Effect of pregnancy prolongation in early-onset pre-eclampsia on postpartum maternal cardiovascular, renal and metabolic function in primiparous women: an observational study.

OBJECTIVE: To evaluate the association between deferred delivery in early-onset pre-eclampsia and offspring outcome and maternal cardiovascular, renal and metabolic function in the postpartum period. DESIGN: Observational study. SETTING: Tertiary referral hospital. POPULATION: Nulliparous women diagnosed with pre-eclampsia before 34 weeks' gestation who participated in a routine postpartum cardiovascular risk assessment programme. Women with hypertension, diabetes mellitus or renal disease prior to pregnancy were excluded. METHODS: Regression analyses were performed to assess the association between pregnancy prolongation and outcome measures. MAIN OUTCOME MEASURES: Offspring outcome and prevalence of deviant maternal cardiovascular, renal and metabolic function. RESULTS: The study population included 564 women with a median pregnancy prolongation of 10 days (interquartile range [IQR] 4-18) who were assessed at on average 8 months (IQR 6-12) postpartum. Pregnancy prolongation after diagnosis resulted in a decrease in infant mortality (adjusted odd ratio [aOR] 0.907, 95% CI 0.852-0.965 per day prolongation). This improvement in offspring outcome was associated with an elevated risk of moderately increased albuminuria (aOR 1.025, 95% CI 1.006-1.045 per day prolongation), but not with aberrant cardiac geometry, cardiac systolic or diastolic dysfunction, persistent hypertension or metabolic syndrome. CONCLUSION: Pregnancy prolongation in early-onset pre-eclampsia is associated with improved offspring outcome and survival. These effects do not appear to be deleterious to short-term maternal cardiovascular and metabolic function but are associated with a modest increase in risk of residual albuminuria. TWEETABLE ABSTRACT: Pregnancy prolongation in pre-eclampsia has only a limited effect on postpartum maternal cardiovascular function

Mantra: an open method for object and movement tracking

Mantra is a free and open-source software package for object tracking. It is specifically designed to be used as a tool for response collection in psychological experiments and requires only a computer and a camera (a webcam is sufficient). Mantra is compatible with widely used software for creating psychological experiments. In Experiments 1 and 2, we validated the spatial and temporal precision of Mantra in realistic experimental settings. In Experiments 3 and 4, we validated the spatial precision and accuracy of Mantra more rigorously by tracking a computer controlled physical stimulus and stimuli presented on a computer screen

MASTL overexpression promotes chromosome instability and metastasis in breast cancer.

MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial-mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival

The immortalized UROtsa cell line as a potential cell culture model of human urothelium.

The UROtsa cell line was isolated from a primary culture of normal human urothelium through immortalization with a construct containing the SV40 large T antigen. It proliferates in serum-containing growth medium as a cell monolayer with little evidence of uroepithelial differentiation. The working hypothesis in the present study was that this cell line could be induced to differentiate and express known features of in situ urothelium if the original serum-containing growth medium was changed to a serum-free formulation. We demonstrated that the UROtsa cells could be successfully placed into a serum-free growth medium consisting of a 1:1 mixture of Dulbeco\u27s modified Eagle\u27s medium and Ham\u27s F-12 supplemented with selenium (5 ng/mL), insulin (5 microg/mL), transferrin (5 microg/mL), hydrocortisone (36 ng/mL), triiodothyronine (4 pg/mL), and epidermal growth factor (10 ng/mL). Under serum-free growth conditions, confluent UROtsa cells were shown by light microscopy to produce raised, three-dimensional structures. Routine ultrastructural examination disclosed these three-dimensional areas to consist of a stratified layer of cells that strongly resembled in situ urothelium. The cells displayed numerous desmosomal connections, complex interactions of the lateral membranes, and abundant intermediate filaments within the cytoplasm. Freeze fracture analysis demonstrated that the cells possessed tight-junction sealing strands and gap junctions. The overall morphology was most consistent with that found in the intermediate layers of in situ urothelium. The basal expression patterns of the metallothionein (MT) and heat shock proteins 27, 60, and 70 were determined in these cells, and expression was in agreement with that known to occur for in situ urothelium. The cells were also successfully tested for their ability to be stably transfected using expression vectors containing the MT-3 or MT-2A genes. The findings suggest that the UROtsa cells grown with a serum-free medium could be a valuable adjunct for studying environmental insult to the human urothelium in general and for the stress response in particular

Modelling Visual Search with the Selective Attention for Identification Model (VS-SAIM): A Novel Explanation for Visual Search Asymmetries

In earlier work, we developed the Selective Attention for Identification Model (SAIM [16]). SAIM models the human ability to perform translation-invariant object identification in multiple object scenes. SAIM suggests that central for this ability is an interaction between parallel competitive processes in a selection stage and a object identification stage. In this paper, we applied the model to visual search experiments involving simple lines and letters. We presented successful simulation results for asymmetric and symmetric searches and for the influence of background line orientations. Search asymmetry refers to changes in search performance when the roles of target item and non-target item (distractor) are swapped. In line with other models of visual search, the results suggest that a large part of the empirical evidence can be explained by competitive processes in the brain, which are modulated by the similarity between target and distractor. The simulations also suggest that another important factor is the feature properties of distractors. Finally, the simulations indicate that search asymmetries can be the outcome of interactions between top-down (knowledge about search items) and bottom-up (feature of search items) processing. This interaction in VS-SAIM is dominated by a novel mechanism, the knowledge-based on-centre-off-surround receptive field. This receptive field is reminiscent of the classical receptive fields but the exact shape is modulated by both, top-down and bottom-up processes. The paper discusses supporting evidence for the existence of this novel concept

Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue.

E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time