An optimisation-based iterative approach for speckle tracking echocardiography

Speckle tracking is the most prominent technique used to estimate the regional movement of the heart based on echocardiograms. In this study, we propose an optimised-based block matching algorithm to perform speckle tracking iteratively. The proposed technique was evaluated using a publicly available synthetic echocardiographic dataset with known ground-truth from several major vendors and for healthy/ischaemic cases. The results were compared with the results from the classic (standard) two-dimensional block matching. The proposed method presented an average displacement error of 0.57 pixels, while classic block matching provided an average error of 1.15 pixels. When estimating the segmental/regional longitudinal strain in healthy cases, the proposed method, with an average of 0.32 ± 0.53, outperformed the classic counterpart, with an average of 3.43 ± 2.84. A similar superior performance was observed in ischaemic cases. This method does not require any additional ad hoc filtering process. Therefore, it can potentially help to reduce the variability in the strain measurements caused by various post-processing techniques applied by different implementations of the speckle tracking

Population distribution analyses reveal a hierarchy of molecular players underlying parallel endocytic pathways.

Single-cell-resolved measurements reveal heterogeneous distributions of clathrin-dependent (CD) and -independent (CLIC/GEEC: CG) endocytic activity in Drosophila cell populations. dsRNA-mediated knockdown of core versus peripheral endocytic machinery induces strong changes in the mean, or subtle changes in the shapes of these distributions, respectively. By quantifying these subtle shape changes for 27 single-cell features which report on endocytic activity and cell morphology, we organize 1072 Drosophila genes into a tree-like hierarchy. We find that tree nodes contain gene sets enriched in functional classes and protein complexes, providing a portrait of core and peripheral control of CD and CG endocytosis. For 470 genes we obtain additional features from separate assays and classify them into early- or late-acting genes of the endocytic pathways. Detailed analyses of specific genes at intermediate levels of the tree suggest that Vacuolar ATPase and lysosomal genes involved in vacuolar biogenesis play an evolutionarily conserved role in CG endocytosis

The Turbulent Heating Rate in Strong MHD Turbulence with Nonzero Cross Helicity

Different results for the cascade power in strong, incompressible MHD turbulence with nonzero cross helicity appear in the literature. In this paper, we discuss the conditions under which these different results are valid. We define z+ to be the rms amplitude of Alfven waves propagating parallel to the background magnetic field, and z- to be the rms amplitude of Alfven waves propagating anti-parallel to the background magnetic field. Nonzero cross helicity implies that z+ and z- differ, and we take z- to be less than z+. We find that the mechanism that generates the z- fluctuations strongly affects the cascade power, because it controls the coherence time for interactions between oppositely directed wave packets at the outer scale. In particular, for fixed values of z+ and z-, the cascade power is in many cases larger when the z- fluctuations are generated by the reflection of z+ fluctuations than when the z- fluctuations are generated by forcing that is only weakly correlated with the z+ fluctuations.Comment: 16 pages, 2 figures, accepted for publication in Ap

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Measuring Reciprocity in High Functioning Children and Adolescents with Autism Spectrum Disorders

Few instruments have been developed that measure impairments in reciprocity, a defining feature of autism. We introduce a new test assessing the quality of reciprocal behaviour: the interactive drawing test (IDT). Children and adolescents (n = 49) with and without high functioning autism spectrum disorders (HFASD) were invited to collaborate with an experimenter in making a joint drawing. Within both groups the performance on collaborative reciprocity improved with age. However, compared to the control group, HFASD participants showed less collaborative and more basic reciprocal behaviour and preferred to draw their own objects. They were less tolerant of the experimenter’s input as well. Performance on the IDT was independent of estimated verbal IQ. Reciprocal behaviour in self-initiated objects corresponded with more parental reported autistic traits, while reciprocal behaviour in other-initiated objects corresponded with less autistic traits. The findings of this study suggest that IDT is a promising instrument to assess reciprocity

Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer?

The human p53 tumor suppressor gene TP53 is mutated at a high frequency in sporadic breast cancer, and Li-Fraumeni syndrome patients who carry germline mutations in one TP53 allele have a high incidence of breast cancer. In the 10 years since the first knockout of the mouse p53 tumor suppressor gene (designated Trp53) was published, much has been learned about the contribution of p53 to biology and tumor suppression in the breast through the use of p53 transgenic and knockout mice. The original mice deficient in p53 showed no mammary gland phenotype. However, studies using BALB/c-Trp53-deficient mice have demonstrated a delayed involution phenotype and a mammary tumor phenotype. Together with other studies of mutant p53 transgenes and p53 bitransgenics, a greater understanding has been gained of the role of p53 in involution, of the regulation of p53 activity by hormones, of the effect of mouse strain and modifier genes on tumor phenotype, and of the cooperation between p53 and other oncogenic pathways, chemical carcinogens and hormonal stimulation in mammary tumorigenesis. Both p53 transgenic and knockout mice are important in vivo tools for understanding breast cancer, and are yet to be exploited for developing therapeutic strategies in breast cancer

Drug Discovery Using Chemical Systems Biology: Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors

Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery

Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models

The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as ‘Risk factors for schizophrenia—all roads lead to dopamine' or ‘The dopamine hypothesis of schizophrenia—the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start