Memo is a cofilin-interacting protein that influences PLC{gamma}1 and cofilin activities, and is essential for maintaining directionality during ErbB2-induced tumor-cell migration.

Heregulin (HRG) activates ErbB2-ErbB3 heterodimers thereby stimulating many cellular responses, including motility. Memo and PLCgamma1 interact with ErbB2 autophosphorylation sites and are essential for HRG-induced chemotaxis. By tracing HRG-stimulated cell migration in Dunn chambers, we found that Memo- or PLCgamma1 knockdown (KD) strongly impairs cell directionality. Memo has no obvious enzymatic activity and was discovered via its ability to complex with ErbB2. Using the yeast two-hybrid approach to gain insight into Memo function, an interaction between Memo and cofilin, a regulator of actin dynamics, was uncovered. The interaction was confirmed in vitro using recombinant proteins and in vivo in co-immunoprecipitation experiments where Memo was detected in complexes with cofilin, ErbB2 and PLCgamma1. Interestingly, in Memo KD cells, HRG-induced PLCgamma1 phosphorylation was decreased, suggesting that Memo regulates PLCgamma1 activation. Furthermore, HRG-induced recruitment of GFP-cofilin to lamellipodia is impaired in Memo and in PLCgamma1 KD cells, suggesting that both proteins lie upstream of cofilin in models of ErbB2-driven tumor-cell migration. Finally, in vitro F-actin binding and depolymerization assays showed that Memo enhances cofilin depolymerizing and severing activity. In summary, these data indicate that Memo also regulates actin dynamics by interacting with cofilin and enhancing its function

Tumor necrosis factor receptor associated factor 4 (TRAF4) expression pattern during mouse development

International audienceThis is the first in situ hybridization analysis of expression of a tumor necrosis factor (TNF) receptor associated factor (TRAF) during development. TRAF4 is observed throughout mouse embryogenesis, most notably during ontogenesis of the central (CNS) and peripheral (PNS) nervous system, and of nervous tissues of sensory organs. TRAF4 is preferentially expressed by post-mitotic undifferentiated neurons. Interestingly, TRAF4 remains expressed in the adult hippocampus and olfactory bulb, known to contain multipotential cells responsible for neoneurogenesis

J Psychiatr Res

Up to 20% of patients presenting at an emergency room (ER) after a stressful event will for several months suffer from very diverse long-lasting symptoms and a potentially significant decline in quality of life, often described as post concussion-like symptoms (PCLS). The objectives of our randomized open-label single-center study were to assess the feasibility of psychologist-led interventions in the context of the ER and to compare the effect of eye movement desensitization and reprocessing (EMDR) with reassurance and usual care. Conducted in the ER of Bordeaux University Hospital, the study included patients with a high risk of PCLS randomized in three groups: a 15-min reassurance session, a 60-min session of EMDR, and usual care. Main outcomes were the proportion of interventions that could be carried out and the prevalence of PCSL and post-traumatic stress disorder (PTSD) three months after the ER visit. One hundred and thirty patients with a high risk of PCLS were randomized. No logistic problem or patient refusal was observed. In the EMDR, reassurance and control groups, proportions of patients with PCLS at three months were 18%, 37% and 65% and those with PTSD were 3%, 16% and 19% respectively. The risk ratio for PCLS adjusted for the type of event (injury, non-injury) for the comparison between EMDR and control was 0.36 [95% CI 0.20-0.66]. This is the first randomized controlled trial that shows that a short EMDR intervention is feasible and potentially effective in the context of the ER. The study was registered at ClinicalTrials.gov (NCT03194386)

