Just how do we retrieve vivid recollections upon encountering a straightforward cue? Computational versions claim that this feat can be accomplished by design completion processes relating to the hippocampus. discovered that gamma power (50C90 Hz) increases C in conjunction with alpha power (8C12 Hz) decreases not only distinguish AR from IR, but also correlate with the level of hippocampal reinstatement. These results link single-shot hippocampal pattern completion to episodic recollection and reveal how oscillatory dynamics in the gamma and alpha bands orchestrate these mnemonic order AZD5363 processes. DOI: http://dx.doi.org/10.7554/eLife.17397.001 Trial-by-trial Pearson correlations of gamma and alpha timecourses were calculated for each participant for 0.5 to 2 s (spanning the time windows where gamma and alpha effects were observed for AR vs. IR, Figure order AZD5363 3), separately for AR and IR trials. The resulting correlation maps were then collapsed across AR and IR, Fisher z transformed and compared against 0 to reveal positive or negative correlations reliable across participants. Statistical map represents t values for the group-level t test against 0. Values above the diagonal reflect earlier alpha power correlating with later gamma power and values below the diagonal reflect earlier gamma power correlating with later alpha power. Black contour highlights a significant cluster (P 0.05, corrected) in which earlier gamma power from ~.8 to 1 1.5 s correlates negatively with later alpha power from ~1.3 to 1 1.5 s. em Right /em : Across-participant Pearson order AZD5363 correlation of 0.5 to 1 1.3 s gamma power with 1 to 2 2 s alpha power (i.e. the time-frequency clusters showing condition differences between AR vs. IR, Figure 3). Power values were derived separately for AR and IR trials and then collapsed prior to calculating the correlation. DOI: http://dx.doi.org/10.7554/eLife.17397.009 Figure 3figure supplement 3. Open in a separate window No condition differences in the baseline period.Gamma and alpha retrieval time courses (log transformed) are shown without baseline correcting the data, ensuring that condition differences are not driven by pre-stimulus baseline effects (see main text for statistics). DOI: http://dx.doi.org/10.7554/eLife.17397.010 Figure 3figure supplement 4. Open in a separate window Encoding data.(A) Time-frequency representation of the contrast subsequent associative recognition (AR) subsequent non-associative item recognition (IR). Note that the transition in resolution at 30 Hz reflects the switch from Hanning-taper for lower frequencies to multitaper for higher frequencies (Materials?and?methods). (B) Same as A, after statistical thresholding (P 0.05, corrected). Note the pronounced cluster centred on the alpha frequency band (8C12 Hz). order AZD5363 (C) em top /em : Encoding power time courses of AR and IR for 8C12 Hz. em bottom /em : For comparison, alpha power (8C12 Hz) timecourses of AR and IR at retrieval are plotted. When dividing the time axis into an early and a late interval (0 to 1 1 s vs. 1 to 2 2 s), there was a significant interaction of time window (early, late) x memory stage (encoding, retrieval) x condition (AR, IR) (F(1,10) = 10.27, P =?0.009). This interaction reflected the actual fact that there is Ctsk a significant boost of IR versus. AR in the first time home window at encoding (t(10) = 4.25, P =?0.002) however, not in retrieval (t(10) = 1.82, P =?0.099), whereas the enhance of IR vs AR in the past due time window was more pronounced at retrieval (t(10) = 8.47, P 0.001) than in encoding (t(10) = 2.30, P =?0.044). DOI: http://dx.doi.org/10.7554/eLife.17397.011 To make sure that these results are not powered by condition differences in the pre-stimulus baseline period, we omitted baseline correction and log transformed the raw power data instead (Cohen, 2014) (Body 3figure supplement 3). We after that compared AR versus. IR power both in the pre-stimulus baseline home window (?0.5 to 0?s) and in the post-stimulus home window where we observed the consequences above (0.5 to at least one 1.3?s for gamma and one to two 2?s for alpha). Initial, a significant home window x condition conversation for gamma power (F(1,10) = 22.15, P =?0.001) reflected order AZD5363 a substantial boost for AR vs. IR in the post-stimulus home window (t(10) = 2.65, P =?0.024) however, not in the pre-stimulus baseline home window (t(10) = 1.72, P 0.1). Also, a significant home window x condition conversation for alpha power (F(1,10) = 32.62, P 0.001) reflected a substantial boost for IR vs. AR in the post-stimulus home window (t(10) = 4.84, P =?0.001) however, not in the pre-stimulus baseline.
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Cancer invasion is a hallmark of metastasis. as well as invadopodia
Cancer invasion is a hallmark of metastasis. as well as invadopodia formation and matrix degradation were impaired upon Lamellipodin depletion. Mechanistically we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex which stimulates actin branching. In contrast Lamellipodin interaction with Scar/WAVE but not Ena/VASP is required for random 2D cell Panulisib migration. We identify a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP while Src-dependent phosphorylation enhances binding to Scar/WAVE but not Ena/VASP. Through these selective regulated interactions Lamellipodin mediates directional sensing of EGF gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis. we implanted fluorescently labeled MDA-MB-231 breast cancer cells into the perivitelline cavities of zebrafish embryos. In this assay the injected cancer cells intravasate and then infiltrate the trunk of the fish27 28 Overexpression of GFP-Lpd in MDA-MB-231 cells enhanced the frequency of seeding of these breast cancer cells compared to GFP expressing control cells (Figure 2J K). We then performed tail vein injections of the Lpd knockdown and control LM2 cell lines into immunocompromised mice and quantified lung metastases after 28 days to test whether Lpd influenced the later stages of the metastatic cascade. Lpd depletion did not reduce the number of metastatic foci in the lungs of the mice compared to controls (Supplemental Figure 2D E). Taken together our results reveal that Panulisib Lpd promotes local tumor invasion intravasation and metastasis but is not required for extravasation. Breast cancer cell migration towards blood vessels is guided by cues from the tumor microenvironment such as EGF29. We reasoned that the effect of Lpd depletion on EGF-induced 3D invasion might arise from defects in lamellipodial dynamics. Depletion of Lpd in MDA-MB-231 breast cancer cells decreased lamellipodia size (Supplemental Figure 3A) similar to B16-F1 Ctsk mouse melanoma cells in which Lpd-depletion also reduces protrusion speed under steady state conditions17. EGF-stimulated MDA-MB-231 Lpd knockdown cells displayed reduced protrusion persistence and distance without affecting protrusion speed (Supplemental Figure 3B). We chose MTLn3 cells a mammary adenocarcinoma cancer cell line in which protrusion responses to EGF have been extensively characterized to examine EGF-elicited protrusion in more detail since lamellipodial size is least affected by Lpd knockdown in this cell line (Supplemental Figure 3A). In agreement with our findings in MDA-MB-231 cells in EGF-stimulated MTLn3 cells reduced Lpd levels significantly decreased protrusion persistence Panulisib and distance (Figure 3A B) but did not affect protrusion speed (Supplemental Figure 3D) compared to controls. Lpd was diffusely distributed throughout the Panulisib cytoplasm of serum-starved cells but was rapidly recruited to the cell edge following bath Panulisib application of EGF (Figure 3C D). Lamellipodial initiation was detected 30 seconds after EGF stimulation in Ctrl-shRNA-expressing cells but was delayed significantly when Lpd levels were reduced (Figure 3B E F; Supplemental Figure 3E; Supplemental Videos 3 4 Taken together our data suggest that in breast cancer cells Lpd depletion reduces EGF-elicited lamellipodial protrusion formation and persistence but not speed. Figure 3 Lpd is required for EGF-induced membrane-protrusion Membrane extension during lamellipodial protrusion is driven by actin polymerization4-6. To determine how Lpd depletion influences actin polymerization we used a G-actin incorporation assay30 to measure the abundance and distribution of polymerization-competent free (uncapped) F-actin barbed-ends in lamellipodia of living cells. Silencing Lpd significantly reduced free barbed-end formation 1 minute after EGF stimulation relative to Ctrl-shRNA-expressing cells (Figure 4A B). Collectively these data indicate that Lpd promotes lamellipodial protrusion by increasing actin polymerization downstream of EGFR activation. Figure 4 Lpd is required for chemosensing EGF-dependent membrane protrusion in MTLn3.