Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway

The forebrain cholinergic system promotes higher brain function in part by signaling through the M1 muscarinic acetylcholine receptor (mAChR). Long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmis-sion in the hippocampus are also induced by mAChR. An AMPA receptor (AMPAR) trafficking model for hippocampal neurons has been proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the early phase. In this study, we demonstrated the validity of the hypothesis that the mAChR-dependent LTP/LTD shares a common AMPAR trafficking pathway associated with NMDAR-dependent LTP/LTD. However, unlike NMDAR, Ca2+ influx into the spine cytosol occurs owing to the Ca2+ stored inside the ER and is induced via the activation of inositol 1,4,5-trisphosphate (IP3) receptors during M1 mAChR activation. Moreover, the AMPAR trafficking model implies that alterations in LTP and LTD observed in Alzheimer's disease could be attributed to age-dependent reductions in AMPAR expression levels

Immune response to SARS-CoV-2 in severe disease and long COVID-19

COVID-19 is mild to moderate in otherwise healthy individuals but may nonetheless cause life-threatening disease and/or a wide range of persistent symptoms. The general determinant of disease severity is age mainly because the immune response declines in aging patients. Here, we developed a mathematical model of the immune response to SARS-CoV-2 and revealed that typical age-related risk factors such as only a several 10% decrease in innate immune cell activity and inhibition of type-I interferon signaling by autoantibodies drastil ally increased the viral load. It was reported that the numbers of certain dendritic cell subsets remained less than half those in healthy donors even seven months after infection. Hence, the inflammatory response was ongoing. Our model predicted the persistent DC reduction and showed that certain patients with severe and even mild symptoms could not effectively eliminate the virus and could potentially develop long COVID

Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors

N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) of signal transmission form neural circuits and thus are thought to underlie learning and memory. These mechanisms are mediated by AMPA receptor (AMPAR) trafficking in postsynaptic neurons. However, the regulatory mechanism of bidirectional plasticity at excitatory synapses remains unclear. We present a network model of AMPAR trafficking for adult hippocampal pyramidal neurons, which reproduces both LTP and LTD. We show that the induction of both LTP and LTD is regulated by the competition between exocytosis and endocytosis of AMPARs, which are mediated by the calcium-sensors synaptotagmin 1/7 (Syt1/7) and protein interacting with C-kinase 1 (PICK1), respectively. Our result indicates that recycling endosomes containing AMPAR are always ready for Syt1/7-dependent exocytosis of AMPAR at peri-synaptic/synaptic membranes. This is because molecular motor myosin V-b constitutively transports the recycling endosome toward the membrane in a Ca2+-independent manner

Kinetics of the ancestral carbon metabolism pathways in deep-branching bacteria and archaea

The origin of life is believed to be chemoautotrophic, deriving all biomass components from carbon dioxide, and all energy from inorganic redox couples in the environment. The reductive tricarboxylic acid cycle (rTCA) and the Wood-Ljungdahl pathway (WL) have been recognized as the most ancient carbon fixation pathways. The rTCA of the chemolithotrophic Thermosulfidibacter takaii, which was recently demonstrated to take place via an unexpected reverse reaction of citrate synthase, was reproduced using a kinetic network model, and a competition between reductive and oxidative fluxes on rTCA due to an acetyl coenzyme A (ACOA) influx upon acetate uptake was revealed. Avoiding ACOA direct influx into rTCA from WL is, therefore, raised as a kinetically necessary condition to maintain a complete rTCA. This hypothesis was confirmed for deep-branching bacteria and archaea, and explains the kinetic factors governing elementary processes in carbon metabolism evolution from the last universal common ancestor

Septic Tanks need Urgent Improvement for Management of Urban Sanitation in Hanoi Vietnam

Joint Research on Environmental Science and Technology for the Eart

同種移植後のHBV再活性化の後方視的検討

Reactivation of hepatitis B has been recognized as a careful adverse event after chemotherapies or immunosuppressive therapies because chronic hepatitis B leads to carcinoma and/or liver cirrhosis. Allogenic hematopoietic stem cell transplantation（allo-HSCT）against hematological diseases induces severe immunosuppression including reconstitution of naïve donor immunity against HBV-infected hepatocytes and we therefore need to follow-up HBV testing for a long term. In order to establish how to follow-up HBV-infected patients with receiving allo-HSCT, we retrospectively studied HBV serological markers and HBV-DNA in the HBV-infected patients, who received allo-HSCT and followed-up more than １ year in our single center. We detected ７ HBV-infected and allo-HSCT-received patients, and HBV reactivation was occurred in ３ patients with detecting HBV-DNA. No patients were died due to HBV reactivation. The HBV reactivation period after receiving allo-HSCT was １６，２０，７９ months, respectively. All the ３ patients received nucleoside analogues（NUCs）; however, the appearance of viral mutation was occurred in one patient who received lamivudine and already detected HBs-Ag before allo-HSCT. The HBV reactivation was controlled with addition of adefovir. Others were due to discontinuation of entecavir, which reason was poor medication-adherence after stopping immunosuppressive therapies. These two patients received tenofovir alafenamide in addition or retreated with entecavir, respectively, leading to disappearing of HBV-DNA. HBs-Ab were disappeared in ３１ months after allo-HSCT in one patient, and then the Ab was detected after occurring HBV reactivation, suggesting reconstitution of donor immunity. Taken together, our findings suggest that we need to follow-up immune-reconstitution and regularly evaluate HBV serological markers and HBV-DNA, in addition to maintain medication-adherence

コウド シンコウ カンサイボウ ガン ニ タイスル ホウシャセン ヘイヨウ ドウチュウ カガク リョウホウ ノ ユウヨウセイ

OBJECTIVE : The purpose of this study is to assess the treatment outcomes and adverse effects of concurrent chemotherapy and radiotherapy for hepatocellular carcinoma with portal vein tumor thrombus. METHODS : Twelve unresectable hepatocellular carcinoma patients with portal vein tumor thrombosis were treated using concurrent chemotherapy and radiation therapy. Four patients received transcatheter arterial chemoembolization using miriplatin-lipiodol suspension. Eight patients received interferon-α (IFN) and 5‐fluorouracil (5‐FU) combination therapy. The total radiation dose was 30‐50Gy. The response rate and overall survival and the toxicity were analyzed. RESULTS : Concurrent chemotherapy and radiotherapy was associated with a 50.0% objective response rate for primary tumors (miriplatin-lipiodol : 50.0%, IFN‐5FU : 50.0%). And a 66.7% objective response rate for portal vein tumor thrombus (miriplatin-lipiodol : 75.0%, IFN‐5FU : 62.5%). The median survival was 273 days (miriplatin-lipiodol : 273 days, IFN‐5FU : 262 days). Myelosuppression was observed in two patients, but no treatment-related deaths were observed. CONCLUSIONS : The present results suggest concurrent chemotherapy and radiotherapy is a practical and safe treatment option in hepatocellular carcinoma patients with extensive portal vein tumor thrombus

APOBコドン4311遺伝子多型は脂質代謝を変化させることによりC型肝炎ウイルスの感染性に関与する

Background: It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. Methods: Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequencespecific oligonucleotide probe-Luminex method. Results: An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non-AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). Conclusion: An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR