Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia

Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). They have a key role in ITP, acting both as effector cells, phagocytizing platelets, and, as antigen presenting cells, stimulating auto-antibodies against platelets production. Eltrombopag (ELT) is a thrombopoietin receptor agonist licensed for chronic ITP to stimulate platelet production. Moreover, it improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation. We analyzed the effect of ELT on macrophage phenotype polarization, proposing a new possible mechanism of action. We suggest it as a mediator of macrophage phenotype switch from the M1 pro-inflammatory type to the M2 anti-inflammatory one in paediatric patients with ITP, in order to reduce inflammatory state and restore the immune system function. Our results provide new insights into the therapy and the management of ITP, suggesting ELT also as immune-modulating drug.     

AP2M1 Supports TGF-β Signals to Promote Collagen Expression by Inhibiting Caveolin Expression

The extracellular matrix (ECM) is important for normal development and disease states, including inflammation and fibrosis. To understand the complex regulation of ECM, we performed a suppressor screening using Caenorhabditis elegans expressing the mutant ROL-6 collagen protein. One cuticle mutant has a mutation in dpy-23 that encodes the μ2 adaptin (AP2M1) of clathrin-associated protein complex II (AP-2). The subsequent suppressor screening for dpy-23 revealed the lon-2 mutation. LON-2 functions to regulate body size through negative regulation of the tumor growth factor-beta (TGF-β) signaling pathway responsible for ECM production. RNA-seq analysis showed a dominant change in the expression of collagen genes and cuticle components. We noted an increase in the cav-1 gene encoding caveolin-1, which functions in clathrin-independent endocytosis. By knockdown of cav-1, the reduced TGF-β signal was significantly restored in the dpy-23 mutant. In conclusion, the dpy-23 mutation upregulated cav-1 expression in the hypodermis, and increased CAV-1 resulted in a decrease of TβRI. Finally, the reduction of collagen expression including rol-6 by the reduced TGF-β signal influenced the cuticle formation of the dpy-23 mutant. These findings could help us to understand the complex process of ECM regulation in organism development and disease conditions.     

Electron Paramagnetic Resonance and Magnetic Circular Dichroism Spectra of the Nitrogenase M Cluster Precursor Suggest Sulfur Migration upon Oxidation: A Proposal for Substrate and Inhibitor Binding

The active site of the nitrogen-fixing enzyme Mo-nitrogenase is the M cluster ([MoFe₇S₉C ⋅ R-homocitrate]), also known as the FeMo cofactor or FeMoco. The biosynthesis of this highly complex metallocluster involves a series of proteins. Among them, NifB, a radical-SAM enzyme, is instrumental in the assembly of the L cluster ([Fe₈S₉C]), a precursor and all-iron core of the M cluster. In the absence of sulfite, NifB assembles a precursor form of the L cluster called the L* cluster ([Fe₈S₈C]), which lacks the final ninth sulfur. EPR and MCD spectroscopies are used to probe the electronic structures of the paramagnetic, oxidized forms of both the L and L* clusters, labeled L^Ox and [ L* ] ^Ox . This study shows that both L^Ox and [ L* ] ^Ox have nearly identical EPR and MCD spectra, thus suggesting that the two clusters have identical structures upon oxidation; in other words, a sulfur migrates away from L^Ox following oxidation, thereby rendering the cluster identical to [ L* ] ^Ox . It is proposed that a similar migration could occur to the M cluster upon oxidation, and that this is an instrumental part of both M cluster formation and nitrogenase substrate/inhibitor binding.     

Synthesis of red mud derived M-type barium hexaferrites with tuneable coercivity

Hexagonal ferrites can be employed in a multitude of applications, the most common hexaferrites are the M ferrites such as BaFe₁₂O₁₉ (barium hexaferrite, BaM). It is known that if Fe³⁺ is substituted with a combination of Ti⁴⁺/Co²⁺ the coercivity of BaM can be reduced to produce soft M ferrites with easily switchable magnetisation. They can be utilised as powders, films or bulk ceramics, and can be manufactured from a wide variety of synthesis methods. The production of hexaferrites usually requires commercial raw materials, but if an industrial waste can be utilised, this will help to ease waste disposal and storage costs, valorise a waste material and encourage circular economy. In this study, bauxite residue (red mud) from the production of alumina was used to synthesise M-type hexaferrites, using a simple ceramic process. BaCO₃, or BaCO₃+Co₃O₄, were added to the red mud, blended and heated at 1000 °C to produce the M-type hexaferrites. Without cobalt addition up to 81.1 wt% M ferrite was produced, and with Co addition up to 74.3 wt% M ferrite was formed. Without cobalt, the M ferrite phase closely resembled BaFe₉Al₃O₁₉, and was a hard ferrite with a magnetisation of 12–19 A m²/kg for the whole powder (up to 23.6 A m²/kg for the M ferrite phase) and a coercivity of ~290 kA/m. When cobalt was added, secondary titanate phases vanished, and Ti⁴⁺/Co²⁺ partially substituted very soft M ferrite was formed with a low coercivity of ~16 kA/m but a higher magnetisation of 24.5 A m²/kg for the whole powder (up to 34.9 A m²/kg for the M ferrite phase). Therefore, not only can good quality magnetic materials be easily produced from this common waste material, but its magnetic properties can be tuned by varying the 2 + ions added during the process.     

