Golgi Complex Dynamics and Its Implication in Prevalent Neurological Disorders

Coupling of protein synthesis with protein delivery to distinct subcellular domains is essential for maintaining cellular homeostasis, and defects thereof have consistently been shown to be associated with several diseases. This function is particularly challenging for neurons given their polarized nature and differential protein requirements in synaptic boutons, dendrites, axons, and soma. Long-range trafficking is greatly enhanced in neurons by discrete mini-organelles resembling the Golgi complex (GC) referred to as Golgi outposts (GOPs) which play an essential role in the development of dendritic arborization. In this context, the morphology of the GC is highly plastic, and the polarized distribution of this organelle is necessary for neuronal migration and polarized growth. Furthermore, synaptic components are readily trafficked and modified at GOP suggesting a function for this organelle in synaptic plasticity. However, little is known about GOPs properties and biogenesis and the role of GOP dysregulation in pathology. In this review, we discuss current literature supporting a role for GC dynamics in prevalent neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and epilepsy, and examine the association of these disorders with the wide-ranging effects of GC function on common cellular pathways regulating neuronal excitability, polarity, migration, and organellar stress. First, we discuss the role of Golgins and Golgi-associated proteins in the regulation of GC morphology and dynamics. Then, we consider abnormal GC arrangements observed in neurological disorders and associations with common neuronal defects therein. Finally, we consider the cell signaling pathways involved in the modulation of GC dynamics and argue for a master regulatory role for Reelin signaling, a well-known regulator of neuronal polarity and migration. Determining the cellular pathways involved in shaping the Golgi network will have a direct and profound impact on our current understanding of neurodevelopment and neuropathology and aid the development of novel therapeutic strategies for improved patient care and prognosis

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

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Treatment decision-making of secondary prevention after venous thromboembolism. data from the real-life START2-POST-VTE register

Patients with venous thromboembolism (VTE) should receive a decision on the duration of anticoagulant treatment (AT) that is often not easy to make. Sixteen Italian clinical centers included patients with recent VTE in the START2-POST-VTE register and reported the decisions taken on duration of AT in each patient and the reasons for them. At the moment of this report, 472 (66.9%) of the 705 patients included in the registry were told to stop AT in 59.3% and to extend it in 40.7% of patients. Anticoagulant treatment lasted ≥3 months in >90% of patients and was extended in patients with proximal deep vein thrombosis because considered at high risk of recurrence or had thrombophilic abnormalities. d-dimer testing, assessment of residual thrombus, and patient preference were also indicated among the criteria influencing the decision. In conclusion, Italian doctors stuck to the minimum 3 months AT after VTE, while the secondary or unprovoked nature of the event was not seen as the prevalent factor influencing AT duration which instead was the result of a complex and multifactorial evaluation of each patient

A catalog of new Blazar candidates with Open Universe by High School students

Blazars are active galactic nuclei whose ultra-relativistic jets are coaligned with the observer direction. They emit throughout the whole e.m. spectrum, from radio waves to VHE gamma rays. Not all blazars are discovered. In this work, we propose a catalog of 54 new candidates based on the association of HE gamma ray emission and radio, X-ray an optical signatures. The relevance of this work is also that it was performed by four high school students from the Liceo Scientifico Statale Ugo Morin in Venice, Italy using the open-source platform Open Universe, in collaboration with the University of Padova. The framework of the activity is the Italian MIUR PCTO programme. The success of this citizen-science experience and results are hereafter reported and discussed.Comment: Proceedings of the 12th Cosmic Ray International Symposium (CRIS 2022), 12-16 September 2022, Naples (Italy). Send correspondence to: [email protected], [email protected]

Megalin/LRP2 Expression Is Induced by Peroxisome Proliferator-Activated Receptor -Alpha and -Gamma: Implications for PPARs' Roles in Renal Function

BACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPARα or PPARγ ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPARα or PPARγ antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPARα and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPARα and PPARγ enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPARα and PPARγ agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPARγ agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPARα/γ and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired

Thrombocytopenia and Mortality Risk in Patients With Atrial Fibrillation: An Analysis From the START Registry

