory and Langmuir isotherm concept. The applicability of the model has been tested by comparing the experimental results for diverse reaction systems, obtained in the present study or taken from the literature, and those predicted from the model. The degree of agreement was within ±2–11%.     

A Mechanism for Ultra-Slow Oscillations in the Cortical Default Network

When the brain is in its noncognitive “idling” state, functional MRI measurements reveal the activation of default cortical networks whose activity is suppressed during cognitive processing. This default or background mode is characterized by ultra-slow BOLD oscillations (∼0.05 Hz), signaling extremely slow cycling in cortical metabolic demand across distinct cortical regions. Here we describe a model of the cortex which predicts that slow cycling of cortical activity can arise naturally as a result of nonlinear interactions between temporal (Hopf) and spatial (Turing) instabilities. The Hopf instability is triggered by delays in the inhibitory postsynaptic response, while the Turing instability is precipitated by increases in the strength of the gap-junction coupling between interneurons. We comment on possible implications for slow dendritic computation and information processing.     

Production of the stable human histamine H₁ receptor in Pichia pastoris for structural determination

G-protein coupled receptors (GPCRs) play essential roles in regulation of many physiological processes and are one of the major targets of pharmaceutical drugs. The 3D structure can provide important information for the understanding of GPCR function and the design of new drugs. However, the success of structure determination relies largely on the production of recombinant GPCRs, because the expression levels of GPCRs are very low in native tissues except rhodopsin. All non-rhodopsin GPCRs whose structures were determined so far were expressed in insect cells and the availability of other hosts was unknown. Recently, we succeeded to determine the structure of human histamine H(1) receptor (H(1)R) expressed in Pichia pastoris. Here, we report the expression and purification procedures of recombinant H(1)R used in the structural determination. The receptor was designed to possess a N-terminal 19-residue deletion and a replacement of the third cytoplasmic loop with T4-lysozyme. The receptor was verified to show similar binding activities with the receptor expressed in other hosts. The receptor was purified by the immobilized metal ion affinity chromatography and used for the crystallographic study that resulted in the successful structure determination.     

Metal toxicity characterization factors for marine ecosystems—considering the importance of the estuary for freshwater emissions

Purpose

The study develops site-dependent characterization factors (CFs) for marine ecotoxicity of metals emitted to freshwater, taking their passage of the estuary into account. To serve life cycle assessment (LCA) studies where emission location is often unknown, site-generic marine CFs were developed for metal emissions to freshwater and coastal seawater, respectively. The new CFs were applied to calculate endpoint impact scores for the same amount of metal emission to each compartment, to compare the relative ecotoxicity damages in freshwater and marine ecosystems in LCA.

Methods

Site-dependent marine CFs for emission to freshwater were calculated for 64 comparatively independent seas (large marine ecosystems, LMEs). The site-dependent CF was calculated as the product of fate factor (FF), bioavailability factor (BF), and effect factor (EF). USEtox modified with site-dependent parameters was extended with an estuary removal process to calculate FF. BF and EF were taken from Dong et al. Environ Sci Technol 50:269–278 (2016). Site-generic marine CFs were derived from site-dependent marine CFs. Different averaging principles were tested, and the approach representing estuary discharge rate was identified as the best one. Endpoint marine and freshwater metals CFs were developed to calculate endpoint ecotoxicity impact scores.

Results and discussion

Marine ecotoxicity CFs are 1.5 orders of magnitude lower for emission to freshwater than for emission to seawater for Cr, Cu, and Pb, due to notable removal fractions both in freshwater and estuary. For the other metals, the difference is less than half an order of magnitude, mainly due to removal in freshwater. The site-dependent CFs generally vary within two orders of magnitude around the site-generic CF. Compared to USES-LCA 2.0 CFs (egalitarian perspective), the new site-generic marine CFs for emission to seawater are 1–4 orders of magnitude lower except for Pb. The new site-generic marine CFs for emission to freshwater lie within two orders of magnitude difference from USES-LCA 2.0 CFs. The comparative contribution share analysis shows a poor agreement of metal toxicity ranking between both methods.

Conclusions

Accounting for estuary removal particularly influences marine ecotoxicity CFs for emission to freshwater of metals that have a strong tendency to complex-bind to particles. It indicates the importance of including estuary in the characterization modelling when dealing with those metals. The resulting endpoint ecotoxicity impact scores are 1–3 orders of magnitude lower in seawater than in freshwater for most metals except Pb, illustrating the higher sensitivity of freshwater ecosystems to metal emissions, largely due to the higher species density there.

     

Do we underestimate the importance of water in cell biology?

Liquid water is a highly versatile material. Although it is formed from the tiniest of molecules, it can shape and control biomolecules. The hydrogen-bonding properties of water are crucial to this versatility, as they allow water to execute an intricate three-dimensional 'ballet', exchanging partners while retaining complex order and enduring effects. Water can generate small active clusters and macroscopic assemblies, which can both transmit information on different scales.     

Elemental levels and relationships in the Flacourtiaceae of New Caledonia and their significance for the evaluation of the ‘serpentine problem’

Summary Sixteen elements were determined in 156 specimens of 47 species of New Caledonian Flacourtiaceae including the genera Casearia, Homalium, Lasiochlamys and Xylosma. The data were used to study inter-elemental relationships, particularly those involving nutrient elements, magnesium and phytotoxic elements such as chromium, cobalt and nickel. Phytotoxic chromium was not accumulated to any marked degree by any taxon. Cobalt was inversely correlated with boron and sodium, and nickel with both nutrients as well as manganese. The data seemed to indicate the overriding controlling factor of reduced nutrient uptake caused by elements present in high concentrations in serpentinic substrates. It would seem that this reduced uptake is a major factor in the serpentine problem, at least as far as the Flacourtiaceae and the New Caledonian environment is concerned. By contrast, the toxic effects of elements such as nickel, cobalt and chromium seems less important.