Diffusion changes in patients with systemic lupus erythematosus

BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disease in which almost all the organs are involved. Neuropsychiatric SLE is of one of the major concerns in the clinical evaluation of this disease. Routine magnetic resonance imaging (MRI) findings are often nonspecific or negative. In this study, we explored the use of diffusion tensor imaging in assisting with the diagnosis of SLE. METHODS: Data from 34 SLE patients (age range, 18-73 years) and 29 age-matched volunteers (age range, 29-64 years) were analyzed. MRI was performed on a 1.5-T clinical MR scanner with a quadrature head coil. The average diffusion constant (D(av)) and diffusion anisotropy maps [fractional anisotropy (FA)] were determined on a pixel-by-pixel basis. Regional diffusion measurements were made by region of interest in the genu and splenium of the corpus callosum (CC), anterior and posterior limb of the internal capsule (IC) and frontal lobe and thalamus. The diffusion distribution was fitted to a triple-Gaussian model. The mean of the brain tissue distribution was determined as a mean diffusion constant for the whole brain (BD(av)). Student's t test was used to determine the diffusion difference between SLE patients and control subjects. The SLE patients were separated into two groups according to their MRI results. A P value lower than .05 was considered to be statistically significant. RESULTS: Twenty of the 34 SLE patients with abnormal MRI results showed findings dominated by nonspecific white matter disease. The BD(av) and D(av) values of the frontal lobe, splenium CC and anterior IC were significantly higher in all SLE patients as compared with the control subjects. The SLE patients with normal MRI results also showed higher BD(av) and D(av) values in the frontal lobe, splenium and anterior and posterior limbs of the IC as compared with the control subjects. There was no significant difference in the D(av) values of the thalamus between the SLE patients and the control subjects. The BD(av) value in the SLE patient group was robustly correlated with the D(av) values of the frontal lobe, splenium and thalamus. These correlations were found to be similarly significant for the SLE patients with normal MRI findings. The diffusion anisotropy measurements showed that splenium CC had the highest FA value in both the control subjects and SLE patients. Overall, SLE patients had lower FA values in the genu and splenium CC as compared with the control subjects. In the group of patients with normal MRI findings, the FA values of the genu and splenium CC as well as the anterior IC were also lower than those in the control subjects. Pearson's correlation statistics revealed robust correlations between the measurements of D(av) and FA values in the SLE patient group. CONCLUSION: Quantitative diffusion imaging and diffusion anisotropy showed early changes in the brains of the SLE patients. Increased BD(av) and D(av) values of the frontal lobe as well as decreased anisotropy in the genu CC and anterior IC may represent preclinical signs of central nervous system involvement of SLE even when the routine MRI findings are negative or nonspecific. Quantitative diffusion analysis may prove to be useful in detecting the initial brain involvement of SLE and may enable monitoring of early disease progression and treatment efficacy.     

Tailoring Chimeric Ligands for Studying and Biasing ErbB Receptor Family Interactions

Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase‐mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR‐HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance‐dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor‐mediated cell signaling pathways.     

Reactions in Nitroimidazole Triggered by Low‐Energy (0–2 eV) Electrons: Methylation at N1‐H Completely Blocks Reactivity

Low‐energy electrons (LEEs) at energies of less than 2 eV effectively decompose 4‐nitroimidazole (4NI) by dissociative electron attachment (DEA). The reactions include simple bond cleavages but also complex reactions involving multiple bond cleavages and formation of new molecules. Both simple and complex reactions are associated with pronounced sharp features in the anionic yields, which are interpreted as vibrational Feshbach resonances acting as effective doorways for DEA. The remarkably rich chemistry of 4NI is completely blocked in 1‐methyl‐4‐nitroimidazole (Me4NI), that is, upon methylation of 4NI at the N1 site. These remarkable results have also implications for the development of nitroimidazole based radiosensitizers in tumor radiation therapy.     

