Similarities in B cell repertoire development between autoimmune and aging normal mice.

B cell repertoire changes that characterize systemic autoimmune disease may be linked to an acceleration of normal immune aging. To examine this issue, the repertoires expressed by lupus-prone and geriatric normal mice were compared. An ELISA-spot assay was used to identify and quantitate individual lymphocytes secreting antibodies reactive with a panel of five autoantigens and three conventional Ag. Over half of autoimmune NZB and MRL/lpr mice developed repertoires biased toward the production of specific autoantibodies by 8 mo of age. The B cell repertoires expressed by normal BALB/c mice were stable over this period but developed a similar bias toward the production of autoantibodies by 18 to 22 mo of age. As both normal and autoimmune mice grew older, they expressed repertoires that increasingly diverged from those of other members of the same strain--a process whose onset and rate of development was accelerated in lupus-prone animals. By analyzing B cells from individual MRL/lpr mice at multiple time points, we found that 1) autoreactivity developed over a specific time period, 2) individual animals developed increased responsiveness against different autoantigens, and 3) this increased responsiveness persisted for life. These results suggest that the repertoires of adult autoimmune mice are generated and maintained by a process of continuous (auto)antigenic stimulation similar to that associated with normal immune aging.     

A Systems Immunology Approach to the Host-Tumor Interaction: Large-Scale Patterns of Natural Autoantibodies Distinguish Healthy and Tumor-Bearing Mice

Traditionally, immunology has considered a meaningful antibody response to be marked by large amounts of high-affinity antibodies reactive with the specific inciting antigen; the detection of small amounts of low-affinity antibodies binding to seemingly unrelated antigens has been considered to be beneath the threshold of immunological meaning. A systems-biology approach to immunology, however, suggests that large-scale patterns in the antibody repertoire might also reflect the functional state of the immune system. To investigate such global patterns of antibodies, we have used an antigen-microarray device combined with informatic analysis. Here we asked whether antibody-repertoire patterns might reflect the state of an implanted tumor. We studied the serum antibodies of inbred C57BL/6 mice before and after implantation of syngeneic 3LL tumor cells of either metastatic or non-metastatic clones. We analyzed patterns of IgG and IgM autoantibodies binding to over 300 self-antigens arrayed on slides using support vector machines and genetic algorithm techniques. We now report that antibody patterns, but not single antibodies, were informative: 1) mice, even before tumor implantation, manifest both individual and common patterns of low-titer natural autoantibodies; 2) the patterns of these autoantibodies respond to the growth of the tumor cells, and can distinguish between metastatic and non-metastatic tumor clones; and 3) curative tumor resection induces dynamic changes in these low-titer autoantibody patterns. The informative patterns included autoantibodies binding to self-molecules not known to be tumor-associated antigens (including insulin, DNA, myosin, fibrinogen) as well as to known tumor-associated antigens (including p53, cytokeratin, carbonic anhydrases, tyrosinase). Thus, low-titer autoantibodies that are not the direct products of tumor-specific immunization can still generate an immune biomarker of the body-tumor interaction. System-wide profiling of autoantibody repertoires can be informative.     

New autoantibodies in early rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease causing articular cartilage and bone destruction. Since irreversible joint destruction can be prevented by intervention at the early stages of disease, early diagnosis of RA is important. In this study, we identified new autoantibodies in the sera of patients with early (less than one year) RA.

Methods

We screened the sera of 20 RA patients with disease duration less than one year, 19 RA patients with disease duration more than five years and 23 controls on 8,268 human protein arrays. We confirmed the validity of protein array detection by ELISA assays. We then performed epitope mapping with overlapping 15-mers to analyze RA sera reactivity.

Results

WIBG (within BGCN homolog (Drosophila)), GABARAPL2 (GABA(A) receptor associated protein like 2) and ZNF706 (zinc finger protein 706) proteins are preferentially recognized by autoantibodies from early RA patients. Of interest, autoantibodies to WIBG are very specific for early RA. Indeed, 33% of early RA patients'' sera recognize WIBG versus 5% of RA patients with disease duration more than 5 years and 2% of controls. We identified three linear peptides on WIBG GABARAPL2 and ZNF706 that are preferentially recognized by sera of early RA patients.

Conclusions

We identified new autoantibodies associated with RA with disease duration less than one year. These autoantibodies could be used as diagnosis markers in RA patients.     

