Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Evaluation of simultaneous 201Tl/99mTc dual-isotope cardiac SPECT imaging with model-based crosstalk compensation using canine studies.

BACKGROUND: Simultaneous (201)Tl/(99m)Tc-sestamibi dual-isotope myocardial perfusion SPECT imaging can reduce imaging time and produce perfectly registered rest/stress images. However, crosstalk from (99m)Tc into (201)Tl images can significantly reduce (201)Tl image quality. We have developed a model-based compensation (MBC) method to compensate for this crosstalk. The method has previously been validated with phantom and simulation studies. In this study, we evaluated the MBC method using a canine model. METHODS: Left anterior descending or left circumflex coronary artery stenoses were created in 50 adult mongrel dogs weighing 20-30 kg. The dogs were injected with 111 MBq (3 mCi) of (201)Tl at rest, and a SPECT study acquired. Stress was induced by administering adenosine to the dog, followed by injection of 740 MBq (20 mCi) of (99m)Tc-sestamibi at peak stress. A second SPECT study was performed with data acquired in both (201)Tl and (99m)Tc energy windows to provide simultaneous dual-isotope projection data. The images were reconstructed using the ordered-subsets expectation-maximization reconstruction algorithm with compensation for attenuation, scatter, and detector response. For simultaneously acquired (201)Tl data, we also applied the MBC method to compensate for crosstalk contamination from (99m)Tc. RESULTS: Without compensation, (99m)Tc crosstalk increased the estimated (201)Tl activity concentration in the rest images and reduced defect contrast. After MBC, the (201)Tl images were in good agreement with the registered single-isotope images and ex vivo count data. The ischemic (IS) to non-ischemic (NIS) region (201)Tl activity concentration ratios were computed for single-isotope and dual-isotope studies. The correlation with ex vivo IS-NIS ratios was 0.815 after MBC, compared to the 0.495 from data without compensation. In addition, the regression line for the IS-NIS ratios with MBC was almost parallel to the line of identity with a slope of 0.93, compared to a slope of 0.45 without compensation. CONCLUSIONS: These results demonstrate that model-based crosstalk compensation can provide substantial reduction of crosstalk effects in simultaneously acquired myocardial perfusion SPECT images in living biological systems.

Long-range ordering of vibrated polar disks.

Vibrated polar disks have been used experimentally to investigate collective motion of driven particles, where fully ordered asymptotic regimes could not be reached. Here we present a model reproducing quantitatively the single, binary, and collective properties of this granular system. Using system sizes not accessible in the laboratory, we show in silico that true long-range order is possible in the experimental system. Exploring the model's parameter space, we find a phase diagram qualitatively different from that of dilute or pointlike particle systems.

Exploring companion animal caretakers' attitudes, perceptions and behavioural drivers of antimicrobial use within the social context of veterinary care.

OBJECTIVE: To explore companion animal caretakers' attitudes, perceptions and behavioural drivers of antimicrobial use within the social context of veterinary care. MATERIALS AND METHODS: Five semi-structured focus groups were conducted with 26 cat and dog owners. Transcripts were subjected to thematic analysis to systematically code and classify themes related to the study objectives. RESULTS: Thematic analysis revealed five themes - trust-building/relationships, shared decision-making/empowerment, clear communication, judicious use and concerns surrounding antimicrobial use. Strong veterinarian-client relationships were the underlying factor influencing acceptance of antimicrobial use stewardship principles. Participants viewed themselves as advocates for their animals and preferred a relationship-centred approach to care facilitated through competent communication. They cited the importance of clear communication related to diagnosis and antimicrobial recommendations including using client-friendly terminology, providing explicit instructions for antimicrobial use, and having a shared plan for next steps and follow-up communication. Participants reported challenges with administering antimicrobial drugs, expressed concerns with potential side effects and development of antimicrobial resistance. Consequently, they reported an interest in alternatives to antimicrobial drugs and a focus on preventive medicine that was counterbalanced with concerns for animal comfort and welfare. CLINICAL SIGNIFICANCE: Conversations about antimicrobial use can be reframed to include alternatives to antimicrobials as part of the treatment plan, and clients can be empowered to play a more active role in their animals' care. Veterinarians can apply core communication skills to advance antimicrobial stewardship principles and thereby contribute to preserving the effectiveness and availability of antimicrobials while preserving the trusting relationship and shared decision-making between clients and veterinarians.

