Exposure of cells to a variety of external signals causes rapid changes in plasma membrane morphology. Plasma membrane dynamics, including membrane ruffle and microspike formation, fusion or fission of intracellular vesicles, and the spatial organization of transmembrane proteins, is directly controlled by the dynamic reorganization of the underlying actin cytoskeleton. Two members of the Rho family of small GTPases, Cdc42 and Rac, have been well established as mediators of extracellular signaling events that impact cortical actin organization. Actin-based signaling through Cdc42 and Rac ultimately results in activation of the actin-related protein (Arp) 2/3 complex, which promotes the formation of branched actin networks. In addition, the activity of both receptor and non-receptor protein tyrosine kinases along with numerous actin binding proteins works in concert with Arp2/3-mediated actin polymerization in regulating the formation of dynamic cortical actin-associated structures. In this review we discuss the structure and role of the cortical actin binding protein cortactin in Rho GTPase and tyrosine kinase signaling events, with the emphasis on the roles cortactin plays in tyrosine phosphorylation-based signal transduction, regulating cortical actin assembly, transmembrane receptor organization and membrane dynamics. We also consider how aberrant regulation of cortactin levels contributes to tumor cell invasion and metastasis.

Cortactin: coupling membrane dynamics to cortical actin assembly.

In a previous paper, we reviewed the range of therapies available for the treatment of super-refractory status epilepticus. Here we report a review of the outcome of therapies in refractory and super-refractory status epilepticus. Patients (n = 1168) are reported who had therapy with: thiopental, pentobarbital, midazolam, propofol, ketamine, inhalational anaesthetics (isoflurane, desflurane), antiepileptic drugs (topiramate, lacosamide, pregabalin, levetiracetam), hypothermia, magnesium, pyridoxine, immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve stimulation and deep brain stimulation. The outcome parameters reported include control of status epilepticus, relapse on withdrawal, breakthrough seizures and mortality. Where reported (596 cases), the long-term outcome was found to be death (35%), severe neurological deficit (13%), mild neurological deficit (13%), undefined deficit (4%) and recovery to baseline (35%). The quality of reported outcome data is generally poor and the number of cases reported for all non-anaesthetic therapies is low. Outcome assessment is complicated by changes in co-medication, delay in response and publication bias. Given these deficits, only broad recommendations can be made regarding optimal therapy. An approach to therapy, divided into first-line, second-line and third-line therapy, is suggested on the basis of this outcome evaluation. The importance of treatments directed at the cause of the status epilepticus, and of supportive ITU care is also emphasized.

The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.

The QPCR assay for analysis of mitochondrial DNA damage, repair, and relative copy number.

Invadosome regulation by adhesion signaling

Both high and low molecular weight hyaluronan (HMW-HA vs. LMW-HA) exist in various tissues and cells. In this study, we investigated LMW-HA-mediated CD44 interaction with Toll-like receptors (TLRs), the actin filament-associated protein (AFAP-110), and a myeloid differentiation factor (MyD88) in breast tumor cells (MDA-MB-231 cells). Our data indicate that LMW-HA (but not HMW-HA) preferentially stimulates a physical association between CD44 and TLRs followed by a concomitant recruitment of AFAP-110 and MyD88 into receptor-containing complexes in breast tumor cells. LMW-HA-activated AFAP-110 then binds to filamentous actin (F-actin) resulting in MyD88/nuclear factor-κB (NF-κB) nuclear translocation, NF-κB-specific transcription, and target gene [interleukine 1β and interleukine-8 (IL-1β and IL-8)] expression. These signaling events lead to proinflammatory cytokine/chemokine production in the breast tumor cells. AFAP-110-F-actin (activated by LMW-HA) also promotes tumor cell invasion. Downregulation of AFAP-110 or MyD88 by transfecting breast tumor cells with AFAP-110 siRNA or MyD88 siRNA, respectively not only blocks the ability of LMW-HA to stimulate AFAP-110-actin function, but also impairs MyD88-NF-κB nuclear translocation and NF-κB transcriptional activation. Consequently, both IL-1β/IL-8 production and tumor cell invasion are impaired. Taken together, these findings suggest that LMW-HA plays an important role in CD44-TLR-associated AFAP-110-actin interaction and MyD88-NF-κB signaling required for tumor cell behaviors, which may contribute to the progression of breast cancer.

/pdf/interaction-of-low-molecular-weight-hyaluronan-with-cd44-and-3mh5071kku.pdf

Interaction of low molecular weight hyaluronan with CD44 and toll-like receptors promotes the actin filament-associated protein 110-actin binding and MyD88-NFκB signaling leading to proinflammatory cytokine/chemokine production and breast tumor invasion.

The actin-filament-associated protein (AFAP-1 10) forms a stable complex with activated variants of the Pp60c-src (Src) non-receptor tyrosine kinase through SH2 and SH3 interactions. In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. These data indicate that the major sites for tyrosine phosphorylation are among these four tyrosine residues and that one or more of these tyrosines may function as an SH2-binding motif. Mutagenesis of just two tyrosines in either the amino terminus (Y93/Y94) or in the carboxy terminus (Y451/Y453) to phenylalanine had only a modest effect on steady-state levels of tyrosine phosphorylation and was not sufficient to abrogate stable-complex formation. These data suggest that Src527F can form a stable complex with AFAP-110 through either of two independently functional SH2-binding motifs. Triple-tyrosine mutation demonstrated that Y93 was not significantly phosphorylated on tyrosine and would not facilitate stable complex formation, whereas Y94, Y451, and Y453 could be phosphorylated on tyrosine and would facilitate stable-complex formation. We hypothesize that Src527F and AFAP-110 interact through a multistep binding mechanism that may either extend interactions between Src527F and actin filaments or permit reorientation of Src527F on AFAP-110, which could facilitate the presentation of Src527F toward other signaling molecules.

Formation of a stable src-afap-110 complex through either an amino-terminal or a carboxy-terminal sh2-binding motif

The actin filament-associated protein, AFAP-110, forms a stable complex with activated pp60src (Src) as both an SH2 and SH3 binding partner. AFAP-110 contains two putative SH3 binding motifs and six putative SH2 binding motifs, indicating that interactions with Src may be complex. In order to evaluate the mechanism by which AFAP-110 and Src form a stable complex, an in vivo expression system was utilized that permits co-expression of each protein from the same plasmid construct subsequent to transient transfection of Cos-1 cells. Sixty hours post-transfection, western blot analysis indicated that both Src and AFAP-110 were expressed efficiently. Furthermore, Src phosphorylated AFAP-110 on tyrosine and was in stable complex with this protein. These results reflect observations detected in chick embryo fibroblast (CEF) cells. This system has several advantages in that (a) it is rapid, (b) high levels of protein can be overexpressed, stable complex formation occurs, and all transfected cells have the potential of expressing both protein products, (c) proper protein folding and post-translational modifications are likely to occur, (d) mAbs directed against Src and AFAP-110 are specific for these avian cDNA gene products, and (e) the plasmid constructs are amenable to site-directed mutagenesis, allowing for rapid analysis of the mechanism of stable complex formation.

An in vivo system for analysis of stable complex formation between Src and AFAP-110

The authors report a case of status epilepticus localized to sensorimotor cortex that was successfully treated with surgical resection and multiple subpial transections (MST). A 43 year old woman presented in status epilepticus emanating from a right central area focus as verified by subdural grid and strip electrodes. The seizures were medically intractable but were successfully aborted after surgical intervention. The authors describe their case and review the literature on central area status epilepticus.

Neurosurgical therapy for central area status epilepticus.

Laparoscopic adjustable gastric banding is being increasingly utilized for therapy of obesity in the United States. It is a relatively newer technique and little is known about neurologic complications resulting from this procedure. We present a case of disabling peripheral neuropathy occurring after gastric banding. While this type of complication has seen following older weight loss techniques, it has only rarely been documented following adjustable gastric banding. The patient was treated with adjustment of the lap band in combination with plasmapheresis. Plasmapheresis is a novel therapy for treatment of this type of neuropathy and resulted in significant improvement in the patients' strength and functioning.

Neuropathy following laparoscopic adjustable gastric banding: treatment with plasmapheresis.

The authors report a case of status epilepticus secondary to limbic encephalitis that was successfully treated with temporal lobectomy. A 45-year-old woman presented in status epilepticus refractory to high-dose suppressive medical therapy. Magnetic resonance imaging of the brain showed T2- and FLAIR-weighted hyperintensities in the right temporal lobe, left and right frontal lobes, and pons. A lumbar puncture revealed normal findings. Continuous electroencephalography monitoring showed continued right temporal seizure activity. A paraneoplastic panel was positive for N-type voltage-gated calcium channels. Subsequent bronchial biopsy revealed small cell carcinoma of the lung. A right temporal lobectomy was performed due to refractory status, resulting in resolution of seizure activity and recovery of good neurological function. The authors describe their case and review the literature on surgical therapy for refractory status epilepticus and limbic encephalitis.

Temporal lobectomy for refractory status epilepticus in a case of limbic encephalitis.

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