Recognition of defined epitopes by affinity‐purified anti‐immunoglobulin Fab autoantibodies isolated from HIV‐infected humans

Infection of humans with HIV‐1 has previously been independently shown to result in the generation of autoantibodies (AAbs) reactive with immunoglobulin Fab fragments (Heidelberg), and with autoantibodies to T‐cell receptors (TCRs) (Tucson). Here, we carry out epitope mapping studies of affinity‐purified AAbs to Fab fragments prepared from individual HIV‐positive patients for their capacity to bind recombinant constructs and peptide‐defined epitopes modeling TCR and Ig light chains. Some affinity‐purified autoantibodies reacted strongly with TCRs expressed by intact T‐cells, and recombinant V_α/V_β constructs as well as with certain synthetic peptide epitopes. The binding reactions of affinity‐purified AAbs of individual patients were distinct, and the AAb preparations consisted of populations of polyclonal lgs as reflected in specificity and isotype. AAb pools from individual patients all bound particular regions of TCR and Ig chains defined by comprehensive peptide synthesis including the CDR1 and Fr3 segments of the variable domains and the joining segment/switch peptide. In addition, other reactivities to restricted regions of α, β and λ light chains were documented. These results substantiate the cross‐reactivity of TCR and Ig–Fab determinants, and are consistent with the hypothesis that autoantibodies arising as a consequence of HIV infection can have an immunomodulatory role. Copyright © 1999 John Wiley & Sons, Ltd.     

Functional mapping of human growth trajectories

Human height is an important trait from biological and social perspectives. Genes have been widely recognized to be involved in human body growth, but their detailed controlling mechanisms are poorly understood. Here, we present a computational model for functional mapping of quantitative trait loci (QTLs) that control trajectories of human height growth through an interactive network. The model integrates mathematical equations of human growth curves into the mixture model-based functional mapping framework, allowing the identification and mapping of individual QTLs responsible for the developmental pattern of human growth. The model was derived on a random sample of subjects from a natural population, for each of which molecular markers within candidate genes or throughout the entire genome are typed and height data from childhood to adulthood are collected. A series of testable hypotheses are formulated about the genetic control of developmental timing and duration at different stages. The model was used to characterize epistatic QTLs for height growth hidden in 548 Japanese girls which is a semi-real data set with simulated the marker genotypes. With an increasing availability of genetic polymorphic data, the model will have great implications for probing the genetic and developmental mechanisms of human body growth and its associated diseases.     

Use of synthetic peptides for the detection and quantification of autoantibodies

Summary and conclusions The rapid progress made over the last 10 years in the identification of individual autoantigens and in the localization of the epitopes involved, has resulted in a parallel reduction in the complexity of the antigen required for the detection of autoantibodies. The ability to use synthetic peptides as antigens is a remarkable culmination of this process considering that many antigenic particles contain multiple proteins (eg. Sm consist of 8 or more individual proteins).Despite the fact that patients with SLE have a polyclonal hypergammaglobulinemia, excellent correlations between ELISAs utilizing the P2 or SmB/B synthetic peptides, ELISAs utilizing r proteins and immunoblotting were obtained [28, 38, 50]. However, false positive/non-specific binding to a P2-BSA-glutaraldehyde conjugate has been observed with serum from old MRL/lpr mice (unpublished observations). In addition, some of the results obtained in human autoimmune diseases suggest that non-specific binding may be problematic in some instances. It is difficult, at present, to know whether the higher frequencies of detection of autoantibodies to certain synthetic peptide antigens reflect increased sensitivity or decreased specificity.Synthetic peptide antigens have beeen used to detect autoantibodies in both organ specific and multisystem autoimmune diseases. In only a small number of cases have these reagents been rigorously tested for sensitivity and specificity. Despite this, synthetic peptides have been shown to be valuable for detection and quantification of autoantibodies in certain clinical situations. Undoubtedly, further progress in epitope mapping of autoantigens coupled with technological advances in protein synthesis and improved prediction of protein structure will lead to a large number of synthetic peptide antigens for research and clinical applications. It is unlikely that short synthetic peptides will substitute for native proteins in all instances since some autoantibodies show a striking preference for conformational epitopes.Abbreviations r recombinant - SLE systemic lupus erythematosus     

Identification of distributed metabolic objectives in the hypermetabolic liver by flux and energy balance analysis

