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Impact of PICALM and CLU on hippocampal degeneration.

PICALM and CLU are two major risk genes of late-onset Alzheimer's disease (LOAD), and there is strong molecular evidence suggesting their interaction on amyloid-beta deposition, hence finding functional dependency between their risk genotypes may lead to better understanding of their roles in LOAD development and greater clinical utility. In this study, we mainly investigated interaction effects of risk loci PICALM rs3581179 and CLU rs11136000 on hippocampal degeneration in both young and elderly adults in order to understand their neural mechanism on aging process, which may help identify rob

Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.

We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memor

Exploration of deleterious single nucleotide polymorphisms in late-onset Alzheimer disease susceptibility genes.

Non-synonymous single nucleotide polymorphisms (nsSNPs) are considered as biomarkers to disease susceptibility. In the present study, nsSNPs in CLU, PICALM and BIN1 genes were screened for their functional impact on concerned proteins and their plausible role in Alzheimer disease (AD) susceptibility. Initially, SNPs were retrieved from dbSNP database, followed by identification of potentially deleterious nsSNPs and prediction of their effect on proteins by PolyPhen and SIFT. Protein stability and the probability of mutation occurrence were predicted using I-Mutant and PANTHER respectively. SNP

Selective Endocytosis-Mediated Omicron S1-RBD Internalization Revealed by Reconstitution of ACE2-S1-RBD Interaction on Micropatterned Membrane Substrates.

The SARS-CoV-2 spike protein, through its receptor binding domain (S1-RBD), binds to the angiotensin-converting enzyme 2 (ACE2) receptor on … with the localization of the early endosomal marker EEA1. Importantly, treatment of cells with the clathrin inhibitor, pitstop 2, but not the myosin II inhibitor, blebbistatin, significantly reduced Omicron S1-RBD depletion. Collectively, these observations suggest that the SARS-CoV-2 Omicron variant has evolved, through mutations in its S1-RBD, to take a …

Dynamin 1- and 3-Mediated Endocytosis Is Essential for the Development of a Large Central Synapse In Vivo.

UNLABELLED: Dynamin is a large GTPase crucial for endocytosis and sustained neurotransmission, but its role in synapse development in the ma … pment has been increasingly implicated in numerous brain disorders. Dynamin plays a crucial role in clathrin-mediated endocytosis and synaptic transmission at nerve terminals, but its potential role in synaptic development in the native brain circuitry is unclear. Using the calyx of Held, a giant nerve terminal in the mouse brainstem, we evaluated the role …

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A.

UNLABELLED: In our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular pH, on the hepatiti … cted a monensin-resistant virus which has evolved to use a new entry route that is partially pH and clathrin independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, the Y297H mutation in E1 and the I399T mutation in hypervariable region 1 (HVR1) of E2, which confer resistance to monensin and thus allow …

Accessible STORM Imaging: An Optimized Workflow for Conventional Widefield Epifluorescence/TIRF Setups.

Stochastic optical reconstruction microscopy (STORM) is a single-molecule localization microscopy technique that enables visualization of cellular structures beyond the diffraction limit. This approach has revealed previously inaccessible ultrastructural details in a wide range of cellular components, including the actin cytoskeleton, clathrin-coated pits, mitochondria, and bacterial nucleoid-associated proteins. STORM relies on the sequential emission of single photons from photosensitive fluorophores, which are precisely localized before entering a dark state or undergoing photobleaching. By…

Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects.

BACKGROUND: Genetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects. METHODS: We pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at May

Rational Design of Modular Elastin-like Polypeptide Nanoparticles for Nonviral Gene Delivery.

Gene therapy has evolved into a cornerstone modality in modern medicine, with applications spanning antisense oligonucleotide treatments, RN … g efficient mRNA expression and siRNA knockdown. Mechanistic studies confirm cellular entry via the clathrin-mediated uptake pathway and activation of lipid remodeling processes that facilitate cargo release. In an initial proof-of-concept study, EGF-modified LENN exhibited tumor association following intravesical administration in orthotopic bladder cance …

Childhood-onset parkinsonism, dystonia and severe muscle wasting in a Sudanese girl caused by a novel homozygous DnaJ heat shock protein family (heat shock protein 40) member C6 frameshift variant, with an incidental pathogenic breast cancer 1 gene secondary finding: a case report.

BACKGROUND: DNAJC6-related juvenile parkinsonism is a rare autosomal recessive disorder of auxilin, a co-chaperone essential for clathrin-mediated synaptic vesicle recycling. Fewer than 50 kindreds have been reported worldwide, and the condition is easily missed when first-line investigations come back normal. We describe a Sudanese adolescent in whom a previously unreported homozygous DNAJC6 frameshift variant was identified only after a prolonged diagnostic journey that included a period during which her illness was mistakenly attributed to a functional neurological disorder. Clinical whole-…

Proteomic characterization of Opisthorchis felineus exosome-like vesicles and their uptake by human cholangiocytes.

