Abp1p and cortactin, new “hand-holds” for actin

Recently, two new ligands of the Arp2/3 complex have been described that may shed light on the way cells organize complex networks of actin in response to signals. Abp1p, a yeast protein involved in endocytosis, and cortactin, a mammalian src substrate, both enhance the ability of the Arp2/3 complex to assemble branched actin filament networks

Aging dependent effect of nuclear tau

Tau protein is characterized by a complex pattern of phosphorylation and is localized in the cytoplasm and nucleus in both neuronal and non-neuronal cells. Human AT100 nuclear tau, endowed by phosphorylation in Thr212/Ser214, was recently shown to decline in cornus ammonis 1 (CA1) and dentate gyrus (DG) in Alzheimer's disease (AD), but a defined function for this nuclear tau remains unclear. Here we show that AT100 progressively increases in the nuclei of neuronal and non-neuronal cells during aging, and decreases in the more severe AD stages, as recently shown, and in cancer cells (colorectal adenocarcinoma and breast cancer). AT100, in addition to a co-localization with the DAPIpositive heterochromatin, was detected in the nucleolus of pyramidal cells from the CA1 region, shown to be at its highest level in the more senescent cells and in the first stage of AD (ADI), and disappearing in the more severe AD cases (ADIV). Taking into account the nuclear distribution of AT100 during cell aging and its relation to the chromatin changes observed in degenerated neurons, as well as in cancerous cells, which are both cellular pathologies associated with age, we can consider the Thr212/Ser214 phosphorylated nuclear tau as a molecular marker of cell aging

Signalling to the actin cytoskeleton via the WASP-family proteins and the Arp2/3 complex

No abstract available

Rho-kinase and myosin-II control phagocytic cup formation during CR, but not FcγR, phagocytosis

Phagocytosis through Fcγ receptor (FcγR) or complement receptor 3 (CR) requires Arp2/3 complex-mediated actin polymerization, although each receptor uses a distinct signaling pathway [1]. Rac and Cdc42 are required for actin and Arp2/3 complex recruitment during FcγR phagocytosis, while Rho controls actin assembly at CR phagosomes 2, 3. To better understand the role of Rho in CR phagocytosis, we tested the idea that a known target of Rho, Rho-kinase (ROK), might control phagocytic cup formation and/or engulfment of particles. Inhibitors of ROK (dominant-negative ROK and Y-27632) and of the downstream target of ROK, myosin-II (ML7, BDM, and dominant-negative myosin-II), were used to test this idea. We found that inhibition of the Rho → ROK → myosin-II pathway caused a decreased accumulation of Arp2/3 complex and F-actin around bound particles, which led to a reduction in CR-mediated phagocytic engulfment. FcγR-mediated phagocytosis, in contrast, was independent of Rho or ROK activity and was only dependent on myosin-II for particle internalization, not for actin cup formation. While myosins have been previously implicated in FcγR phagocytosis 4, 5, 6, to our knowledge, this is the first demonstration of a role for myosin-II in CR phagocytosis

Economic Impact of the Implementation of an Enhanced Recovery after Surgery (ERAS) Protocol in a Bariatric Patient Undergoing a Roux-En-Y Gastric Bypass

Introduction: Enhanced Recovery After Surgery (ERAS) protocols have proven to be cost-effective in various surgical procedures, mainly in colorectal surgeries. However, there is still little scientific evidence evaluating the economic impact of their application in bariatric surgery. The present study aimed to compare the economic cost of performing a laparoscopic Roux-en-Y gastric bypass following an ERAS protocol, with the costs of following a standard-of-care protocol. Patients and methods: A prospective non-randomized study of patients undergoing Roux-en-Y gastric bypass was performed. Patients were divided into two groups: patients following an ERAS protocol and patients following a standard-of-care protocol. The total costs of the procedure were subdivided into pharmacological expenditures, surgical material, and time expenses, the price of complementary tests performed during the hospital stay, and costs related to the hospital stay. Results: The 84 patients included 58 women (69%) and 26 men (31%) with a mean age of 44.3 ± 11.6 years. There were no significant differences in age, gender, and distribution of comorbidities between groups. Postoperative pain, nausea or vomiting, and hospital stay were significantly lower within the ERAS group. The pharmacological expenditures, the price of complementary tests performed during the hospital stay, and the costs related to the hospital stay, were significantly lower in the ERAS group. There were no significant differences in the surgical material and surgical time costs between groups. Globally, the total cost of the procedure was significantly lower in the ERAS group with a mean saving of 1458.62$ per patient. The implementation of an ERAS protocol implied a mean saving of 21.25% of the total cost of the procedure. Conclusions: The implementation of an ERAS protocol significantly reduces the perioperative cost of Roux-en-Y gastric bypass

