Mon1-Ccz1 activates Rab7 only on late endosomes and dissociates from the lysosome in mammalian cells

Rab GTPases act as molecular switches regulating various aspects of membrane trafficking. Among them, Rab5 and Rab7 play central roles in the endolysosomal network. Although many effectors downstream of Rab7 have been elucidated, our present understanding of the mechanism regulating Rab7 activity is extremely limited. It has only recently been accepted that the Mon1-Ccz1 complex is a Rab7 guanine nucleotide exchange factor, but it still remains unclear what the location where Mon1-Ccz1 works with Rab7 is. To address what kind of change or switch exists in the regulatory mechanism upstream of Rab7 during its transition from the late endosome to lysosome, we examined Rab7 activity in steady-state cells and during EGF-induced macropinocytosis using a newly developed FRET sensor. A combination of a Rab7 sensor and confocal FRET imaging techniques revealed that the activation of Rab7 on late endosomes depends on Mon1-Ccz1 and is implicated in late-endosome-lysosome fusion. In contrast, Rab7 activity on lysosomes was independent of Mon1-Ccz1 and active Rab7 played a role in perinuclear clustering of lysosomes

Using transcranial Direct Current Stimulation (tDCS) to investigate why faces are and are not special

This is the final version. Available on open access from Nature Research via the DOI in this recordWe believe we are now in a position to answer the question, "Are faces special?" inasmuch as this applies to the face inversion effect (better performance for upright vs inverted faces). Using a double-blind, between-subject design, in two experiments (n=96) we applied a specific tDCS procedure targeting the Fp3 area while participants performed a matching-task with faces (Experiment 1a) or checkerboards from a familiar prototypedefined category (Experiment 1b). Anodal tDCS eliminated the checkerboard inversion effect reliably obtained in the sham group, but only reduced it for faces (although the reduction was significant). Thus, there is a component to the face inversion effect that we are not affecting with a tDCS procedure that can eliminate the checkerboard inversion effect. We suggest that the reduction reflects the loss of an expertise-based component in the face inversion effect, and the residual is due to a face-specific component of that effect.Economic and Social Research Council (ESRC)Experimental Psychology SocietyEuropean Union Horizon 2020Marie Curie Alumni Association (MCAA

Testing the effects of transcranial Direct Current Stimulation (tDCS) on the Face Inversion Effect and the N170 Event-Related Potentials (ERPs) component

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordThe following study investigates the effects of tDCS on face recognition skills indexed by the face inversion effect (better recognition performance for upright vs. inverted faces). We combined tDCS and EEG simultaneously to examine the effects of tDCS on the face inversion effect behaviourally and on the N170 ERPs component. The results from two experiments (overall N=112) show that anodal tDCS delivered at Fp3 site for 10 min at 1.5mA (double-blind and between-subjects) can reduce behaviourally the face inversion effect compared to sham (control) stimulation. The ERP results provide some evidence for tDCS being able to influence the face inversion effect on the N170. Specifically, we find a dissociation of the tDCS-induced effects where for the N170 latencies the tDCS reduces the usual face inversion effect (delayed N170 in response to inverted vs. upright faces) compared to sham. Contrarily, the same tDCS procedure on the same participants increased the inversion effect seen in the N170 amplitudes by making the negative deflection for the inverted faces that much greater than that for upright faces. We interpret our results in the context of the literature on the face inversion effect and the N170 peak component. In doing so, we extend our results to previous studies investigating the effects of tDCS on perceptual learning and face recognition.Economic and Social Research Council (ESRC

Septin6 and Septin7 GTP binding proteins regulate AP-3- and ESCRT-dependent multivesicular body biogenesis