A methodology for inferring distributed metabolic objectives from time series flux data is developed by combining metabolic flux analysis, pathway identification, free energy balances, and nested optimization. This methodology is used to investigate the metabolic response of the rat liver to burn injury-induced whole body inflammation. Gibbs free energy changes were computed for stoichiometrically balanced sequences of reactions, or pathways, rather than individual reactions, to account for energetic coupling between reactions. Systematic enumeration of pathways proceeded by elementary flux mode (EFM) analysis. Together with stoichiometric balances and external metabolite flux measurements, the DeltaG(PATH)(o) criterion provided sufficient constraints to solve a series of nested optimization problems on the metabolic goal functions and associated flux distributions of fasted livers during the first-week time course of burn injury. The optimization results suggest that there is a consistent metabolic goal function for the liver that is insensitive to the changing metabolic burdens experienced by the liver during the first-week time course. As defined by the goal function coefficients, the global metabolic objective was to distribute the metabolic resources between amino acid metabolism and ketone body synthesis. These findings point to a role for the time-invariant structure of the metabolic reaction network, expressed as stoichiometric and thermodynamic constraints, in shaping the cellular metabolic objective.     

Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice

FoxO1 integrates multiple metabolic pathways. Nutrient levels modulate FoxO1 acetylation, but the functional consequences of this posttranslational modification are unclear. To answer this question, we generated mice bearing alleles that encode constitutively acetylated and acetylation-defective FoxO1 proteins. Homozygosity for an allele mimicking constitutive acetylation (Foxo1(KQ/KQ)) results in embryonic lethality due to cardiac and angiogenesis defects. In contrast, mice homozygous for?a constitutively deacetylated Foxo1 allele (Foxo1(KR/KR)) display a unique metabolic phenotype of impaired insulin action on hepatic glucose metabolism but decreased plasma lipid levels and low respiratory quotient that are consistent with a state of preferential lipid usage. Moreover, Foxo1(KR/KR) mice show?a dissociation between weight gain and insulin resistance in predisposing conditions (high fat diet, diabetes, and insulin receptor mutations), possibly due to decreased cytokine production in adipose tissue. Thus, acetylation inactivates FoxO1 during nutrient excess whereas deacetylation selectively potentiates FoxO1 activity, protecting against excessive catabolism during nutrient deprivation.     

Characterization of metabolite quantitative trait loci and metabolic networks that control glucosinolate concentration in the seeds and leaves of Brassica napus

? Glucosinolates are a major class of secondary metabolites found in the Brassicaceae, whose degradation products are proving to be increasingly important for human health and in crop protection. ? The genetic and metabolic basis of glucosinolate accumulation was dissected through analysis of total glucosinolate concentration and its individual components in both leaves and seeds of a doubled-haploid (DH) mapping population of oilseed rape/canola (Brassica napus). ? The quantitative trait loci (QTL) that had an effect on glucosinolate concentration in either or both of the organs were integrated, resulting in 105 metabolite QTL (mQTL). Pairwise correlations between individual glucosinolates and prior knowledge of the metabolic pathways involved in the biosynthesis of different glucosinolates allowed us to predict the function of genes underlying the mQTL. Moreover, this information allowed us to construct an advanced metabolic network and associated epistatic interactions responsible for the glucosinolate composition in both leaves and seeds of B. napus. ? A number of previously unknown potential regulatory relationships involved in glucosinolate synthesis were identified and this study illustrates how genetic variation can affect a biochemical pathway.     

Metabolic profiling of a mapping population exposes new insights in the regulation of seed metabolism and seed, fruit, and plant relations

To investigate the regulation of seed metabolism and to estimate the degree of metabolic natural variability, metabolite profiling and network analysis were applied to a collection of 76 different homozygous tomato introgression lines (ILs) grown in the field in two consecutive harvest seasons. Factorial ANOVA confirmed the presence of 30 metabolite quantitative trait loci (mQTL). Amino acid contents displayed a high degree of variability across the population, with similar patterns across the two seasons, while sugars exhibited significant seasonal fluctuations. Upon integration of data for tomato pericarp metabolite profiling, factorial ANOVA identified the main factor for metabolic polymorphism to be the genotypic background rather than the environment or the tissue. Analysis of the coefficient of variance indicated greater phenotypic plasticity in the ILs than in the M82 tomato cultivar. Broad-sense estimate of heritability suggested that the mode of inheritance of metabolite traits in the seed differed from that in the fruit. Correlation-based metabolic network analysis comparing metabolite data for the seed with that for the pericarp showed that the seed network displayed tighter interdependence of metabolic processes than the fruit. Amino acids in the seed metabolic network were shown to play a central hub-like role in the topology of the network, maintaining high interactions with other metabolite categories, i.e., sugars and organic acids. Network analysis identified six exceptionally highly co-regulated amino acids, Gly, Ser, Thr, Ile, Val, and Pro. The strong interdependence of this group was confirmed by the mQTL mapping. Taken together these results (i) reflect the extensive redundancy of the regulation underlying seed metabolism, (ii) demonstrate the tight co-ordination of seed metabolism with respect to fruit metabolism, and (iii) emphasize the centrality of the amino acid module in the seed metabolic network. Finally, the study highlights the added value of integrating metabolic network analysis with mQTL mapping.     