RIAM (Rap1-interacting adaptor molecule) regulates complement-dependent phagocytosis

Phagocytosis mediated by the complement receptor CR3 (also known as integrin αMß2 or Mac-1) is regulated by the recruitment of talin to the cytoplasmic tail of the ß2 integrin subunit. Talin recruitment to this integrin is dependent on Rap1 activation. However, the mechanism by which Rap1 regulates this event and CR3-dependent phagocytosis remains largely unknown. In the present work, we examined the role of the Rap1 effector RIAM, a talin-binding protein, in the regulation of complement-mediated phagocytosis. Using the human myeloid cell lines HL-60 and THP-1, we determined that knockdown of RIAM impaired αMß 2 integrin affinity changes induced by stimuli fMLP and LPS. Phagocytosis of complement-opsonized RBC particles, but not of IgG-opsonized RBC particles, was impaired in RIAM knockdown cells. Rap1 activation via EPAC induced by 8-pCPT-2′-O-Me-cAMP resulted in an increase of complement-mediated phagocytosis that was abrogated by knockdown of RIAM in HL-60 and THP-1 cell lines and in macrophages derived from primary monocytes. Furthermore, recruitment of talin to ß2 integrin during complement-mediated phagocytosis was reduced in RIAM knockdown cells. These results indicate that RIAM is a critical component of the phagocytosis machinery downstream of Rap1 and mediates its function by recruiting talin to the phagocytic complement receptors. © 2013 Springer Basel.SAF2007-60578 and SAF2012-34561 from MICINN; CCG10-UCM/BIO-4795 and CCG08-UCM/SAL-4259 from Comunidad Autonoma de Madrid; BFU2007-66443/BMC and BFU2010-19144/BMC and SAF2012-34561 from MICINN; grant SAF2009-08103 from MICINN (to P.A.R.), NIH grants HL107997-01 and R56AI43552 and the Leukemia and Lymphoma Society Translational Research Program TRP 6222-11 (to V.A.B.).Peer Reviewe

Pathological Nuclear Hallmarks in Dentate Granule Cells of Alzheimer’s Patients: A Biphasic Regulation of Neurogenesis

The dentate gyrus (DG) of the human hippocampus is a complex and dynamic structure harboring mature and immature granular neurons in diverse proliferative states. While most mammals show persistent neurogenesis through adulthood, human neurogenesis is still under debate. We found nuclear alterations in granular cells in autopsied human brains, detected by immunohistochemistry. These alterations differ from those reported in pyramidal neurons of the hippocampal circuit. Aging and early AD chromatin were clearly differentiated by the increased epigenetic markers H3K9me3 (heterochromatin suppressive mark) and H3K4me3 (transcriptional euchromatin mark). At early AD stages, lamin B2 was redistributed to the nucleoplasm, indicating cell-cycle reactivation, probably induced by hippocampal nuclear pathology. At intermediate and late AD stages, higher lamin B2 immunopositivity in the perinucleus suggests fewer immature neurons, less neurogenesis, and fewer adaptation resources to environmental factors. In addition, senile samples showed increased nuclear Tau interacting with aged chromatin, likely favoring DNA repair and maintaining genomic stability. However, at late AD stages, the progressive disappearance of phosphorylated Tau forms in the nucleus, increased chromatin disorganization, and increased nuclear autophagy support a model of biphasic neurogenesis in AD. Therefore, designing therapies to alleviate the neuronal nuclear pathology might be the only pathway to a true rejuvenation of brain circuits

Aging dependent effect of nuclear tau

Tau protein is characterized by a complex pattern of phosphorylation and is localized in the cytoplasm and nucleus in both neuronal and non-neuronal cells. Human AT100 nuclear tau, endowed by phosphorylation in Thr212/Ser214, was recently shown to decline in cornus ammonis 1 (CA1) and dentate gyrus (DG) in Alzheimer's disease (AD), but a defined function for this nuclear tau remains unclear. Here we show that AT100 progressively increases in the nuclei of neuronal and non-neuronal cells during aging, and decreases in the more severe AD stages, as recently shown, and in cancer cells (colorectal adenocarcinoma and breast cancer). AT100, in addition to a co-localization with the DAPIpositive heterochromatin, was detected in the nucleolus of pyramidal cells from the CA1 region, shown to be at its highest level in the more senescent cells and in the first stage of AD (ADI), and disappearing in the more severe AD cases (ADIV). Taking into account the nuclear distribution of AT100 during cell aging and its relation to the chromatin changes observed in degenerated neurons, as well as in cancerous cells, which are both cellular pathologies associated with age, we can consider the Thr212/Ser214 phosphorylated nuclear tau as a molecular marker of cell aging