Skin simulants for wound ballistic investigation - an experimental study.

Gunshot wound analysis is an important part of medicolegal practice, in both autopsies and examinations of living persons. Well-established and studied simulants exist that exhibit both physical and biomechanical properties of soft-tissues and bones. Current research literature on ballistic wounds focuses on the biomechanical properties of skin simulants. In our extensive experimental study, we tested numerous synthetic and natural materials, regarding their macromorphological bullet impact characteristics, and compared these data with those from real bullet injuries gathered from medicolegal practice. Over thirty varieties of potential skin simulants were shot perpendicularly, and at 45°, at a distance of 10 m and 0.3 m, using full metal jacket (FMJ) projectiles (9 × 19 mm Luger). Simulants included ballistic gelatine at various concentrations, dental silicones with several degrees of hardness, alginates, latex, chamois leather, suture trainers for medical training purposes and various material compound models. In addition to complying to the general requirements for a synthetic simulant, results obtained from dental silicones shore hardness 70 (backed with 20 % by mass gelatine), were especially highly comparable to gunshot entry wounds in skin from real cases. Based on these results, particularly focusing on the macroscopically detectable criteria, we can strongly recommend dental silicone shore hardness 70 as a skin simulant for wound ballistics examinations.

Presence of a remote fear memory engram in the central amygdala.

Fear memory formation and recall are highly regulated processes, with the central amygdala (CeA) contributing to fear memory-related behaviors. We recently reported that a remote fear memory engram is resident in the anterior basolateral amygdala (aBLA). However, the extent to which downstream neurons in the CeA participate in this engram is unknown. We tested the hypothesis that CeA neurons activated during fear memory formation are reactivated during remote memory retrieval such that a CeA engram participates in remote fear memory recall and its associated behavior. Using contextual fear conditioning in TRAP2;Ai14 mice, we identified, by persistent Cre-dependent tdTomato expression (i.e., "TRAPing"), CeA neurons that were c-fos-activated during memory formation. Twenty-one days later, we quantified neurons activated during remote memory recall using Fos immunohistochemistry. Dual labeling was used to identify the subpopulation of CeA neurons that was both activated during memory formation and reactivated during recall. Compared with their context-conditioned (no shock) controls, fear-conditioned (electric shock) mice (n = 5/group) exhibited more robust fear memory-related behavior (freezing) as well as larger populations of activated (tdTomato+) and reactivated (dual-labeled) CeA neurons. Most neurons in both groups were mainly located in the capsular CeA subdivision (CeAC). Notably, however, only the size of the TRAPed population distributed throughout the CeA was significantly correlated with time spent freezing during remote fear memory recall. Our findings indicate that fear memory formation robustly activates CeA neurons and that a subset located mainly in the CeAC may contribute to both remote fear memory storage/retrieval and the resulting fear-like behavior.

Increased quinolinic acid in peripheral mononuclear cells in Alzheimer's dementia.

The role of monocytes and macrophages in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) is poorly understood. Recently, we have shown that the number of CD14+ monocytes remained constant during healthy aging and in AD patients. Although only little is known about the function of activated macrophages and microglia in AD, one important mechanism involves the expression of quinolinic acid (QUIN), an endogenous N-methyl-D-aspartate glutamate receptor (NMDA-R) agonist which mediates excitotoxicity especially in the hippocampus. We used immunofluorescence stainings of PBMCs to determine the expression of quinolinic acid (QUIN) and the MHC class II molecule HLA-DR in peripheral monocytic cells in 51 healthy volunteers aged 22-87 years and 43 patients with AD at diagnosis (0 weeks) and during the course of rivastigmine treatment at 0.25 year (12 weeks), 0.5 year (30 weeks), 1 year, and 1.5 years. The number of QUIN+ HLA-DR+ cells rises in healthy persons aged 30-40 years compared to persons aged 60-70 years, indicating that this cell population increases with aging. AD patients at diagnosis had an increased frequency of QUIN+, QUIN+ HLA-DR+, and QUIN+ HLA-DR+/HLA-DR+ cells compared to aged-matched controls. These cell populations remained increased in AD for up to one year after initiation of treatment with rivastigmine; no alterations were detected in aged healthy persons. We conclude that the expression of the neurotoxic agent QUIN is increased in peripheral monocytes from AD patients. These cells could enter the brain and contribute to excitotoxicity.