Molecular jigsaw: pattern diversity encoded by elementary geometrical features.

Scanning tunneling microscopy (STM) images of self-organized monolayers of Frechet dendrons display a variety of two-dimensional ordering motifs, which are influenced by engineering the molecular interactions. An interaction-site model condenses the essential molecular properties determined by molecular mechanics modeling, which in a Monte Carlo approach successfully predicts the various ordering motifs. This confirms that geometry as well as a few salient weak interaction sites encode these structural motifs.

Soluble CD14 participates in the response of cells to lipopolysaccharide.

CD14 is a 55-kD protein found both as a glycosylphosphatidyl inositol-linked protein on the surface of mononuclear phagocytes and as a soluble protein in the blood. CD14 on the cell membrane (mCD14) has been shown to serve as a receptor for complexes of lipopolysaccharide (LPS) with LPS binding protein, but a function for soluble CD14 (sCD14) has not been described. Here we show that sCD14 enables responses to LPS by cells that do not express CD14. We have examined induction of endothelial-leukocyte adhesion molecule 1 expression by human umbilical vein endothelial cells, interleukin 6 secretion by U373 astrocytoma cells, and cytotoxicity of bovine endothelial cells. None of these cell types express mCD14, yet all respond to LPS in a serum-dependent fashion, and all responses are completely blocked by anti-CD14 antibodies. Immunodepletion of sCD14 from serum prevents responses to LPS, and the responses are restored by addition of sCD14. These studies suggest that a surface anchor is not needed for the function of CD14 and further imply that sCD14 must bind to additional proteins on the cell surface to associate with the cell and transduce a signal. They also indicate that sCD14 may have an important role in potentiating responses to LPS in cells lacking mCD14.

Quantitative predictions on auxin-induced polar distribution of PIN proteins during vein formation in leaves.

The dynamic patterning of the plant hormone auxin and its efflux facilitator the PIN protein are the key regulators for the spatial and temporal organization of plant development. In particular auxin induces the polar localization of its own efflux facilitator. Due to this positive feedback, auxin flow is directed and patterns of auxin and PIN arise. During the earliest stage of vein initiation in leaves auxin accumulates in a single cell in a rim of epidermal cells from which it flows into the ground meristem tissue of the leaf blade. There the localized auxin supply yields the successive polarization of PIN distribution along a strand of cells. We model the auxin and PIN dynamics within cells with a minimal canalization model. Solving the model analytically we uncover an excitable polarization front that triggers a polar distribution of PIN proteins in cells. As polarization fronts may extend to opposing directions from their initiation site, we suggest a possible resolution to the puzzling occurrence of bipolar cells, thus we offer an explanation for the development of closed, looped veins. Employing non-linear analysis, we identify the role of the contributing microscopic processes during polarization. Furthermore, we deduce quantitative predictions on polarization fronts establishing a route to determine the up to now largely unknown kinetic rates of auxin and PIN dynamics.

Cooperation in Microbial Populations: Theory and Experimental Model Systems.

Cooperative behavior, the costly provision of benefits to others, is common across all domains of life. This review article discusses cooperative behavior in the microbial world, mediated by the exchange of extracellular products called public goods. We focus on model species for which the production of a public good and the related growth disadvantage for the producing cells are well described. To unveil the biological and ecological factors promoting the emergence and stability of cooperative traits we take an interdisciplinary perspective and review insights gained from both mathematical models and well-controlled experimental model systems. Ecologically, we include crucial aspects of the microbial life cycle into our analysis and particularly consider population structures where ensembles of local communities (subpopulations) continuously emerge, grow, and disappear again. Biologically, we explicitly consider the synthesis and regulation of public good production. The discussion of the theoretical approaches includes general evolutionary concepts, population dynamics, and evolutionary game theory. As a specific but generic biological example, we consider populations of Pseudomonas putida and its regulation and use of pyoverdines, iron scavenging molecules, as public goods. The review closes with an overview on cooperation in spatially extended systems and also provides a critical assessment of the insights gained from the experimental and theoretical studies discussed. Current challenges and important new research opportunities are discussed, including the biochemical regulation of public goods, more realistic ecological scenarios resembling native environments, cell-to-cell signaling, and multispecies communities.