Effects of ionic radius on phase evolution in Ln-Al co-doped Ca1-xLnxZrTi2-xAlxO7 (Ln = La,Nd, Gd,Ho, Yb) solid solutions

Zirconolite ceramic has been considered as a promising matrix to dispose high-level radioactive waste due to its excellent performance in immobilizing radionuclides. In this work, a series of zirconate solid solutions with stoichiometric Ca_1-xLn_xZrTi_2-xAl_xO₇ (Ln = La, Nd, Gd, Ho, Yb; x?=?0.1–1) were systematically studied to investigate the radius effect on their phase evolution. Powder X-ray diffraction (XRD) and scanning electron microscopy with energy dispersive X-Ray spectrometry (SEM-EDX) were used to characterize the products. XRD and SEM results show that complete solid solutions of Ln and Al in zirconolite phase for Ca_1-xLn_xZrTi_2-xAl_xO₇ cannot found. In the Ca_1-xLa_xZrTi_2-xAl_xO₇ ceramics, single zirconolite phase cannot form, instead of multiple phases, such as zirconolite-2M, zirconia, perovskite and LaTi₂Al₉O₁₉. In the Nd-Al co-doping ceramics, nearly single zirconolite-2M and zirconolite-3O were found at x?≤?0.6 and 0.8?≤?x?≤?0.9, respectively. The miscibility gap between zirconolite-2M and 3O was found at x?=?0.7. Single zirconolite-2M formed in the Gd-Al, Ho-Al and Yb-Al co-doped ceramics can only be detected in a compositional range of 0.1?≤?x?≤?0.8. Higher incorporation contents in these three series can form an additional phase cubic zirconia which is usually a ceramic waste form for radionuclides. Based on the XRD data, lattice parameters of zirconolite-2M and zirconolite-3O were calculated by Pawley refinement method. The evolution of lattice parameters of zirconolite-2M shows great difference between different lanthanide ions, indicating different substitution mechanisms in the Ln-Al co-doped zirconolite-2M.     

Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.     

Comparison of two Analytical Methods (ELISA and LC-MS/MS) for Determination of Aflatoxin B1 in Corn and Aflatoxin M1 in Milk

The aim of this paper is to assess the closeness of agreement between results of ELISA and LC-MS/MS methods for determination of aflatoxin B₁ in corn and aflatoxin M₁ in milk. Samples of corn (n=100) and milk (n=250) were simultaneously analyzed using ELISA and LC-MS/MS methods, after the severe drought that affected Serbia in summer 2012 resulting in occurrence of aflatoxin B1 in corn and aflatoxin M₁ in milk. Regression analysis showed higher level of agreement between aflatoxin B₁ samples (R²=0.994), compared to aflatoxin M₁ samples (R²=0.920). However, both techniques were satisfactory in meeting the requirements for official control purposes.     

The periodic system and the idea of a chemical element: From Mendeleev to superheavy elements

Like other scientific concepts, the idea of a chemical element has changed considerably over time, since it was first established in the Enlightenment era. In Dmitri Mendeleev's construction of the periodic system, he distinguished between simple substances and elements as defined by their atomic weights. The foundation of the periodic system on the latter concept led to several challenges. For example, the system seemed unable to accommodate the radioactive substances eventually recognised as isotopes. Around 1920, elements were consequently redefined in terms of their atomic numbers, a nuclear property that could be determined by X‐ray spectroscopy. Although this understanding of an element has stood the test of time, new questions turned up relating to the concept of an element following the syntheses of transuranic elements since the early 1940s. These syntheses of very heavy elements have additionally led chemists and physicists to reconsider the criteria for the discovery of a new element. Recently, elements have been officially recognised on the sole ground that a small number of very heavy atomic nuclei were identified. The paper discusses how the notion of an element was modified during different periods of time, the reasons for the modifications, and the values ascribed to them in the communities of chemists and physicists.