The epidemiologically important food-borne trematode Opisthorchis felineus infests the liver biliary tract of fish-eating mammals and causes … esis-related protein 1 (GAPR1). We showed that EVs are internalized by human H69 cholangiocytes via clathrin-dependent endocytosis, whereas phagocytosis and caveolin-dependent endocytosis do not play a substantial role in this process. Our study describes for the first time proteomes and differential abundance of proteins in whole adult O. felineus worms a …

Preconditioning With Intermittent Hypobaric Hypoxia Attenuates Stroke Damage and Modulates Endocytosis in Residual Neurons.

Background: Moderate hypobaric hypoxia induces cerebral ischemic tolerance. We investigated the optimal method for applying hypobaric hypoxi … ve effect. Intermittent hypoxic preconditioning for 6 h/day for 10 days upregulates key proteins in clathrin-dependent endocytosis of neurons in the cortex.

CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation.

Hepatitis B virus (HBV) particles are thought to be secreted from hepatocytes through multivesicular bodies (MVBs); however, the cellular tr … nge; ATF6: activating transcription factor 6; CCDC88A/GIV: coiled-coil domain containing 88A; CLTC: clathrin heavy chain; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM2: dynamin 2; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; EIF2A: eukaryotic translation initiation factor 2A; FBS: fetal bovine serum; GNAI3: G …

A systematic comparison of lipopolymers for siRNA delivery to multiple breast cancer cell lines: In vitro studies.

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that displa … hase transfer associated with dextran uptake. Consistent with this, specific inhibitors involved in clathrin- and caveolin-mediated endocytosis significantly (>50%) reduced the internalization of siRNA complexes in all cell types. Using JAK2 and STAT3 silencing in MDA-MB-231 and MDA-MB-468 cells, a general correlation between the uptake and silencing effic …

Sulfatase-responsive phase-separating peptide coacervates target stress granules to reverse sorafenib resistance in hepatocellular carcinoma.

Acquired drug resistance in hepatocellular carcinoma (HCC) hinders the clinical therapeutic efficacy of various drugs, but efficient interve … Investigations of HCC-SFR cells confirm that the YsF-LSG mixtures are efficiently internalized via clathrin-mediated endocytosis, experience ARSA-responsive hydrolysis in lysosomes and lysosomal escape, and undergo in situ LLPS into droplets. Notably, in situ-formed coacervates YsF-LSG recruit G3BP2 and target SGs with high tumor permeability. YsF-LSG coa …

Oligo(ethylene glycol)-functionalized polycarbonate lipid nanoparticles for mRNA delivery with attenuated PEG immunogenicity.

mRNA vaccines delivered by lipid nanoparticles (LNPs) have enabled clinical success in combating the COVID-19 pandemic, demonstrating LNPs a … ellular uptake as evidenced by flow cytometry analysis. Endocytosis inhibition assay suggested that clathrin-mediated endocytosis was a major pathway for cellular uptake of LNPs, with caveolae-dependent endocytosis also contributing. A confocal microscopic study indicated comparable endosomal escape of OPL and ALC-0159 LNPs. In vivo and ex vivo bioimaging …

Доказательства того, что после вторжения хламидийский трахоматис типа III был скрытым эффектором ТМЕА в процессе перенаправления материала, полученного из плазменной мембраны.

Инфекционная мукозаальная эпителия и развитие в мембранном вакуоле, называемом включением. Параситизм ресурсов, поступающих от принимающих организаций, и эксплуатация цитоскелета на базе актина представляют собой центральные парадигмы создания и поддержания внутриклеточной ниши, созданной Hlamidia spp. Манипулирование биологией хост-клеток в значительной степени происходит за счет использования секретных белков с эффектом типа III. Перераспределенный эффект, связанный с мембраной A (TmeA) — скрытый эффект типа III, который впервые был установлен во время вторжения, когда он необходим для эффек

Совпадение в аннотации оригинала
Chlamydia spp. infect mucosal epithelia and develop within a membrane-bound vacuole termed an inclusion. Parasitism of resources from host o … d with internalized DiI in vesicle-like structures that also depended on the N-WASP binding domain. Clathrin and dynamin were also required but likely contribute independently of direct TmeA-mediated activation. Overall, our data provide evidence that Chlamydia repurposes TmeA to accomplish development-specific tasks and parasitizes the host surface to sup …

BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons.

Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-on … ridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco's modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance …

Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors.

BACKGROUND: Modified vaccinia virus Ankara (MVA) are genetically engineered non-replicating viral vectors. Intratumoral administration of MV … bitors due to their ability to reduce surface expression levels of IFN-α/β receptor 1 and to reduce clathrin-mediated endocytosis. Simvastatin and atorvastatin efficiently abrogated for 8 hours the transcriptomic response to IFNα and enhanced the number of dendritic cells presenting an OVA-derived peptide bound to major histocompatibility complex (MHC) cla …

Identification of proteins differentially expressed in human monocytes exposed to Porphyromonas gingivalis and its purified components by high-throughput immunoblotting.

To characterize the roles of Porphyromonas gingivalis and its components in disease processes, we investigated the cytokine profiles induced … retinoid interferon-induced mortality 19 [GRIM19]), and other fundamental cellular processes (e.g., clathrin heavy-chain polypeptide, culreticulin, and Ras-associated protein RAB27A) was found to be modulated differentially by P. gingivalis, LPS, and FimA. These differential changes are interpreted as preferential signal pathway activation in host immune/i …