Realistic CT simulation using the 4D XCAT phantom.

The authors develop a unique CT simulation tool based on the 4D extended cardiac-torso (XCAT) phantom, a whole-body computer model of the human anatomy and physiology based on NURBS surfaces. Unlike current phantoms in CT based on simple mathematical primitives, the 4D XCAT provides an accurate representation of the complex human anatomy and has the advantage, due to its design, that its organ shapes can be changed to realistically model anatomical variations and patient motion. A disadvantage to the NURBS basis of the XCAT, however, is that the mathematical complexity of the surfaces makes the calculation of line integrals through the phantom difficult. They have to be calculated using iterative procedures; therefore, the calculation of CT projections is much slower than for simpler mathematical phantoms. To overcome this limitation, the authors used efficient ray tracing techniques from computer graphics, to develop a fast analytic projection algorithm to accurately calculate CT projections directly from the surface definition of the XCAT phantom given parameters defining the CT scanner and geometry. Using this tool, realistic high-resolution 3D and 4D projection images can be simulated and reconstructed from the XCAT within a reasonable amount of time. In comparison with other simulators with geometrically defined organs, the XCAT-based algorithm was found to be only three times slower in generating a projection data set of the same anatomical structures using a single 3.2 GHz processor. To overcome this decrease in speed would, therefore, only require running the projection algorithm in parallel over three processors. With the ever decreasing cost of computers and the rise of faster processors and multi-processor systems and clusters, this slowdown is basically inconsequential, especially given the vast improvement the XCAT offers in terms of realism and the ability to generate 3D and 4D data from anatomically diverse patients. As such, the authors conclude that the efficient XCAT-based CT simulator developed in this work will have applications in a broad range of CT imaging research.

Self-organization principles of intracellular pattern formation.

Dynamic patterning of specific proteins is essential for the spatio-temporal regulation of many important intracellular processes in prokaryotes, eukaryotes and multicellular organisms. The emergence of patterns generated by interactions of diffusing proteins is a paradigmatic example for self-organization. In this article, we review quantitative models for intracellular Min protein patterns in Escherichia coli, Cdc42 polarization in Saccharomyces cerevisiae and the bipolar PAR protein patterns found in Caenorhabditis elegans By analysing the molecular processes driving these systems we derive a theoretical perspective on general principles underlying self-organized pattern formation. We argue that intracellular pattern formation is not captured by concepts such as 'activators', 'inhibitors' or 'substrate depletion'. Instead, intracellular pattern formation is based on the redistribution of proteins by cytosolic diffusion, and the cycling of proteins between distinct conformational states. Therefore, mass-conserving reaction-diffusion equations provide the most appropriate framework to study intracellular pattern formation. We conclude that directed transport, e.g. cytosolic diffusion along an actively maintained cytosolic gradient, is the key process underlying pattern formation. Thus the basic principle of self-organization is the establishment and maintenance of directed transport by intracellular protein dynamics.This article is part of the theme issue 'Self-organization in cell biology'.

Emergence of coexisting ordered states in active matter systems.

Active systems can produce a far greater variety of ordered patterns than conventional equilibrium systems. In particular, transitions between disorder and either polar- or nematically ordered phases have been predicted and observed in two-dimensional active systems. However, coexistence between phases of different types of order has not been reported. We demonstrate the emergence of dynamic coexistence of ordered states with fluctuating nematic and polar symmetry in an actomyosin motility assay. Combining experiments with agent-based simulations, we identify sufficiently weak interactions that lack a clear alignment symmetry as a prerequisite for coexistence. Thus, the symmetry of macroscopic order becomes an emergent and dynamic property of the active system. These results provide a pathway by which living systems can express different types of order by using identical building blocks.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Enteropathogenic E. coli translocated intimin receptor, Tir, interacts directly with alpha-actinin.