Int Emerg Nurs

Introduction Recent research suggests that up to 20% of minor trauma patients admitted to the emergency department (ED) will suffer from non-specific chronic conditions over the subsequent several months. Thus, the present study assessed the correlates of symptoms that persisted at 4 months after an ED visit and, in particular, evaluated the associations between these symptoms and self-reported stress levels at ED admission and discharge. Method This study was a prospective observational investigation conducted in the ED of Bordeaux University Hospital that included patients admitted for minor trauma. All participants were contacted by phone 4 months after presentation at the ED to assess the occurrence of post-concussion-like symptoms (PCLS). Results A total of 193 patients completed the follow-up assessment at 4 months; 5.2% of the participants suffered from post-traumatic stress disorder (PTSD) and 24.5% suffered from PCLS. A multivariate analysis revealed an association between PCLS and stress level at discharge from the ED (odds ratios [OR]: 2.85, 95% confidence interval [CI]: 1.10–7.40). Conclusions The risk of PCLS at 4 months after an ED visit for a minor injury increased in association with the level of stress at discharge from the ED. These results may improve the quality of life for the millions of patients who experience a stressful injury event every year

Memo has a novel role in S1P signaling and crucial for vascular development

Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation

Atrophic Gastritis and Autoimmunity: Results from a Prospective, Multicenter Study

Despite a global decrease, gastric cancer (GC) incidence appears to be increasing recently in young, particularly female, patients. The causal mechanism for this “new” type of GC is unknown, but a role for autoimmunity is suggested. A cascade of gastric precancerous lesions, beginning with chronic atrophic gastritis (CAG), precedes GC. To test the possible existence of autoimmunity in patients with CAG, we aimed to analyze the prevalence of several autoantibodies in patients with CAG as compared to control patients. Sera of 355 patients included in our previous prospective, multicenter study were tested for 19 autoantibodies (anti-nuclear antibodies, ANA, anti-parietal cell antibody, APCA, anti-intrinsic factor antibody, AIFA, and 16 myositis-associated antibodies). The results were compared between CAG patients (n = 154), including autoimmune gastritis patients (AIG, n = 45), non-autoimmune gastritis patients (NAIG, n = 109), and control patients (n = 201). ANA positivity was significantly higher in AIG than in NAIG or control patients (46.7%, 29%, and 27%, respectively, p = 0.04). Female gender was positively associated with ANA positivity (OR 0.51 (0.31–0.81), p = 0.005), while age and H. pylori infection status were not. Myositis-associated antibodies were found in 8.9% of AIG, 5.5% of NAIG, and 4.4% of control patients, without significant differences among the groups (p = 0.8). Higher APCA and AIFA positivity was confirmed in AIG, and was not associated with H. pylori infection, age, or gender in the multivariate analysis. ANA antibodies are significantly more prevalent in AIG than in control patients, but the clinical significance of this finding remains to be established. H. pylori infection does not affect autoantibody seropositivity (ANA, APCA, AIFA). The positivity of myositis-associated antibodies is not increased in patients with CAG as compared to control patients. Overall, our results do not support an overrepresentation of common autoantibodies in patients with CAG

Iron and Vitamin B12 Deficiency in Patients with Autoimmune Gastritis and <i>Helicobacter pylori</i> Gastritis: Results from a Prospective Multicenter Study

International audienceIntroduction : Iron and vitamin B12 deficiencies are common in patients with atrophic gastritis, but there are limited data on the prevalence of these deficiencies in different types of atrophic gastritis.Methods : This multicenter, prospective study assessed micronutrient concentrations in histologically confirmed autoimmune gastritis (AIG, n= 45),Helicobacter pylori related non-autoimmune gastritis (NAIG, n= 109), and control patients (n= 201). A multivariate analysis was performed to determine factors influencing those deficiencies. Results : The median vitamin B12 concentration was significantly lower in AIG (367.5 pg/mL, Q1, Q3: 235.5, 524.5) than in NAIG (445.0 pg/mL, Q1, Q3: 355.0, 565.0, p= 0.001) and control patients (391.0 pg/mL, Q1, Q3: 323.5, 488.7, p= 0.001). Vitamin B12 deficiency was found in 13.3%, 1.5%, and 2.8% of AIG, NAIG, and control patients, respectively. Similarly, the median ferritin concentration was significantly lower in AIG (39.5 ng/mL, Q1, Q3: 15.4, 98.3 ng/mL) than in NAIG (80.5 ng/mL, Q1, Q3: 43.6, 133.9, p = 0.04) and control patients (66.5 ng/mL, Q1, Q3: 33.4, 119.8, p = 0.007). Iron deficiency and iron deficiency adjusted to CRP were present in 28.9% and 33.3% of AIG, 12.8% and 16.5% of NAIG, and 12.9% and 18.4% of controls, respectively. Multivariate analysis demonstrated that AIG patients had a higher risk of developing vitamin B12 deficiency (OR: 11.52 [2.85–57.64, p = 0.001]) and iron deficiency (OR: 2.92 [1.32–6.30, p= 0.007]) compared to control patients. Factors like age, sex, and H. pylori status did not affect the occurrence of vitamin B12 or iron deficiency. Conclusion:Iron and vitamin B12 deficiencies are more commonly observed in patients with AIG than in those with NAIG or control patients. Therefore, it is essential to screen for both iron and vitamin B12 deficiencies in AIG patients and include the treatment of micronutrient deficiencies in the management of atrophic gastritis patients

Histological analyses of the vasculature in control and Memo KO embryos.

<p><b>A</b>, Whole-mount immunostaining with anti-CD31 (PECAM-1) antibody on control and Memo KO yolk sacs at E13.5. Scale bar, 500 μm. Representatives images of two different regions are shown. <b>B</b>, Immunostaining with anti-smooth muscle actin (SMA) antibody on dorsal aorta of control and Memo KO embryos at E14.5. Note that the dorsal aorta of the Memo KO embryo was covered by a layer of smooth muscle cells of the same width as control (indicated with the markers of the same scale). Scale bar, 50 μm. <b>C</b>, Electron microscopy micrographs (EM) of tight junctions (indicated as arrowheads) formed in limb bud capillary vessels in control and Memo KO embryos at E12.5 (upper panel) and E13.5 (lower panel). Scale bar, 1 μm. Only Memo KO embryos with obvious abnormalities (pale yolk sac and bleeding) were used for the analyses. In all images, Memo KO is presented with the littermate control.</p

Memo has an important role in cell-autonomous S1PR signaling.

<p>S1PR1 can be activated by extracellular (red arrow) and intracellular (blue arrow) S1P. Our <i>in vitro</i> data demonstrate that Memo has an important role in the cell-autonomous pathway activating S1PR1 by intracellular S1P. In MEFs, absence of Memo results in a defect in cell-autonomous activation of S1PR1 during cell migration induced by PDGF. In HUVECs, knockdown of Memo results in defects in survival and junction stabilization, both of which were rescued by addition of exogenous S1P.</p

Memo KO MEFs have defects in cell-autonomous S1PR signaling induced by PDGF.

<p><b>A</b>, MEFs with the indicated treatments were starved overnight and stimulated with PDGF (20 ng/ml) for 5 min. Western analyses were performed with the indicated antibodies. <b>B</b>, Transwell cell migration of control and Memo KO MEFs was induced by PDGF (5 ng/ml) in serum-free media with or without the SphK1-specific inhibitor, VPC96091 (1 μM) or the S1PR1/S1PR3-specific antagonist, VPC23019 (1 μM). <b>C</b>, Transwell cell migration of control and Memo KO MEFs was induced by S1P (5 nM) in serum-free media. In B and C, data were normalized to the average value for basal migration in serum-free media and are presented as means ± S.D. of three individual wells. Similar results were obtained in three independent experiments. <b>D</b>, Time course of ERK activation after S1P treatment of control and Memo KO MEFs. Control and Memo KO MEFs were starved overnight and stimulated with 1 μM S1P for the indicated time. Western analyses were performed with the indicated antibodies. <b>E</b>, S1P levels in control and Memo KO MEFs (upper panel) and their culture media (lower panel) after PDGF-stimulation. Starved cultures were treated with PDGF (50 ng/ml) and at the indicated time points, culture media and cells were harvested and analyzed for S1P levels by LC-ECI-MS/MS. Data are presented as means ± S.D. of three individual plates. In E, <i>p</i> values were calculated with respect to levels at the 0 time point. *, <i>p</i><0.05; **, <i>p</i><0.01; ***, <i>p</i><0.001</p