Theoretical and methodological bases of experimental simulation of the prepathological state under membrane-damaging effects of environmental factors

The paper theoretically substantiates the importance for detecting the prepathological state of experimental simulation of those situations in the organism which adequately reflect changes in human metabolism exposed to multiple environmental factors. A putative experimental model has been proposed in the shape of sexually immature and mature generations of animals of differing age with a "metabolic burden" whose characteristics, as regards impairments in biochemical, immunological and other functional reactions in biological fluids, are to some extent similar to those occurring in certain groups of humans. It has been suggested that the further investigation of the mechanisms and biological significance of systemic changes of the body's internal milieu may hold promise for studies of environmental hygiene in evaluating populational health and detecting the early signs of metabolic alterations with the aim of their timely prevention.     

Beyond topology: coevolution of structure and flux in metabolic networks

Interactions between the structure of a metabolic network and its functional properties underlie its evolutionary diversification, but the mechanism by which such interactions arise remains elusive. Particularly unclear is whether metabolic fluxes that determine the concentrations of compounds produced by a metabolic network, are causally linked to a network's structure or emerge independently of it. A direct empirical study of populations where both structural and functional properties vary among individuals’ metabolic networks is required to establish whether changes in structure affect the distribution of metabolic flux. In a population of house finches (Haemorhous mexicanus), we reconstructed full carotenoid metabolic networks for 442 individuals and uncovered 11 structural variants of this network with different compounds and reactions. We examined the consequences of this structural diversity for the concentrations of plumage‐bound carotenoids produced by flux in these networks. We found that concentrations of metabolically derived, but not dietary carotenoids, depended on network structure. Flux was partitioned similarly among compounds in individuals of the same network structure: within each network, compound concentrations were closely correlated. The highest among‐individual variation in flux occurred in networks with the strongest among‐compound correlations, suggesting that changes in the magnitude, but not the distribution of flux, underlie individual differences in compound concentrations on a static network structure. These findings indicate that the distribution of flux in carotenoid metabolism closely follows network structure. Thus, evolutionary diversification and local adaptations in carotenoid metabolism may depend more on the gain or loss of enzymatic reactions than on changes in flux within a network structure.     

Trends in water quality and subtidal benthic communities in a temperate estuary: Is the response to restoration efforts hidden by climate variability and the Estuarine Quality Paradox?

The analysis of temporal patterns in water quality and benthic assemblages in estuaries constitutes an important methodological issue for discriminating the effects of natural and anthropogenic pressures. Temporal trends in water quality and in the subtidal benthic community over a 5-year interval in the Mondego estuary (Portugal) were investigated with the aim of assessing changes in environmental quality as a response to restoration efforts and climate variability. Particularly, we addressed the following questions: (a) Would trends in water quality and benthos behave consistently over the whole study period for the different zones of the monitoring network and indicate improvement or degradation in ecological condition? (b) Could we distinguish the effects of climate variability and restoration efforts in water quality and benthos from trend analysis results? (c) Could the response of the benthic communities and water quality be useful to guide the planning of future management actions in this system?Clear cause–effect relationships regarding the ecological response to restoration efforts and climate variability were indeed challenging to identify and interpret. In fact, the response of water quality and benthic communities to restoration efforts seemed to have been masked by the effects of climatic variability. Furthermore, the present study illustrated clearly the high environmental variability inherent to estuarine systems and the difficulty of clearly distinguishing natural from anthropogenic stressors, in agreement with the “Estuarine Quality Paradox”. Implications for ecological quality assessment and management of the Mondego estuary and other poikilohaline systems are discussed, namely with regard to the “one-out, all-out” principle required by the European Water Framework Directive (WFD).     

