Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGF-β to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGF-β-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy related 7 (ATG7) or pharmacological inhibition of SYK activity with fostamatib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, the current study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells

Microstructural white matter changes mediated age- related cognitive decline in the Montreal Cognitive Assessment (MoCA)

Although the relationship between aging and cognitive decline is well established, there is substantial individual variability in the degree of cognitive decline in older adults. The present study investigates whether variability in cognitive performance in community-dwelling older adults is related to the presence of whole brain or tract-specific changes in white matter microstructure. Specifically, we examine whether age-related decline in performance on the Montreal Cognitive Assessment (MoCA), a cognitive screening tool, is mediated by the white matter microstructural decline. We also examine if this relationship is driven by the presence of cardiovascular risk factors or variability in cerebral arterial pulsatility, an index of cardiovascular risk. Sixty-nine participants (aged 43–87) completed behavioral and MRI testing including T1 structural, T2-weighted FLAIR, and diffusion-weighted imaging (DWI) sequences. Measures of white matter microstructure were calculated using diffusion tensor imaging analyses on the DWI sequence. Multiple linear regression revealed that MoCA scores were predicted by radial diffusivity (RaD) of white matter beyond age or other cerebral measures. While increasing age and arterial pulsatility were associated with increasing RaD, these factors did not mediate the relationship between total white matter RaD and MoCA. Further, the relationship between MoCA and RaD was specific to participants who reported at least one cardiovascular risk factor. These findings highlight the importance of cardiovascular risk factors in the presentation of cognitive decline in old age. Further work is needed to establish whether medical or lifestyle management of these risk factors can prevent or reverse cognitive decline in old age

Ice and pulsed electromagnetic field to reduce pain and swelling after distal radius fractures

Objective: To examine the relative effectiveness of ice therapy and/or pulsed electromagnetic field in reducing pain and swelling after the immobilization period following a distal radius fracture.Methods: A total of 83 subjects were randomly allocated to receive 30 minutes of either ice plus pulsed electromagnetic field (group A); ice plus sham pulsed electromagnetic field (group B); pulsed electromagnetic field alone (group C), or sham pulsed electromagnetic field treatment for 5 consecutive days (group D). All subjects received a standard home exercise programme. A visual analogue scale was used for recording pain; volumetric displacement for measuring the swelling of the forearm; and a hand-held goniometer for measuring the range of wrist motions before treatment on days 1, 3 and 5.Results: At day 5, a significantly greater cumulative reduction in the visual analogue scores as well as ulnar deviation range of motion was found in group A than the other 3 groups. For volumetric measurement and pronation, participants in group A performed better than subjects in group D but not those in group B.Conclusion: The addition of pulsed electromagnetic field to ice therapy produces better overall treatment outcomes than ice alone, or pulsed electromagnetic field alone in pain reduction and range of joint motion in ulnar deviation and flexion for a distal radius fracture after an immobilization period of 6 weeks.<br /

Strategies for Multiplexed Electrochemical Sensor Development

Detection of multiple biomarkers for disease diagnosis or treatment monitoring has received a lot of attention due to their potential impact on clinical decision making. Electrochemical biosensors have become one of the preferred detection approaches, due to the simplicity of the accompanying instrumentation. This chapter will explore how electrochemical sensors can be utilized for detection of multiple analytes by integration of sensors into microfluidic microsystems. Some key fabrication technologies for such devices will be presented utilizing polymer microfabrication, paper-based approaches, and the use of printed circuit boards. Next, the use of electrode arrays will be presented along with some commercial platforms, outlining plausible paths towards a successful electrochemical multiplexed sensor. Novel approaches based on microbeads and various labels will then be introduced along with various strategies and technologies utilized to achieve ultrasensitive multiplexed detection

Roadmap on spatiotemporal light fields

Spatiotemporal sculpturing of light pulse with ultimately sophisticated structures represents the holy grail of the human everlasting pursue of ultrafast information transmission and processing as well as ultra-intense energy concentration and extraction. It also holds the key to unlock new extraordinary fundamental physical effects. Traditionally, spatiotemporal light pulses are always treated as spatiotemporally separable wave packet as solution of the Maxwell's equations. In the past decade, however, more generalized forms of spatiotemporally nonseparable solution started to emerge with growing importance for their striking physical effects. This roadmap intends to highlight the recent advances in the creation and control of increasingly complex spatiotemporally sculptured pulses, from spatiotemporally separable to complex nonseparable states, with diverse geometric and topological structures, presenting a bird's eye viewpoint on the zoology of spatiotemporal light fields and the outlook of future trends and open challenges.Comment: This is the version of the article before peer review or editing, as submitted by an author to Journal of Optics. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from i

Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection

Contact with HIV-1 envelope protein elicits release of ATP through pannexin-1 channels on target cells; by activating purinergic receptors and Pyk2 kinase in target cells, this extracellular ATP boosts HIV-1 infectivity

The development of sex differences in ring-tailed lemur feeding ecology

Sex differences in feeding ecology may develop in response to fluctuations in physiological costs to females over their reproductive cycles, or to sexual size dimorphism, or function to minimize feeding competition within a group via resource partitioning. For most mammal species, it is unknown how these factors contribute to sex differences in feeding, or how the development of males and females reflects these intraspecific feeding differences. We show changes in dietary composition, diversity, overlap, and foraging behavior throughout development in ring-tailed lemurs (Lemur catta) and test how the development of sex differences in feeding is related to female costs of reproduction and year-round resource partitioning. Sex differences in dietary composition were only present when females were lactating, but sex differences in other aspects of feeding, including dietary diversity, and relative time spent feeding and foraging, developed at or near the time of weaning. Sex difference in juveniles and subadults, when present, were similar to the differences found in adults. The low year-round dietary overlap and early differences in dietary diversity indicate that some resource partitioning may begin with young individuals and fluctuate throughout development. The major differences between males and females in dietary composition suggest that these larger changes in diet are closely tied to female reproductive state when females must shift their diet to meet energetic and nutritional requirements

Temporal variations of disinfection byproduct precursors in wildfire detritus

The Rim Fire ignited on August 17, 2013 and became the third largest wildfire in California history. The fire consumed 104,131&nbsp;ha of forested watersheds that were the drinking water source for 2.6 million residents in the San Francisco Bay area. To understand temporal variations in dissolved organic matter (DOM) after the wildfire and its potential impacts on disinfection byproduct (DBP) formation in source water supply, we collected the 0-5&nbsp;cm ash/soil layer with surface deposits of white ash (high burn severity) and black ash (moderate burn severity) within the Rim Fire perimeter in Oct 2013 (pre-rainfall) for five sequential extractions, and in Dec 2013 (∼87&nbsp;mm cumulative precipitation) and Aug 2014 (∼617&nbsp;mm cumulative precipitation) for a single water extraction. Water-extractable DOM was characterized by absorption and fluorescence spectroscopy and DBP formation tests. Both increasing cumulative precipitation in the field or number of extractions in the lab resulted in a significant decrease in specific conductivity, dissolved organic carbon, and DBP formation potential, but an increase in DOM aromaticity (reflected by specific UV absorbance). However, the lab sequential leaching failed to capture the increase of the NOx(-)-N/NH4(+)-N ratio and the decrease in pH and dissolved organic carbon/nitrogen ratio of ash/soil extracts from Oct 2013 to Aug 2014. Increasing cumulative precipitation, inferring an increase in leaching after fire, led to an increase in DOM reactivity to form trihalomethanes, haloacetic acids, and chloral hydrate, but not for haloketones, haloacetonitrile, or N-nitrosodimethylamine, which were more related to the original burn severity. This study highlights that fire-affected DBP precursors for different DBP species have distinct temporal variation possibly due to their various sensitivity to biogeochemical alterations

Risk to human health related to the presence of perfluoroalkyl substances in food

Acknowledgements: The Panel wishes to thank the following for their support provided to this scientific output as Hearing experts: Klaus Abraham, Esben Budtz-Jørgensen, Tony Fletcher, Philippe Grandjean, Hans Mielke and Hans Rumke and EFSA staff members: Davide Arcella, Marco Binaglia, Petra Gergelova, Elena Rovesti and Marijke Schutte. The Panel wishes to acknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output. The Panel would also like to thank the following authors and co-authors for providing additional information in relation to their respective studies: Berit Granum, Margie M Peden-Adams, Thomas Webster.Peer reviewedPublisher PD