Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration

Precise spatial and temporal regulation of cell adhesion and de-adhesion is critical for dynamic lymphocyte migration. Although a great deal of information has been learned about integrin lymphocyte function–associated antigen (LFA)-1 adhesion, the mechanism that regulates efficient LFA-1 de-adhesion from intercellular adhesion molecule (ICAM)-1 during T lymphocyte migration is unknown. Here, we show that nonmuscle myosin heavy chain IIA (MyH9) is recruited to LFA-1 at the uropod of migrating T lymphocytes, and inhibition of the association of MyH9 with LFA-1 results in extreme uropod elongation, defective tail detachment, and decreased lymphocyte migration on ICAM-1, without affecting LFA-1 activation by chemokine CXCL-12. This defect was reversed by a small molecule antagonist that inhibits both LFA-1 affinity and avidity regulation, but not by an antagonist that inhibits only affinity regulation. Total internal reflection fluorescence microscopy of the contact zone between migrating T lymphocytes and ICAM-1 substrate revealed that inactive LFA-1 is selectively localized to the posterior of polarized T lymphocytes, whereas active LFA-1 is localized to their anterior. Thus, during T lymphocyte migration, uropodal adhesion depends on LFA-1 avidity, where MyH9 serves as a key mechanical link between LFA-1 and the cytoskeleton that is critical for LFA-1 de-adhesion

High Density SNP Screen in A Large Multiplex Neural Tube Defect Family Refines Linkage to Loci at 7p21-Pter And 2q33.1-35

Neural tube defects (NTDs) are considered complex with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs (Rampersaud et al. 2005) demonstrated evidence of linkage to chromosomes 7 and 10. This screen included forty-four multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7

Faking Heaven: The Utopian Will to Order in China

Now that the 2008 Olympics have come and gone, Beijing can perhaps breathe a sigh of relief that after two weeks of intensive scrutiny, the most embarrassing thing the foreign media could come up with during the Games was that some of the events in the spectacular opening ceremony were faked. First, we learned that 9-year old Lin Miaoke was not in fact singing a revised “Song of the Motherland” at all, but was lip-synching the voice of the less photogenic Yang Peiyi (see Geremie Barmé’s “Painting Over Mao”). Then, we learned that at least some of thefirework footprints leading up to the National Stadium were photo-shopped versions of one that had been done ahead of time. And finally, we learned all of the children dressed in nationality costumes were not minority children at all but Han Chinese. A few newscasters and pundits did their best to muster some shock (shock!) that the world had been hoodwinked into believing China could really pull off the perfection we saw on our television screens. We tend to smell in fakery like this the whiff of scandal. The fake carries with it the stain of deception, of shame, even immorality. And yet, it turns out that fakery is an important part of our ability to imagine perfection. This is not because perfection is the opposite of fakery, but because perfection depends upon the fake. Only the real world is imperfect, blemished, and full of chaos and unpredictability. The fake world of televised opening ceremonies, by contrast, is dependable, predictable, and orderly. And while we may live in the messiness of the real world, we yearn to believe in the more ordered and dependable replica we see on television. Of course, it also turned out that during the 2000 Olympics, Sydney faked their opening ceremony too. The Sydney Symphony mimed its entire performance. In fact, some of it wasn’t even the Sydney Symphony playing on the backing tape, but their archrival, the Melbourne Symphony Orchestra. Such orchestral maneuvers, it seems, are routine for important events where nothing can be left to chance. And so, China apparently has no monopoly on faking it. Nevertheless, the situation in Beijing gave Ai Weiwei occasion to lament in The Guardian about how China may be able to fake its way to a perfect Olympics – to the “fake applause” of the media and the public – but “true happiness” can never be faked: “This nation is notorious for its ability to make or fake anything cheaply,” he wrote. “‘Made-in-China’ goods now fill homes around the world. But our giant country has a small problem. We can’t manufacture the happiness of our people.” He added that, “Real public contentment can’t be pirated or copied.

Hsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia

Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression

Noncovalent Pi–Pi Stacking at the Carbon–Electrolyte Interface: Controlling the Voltage Window of Electrochemical Supercapacitors

A key parameter in the operation of an electrochemical double-layer capacitor is the voltage window, which dictates the device energy density and power density. Here we demonstrate experimental evidence that π–π stacking at a carbon–ionic liquid interface can modify the operation voltage of a supercapacitor device by up to 30%, and this can be recovered by steric hindrance at the electrode–electrolyte interface introduced by poly­(ethylene oxide) polymer electrolyte additives. This observation is supported by Raman spectroscopy, electrochemical impedance spectroscopy, and differential scanning calorimetry that each independently elucidates the signature of π–π stacking between imidazole groups in the ionic liquid and the carbon surface and the role this plays to lower the energy barrier for charge transfer at the electrode–electrolyte interface. This effect is further observed universally across two separate ionic liquid electrolyte systems and is validated by control experiments showing an invariant electrochemical window in the absence of a carbon–ionic liquid electrode–electrolyte interface. As interfacial or noncovalent interactions are usually neglected in the mechanistic picture of double-layer capacitors, this work highlights the importance of understanding chemical properties at supercapacitor interfaces to engineer voltage and energy capability

Genetic Studies in Neural Tube Defects

Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families