Scintillation arcs in low-frequency observations of the timing-array millisecond pulsar PSR J0437–4715

© 2016. The American Astronomical Society. All rights reserved. Low-frequency observations of pulsars provide a powerful means for probing the microstructure in the turbulent interstellar medium (ISM). Here we report on high-resolution dynamic spectral analysis of our observations of the timing-array millisecond pulsar PSR J0437-4715 with the Murchison Widefield Array (MWA), enabled by our recently commissioned tied-array beam processing pipeline for voltage data recorded from the high time resolution mode of the MWA. A secondary spectral analysis reveals faint parabolic arcs akin to those seen in high-frequency observations of pulsars with the Green Bank and Arecibo telescopes. Data from Parkes observations at a higher frequency of 732 MHz reveal a similar parabolic feature with a curvature that scales approximately as the square of the observing wavelength (?2) to the MWA's frequency of 192 MHz. Our analysis suggests that scattering toward PSR J0437-4715 predominantly arises from a compact region about 115 pc from the Earth, which matches well with the expected location of the edge of the Local Bubble that envelopes the local Solar neighborhood. As well as demonstrating new and improved pulsar science capabilities of the MWA, our analysis underscores the potential of low-frequency pulsar observations for gaining valuable insights into the local ISM and for characterizing the ISM toward timing-array pulsars

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Chimpanzees modify intentional gestures to coordinate a search for hidden food

Humans routinely communicate to coordinate their activities, persisting and elaborating signals to pursue goals that cannot be accomplished individually. Communicative persistence is associated with complex cognitive skills such as intentionality, because interactants modify their communication in response to another's understanding of their meaning. Here we show that two language-trained chimpanzees effectively use intentional gestures to coordinate with an experimentally naive human to retrieve hidden food, providing some of the most compelling evidence to date for the role of communicative flexibility in successful coordination in nonhumans. Both chimpanzees (named Panzee and Sherman) increase the rate of nonindicative gestures when the experimenter approaches the location of the hidden food. Panzee also elaborates her gestures in relation to the experimenter's pointing, which enables her to find food more effectively than Sherman. Communicative persistence facilitates effective communication during behavioural coordination and is likely to have been important in shaping language evolution

Tunable Growth Factor Delivery from Injectable Hydrogels for Tissue Engineering

Current sustained delivery strategies of protein therapeutics are limited by the fragility of the protein, resulting in minimal quantities of bioactive protein delivered. In order to achieve prolonged release of bioactive protein, an affinity-based approach was designed which exploits the specific binding of the Src homology 3 (SH3) domain with short proline-rich peptides. Specifically, methyl cellulose was modified with SH3-binding peptides (MC-peptide) with either a weak affinity or strong affinity for SH3. The release profile of SH3-rhFGF2 fusion protein from hyaluronan MC-SH3 peptide (HAMC-peptide) hydrogels was investigated and compared to unmodified controls. SH3-rhFGF2 release from HAMC-peptide was extended to 10 days using peptides with different binding affinities compared to the 48 h release from unmodified HAMC. This system is capable of delivering additional proteins with tunable rates of release, while maintaining bioactivity, and thus is broadly applicable

Regulation of STIM1 and SOCE by the Ubiquitin-Proteasome System (UPS)

The ubiquitin proteasome system (UPS) mediates the majority of protein degradation in eukaryotic cells. The UPS has recently emerged as a key degradation pathway involved in synapse development and function. In order to better understand the function of the UPS at synapses we utilized a genetic and proteomic approach to isolate and identify novel candidate UPS substrates from biochemically purified synaptic membrane preparations. Using these methods, we have identified Stromal interacting molecule 1 (STIM1). STIM1 is as an endoplasmic reticulum (ER) calcium sensor that has been shown to regulate store-operated Ca2+ entry (SOCE). We have characterized STIM1 in neurons, finding STIM1 is expressed throughout development with stable, high expression in mature neurons. As in non-excitable cells, STIM1 is distributed in a membranous and punctate fashion in hippocampal neurons. In addition, a population of STIM1 was found to exist at synapses. Furthermore, using surface biotinylation and live-cell labeling methods, we detect a subpopulation of STIM1 on the surface of hippocampal neurons. The role of STIM1 as a regulator of SOCE has typically been examined in non-excitable cell types. Therefore, we examined the role of the UPS in STIM1 and SOCE function in HEK293 cells. While we find that STIM1 is ubiquitinated, its stability is not altered by proteasome inhibitors in cells under basal conditions or conditions that activate SOCE. However, we find that surface STIM1 levels and thapsigargin (TG)-induced SOCE are significantly increased in cells treated with proteasome inhibitors. Additionally, we find that the overexpression of POSH (Plenty of SH3′s), an E3 ubiquitin ligase recently shown to be involved in the regulation of Ca2+ homeostasis, leads to decreased STIM1 surface levels. Together, these results provide evidence for previously undescribed roles of the UPS in the regulation of STIM1 and SOCE function

Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis

Tumour angiogenesis and cellular pH regulation, mainly represented by Na+/H+ antiporter exchange, have been heretofore considered unrelated subfields of cancer research. In this short review, the available experimental evidence relating these areas of modern cancer research is introduced. This perspective also helps to design a new approach that facilitates the opening and development of novel research lines oriented towards a rational incorporation of anticancer drugs into more selective and less toxic therapeutic protocols. The final aim of these efforts is to control cancer progression and dissemination through the control of tumour angiogenesis. Finally, different antiangiogenic drugs that can already be clinically used to this effect are briefly presented

Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn2+ sensing G-protein coupled receptor (ZnR) that activates Ca2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na+/H+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na+/H+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes

Activation of store-operated calcium entry in airway smooth muscle cells: insight from a mathematical model

Intracellular dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper-responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated entry (SOCE) in these dynamics by constructing a mathematical model of ASMC signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient depletion of the sarcoplasmic reticulum (SR), while receptor-operated entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced oscillations in the absence of other influx. SOCE up-regulation may thus contribute to AHR by increasing the oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of . This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC