Cassini ISS mutual event astrometry of the mid-sized Saturnian satellites 2005-2012

Reproduced with permission from Astronomy & Astrophysics, © ES

Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection

Abstract: Bcl-2 family proteins including the pro-apoptotic BH3-only proteins are central regulators of apoptotic cell death. Here we show by a focused siRNA miniscreen that the synergistic action of the BH3-only proteins Bim and Bmf is required for apoptosis induced by infection with Neisseria gonorrhoeae (Ngo). While Bim and Bmf were associated with the cytoskeleton of healthy cells, they both were released upon Ngo infection. Loss of Bim and Bmf from the cytoskeleton fraction required the activation of Jun-N-terminal kinase-1 (JNK-1), which in turn depended on Rac-1. Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases. Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-XL, respectively. Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells. Author Summary: A variety of physiological death signals, as well as pathological insults, trigger apoptosis, a genetically programmed form of cell death. Pathogens often induce host cell apoptosis to establish a successful infection. Neisseria gonorrhoeae (Ngo), the etiological agent of the sexually transmitted disease gonorrhoea, is a highly adapted obligate human-specific pathogen and has been shown to induce apoptosis in infected cells. Here we unveil the molecular mechanisms leading to apoptosis of infected cells. We show that Ngo-mediated apoptosis requires a special subset of proapoptotic proteins from the group of BH3-only proteins. BH3-only proteins act as stress sensors to translate toxic environmental signals to the initiation of apoptosis. In a siRNA-based miniscreen, we found Bim and Bmf, BH3-only proteins associated with the cytoskeleton, necessary to induce host cell apoptosis upon infection. Bim and Bmf inactivated different inhibitors of apoptosis and thereby induced cell death in response to infection. Our data unveil a novel pathway of infection-induced apoptosis that enhances our understanding of the mechanism by which BH3-only proteins control apoptotic cell death

Activation of TRPC1 Channel by Metabotropic Glutamate Receptor mGluR5 Modulates Synaptic Plasticity and Spatial Working Memory

Group I metabotropic glutamate receptors, in particular mGluR5, have been implicated in various forms of synaptic plasticity that are believed to underlie declarative memory. We observed that mGluR5 specifically activated a channel containing TRPC1, an isoform of the canonical family of transient receptor potential (TRPC) channels highly expressed in CA1-3 regions of the hippocampus. TRPC1 is able to form tetrameric complexes with TRPC4 and/or TRPC5 isoforms. TRPC1/4/5 complexes have recently been involved in the efficiency of synaptic transmission in the hippocampus. We therefore used a mouse model devoid of TRPC1 expression to investigate the involvement of mGluR5-TRPC1 pathway in synaptic plasticity and memory formation. Trpc1-/- mice showed alterations in spatial working memory and fear conditioning. Activation of mGluR increased synaptic excitability in neurons from WT but not from Trpc1-/- mice. LTP triggered by a theta burst could not maintain over time in brain slices from Trpc1-/- mice. mGluR-induced LTD was also impaired in these mice. Finally, acute inhibition of TRPC1 by Pico145 on isolated neurons or on brain slices mimicked the genetic depletion of Trpc1 and inhibited mGluR-induced entry of cations and subsequent effects on synaptic plasticity, excluding developmental or compensatory mechanisms in Trpc1-/- mice. In summary, our results indicate that TRPC1 plays a role in synaptic plasticity and spatial working memory processes

New constraints on Saturn's interior from Cassini astrometric data

This work has been supported by the European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement 263466 for the FP7-ESPaCE project, the International Space Science Institute (ISSI), PNP (INSU/CNES) and AS GRAM (INSU/CNES/INP). The work of R. A. J. was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with NASA. N.C. and C.M. were supported by the UK Science and Technology Facilities Council (Grant No. ST/M001202/1) and are grateful to them for financial assistance. C.M. is also grateful to the Leverhulme Trust for the award of a Research Fellowship. N.C. thanks the Scientific Council of the Paris Observatory for funding. S. Mathis acknowledge funding by the European Research Council through ERC grant SPIRE 647383

Vascular endothelial growth factor signaling requires glycine to promote angiogenesis

Peripheral vascular occlusive disease (PVOD) is a common manifestation of atherosclerosis, and it has a high rate of morbidity. Therapeutic angiogenesis would re-establish blood perfusion and rescue ischemic tissue. Vascular endothelial growth factor (VEGF) induces angiogenesis and can potentially be used to treat ischemic diseases, yet in clinical trials VEGF has not fulfilled its full potential with side effects. Whether amino acids promote angiogenesis and the molecular mechanisms are largely unknown. Here we showed that (1) Glycine significantly promoted angiogenesis both in vitro and in vivo and effectively protected mitochondrial function. (2) Activation of glycine transporter 1(GlyT1) induced by VEGF led to an increase in intracellular glycine. (3) Glycine directly bounded to voltage dependent anion channel 1 (VDAC1) on the mitochondrial outer membrane and inhibited its opening. These original results highlight glycine as a necessary mediator in VEGF signalling via the GlyT1-glycine-mTOR-VDAC1 axis pathway. Therefore, the findings in this study are of significance providing new mechanistic insights into angiogenesis and providing better understanding of glycine function in angiogenesis, which may provide valuable information for development of novel therapeutic targets for the treatment of angiogenic vascular disorders

Involvement of VDAC, Bax and Ceramides in the Efflux of AIF from Mitochondria during Curcumin-Induced Apoptosis

Contains fulltext : 80085.pdf (publisher's version ) (Open Access)BACKGROUND: We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process. PRINCIPAL FINDINGS: Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3beta (GSK-3beta) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion. CONCLUSIONS: Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial formation of ROS and the subsequent nuclear translocation of AIF, which is released from a mitochondrial pore that involves VDAC, Bax and possibly ceramides. The composition of the AIF-releasing channel seems to be much more complex than previously thought

DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma

BackgroundGlioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors.MethodsWe analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient’s survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach.ResultsWe found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient’s survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region.ConclusionWe propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma