Tellurium Compounds Prevent and Reverse Type-1 Diabetes in NOD Mice by Modulating α4β7 Integrin Activity, IL-1β, and T Regulatory Cells

The study shows that treatment of NOD mice with either of two tellurium-based small molecules, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate] or SAS [octa-O-bis-(R,R)-tartarate ditellurane] could preserve β cells function and mass. These beneficial effects were reflected in decreased incidence of diabetes, improved glucose clearance, preservation of body weight, and increased survival. The normal glucose levels were associated with increased insulin levels, preservation of β cell mass and increased islet size. Importantly, this protective activity could be demonstrated when the compounds were administered either at the early pre-diabetic phase with no or initial insulitis, at the pre-diabetic stage with advanced insulitis, or even at the advanced, overtly diabetic stage. We further demonstrate that both tellurium compounds prevent migration of autoimmune lymphocytes to the pancreas, via inhibition of the α4β7 integrin activity. Indeed, the decreased migration resulted in diminished pancreatic islets damage both with respect to their size, β cell function, and caspase-3 activity, the hallmark of apoptosis. Most importantly, AS101 and SAS significantly elevated the number of T regulatory cells in the pancreas, thus potentially controlling the autoimmune process. We show that the compounds inhibit pancreatic caspase-1 activity followed by decreased levels of the inflammatory cytokines IL-1β and IL-17 in the pancreas. These properties enable the compounds to increase the proportion of Tregs in the pancreatic lymph nodes. AS101 and SAS have been previously shown to regulate specific integrins through a unique redox mechanism. Our current results suggest that amelioration of disease in NOD mice by this unique mechanism is due to decreased infiltration of pancreatic islets combined with increased immune regulation, leading to decreased inflammation within the islets. As these tellurium compounds show remarkable lack of toxicity in clinical trials (AS101) and pre-clinical studies (SAS), they may be suitable for the treatment of type-1 diabetes

RNA editing signature during myeloid leukemia cell differentiation

Adenosine deaminases acting on RNA (ADARs) are key proteins for hematopoietic stem cell self-renewal and for survival of differentiating progenitor cells. However, their specific role in myeloid cell maturation has been poorly investigated. Here we show that ADAR1 is present at basal level in the primary myeloid leukemia cells obtained from patients at diagnosis as well as in myeloid U-937 and THP1 cell lines and its expression correlates with the editing levels. Upon phorbol-myristate acetate or Vitamin D3/granulocyte macrophage colony-stimulating factor (GM-CSF)-driven differentiation, both ADAR1 and ADAR2 enzymes are upregulated, with a concomitant global increase of A-to-I RNA editing. ADAR1 silencing caused an editing decrease at specific ADAR1 target genes, without, however, interfering with cell differentiation or with ADAR2 activity. Remarkably, ADAR2 is absent in the undifferentiated cell stage, due to its elimination through the ubiquitin–proteasome pathway, being strongly upregulated at the end of the differentiation process. Of note, peripheral blood monocytes display editing events at the selected targets similar to those found in differentiated cell lines. Taken together, the data indicate that ADAR enzymes play important and distinct roles in myeloid cells

Multi-Temperature <i>in Situ</i> Magnetic Resonance Imaging of Polarization and Salt Precipitation in Lithium-Ion Battery Electrolytes