Septins (SEPTs) form a family of GTP-binding proteins implicated in cytoskeleton and membrane organization, cell division and host/pathogen interactions. The precise function of many family members remains elusive. We show that SEPT6 and SEPT7 complexes bound to F-actin regulate protein sorting during multivesicular body (MVB) biogenesis. These complexes bind AP-3, an adapter complex sorting cargos destined to remain in outer membranes of maturing endosomes, modulate AP-3 membrane interactions and the motility of AP-3-positive endosomes. These SEPT-AP interactions also influence the membrane interaction of ESCRT (endosomal-sorting complex required for transport)-I, which selects ubiquitinated cargos for degradation inside MVBs. Whereas our findings demonstrate that SEPT6 and SEPT7 function in the spatial, temporal organization of AP-3- and ESCRT-coated membrane domains, they uncover an unsuspected coordination of these sorting machineries during MVB biogenesis. This requires the E3 ubiquitin ligase LRSAM1, an AP-3 interactor regulating ESCRT-I sorting activity and whose mutations are linked with Charcot-Marie-Tooth neuropathies

AP-1 and KIF13A coordinate endosomal sorting and positioning during melanosome biogenesis

The clathrin adaptor protein AP-1 and the motor KIF13A work together to deliver cargo into maturing melanosomes

The discovery of Hepatocyte Growth Factor (HGF) and its significance for cell biology, life sciences and clinical medicine

It has been more than 25 years since HGF was discovered as a mitogen of hepatocytes. HGF is produced by stromal cells, and stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its receptor, c-Met. In fetal stages, HGF-neutralization, or c-Met gene destruction, leads to hypoplasia of many organs, indicating that HGF signals are essential for organ development. Endogenous HGF is required for self-repair of injured livers, kidneys, lungs and so on. In addition, HGF exerts protective effects on epithelial and non-epithelial organs (including the heart and brain) via anti-apoptotic and anti-inflammatory signals. During organ diseases, plasma HGF levels significantly increased, while anti-HGF antibody infusion accelerated tissue destruction in rodents. Thus, endogenous HGF is required for minimization of diseases, while insufficient production of HGF leads to organ failure. This is the reason why HGF supplementation produces therapeutic outcomes under pathological conditions. Moreover, emerging studies delineated key roles of HGF during tumor metastasis, while HGF-antagonism leads to anti-tumor outcomes. Taken together, HGF-based molecules, including HGF-variants, HGF-fragments and c-Met-binders are available as regenerative or anti-tumor drugs. Molecular analysis of the HGF-c-Met system could provide bridges between basic biology and clinical medicine

A novel biomarker TERTmRNA is applicable for early detection of hepatoma

<p>Abstract</p> <p>Backgrounds</p> <p>We previously reported a highly sensitive method for serum human telomerase reverse transcriptase (hTERT) mRNA for hepatocellular carcinoma (HCC). α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) are good markers for HCC. In this study, we verified the significance of hTERTmRNA in a large scale multi-centered trial, collating quantified values with clinical course.</p> <p>Methods</p> <p>In 638 subjects including 303 patients with HCC, 89 with chronic hepatitis (CH), 45 with liver cirrhosis (LC) and 201 healthy individuals, we quantified serum hTERTmRNA using the real-time RT-PCR. We examined its sensitivity and specificity in HCC diagnosis, clinical significance, ROC curve analysis in comparison with other tumor markers, and its correlations with the clinical parameters using Pearson relative test and multivariate analyses. Furthermore, we performed a prospective and comparative study to observe the change of biomarkers, including hTERTmRNA in HCC patients receiving anti-cancer therapies.</p> <p>Results</p> <p>hTERTmRNA was demonstrated to be independently correlated with clinical parameters; tumor size and tumor differentiation (P < 0.001, each). The sensitivity/specificity of hTERTmRNA in HCC diagnosis showed 90.2%/85.4% for hTERT. hTERTmRNA proved to be superior to AFP, AFP-L3, and DCP in the diagnosis and underwent an indisputable change in response to therapy. The detection rate of small HCC by hTERTmRNA was superior to the other markers.</p> <p>Conclusions</p> <p>hTERTmRNA is superior to conventional tumor markers in the diagnosis and recurrence of HCC at an early stage.</p