Hierarchical clustering of the genetic connectivity matrix reveals the network topology of gene action on brain microstructure: An N=531 twin study

Genetic correlation (rg) analysis determines how much of the correlation between two measures is due to common genetic influences. In an analysis of 4 Tesla diffusion tensor images (DTI) from 531 healthy young adult twins and their siblings, we generalized the concept of genetic correlation to determine common genetic influences on white matter integrity, measured by fractional anisotropy (FA), at all points of the brain, yielding an NxN genetic correlation matrix rg(x,y) between FA values at all pairs of voxels in the brain. With hierarchical clustering, we identified brain regions with relatively homogeneous genetic determinants, to boost the power to identify causal single nucleotide polymorphisms (SNP). We applied genome-wide association (GWA) to assess associations between 529,497 SNPs and FA in clusters defined by hubs of the clustered genetic correlation matrix. We identified a network of genes, with a scale-free topology, that influences white matter integrity over multiple brain regions.

Negative priming in naming of categorically related objects: An fMRI study

Ignoring an object slows subsequent naming responses to it, a phenomenon known as negative priming (NP). A central issue in NP research concerns the level of representation at which the effect occurs. As object naming is typically considered to involve access to abstract semantic representations, Tipper 1985 proposed that the NP effect occurred at this level of processing, and other researchers supported this proposal by demonstrating a similar result with categorically related objects (e.g., Allport et al., 1985; Murray, 1995), an effect referred to as semantic NP. However, objects within categories share more physical or structural features than objects from different categories. Consequently, the NP effect observed with categorically related objects might occur at a structural rather than semantic level of representation. We used event related fMRI interleaving overt object naming and image acquisition to demonstrate for the first time that the semantic NP effect activates the left posterior-mid fusiform and insular-opercular cortices. Moreover, both naming latencies and left posterior-mid fusiform cortex responses were influenced by the structural similarity of prime-probe object pairings in the categorically related condition, increasing with the number of shared features. None of the cerebral regions activated in a previous fMRI study of the identity NP effect (de Zubicaray et al., 2006) showed similar activation during semantic NP, including the left anterolateral temporal cortex, a region considered critical for semantic processing. The results suggest that the identity and semantic NP effects differ with respect to their neural mechanisms, and the label "semantic NP" might be a misnomer. We conclude that the effect is most likely the result of competition between structurally similar category exemplars that determines the efficiency of object name retrieval.

The roles of shared vs. Distinctive conceptual features in lexical access

Contemporary models of spoken word production assume conceptual feature sharing determines the speed with which objects are named in categorically-related contexts. However, statistical models of concept representation have also identified a role for feature distinctiveness, i.e., features that identify a single concept and serve to distinguish it quickly from other similar concepts. In three experiments we investigated whether distinctive features might explain reports of counter-intuitive semantic facilitation effects in the picture word interference (PWI) paradigm. In Experiment 1, categorically-related distractors matched in terms of semantic similarity ratings (e.g., zebra and pony) and manipulated with respect to feature distinctiveness (e.g., a zebra has stripes unlike other equine species) elicited interference effects of comparable magnitude. Experiments 2 and 3 investigated the role of feature distinctiveness with respect to reports of facilitated naming with part-whole distractor-target relations (e.g., a hump is a distinguishing part of a CAMEL, whereas knee is not, vs. an unrelated part such as plug). Related part distractors did not influence target picture naming latencies significantly when the part denoted by the related distractor was not visible in the target picture (whether distinctive or not; Experiment 2). When the part denoted by the related distractor was visible in the target picture, non-distinctive part distractors slowed target naming significantly at SOA of -150 ms (Experiment 3). Thus, our results show that semantic interference does occur for part-whole distractor-target relations in PWI, but only when distractors denote features shared with the target and other category exemplars. We discuss the implications of these results for some recently developed, novel accounts of lexical access in spoken word production.