A case report of lobular intradural extramedullary capillary hemangioma in a 14-year-old patient: resection and reconstruction.

Background: Intradural, extramedullary capillary hemangiomas of the cauda equina are exceedingly rare malformations arising from the endothelial cells of the nervous system vasculature. Roughly 20 cases have been reported in the literature, with the youngest and only pediatric case being in a 17-year-old patient. We report the youngest case of intradural extramedullary capillary hemangioma of the cauda equina in a 14-year-old patient. Case Description: A 14-year-old female presented with two-month history of low back pain with bilateral leg pain and numbness. Magnetic resonance imaging (MRI) revealed an L2 well-defined homogenous contrast-enhancing intradural, extramedullary mass causing severe spinal canal stenosis. Patient underwent laminoplasty for resection of an intradural tumor. Intraoperative hemostasis was readily achieved via early identification and coagulation of the predominate feeding vessel. Postoperatively, the patient awoke with no deficits and resolved leg pain. A 3-month postoperative MRI revealed no tumor recurrence and fully healed lamina. Conclusions: Given the benign nature, the operative goal is complete excision of the tumor without damage to surrounding neural structures. Postoperatively the goal is relief of pain and improvement in neurologic function. To our knowledge we report the first case in which laminoplasty is utilized for the treatment of this pathology in a pediatric patient. Evidence for laminoplasty in this patient population is sparse and future studies are still needed. In any case, reconstruction of the surgical site in a manner that returns the patient's normal anatomy should be strongly considered especially in younger patients.

Fatal intoxication with 1,4-butanediol: Case report and comprehensive review of the literature.

A fatal case of 1,4-butanediol (1,4-BD) oral ingestion is reported here, in which a 51-year-old man was found dead in his bed. According to the police report, the deceased was a known drug user. A glass bottle labeled (and later confirmed to be) "Butandiol 1,4" (1,4-BD) was found in the kitchen. Furthermore, the deceased's friend stated that he consumed 1,4-BD on a regular basis. The autopsy and histological examination of postmortem parenchymatous organ specimens did not revealed a clear cause of death. Chemical-toxicological investigations revealed gammahydroxybutyrat (GHB) in body fluids and tissues in the following quantities: femoral blood 390 mg/L, heart blood 420 mg/L, cerebrospinal fluid 420 mg/L, vitreous humor 640 mg/L, urine 1600 mg/L, and head hair 26.7 ng/mg. In addition, 1,4-BD was qualitatively detected in the head hair, urine, stomach contents, and the bottle. No other substances, including alcohol, were detected at pharmacologically relevant concentrations. 1,4-BD is known as precursor substance that is converted in vivo into GHB. In the synoptic assessment of toxicological findings, the police investigations and having excluded other causes of death, a lethal GHB-intoxication following ingestion of 1,4-BD, can be assumed in this case. Fatal intoxications with 1,4-BD have seldom been reported due to a very rapid conversion to GHB and, among other things, non-specific symptoms after ingestion. This case report aims to give an overview to the published of fatal 1,4-BD-intoxications and to discuss the problems associated with detection of 1,4-BD in (postmortem) specimens.

Anterior basolateral amygdala neurons comprise a remote fear memory engram.

Introduction: Threatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior. Methods: Using adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to "TRAP" aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) (n = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry. Results: TRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group. Discussion: We conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall.

The majority of ruptured aneurysms are small with low rupture risk scores.