Social experience organizes parallel networks in sensory and limbic forebrain

Successful social behavior can directly influence an individual's reproductive success. Therefore, many organisms readily modify social behavior based on past experience. The neural changes induced by social experience, however, remain to be fully elucidated. We hypothesize that social modulation of neural systems not only occurs at the level of individual nuclei, but also of functional networks, and their relationships with behavior. We used the green anole lizard (Anolis carolinensis), which displays stereotyped, visually triggered social behaviors particularly suitable for comparisons of multiple functional networks in a social context, to test whether repeated aggressive interactions modify behavior and metabolic activity in limbic-hypothalamic and sensory forebrain regions, assessed by quantitative cytochrome oxidase (a slowly accumulating endogenous metabolic marker) histochemistry. We found that aggressive interactions potentiate aggressive behavior, induce changes in activities of individual nuclei, and organize context-specific functional neural networks. Surprisingly, this experiential effect is not only present in a limbic-hypothalamic network, but also extends to a sensory forebrain network directly relevant to the behavioral expression. Our results suggest that social experience modulates organisms' social behavior via modifying sensory and limbic neural systems in parallel both at the levels of individual regions and networks, potentially biasing perceptual as well as limbic processing.     

The application of multi-parameter flow cytometry to the study of recombinant <Emphasis Type="Italic">Escherichia coli</Emphasis> batch fermentation processes

Multi-parameter flow cytometric techniques coupled with dual colour fluorescent staining were used to study the physical and metabolic consequences of inclusion body formation in batch cultures of the recombinant Escherichia coli strain MSD3735. This strain contains a plasmid coding for the isopropylthiogalactopyranoside-inducible model eukaryotic protein AP50. It is known that the synthesis of foreign proteins at high concentrations can exert a severe metabolic stress on the host cell and that morphological changes can occur. In this work, using various points of induction, it was shown that inclusion body formation is followed immediately by measurable changes in the characteristic intrinsic light scatter patterns for the individual cell (forward scatter, 90° side scatter) and a concomitant progressive change in the individual cell physiological state with respect to both cytoplasmic membrane polarisation and permeability. This work establishes flow cytometry as a potentially valuable tool for monitoring recombinant fermentation processes, providing important information for scale-up. Further, we discuss the possibility of optimising inclusion body formation by manipulating the fermentation conditions based on these rapid real-time measurements.     

Song Repertoire and Mate Choice in Birds

In many species of birds, individual males possess "repertoires"of multiple versions of the species song. Females of severalof these species have been shown to respond preferentially incourtship to larger song repertoires. The female preferencefor large repertoires usually has little effect on female settlement,but is likely to affect mate choice in extra-pair copulations.A number of hypotheses have been proposed to explain the evolutionof the female preference. Some of these posit a natural selectiveadvantage for the preference, in securing for the female a betterterritory, better paternal care for the offspring, or a matewith good genes. Another hypothesis suggests the male traitand female preference have coevolved in a process of runawaysexual selection. Here I show that female common grackles (Quiscalus quiscula)court preferentially for repertoires of four song types comparedto equal numbers of repetitions of single song types.The femalepreference exists in common grackles despite the fact that malesin this species sing only one song type each. None of the usualhypotheses, based on natural or sexual selection, can explainthe occurrence of the female preference in a species in whichmales lack the preferred trait. Instead, the female preferencemay be a simple consequence of two properties of most responsesystems: habituation and stimulus specificity. If so, femalepreferences for repertoires may in general pre-date the evolutionof male song repertoires, which evolve to exploit the pre-existingfemale response bias.     

Characterization of anti-crystallin autoantibodies in patients with cataract

Anti-crystallin autoantibodies have often been demonstrated in the serum of healthy persons and, especially, patients with cataract. In no case, however, have the specific crystallin subunits been identified against which such antibodies are directed. This information would be of particular interest in view of the recent finding that several crystallin subunits occur constitutively outside the lens. To fill this gap, we analysed the sera of 15 patients with mature cataract by means of 1- and 2-dimensional immunoblotting. The circulating antibodies turned out to be directed against several - and -crystallin subunits. The types of subunits and the intensities of the responses varied considerably between patients. No or only occasional and very weak reactions were observed against the A-, B- and B2-crystallin subunits. These are in fact the only crystallins at present known to occur outside the lens in mammals. Our findings thus indicate that anti-crystallin autoantibodies are specifically directed against those crystallins that appear to be lens-restricted, while immunological tolerance would exist for the extra-lenticularly occurring crystallins.     