Gene regulation by translational inhibition is determined by Dicer partnering proteins

MicroRNAs (miRNAs) are small regulatory RNAs produced by Dicer proteins that regulate gene expression in development and adaptive responses to the environment1,​2,​3,​4. In animals, the degree of base pairing between a miRNA and its target messenger RNA seems to determine whether the regulation occurs through cleavage or translation inhibition1. In contrast, the selection of regulatory mechanisms is independent of the degree of mismatch between a plant miRNA and its target transcript5. However, the components and mechanism(s) that determine whether a plant miRNA ultimately regulates its targets by guiding cleavage or translational inhibition are unknown6. Here we show that the form of regulatory action directed by a plant miRNA is determined by DRB2, a DICER-LIKE1 (DCL1) partnering protein. The dependence of DCL1 on DRB1 for miRNA biogenesis is well characterized7,​8,​9, but we show that it is only required for miRNA-guided transcript cleavage. We found that DRB2 determines miRNA-guided translational inhibition and represses DRB1 expression, thereby allowing the active selection of miRNA regulatory action. Furthermore, our results reveal that the core silencing proteins ARGONAUTE1 (AGO1) and SERRATE (SE) are highly regulated by miRNA-guided translational inhibition. DRB2 has been remarkably conserved throughout plant evolution, raising the possibility that translational repression is the ancient form of miRNA-directed gene regulation in plants, and that Dicer partnering proteins, such as human TRBP, might play a similar role in other eukaryotic systems.

Don't argue with the ref! - Legal liability for incorrect decisions of sports' officials

This paper continues the conversation from recent articles examining potential remedies available for incorrect decisions by sports officials. In particular, this article focuses on bringing an action against an official in negligence for pure economic loss. Using precedent cases, it determines that such an action would have a low chance of success, as a duty of care would be difficult to establish. Even if that could be overcome, an aggrieved player or team would still face further hurdles at the stages of breach, causation and defences. The article concludes by proposing some options to further reduce the small risk of liability to officials.

Adjustable stiffness, external fixator for the rat femur osteotomy and segmental bone defect models

The mechanical environment around the healing of broken bone is very important as it determines the way the fracture will heal. Over the past decade there has been great clinical interest in improving bone healing by altering the mechanical environment through the fixation stability around the lesion. One constraint of preclinical animal research in this area is the lack of experimental control over the local mechanical environment within a large segmental defect as well as osteotomies as they heal. In this paper we report on the design and use of an external fixator to study the healing of large segmental bone defects or osteotomies. This device not only allows for controlled axial stiffness on the bone lesion as it heals, but it also enables the change of stiffness during the healing process in vivo. The conducted experiments have shown that the fixators were able to maintain a 5 mm femoral defect gap in rats in vivo during unrestricted cage activity for at least 8 weeks. Likewise, we observed no distortion or infections, including pin infections during the entire healing period. These results demonstrate that our newly developed external fixator was able to achieve reproducible and standardized stabilization, and the alteration of the mechanical environment of in vivo rat large bone defects and various size osteotomies. This confirms that the external fixation device is well suited for preclinical research investigations using a rat model in the field of bone regeneration and repair.

Australia's disabling income support system: Tracing the history of the disability pension from 1908 to today

This article is based on a historical-comparative policy and discourse analysis of the principles underpinning the Australian disability income support system. It determines that these principles rely on a conception of disability that sustains a system of coercion and paternalism that perpetuates disability and referred to as disablism. The article examines the construction of disability in Australian income support across four major historical epochs spanning the period 1908-2007. Contextualisation of the policy trajectory and discourses of the contemporary disability pension regime for the time period 2008-now is also provided. Two major themes were found to have interacted with the ideology of disablism. This article argues that a non-disabling provision based on social citizenship, rather than responsible or productive citizenship, counters the tendency for authoritarian and paternal approaches. [Abridged]

Reservoir Operation for Hydropower Optimization: A Chance-Constrained Approach

This paper presents a chance-constrained linear programming formulation for reservoir operation of a multipurpose reservoir. The release policy is defined by a chance constraint that the probability of irrigation release in any period equalling or exceeding the irrigation demand is at least equal to a specified value P (called reliability level). The model determines the maximum annual hydropower produced while meeting the irrigation demand at a specified reliability level. The model considers variation in reservoir water level elevation and also the operating range within which the turbine operates. A linear approximation for nonlinear power production function is assumed and the solution obtained within a specified tolerance limit. The inflow into the reservoir is considered random. The chance constraint is converted into its deterministic equivalent using a linear decision rule and inflow probability distribution. The model application is demonstrated through a case study.