BACKGROUND: Understanding the rupture risk of unruptured intracranial aneurysms has important clinical implications given the morbidity and mortality associated with subarachnoid hemorrhage (SAH). The ISUIA, UCAS, and PHASES studies provide rupture risk calculations. OBJECTIVE: We apply the risk calculations to a series ruptured intracranial aneurysms to assess the rupture risk for each aneurysm (had they been discovered in the unruptured state). METHODS: This is a retrospective study of 246 patients with SAH from a ruptured saccular aneurysm. The ISUIA, UCAS, and PHASES calculators were applied to each patient/aneurysm to demonstrate a theoretical annual risk of rupture dichotomized by aneurysm location. RESULTS: The average diameter of the aneurysms was 5.5 ± 3.1 mm. Three quarters (75%) of the aneurysms measured <7 mm and 48.8% were <5 mm. The anterior communicating artery (Acomm) was the most common location of rupture (24.7%). Posterior communicating artery aneurysms (Pcomm) were the third most common at 16.2%. The average ISUIA 1-year rupture risk was 0.46 ± 0.008%. The average UCAS 1-year rupture risk was 0.93% ± 0.01. The annualPHASESrupture risk was0.32 ± 0.004%. The highest risk locations were the vertebral artery (up to 10.3% per year) and superior cerebellar artery (up to 2.7% per year). On average, Acomm aneurysms had 1 year risk no higher than 1.1% and Pcomm aneurysms no higher than 1.2% per year. CONCLUSION: We observed that in a small retrospective series of ruptured aneurysms, the majority were <7 mm and that the theoretical rupture risk of these aneurysms, had they been discovered in the unruptured state, is low (<1% per year). Our study has a number of limitations and these results should be validated in a larger multicenter study.

The Ricochet-Scepter Technique: A Balloon-Assisted Technique to Achieve Outflow Access During Pipeline-Assisted Coil Embolization of a Near-Giant Internal Carotid Artery Ophthalmic Aneurysm.

BACKGROUND: Flow diversion with or without coil embolization has become the first-line treatment for large or giant paraclinoid internal carotid artery intracranial aneurysms. Oftentimes, these sizable aneurysms impose anatomical challenges to endovascular treatment through limiting both distal outflow access and maintenance of distal vessel purchase during catheter reduction, which are required for successful stent placement. Various strategies to obtain and maintain distal access within the parent vessel have been described previously; however, new techniques may need to be employed when more standard maneuvers fail. CASE DESCRIPTION: This paper depicts a case of successful flow diversion of a near-giant internal carotid artery ophthalmic aneurysm in a middle-aged female patient using a balloon-assisted technique, designated the Ricochet-Scepter technique, to achieve distal outflow access followed by secondary system reduction via a stent retriever after standard maneuvers had failed. CONCLUSIONS: Giant, wide-neck aneurysms present treatment challenges that may require using adjunctive devices and advanced endovascular techniques. When routine strategies for gaining distal outflow access fail, the Ricochet-Scepter technique is a viable option for achieving distal access.

Paradoxical Contralateral Herniation Detected by Pupillometry in Acute Syndrome of the Trephined.

Severe traumatic brain injury has historically been a non-survivable injury. Recent advances in neurosurgical care, however, have demonstrated that these patients not only can survive, but they also can recover functionally when they undergo appropriate cerebral decompression within hours of injury. At the present, general surgeons are deployed further forward than neurosurgeons (Role 2 compared to Role 3) and have been provided with guidelines that stipulate conditions where they may have to perform decompressive craniectomies. Unfortunately, Role 2 medical facilities do not have access to computed tomography imaging or intracranial pressure monitoring capabilities rendering the decision to proceed with craniectomy based solely on exam findings. Utilizing a case transferred from downrange to our institution, we demonstrate the utility of a small, highly portable quantitative pupillometer to obtain reliable and reproducible data about a patient's intracranial pressures. Following the case presentation, the literature supporting quantitative pupillometry for surgical decision-making is reviewed.

Spinocerebellar Ataxia Type 3: A Case Report and Literature Review.

Spinocerebellar ataxia type 3 (SCA3), also known by the eponym Machado-Joseph disease, is an autosomal dominant CAG trinucleotide (polyglutamine) repeat disease that presents in young- to middle-aged adults. SCA3 was first described in Azorean individuals and has interesting epidemiological patterns. It is characterized clinically by progressive ataxia and neuropathologically by progressive degenerative changes in the spinal cord and cerebellum, along with degeneration of the cortex and basal ganglia. Here, we describe the clinical and neuropathologic features in a case of SCA3 with unique findings, including involvement of the inferior olivary nucleus and cerebellar Purkinje cell layer, which are classically spared in the disease. We also discuss research into the disease mechanisms of SCA3 and the potential for therapeutic intervention.

Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration.

OBJECTIVE: Meconium aspiration induces acute lung injury (ALI) and subsequent pulmonary arterial hypertension (PAH) which may lead to right ventricular failure. Increase of endothelin-1, thromboxane-A, and phosphodiesterases are discussed molecular mechanisms. We investigated the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration. DESIGN: Animal study. SETTING: University-affiliated research laboratory. SUBJECTS: White farm pigs. INTERVENTIONS: Acute lung injury was induced in 24 pigs by instillation of meconium. Animals were randomly assigned to four groups to receive either intravenous tezosentan, inhalational iloprost, or combined tezosentan and iloprost, or to serve as controls. MEASUREMENTS AND RESULTS: After meconium aspiration-induced lung injury each treatment increased oxyhemoglobin saturations (TEZO: 88 +/- 6% (p = 0.02), ILO: 85 +/- 13% (p = 0.05), TEZO-ILO: 89 +/- 6% (p = 0.02), control: 70 +/- 18%). TEZO but not ILO significantly decreased pulmonary arterial pressure and pulmonary vascular resistance (both p < 0.01). ILO alone decreased intrapulmonary shunt blood flow (p < 0.01). Compared with control, TEZO-ILO yielded the highest arterial partial pressure of oxygen (70 +/- 6 torr vs.49 +/- 9 torr, p = 0.04), although it decreased arterial blood pressure (change from 71 +/- 13 mmHg to 62 +/- 12 mmHg vs.85 +/- 14 mmHg to 80 +/- 11 mmHg (p = 0.01). CONCLUSIONS: Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration. Inhaled ILO improves gas exchange only, thereby reducing intrapulmonary shunt blood flow. Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity.

Intravenous tezosentan and vardenafil attenuate acute hypoxic pulmonary hypertension.

Excessive hypoxic pulmonary hypertension imposes right ventricular strain by increasing afterload that may lead to right heart failure and death. Increased phosphodiesterase activity, as well as increased levels of endothelin-1, has been discussed as molecular mechanisms. We investigated the hemodynamic and intrapulmonary effects of the intravenous dual endothelin A and B receptor blocker tezosentan, and of the phosphodiesterase-5 (PDE-5) antagonist vardenafil in a pig model of acute normobaric hypoxic pulmonary hypertension. Eighteen 4-week-old ventilated white farm pigs were exposed to normobaric hypoxia (FiO2 12%) and randomly assigned to three groups (n = 6) in order to receive either intravenous tezosentan or vardenafil or to serve as control. Arterial alveolar oxygen differences were the same with both drugs. After 90 min of treatment, pulmonary artery pressure and vascular resistance were significantly lower in both treatment groups when compared to controls (p < 0.001). Cardiac index increased significantly with vardenafil alone (2.8 l x min(-1) x m2 +/- 0.7 to 4.2 l x min x m2 +/- 0.7, p = 0.0003). Intravenous tezosentan, as well as vardenafil equipotently attenuate acute hypoxic pulmonary hypertension without afflicting pulmonary gas exchange. However, cardiac index increases with vardenafil only.

Six-minute walk test in children and adolescents.

OBJECTIVE: To evaluate the 6-minute walking distance (6MWD) for healthy Caucasian children and adolescents of a population-based sample from the age of 3 to 18 years. STUDY DESIGN: Two hundred and eighty boys and 248 girls completed a modified test, using a measuring wheel as incentive device. RESULTS: Median 6MWD increased from the age of 3 to 11 years in boys and girls alike and increased further with increasing age in boys (from 667.3 m to 727.6 m), whereas it essentially plateaued in girls (655.8 m to 660.9 m). After adjusting for age, height (P = .001 in boys and P < .001 in girls) remained independently correlated with the 6MWD. In the best fitting and most efficient linear and quadratic regression models, the variables age and height explained about 49% of the variability of the 6MWD in boys and 50% in girls. CONCLUSION: This modified 6-minute walk test (6MWT) proved to be safe, easy to perform, and highly acceptable to children. It provides a simple and inexpensive means to measure functional exercise capacity in children, even of young age, and might be of value when conducting comparable studies.