Secondary sexual ornamentation and non-additive genetic benefits of female mate choice

Ornamental secondary sexual traits are hypothesized to evolve in response to directional mating preferences for more ornamented mates. Such mating preferences may themselves evolve partly because ornamentation indicates an individual's additive genetic quality (good genes). While mate choice can also confer non-additive genetic benefits (compatible genes), the identity of the most 'compatible' mate is assumed to depend on the choosy individual's own genotype. It is therefore unclear how choice for non-additive genetic benefits could contribute to directional mating preferences and consequently the evolution of ornamentation. In free-living song sparrows (Melospiza melodia), individual males varied in their kinship with the female population. Furthermore, a male's song repertoire size, a secondary sexual trait, was negatively correlated with kinship such that males with larger repertoires were less closely related to the female population. After excluding close relatives as potential mates, individual females were on average less closely related to males with larger repertoires. Therefore, female song sparrows expressing directional preferences for males with larger repertoires would on average acquire relatively unrelated mates and produce relatively outbred offspring. Such non-additive genetic fitness benefits of directional mating preferences, which may reflect genetic dominance variance expressed in structured populations, should be incorporated into genetic models of sexual selection.     

A genome-wide screen for non-template nucleotides and isomiR repertoires in miRNAs indicates dynamic and versatile microRNAome

miRNA variants (termed isomiRs) have been reported as potential functional molecules that may affect miRNA stability or target selection. The aims of the present study were to comprehensively survey and characterize non-template nucleotides (NTNs) and isomiR repertoires in miRNAs. Over 50 % of the NTNs were located in the 3′ ends (also termed 3′ additions), followed by the 5′ ends and adjacent positions to 5′ and 3′ ends. The similar distributions of NTNs and isomiR repertoires might be detected between homologous or clustered miRNAs. miRNA might be stably expressed based on the typical analysis, but its isomiRs might be strongly up- or down-regulated. IsomiRs with novel seed sequences were mainly derived from “seed shifting” events in 5′ isomiRs, NTNs in 5′ ends or in seed sequences. IsomiRs from a miRNA locus or homologous miRNA loci maybe have the same seed sequences, but they would have various enrichment levels and 3′ ends. Interestingly, isomiR species with novel seed sequences via NTNs in the seed region were always stably expressed. These novel seed sequences could lead to novel functional roles through driving the potential novel target mRNAs. Integrated predicted target mRNAs and further microarray validation showed that these isomiRs have versatile biological roles. Collectively, multiple isomiR products and miRNA maturation processes provide opportunities to perform versatile roles in the regulatory network, which further enriches and complicates the regulation of biological processes.     

Functional brain network modularity captures inter- and intra-individual variation in working memory capacity

Background

Cognitive abilities, such as working memory, differ among people; however, individuals also vary in their own day-to-day cognitive performance. One potential source of cognitive variability may be fluctuations in the functional organization of neural systems. The degree to which the organization of these functional networks is optimized may relate to the effective cognitive functioning of the individual. Here we specifically examine how changes in the organization of large-scale networks measured via resting state functional connectivity MRI and graph theory track changes in working memory capacity.

Methodology/Principal Findings

Twenty-two participants performed a test of working memory capacity and then underwent resting-state fMRI. Seventeen subjects repeated the protocol three weeks later. We applied graph theoretic techniques to measure network organization on 34 brain regions of interest (ROI). Network modularity, which measures the level of integration and segregation across sub-networks, and small-worldness, which measures global network connection efficiency, both predicted individual differences in memory capacity; however, only modularity predicted intra-individual variation across the two sessions. Partial correlations controlling for the component of working memory that was stable across sessions revealed that modularity was almost entirely associated with the variability of working memory at each session. Analyses of specific sub-networks and individual circuits were unable to consistently account for working memory capacity variability.

Conclusions/Significance

The results suggest that the intrinsic functional organization of an a priori defined cognitive control network measured at rest provides substantial information about actual cognitive performance. The association of network modularity to the variability in an individual''s working memory capacity suggests that the organization of this network into high connectivity within modules and sparse connections between modules may reflect effective signaling across brain regions, perhaps through the modulation of signal or the suppression of the propagation of noise.