Enteropathogenic Escherichia coli (EPEC) triggers a dramatic rearrangement of the host epithelial cell actin cytoskeleton to form an attaching and effacing lesion, or pedestal. The pathogen remains attached extracellularly to the host cell through the pedestal for the duration of the infection. At the tip of the pedestal is a bacterial protein, Tir, which is secreted from the bacterium into the host cell plasma membrane, where it functions as the receptor for an EPEC outer membrane protein, intimin [1]. Delivery of Tir to the host cell results in its tyrosine phosphorylation, followed by Tir-intimin binding. Tir is believed to anchor EPEC firmly to the host cell, although its direct linkage to the cytoskeleton is unknown. Here, we show that Tir directly binds the cytoskeletal protein alpha-actinin. alpha-Actinin is recruited to the pedestal in a Tir-dependent manner and colocalizes with Tir in infected host cells. Binding is mediated through the amino terminus of Tir. Recruitment of alpha-actinin occurs independently of Tir tyrosine phosphorylation. Recruitment of actin, VASP, and N-WASP, however, is abolished in the absence of this tyrosine phosphorylation. These results suggest that Tir plays at least three roles in the host cell during infection: binding intimin on EPEC; mediating a stable anchor with alpha-actinin through its amino terminus in a phosphotyrosine-independent manner; and recruiting additional cytoskeletal proteins at the carboxyl terminus in a phosphotyrosine-dependent manner. These findings demonstrate the first known direct linkage between extracellular EPEC, through the transmembrane protein Tir, to the host cell actin cytoskeleton via alpha-actinin.

Transition guidelines: An important step in the future care for childhood cancer survivors. A comprehensive definition as groundwork.

Evidence-based clinical practice guidelines are essential to ensure that childhood cancer survivors at risk of chronic health conditions receive effective long-term follow-up care. However, adult survivors of childhood cancer are not always engaged in recommended health promotion and follow-up practices, as many centres do not have a formal transition programme that prepares survivors and their families for successful transfer from child-centred to adult-oriented healthcare. The need for a specific pan-European guideline for the transition of care for childhood cancer survivors has been recognised. The first step is to define the concept of transition of care for survivors of childhood cancer based on existing evidence.

Dynamics and cooperativity of microtubule decoration by the motor protein kinesin.

We describe a theoretical and experimental analysis of the interaction between microtubules and dimeric motor proteins (kinesin, NCD), with special emphasis on the stoichiometry of the interaction, cooperative effects, and their consequences for the interpretation of biochemical and image reconstruction results. Monomeric motors can bind equivalently to microtubules without interference, at a stoichiometry of one motor head per tubulin subunit (alphabeta-heterodimer). By contrast, dimeric motors can interact with stoichiometries ranging between one and two heads per tubulin subunit, depending on binding constants of the first head and the subsequent binding of the second head, and the concentration of dimers in solution. Further, we show that an attractive interaction between the bound motor molecules can explain the higher periodicities observed in decorated microtubules (e.g. 16 nm periodicity), and the non-uniform decoration of a population of microtubules and give an estimate of the strength of this interaction.

Fast modelling of the collimator-detector response in Monte Carlo simulation of SPECT imaging using the angular response function.

Interactions of incident photons with the collimator and detector, including septal penetration, scatter and x-ray fluorescence, are significant sources of image degradation in applications of SPECT including dual isotope imaging and imaging using radioisotopes that emit high- or medium-energy photons. Modelling these interactions using full Monte Carlo (MC) simulations is computationally very demanding. We present a new method based on the use of angular response functions (ARFs). The ARF is a function of the incident photon's direction and energy and represents the probability that a photon will either interact with or pass through the collimator, and be detected at the intersection of the photon's direction vector and the detection plane in an energy window of interest. The ARFs were pre-computed using full MC simulations of point sources that include propagation through the collimator-detector system. We have implemented the ARF method for use in conjunction with the SimSET/PHG MC code to provide fast modelling of both interactions in the patient and in the collimator-detector system. Validation results in the three cases studied show that there was good agreement between the projections generated using the ARF method and those from previously validated full MC simulations, but with hundred to thousand fold reductions in simulation time.