The rheological properties of hydrogenated castor oil crystals

The present study focuses on the rheological performance of a surfactant-rich aqueous suspension containing hydrogenated castor oil (HCO) crystals. HCO can be typically crystallized in five distinct shapes: spherically shaped, irregularly shaped, star-shaped (also called rosettes), short needles, and thick or thin fibers. The effect of the differences in shape on the rheological performance is studied, and the rheological properties are compared to the behavior of other triacylglycerol’s (TAG) suspensions. A suspension of TAG crystals usually behaves as a colloidal gel wherein a colloidal gel is defined as a network of flocs, with each floc being an aggregate of smaller subunits. All of these surfactant-rich aqueous suspensions of HCO crystals behaved according to a colloidal gel in the transient regime, independent of the studied crystal shapes, except the long thin fibers at a concentration above 0.1 wt% HCO transitioning from a heterogeneous fractal rod network to a homogeneous rod network, shifting from a colloidal gel to a glass.     

Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation

Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its active metabolite de-Laquinimod on astrocyte functions and the astrocyte–neuron interaction. We show that human iAstrocytes expressed the receptor for the inflammatory mediator IL1 and responded to it via nuclear translocation of NFκB, an event that did not occur if cells were treated with Laquinimod, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Similarly, while exposure to IL1 downregulated glial glutamate transporters GLAST and GLT1, treatment with Laquinimod supported maintenance of physiological levels of these proteins despite the inflammatory milieu. Laquinimod also induced nuclear translocation of the aryl hydrocarbon receptor (AHR), suggesting that drug action was mediated by activation of the AHR pathway. However, the drug was effective despite AHR inhibition via CH223191, indicating that AHR signaling in the astrocyte is dispensable for drug responses. Finally, in vitro experiments with rat spinal neurons showed that laquinimod did not exert neuroprotection directly on the neuron but dampened astrocyte-induced neurodegeneration. Our findings indicate that fibroblast-derived human astrocytes represent a suitable model to study astrocyte–neuron crosstalk and demonstrate indirect, partial neuroprotective efficacy for laquinimod.     

Purification,Characterization, and Structural Studies of a Sulfatase from Pedobacter yulinensis

Sulfatases are ubiquitous enzymes that hydrolyze sulfate from sulfated organic substrates such as carbohydrates, steroids, and flavones. These enzymes can be exploited in the field of biotechnology to analyze sulfated metabolites in humans, such as steroids and drugs of abuse. Because genomic data far outstrip biochemical characterization, the analysis of sulfatases from published sequences can lead to the discovery of new and unique activities advantageous for biotechnological applications. We expressed and characterized a putative sulfatase (PyuS) from the bacterium Pedobacter yulinensis. PyuS contains the (C/S)XPXR sulfatase motif, where the Cys or Ser is post-translationally converted into a formylglycine residue (FGly). His-tagged PyuS was co-expressed in Escherichia coli with a formylglycine-generating enzyme (FGE) from Mycobacterium tuberculosis and purified. We obtained several crystal structures of PyuS, and the FGly modification was detected at the active site. The enzyme has sulfatase activity on aromatic sulfated substrates as well as phosphatase activity on some aromatic phosphates; however, PyuS did not have detectable activity on 17α-estradiol sulfate, cortisol 21-sulfate, or boldenone sulfate.     

Poole-Frenkel effect in amorphous poly(p-phenylene sulfide)

The conductivity of poly(p-phenylene sulfide) (PPS) amorphous samples sandwiched between metallic electrodes has been studied as a function of applied voltage, temperature, and electrode material. The voltage (U) dependence of the currents for electric fields within the range 10³–10⁶ V/cm exhibits exp βU^1/2 behavior with β = β_Schottky below the glass transition temperature (T_g ≊ 90°C), and β = β_{Poole-Frenkel} above T_g. Coordinated temperature measurements of dc currents with different metallic contacts and thermally stimulated currents (TSC) indicate, however, that the conductivity at T < T_g is consistent with the so-called “anomalous” Poole-Frenkel effect rather than the Schottky effect. Consequently, the p-type conductivity in amorphous PPS is proposed to be a bulk-limited process due to ionization of two different types of acceptor centers in the presence of neutral hole traps. © 1996 John Wiley & Sons, Inc.