Defect production due to quenching through a multicritical point

We study the generation of defects when a quantum spin system is quenched through a multicritical point by changing a parameter of the Hamiltonian as t/tau, where tau is the characteristic timescale of quenching. We argue that when a quantum system is quenched across a multicritical point, the density of defects (n) in the final state is not necessarily given by the Kibble-Zurek scaling form n similar to 1/tau(d nu)/((z nu+1)), where d is the spatial dimension, and. and z are respectively the correlation length and dynamical exponent associated with the quantum critical point. We propose a generalized scaling form of the defect density given by n similar to 1/(tau d/(2z2)), where the exponent z(2) determines the behavior of the off-diagonal term of the 2 x 2 Landau-Zener matrix at the multicritical point. This scaling is valid not only at a multicritical point but also at an ordinary critical point.

Organisational driving safety systems analysis: Fleet safety situational issues and system gaps

The identification of safety hazards and risks and their associated control measures provides the foundation for any safety program and essentially determines the scope, content and complexity of an effective occupational health and safety management system. In the case of work-related road safety (WRRS), there is a gap within current knowledge, research and practice regarding the holistic assessment of WRRS safety systems and practice. In order to mitigate this gap, a multi-level process tool for assessing WRRS safety systems was developed from extensive consultation, practice and informed by theoretical models and frameworks. Data collection for the Organisational Driving Safety Systems Analysis (ODSSA) tool utilised a case study methodology and included multiple information sources: such as documents, archival records, interviews, direct observations, participant observations, and physical artefacts. Previous trials and application of the ODSSA has indicated that the tool is applicable to a wide range of organisational fleet environments and settings. This paper reports on the research results and effectiveness of the ODSSA tool to assess WRRS systems across a large organisation that recently underwent considerable organisational change, including amalgamation of multiple organisations. The outcomes of this project identified considerable differences in the degree by which the organisation addressed WRRS across their vehicle fleet operations and provided guidelines for improving organisations’ WRRS systems. The ODSSA tool was pivotal in determining WRRS system deficiencies and provided a platform to inform mitigation and improvement strategies.

Energy-Efficient Decentralized Cooperative Routing in Wireless Networks

Wireless adhoc networks transmit information from a source to a destination via multiple hops in order to save energy and, thus, increase the lifetime of battery-operated nodes. The energy savings can be especially significant in cooperative transmission schemes, where several nodes cooperate during one hop to forward the information to the next node along a route to the destination. Finding the best multi-hop transmission policy in such a network which determines nodes that are involved in each hop, is a very important problem, but also a very difficult one especially when the physical wireless channel behavior is to be accounted for and exploited. We model the above optimization problem for randomly fading channels as a decentralized control problem - the channel observations available at each node define the information structure, while the control policy is defined by the power and phase of the signal transmitted by each node. In particular, we consider the problem of computing an energy-optimal cooperative transmission scheme in a wireless network for two different channel fading models: (i) slow fading channels, where the channel gains of the links remain the same for a large number of transmissions, and (ii) fast fading channels, where the channel gains of the links change quickly from one transmission to another. For slow fading, we consider a factored class of policies (corresponding to local cooperation between nodes), and show that the computation of an optimal policy in this class is equivalent to a shortest path computation on an induced graph, whose edge costs can be computed in a decentralized manner using only locally available channel state information (CSI). For fast fading, both CSI acquisition and data transmission consume energy. Hence, we need to jointly optimize over both these; we cast this optimization problem as a large stochastic optimization problem. We then jointly optimize over a set of CSI functions of the local channel states, and a c- - orresponding factored class of control poli.