Site of pertussis toxin-induced ADP-ribosylation on Gi is critical for receptor modulation of GDP interaction with Gi.

In this study, the influence of the inhibitory mu-opioid receptor on the potencies of 5'-guanosine alpha-thiotriphosphate (GTP gamma S) and GDP at the inhibitory GTP-binding protein (Gi) were investigated in an adenylyl cyclase system. It was hoped that a receptor-mediated change in the potency of either GTP gamma S or GDP in affecting adenylyl cyclase activity may elucidate how a receptor alters cyclase activity via its G-protein. In an adenylyl cyclase system employing 5'-adenylyl imidodiphosphate as substrate, GTP gamma S, a nonhydrolyzable analog of GTP, inhibited forskolin-stimulated adenylyl cyclase activity in the absence of morphine; morphine failed to significantly affect the apparent potency of GTP gamma S. GDP blocked the GTP gamma S-induced inhibition of adenylyl cyclase; morphine profoundly diminished the ability of GDP to block the inhibitory effect of GTP gamma S. The IC50 values of GTP gamma S were 0.02 +/- 0.01, 0.18 +/- 0.04, and 2.2 +/- 0.5 microM in the absence of other drugs, in the presence of a combination of 100 microM GDP and morphine, and in the presence of 100 microM GDP, respectively. GDP blocked the inhibitory effect of GTP gamma S (0.3 microM) in a concentration-dependent manner; the EC50 for GDP was 16 +/- 2.6 microM in the absence of morphine and 170 +/- 32 microM in the presence of morphine. Exposure of 7315c cells to pertussis toxin for 3 h resulted in a small decrease in the potency of GTP gamma S in inhibiting cyclase. However, the relative potency of GDP in blocking the GTP gamma S-mediated inhibition of cyclase was increased: the EC50 values of GDP were 11 +/- 4 and 0.81 +/- 0.2 microM in untreated and pertussis toxin-treated membranes, respectively. In untreated membranes, there was a brief lag in the GTP gamma S-induced inhibition of adenylyl cyclase; morphine diminished this lag. In membranes treated with pertussis toxin, there was an exaggerated lag in the onset of GTP gamma S inhibition of adenylyl cyclase activity; morphine could no longer affect this lag. Thus, uncoupling the mu-opioid receptor from Gi appeared to increase the affinity of Gi for GDP. These data suggest that the effect of an inhibitory receptor is to decrease the affinity of Gi for GDP by virtue of its interaction with the carboxy-terminal region of Gi alpha.(ABSTRACT TRUNCATED AT 400 WORDS)

Bimodality in the transverse fluctuations of a grafted semiflexible polymer and the diffusion-convection analogue: an effective-medium approach.

Recent Monte Carlo simulations of a grafted semiflexible polymer in 1+1 dimensions have revealed a pronounced bimodal structure in the probability distribution of the transverse (bending) fluctuations of the free end, when the total contour length is of the order of the persistence length [G. Lattanzi, Phys. Rev E 69, 021801 (2004)]. In this paper, we show that the emergence of bimodality is related to a similar behavior observed when a random walker is driven in the transverse direction by a certain type of shear flow. We adapt an effective-medium argument, which was first introduced in the context of the sheared random-walk problem [E. Ben-Naim, Phys. Rev. A 45, 7207 (1992)], in order to obtain a simple analytic approximation of the probability distribution of the free-end fluctuations. We show that this approximation captures the bimodality and most of the qualitative features of the free-end fluctuations. We also predict that relaxing the local inextensibility constraint of the wormlike chain could lead to the disappearance of bimodality.