Accurate electrochemical modeling of lithium-ion batteries is an important direction in the development of battery management systems in automotive applications, for both real-time performance control and long-term state-of-health monitoring. Measurements of electrolyte-domain transport parameters, under a wide regime of temperature and current conditions, are a crucial aspect of the parametrization and validation of these models. This study constitutes the first exploration of the temperature dependence for the steady-state electrolyte concentration gradient under applied current with spatial resolution via the <i>in situ</i> magnetic resonance imaging (MRI) technique. The use of complementary pure phase-encoding MRI methods was found to provide quantitatively accurate measurements of the concentration gradient, in strong agreement with predictions based on <i>ex situ</i> NMR and electrochemical techniques. Temperature is demonstrated to have a marked influence on the steady-state concentration gradient as well as the rate of its buildup. This finding underlines the importance of utilizing spatially varying electrolyte transport parameters in modeling approaches. Additionally, a surprising outcome of this investigation was that a conventional 1.00 M LiPF₆ electrolyte in an equal-parts ethylene carbonate/diethylene carbonate solvent mixture generated salt precipitation under polarization at 10 °C. The loss of salt under strong polarization and at low temperature is a previously unaddressed potential source of long-term capacity fade in lithium-ion batteries, and on the basis of this result, warrants further investigation

A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia

Mutation in the insulin-like growth factor-1 receptor (IGF1R) gene is a rare cause for intrauterine and postnatal growth disorders. Patients identified with IGF1R mutations present with either normal or impaired glucose tolerance. None of the cases described so far showed hypoglycemia. We aimed to identify the genetic basis for small for gestational age, short stature and hypoglycemia over three generations in one family. The proband, a 9-year-old male, presented in infancy with recurrent hypoglycemic episodes, symmetric intrauterine growth retardation and postnatal growth retardation. Blood DNA samples from the patient, his parents, a maternal sister and maternal grandmother underwent Sanger sequencing of the IGF1R gene. Primary skin fibroblast cultures of the patient, his mother and age- and sex-matched control donors were used for gene expression and receptor functional analyses. We found a novel heterozygous mutation (c.94 + 1g > a, D1105E) affecting the splicing site of the IGF1R mRNA in the patient, his mother and his grandmother. Primary fibroblast cultures derived from the patient and his mother showed reduced proliferation and impaired activation of the IGF1R, evident by reduced IGF1R and AKT phosphorylation upon ligand binding. In conclusion, the newly identified heterozygous missense mutation in exon 1 of IGF1R (D1105E) results in impaired IGF1R function and is associated with small for gestational age, microcephaly and abnormal glucose metabolism. Further studies are required to understand the mechanisms by which this mutation leads to hypoglycemia

Visualization of Steady-State Ionic Concentration Profiles Formed in Electrolytes during Li-Ion Battery Operation and Determination of Mass-Transport Properties by <i>in Situ</i> Magnetic Resonance Imaging

Accurate modeling of Li-ion batteries performance, particularly during the transient conditions experienced in automotive applications, requires knowledge of electrolyte transport properties (ionic conductivity κ, salt diffusivity <i>D</i>, and lithium ion transference number <i>t</i>⁺) over a wide range of salt concentrations and temperatures. While specific conductivity data can be easily obtained with modern computerized instrumentation, this is not the case for <i>D</i> and <i>t</i>⁺. A combination of NMR and MRI techniques was used to solve the problem. The main advantage of such an approach over classical electrochemical methods is its ability to provide spatially resolved details regarding the chemical and dynamic features of charged species in solution, hence the ability to present a more accurate characterization of processes in an electrolyte under operational conditions. We demonstrate herein data on ion transport properties (<i>D</i> and <i>t</i>⁺) of concentrated LiPF₆ solutions in a binary ethylene carbonate (EC)–dimethyl carbonate (DMC) 1:1 v/v solvent mixture, obtained by the proposed technique. The buildup of steady-state (time-invariant) ion concentration profiles during galvanostatic experiments with graphite–lithium metal cells containing the electrolyte was monitored by pure phase-encoding single point imaging MRI. We then derived the salt diffusivity and Li⁺ transference number over the salt concentration range 0.78–1.27 M from a pseudo-3D combined PFG-NMR and MRI technique. The results obtained with our novel methodology agree with those obtained by electrochemical methods, but in contrast to them, the concentration dependences of salt diffusivity and Li⁺ transference number were obtained simultaneously within the single <i>in situ</i> experiment