Background: Thrombocytopenia is associated with increased mortality in the general population, but few data exist in patients with atrial fibrillation (AF) taking oral anticoagulants. We investigated factor determinants of thrombocytopenia in a large cohort of patients affected by AF and its association with total mortality. Methods and Results: Multicenter prospective cohort study, including 5215 patients with AF from the START (Survey on Anticoagulated Patients Register) registry, 3877 (74.3%) and 1338 (25.7%) on vitamin K or non\u2013vitamin K antagonist oral anticoagulants, respectively. Thrombocytopenia was defined by a platelet count <150 7109/L. Determinants of thrombocytopenia were investigated, and all-cause mortality was the primary survival end point of the study. Thrombocytopenia was present in 592 patients (11.4%). At multivariable logistic regression analysis, chronic kidney disease (odds ratio [OR], 1.257; P=0.030), active cancer (OR, 2.065; P=0.001), liver cirrhosis (OR, 7.635; P<0.001), and the use of diuretics (OR, 1.234; P=0.046) were positively associated with thrombocytopenia, whereas female sex (OR, 0.387; P<0.001) and the use of calcium channel blockers (OR, 0.787; P=0.032) were negatively associated. During a median follow-up of 19.2 months (9942 patient-years), 391 deaths occurred (rate, 3.93%/year). Mortality rate increased from 3.8%/year to 9.9%/year in patients with normal platelet count and in those with moderate-severe thrombocytopenia, respectively (log-rank test, P=0.009). The association between moderate-severe thrombocytopenia and mortality persisted after adjustment for CHA2DS2 VASc score (hazard ratio, 2.431; 95% CI, 1.254\u20134.713; P=0.009), but not in the fully adjusted multivariable Cox regression analysis model. Conclusions: Thrombocytopenia is common in patients with AF. Despite an increased incidence of mortality, thrombocytopenia was not associated with mortality at multivariable analysis. Thrombocytopenia may reflect the presence of comorbidities associated with poor survival in AF

Altering APP Proteolysis: Increasing sAPPalpha Production by Targeting Dimerization of the APP Ectodomain

One of the events associated with Alzheimer's disease is the dysregulation of α- versus β-cleavage of the amyloid precursor protein (APP). The product of α-cleavage (sAPPα) has neuroprotective properties, while Aβ1-42 peptide, a product of β-cleavage, is neurotoxic. Dimerization of APP has been shown to influence the relative rate of α- and β- cleavage of APP. Thus finding compounds that interfere with dimerization of the APP ectodomain and increase the α-cleavage of APP could lead to the development of new therapies for Alzheimer's disease. Examining the intrinsic fluorescence of a fragment of the ectodomain of APP, which dimerizes through the E2 and Aβ-cognate domains, revealed significant changes in the fluorescence of the fragment upon binding of Aβ oligomers—which bind to dimers of the ectodomain— and Aβ fragments—which destabilize dimers of the ectodomain. This technique was extended to show that RERMS-containing peptides (APP695 328–332), disulfiram, and sulfiram also inhibit dimerization of the ectodomain fragment. This activity was confirmed with small angle x-ray scattering. Analysis of the activity of disulfiram and sulfiram in an AlphaLISA assay indicated that both compounds significantly enhance the production of sAPPα by 7W-CHO and B103 neuroblastoma cells. These observations demonstrate that there is a class of compounds that modulates the conformation of the APP ectodomain and influences the ratio of α- to β-cleavage of APP. These compounds provide a rationale for the development of a new class of therapeutics for Alzheimer's disease

Selective targeting of microglia by quantum dots

<p>Abstract</p> <p>Background</p> <p>Microglia, the resident immune cells of the brain, have been implicated in brain injury and various neurological disorders. However, their precise roles in different pathophysiological situations remain enigmatic and may range from detrimental to protective. Targeting the delivery of biologically active compounds to microglia could help elucidate these roles and facilitate the therapeutic modulation of microglial functions in neurological diseases.</p> <p>Methods</p> <p>Here we employ primary cell cultures and stereotaxic injections into mouse brain to investigate the cell type specific localization of semiconductor quantum dots (QDs) in vitro and in vivo. Two potential receptors for QDs are identified using pharmacological inhibitors and neutralizing antibodies.</p> <p>Results</p> <p>In mixed primary cortical cultures, QDs were selectively taken up by microglia; this uptake was decreased by inhibitors of clathrin-dependent endocytosis, implicating the endosomal pathway as the major route of entry for QDs into microglia. Furthermore, inhibiting mannose receptors and macrophage scavenger receptors blocked the uptake of QDs by microglia, indicating that QD uptake occurs through microglia-specific receptor endocytosis. When injected into the brain, QDs were taken up primarily by microglia and with high efficiency. In primary cortical cultures, QDs conjugated to the toxin saporin depleted microglia in mixed primary cortical cultures, protecting neurons in these cultures against amyloid beta-induced neurotoxicity.</p> <p>Conclusions</p> <p>These findings demonstrate that QDs can be used to specifically label and modulate microglia in primary cortical cultures and in brain and may allow for the selective delivery of therapeutic agents to these cells.</p