Chibby1 knockdown promotes mesenchymal-to-epithelial transition-like changes.

Chibby1 (Cby1) was originally isolated as a binding partner for ß-catenin, a dual function protein in cell-cell adhesion and in canonical Wnt signaling. The canonical Wnt/ß-catenin pathway is dysregulated in various diseases including cancer, most notably of the gastrointestinal origin. To investigate the role of Cby1 in colorectal tumorigenesis, we generated stable Cby1-knockdown (KD) SW480 colon cancer cells. Unexpectedly, we found that Cby1 KD induces mesenchymal-to-epithelial transition (MET)-like changes in SW480 as well as in HEK293 cells. Cby1-KD cells displayed a cuboidal epithelial morphology with tight cell-cell contacts. In Cby1-KD cells, the plasma membrane localization of E-cadherin and ß-catenin was dramatically increased with formation of cortical actin rings, while the levels of the mesenchymal marker vimentin were decreased. Consistent with these changes, in wound healing assays, Cby1-KD cells exhibited epithelial cell-like properties as they migrated collectively as epithelial sheets. Furthermore, the anchorage-independent growth of Cby1-KD cells was reduced as determined by soft agar assays. These findings suggest that chronic Cby1 KD in colon cancer cells may counteract tumor progression by promoting the MET process.

Chibby suppresses growth of human SW480 colon adenocarcinoma cells through inhibition of ß-catenin signaling.

The canonical Wnt signaling pathway is crucial for embryonic development and adult tissue homeostasis. Activating mutations in the Wnt pathway are frequently associated with the pathogenesis of various types of cancer, particularly colon cancer. Upon Wnt stimulation, ß-catenin plays a central role as a coactivator through direct interaction with Tcf/Lef transcription factors to stimulate target gene expression. We have previously shown that the evolutionarily conserved protein Chibby (Cby) physically binds to ß-catenin to repress ß-catenin-dependent gene activation by 1) competing with Tcf/Lef factors for binding to ß-catenin and 2) facilitating nuclear export of ß-catenin via interaction with 14-3-3 proteins. In this study, we employed human colon adenocarcinoma SW480 cells with high levels of endogenous ß-catenin to address a potential tumor suppressor role of Cby. In SW480 stable cells expressing wild-type Cby (CbyWT), but not 14-3-3-binding- defective Cby mutant CbyS20A, a significant fraction of endogenous ß-catenin was detected in the cytoplasm. Consistent with this, CbyWT-expressing cells showed low levels of ß-catenin signaling activity, leading to reduced growth. Our results suggest that Cby, in collaboration with 14-3-3 proteins, can counteract oncogenic ß-catenin signaling in colon cancer cells.

Generation and characterization of monoclonal antibodies against human Chibby protein.

Chibby (Cby) was originally identified as an antagonist of the Wnt/ß-catenin signaling pathway. It physically interacts with the key co-activator ß-catenin and inhibits ß-catenin-mediated transcriptional activation. More recently, we demonstrated that Cby protein localizes to the base of motile cilia and is required for ciliogenesis in the respiratory epithelium of mice. To gain further insight into the physiological function of Cby, we developed mouse monoclonal antibodies (MAbs) against human Cby protein and characterized two Cby MAbs, designated 8-2 and 27-11, in depth. Western blot analysis revealed that 8-2 reacts with both human and mouse Cby proteins, whereas 27-11 is specific to human Cby. The epitopes of 8-2 and 27-11 were narrowed down to the middle portion (aa 49-63) and N-terminal region (aa 1-31) of the protein, respectively. We also determined their isotypes and found that 8-2 and 27-11 belong to IgG2a and IgG1 with κ light chains, respectively. Both MAbs can be employed for immunoprecipitation assays. Moreover, 8-2 detects endogenous Cby protein on Western blots, and marks the ciliary base of motile cilia in the murine lung and trachea as shown by immunofluorescence staining. These Cby MAbs therefore hold promise as useful tools for the investigation of Wnt signaling and ciliogenesis.

Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells.

The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors. Importantly, mutant p53 hyperstabilization is critical for oncogenic gain of function of mutant p53 in vivo. Current insight into the mechanism of this dysregulation is fragmentary and largely derived from ectopically constructed cell systems. Importantly, mutant p53 knock-in mice established that normal mutant p53 tissues have sufficient enzymatic reserves in MDM2 and other E3 ligases to maintain full control of mutant p53. We find that in human cancer cells, endogenous mutant p53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wild-type p53, the many mutant p53 proteins which are conformationally aberrant are engaged in complexes with the HSP90 chaperone machinery to prevent its aggregation. In contrast to wild-type p53 cancer cells, we show that in mutant p53 cancer cells, this HSP90 interaction blocks the endogenous MDM2 and CHIP (carboxy-terminus of Hsp70-interacting protein) E3 ligase activity. Interference with HSP90 either by RNA interference against HSF1, the transcriptional regulator of the HSP90 pathway, or by direct knockdown of Hsp90 protein or by pharmacologic inhibition of Hsp90 activity with 17AAG (17-allylamino-17-demethoxygeldanamycin) destroys the complex, liberates mutant p53, and reactivates endogenous MDM2 and CHIP to degrade mutant p53. Of note, 17AAG induces a stronger viability loss in mutant p53 than in wild-type p53 cancer cells. Our data support the rationale that suppression of mutant p53 levels in vivo in established cancers might achieve clinically significant effects.

Nuclear-cytoplasmic shuttling of Chibby controls beta-catenin signaling.

In the canonical Wnt pathway, beta-catenin acts as a key coactivator that stimulates target gene expression through interaction with Tcf/Lef transcription factors. Its nuclear accumulation is the hallmark of active Wnt signaling and is frequently associated with cancers. Chibby (Cby) is an evolutionarily conserved molecule that represses beta-catenin-dependent gene activation. Although Cby, in conjunction with 14-3-3 chaperones, controls beta-catenin distribution, its molecular nature remains largely unclear. Here, we provide compelling evidence that Cby harbors bona fide nuclear localization signal (NLS) and nuclear export signal (NES) motifs, and constitutively shuttles between the nucleus and cytoplasm. Efficient nuclear export of Cby requires a cooperative action of the intrinsic NES, 14-3-3, and the CRM1 nuclear export receptor. Notably, 14-3-3 docking provokes Cby binding to CRM1 while inhibiting its interaction with the nuclear import receptor importin-alpha, thereby promoting cytoplasmic compartmentalization of Cby at steady state. Importantly, the NLS- and NES-dependent shuttling of Cby modulates the dynamic intracellular localization of beta-catenin. In support of our model, short hairpin RNA-mediated knockdown of endogenous Cby results in nuclear accumulation of beta-catenin. Taken together, these findings unravel the molecular basis through which a combinatorial action of Cby and 14-3-3 proteins controls the dynamic nuclear-cytoplasmic trafficking of beta-catenin.

Fine-tuning of nuclear-catenin by Chibby and 14-3-3.

Chibby (Cby) is an evolutionarily conserved antagonist of beta-catenin, a central player of the canonical Wnt signaling pathway, which acts as a transcriptional coactivator. Cby physically interacts with the C-terminal activation domain of beta-catenin and blocks its transcriptional activation potential through competition with DNA-binding Tcf/Lef transcription factors. Our recent study revealed a second mechanism for Cby-mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin, following phosphorylation of Cby by Akt kinase. Therefore, our findings unravel a novel molecular mechanism regulating the dynamic nucleo-cytoplasmic trafficking of beta-catenin and provide new insights into the cross-talk between the Wnt and Akt signaling pathways. Here, we review recent literature concerning Cby function and discuss our current understanding of the relationship between Wnt and Akt signaling.