Multiscale modeling of lamellar mesophases

The mesoscale simulation of a lamellar mesophase based on a free energy functional is examined with the objective of determining the relationship between the parameters in the model and molecular parameters. Attention is restricted to a symmetric lamellar phase with equal volumes of hydrophilic and hydrophobic components. Apart from the lamellar spacing, there are two parameters in the free energy functional. One of the parameters, r, determines the sharpness of the interface, and it is shown how this parameter can be obtained from the interface profile in a molecular simulation. The other parameter, A, provides an energy scale. Analytical expressions are derived to relate these parameters to r and A to the bending and compression moduli and the permeation constant in the macroscopic equation to the Onsager coefficient in the concentration diffusion equation. The linear hydrodynamic response predicted by the theory is verified by carrying out a mesoscale simulation using the lattice-Boltzmann technique and verifying that the analytical predictions are in agreement with simulation results. A macroscale model based on the layer thickness field and the layer normal field is proposed, and the relationship between the parameters in the macroscale model from the parameters in the mesoscale free energy functional is obtained.

The cross-talk of LDL-cholesterol with cell migration: Insights from the Niemann Pick Type C1 mutation

Cholesterol is considered indispensible for the recruitment and functioning of integrins in focal adhesions for cell migration. However, the physiological cholesterol pools that control integrin trafficking and focal adhesion assembly remain unclear. Using Niemann Pick Type C1 (NPC) mutant cells, which accumulate Low Density lipoprotein (LDL)-derived cholesterol in late endosomes (LE), several recent studies indicate that LDL-cholesterol has multiple roles in regulating focal adhesion dynamics. Firstly, targeting of endocytosed LDL-cholesterol from LE to focal adhesions controls their formation at the leading edge of migrating cells. Other newly emerging literature suggests that this may be coupled to vesicular transport of integrins, Src kinase and metalloproteases from the LE compartment to focal adhesions. Secondly, our recent work identified LDL-cholesterol as a key factor that determines the distribution and ability of several Soluble NSF Attachment Protein (SNAP) Receptor (SNARE) proteins, key players in vesicle transport, to control integrin trafficking to the cell surface and extracellular matrix (ECM) secretion. Collectively, dietary, genetic and pathological changes in cholesterol metabolism may link with efficiency and speed of integrin and ECM cell surface delivery in metastatic cancer cells. This commentary will summarize how direct and indirect pathways enable LDL-cholesterol to modulate cell motility.

A Jacobian-Based Algorithm for Planning Attitude Maneuvers Using Forward and Reverse Rotations

Algorithms for planning quasistatic attitude maneuvers based on the Jacobian of the forward kinematic mapping of fully-reversed (FR) sequences of rotations are proposed in this paper. An FR sequence of rotations is a series of finite rotations that consists of initial rotations about the axes of a body-fixed coordinate frame and subsequent rotations that undo these initial rotations. Unlike the Jacobian of conventional systems such as a robot manipulator, the Jacobian of the system manipulated through FR rotations is a null matrix at the identity, which leads to a total breakdown of the traditional Jacobian formulation. Therefore, the Jacobian algorithm is reformulated and implemented so as to synthesize an FR sequence for a desired rotational displacement. The Jacobian-based algorithm presented in this paper identifies particular six-rotation FR sequences that synthesize desired orientations. We developed the single-step and the multiple-step Jacobian methods to accomplish a given task using six-rotation FR sequences. The single-step Jacobian method identifies a specific FR sequence for a given desired orientation and the multiple-step Jacobian algorithm synthesizes physically feasible FR rotations on an optimal path. A comparison with existing algorithms verifies the fast convergence ability of the Jacobian-based algorithm. Unlike closed-form solutions to the inverse kinematics problem, the Jacobian-based algorithm determines the most efficient FR sequence that yields a desired rotational displacement through a simple and inexpensive numerical calculation. The procedure presented here is useful for those motion planning problems wherein the Jacobian is singular or null.

High-Pressure Magnetic-Susceptibility Studies of Spin-State Transaction

High-pressure magnetic susceptibility measurements have been carried out on Fe(dipy)2(NCS)2 and Fe(phen)2(NCS)2 in the pressure range 1–10 kbar and tempeature range 80–300 K in order to investigate the factors responsible for the spin-state transitions. The transitions change from first order to second or higher order upon application of pressure. The temperature variation of the susceptibility at different pressures has been analysed quantitatively within the framework of available models. It is shown that the relative magnitudes of the ΔG0 of high-spin and low-spin conversion and the ferromagnetic interaction between high-spin complexes determines the nature of the transition.