A multivariate hypothesis testing framework for tissue clustering and classification of DTI data

The primary aim of this work is to propose and investigate the effectiveness of a novel unsupervised tissue clustering and classification algorithm for diffusion tensor MRI (DTI) data. The proposed algorithm utilizes information about the degree of homogeneity of the distribution of diffusion tensors within voxels. We adapt frameworks proposed by Hext and Snedecor, where the null hypothesis of diffusion tensors belonging to the same distribution is assessed by an F‐test. Tissue type is classified according to one of the four possible diffusion models, the assignment of which is determined by a parsimonious model selection framework based on Schwarz Criterion. Both numerical phantoms and diffusion‐weighted imaging (DWI) data obtained from excised rat and pig spinal cords are used to test and validate these tissue clustering and classification approaches. The unsupervised clustering method effectively identifies distinct regions of interest (ROIs) in phantoms and real experimental DTI data. Copyright © 2009 John Wiley & Sons, Ltd.     

Human recombinant interferon-alpha2a and interferon-alphaA/D have different effects on bleomycin-induced lung injury

BACKGROUND: Bleomycin (Bleo)-induced lung injury in mice serves as an animal model of pulmonary fibrosis. The pathogenesis of pulmonary fibrosis remains unclear, but it comprises both inflammatory and fibrotic components. The cytokine interferon (IFN)-alpha is produced by macrophages and may modulate both fibrogenesis and the determination of T lymphocyte phenotype in pulmonary fibrosis. OBJECTIVE: To investigate the effect of two preparations of recombinant IFN-alpha (IFN-alphaA/D and IFN-alpha2a) on Bleo-induced lung injury in C57BL/6 mice. METHODS: Mice were treated by a single intratracheal (IT) instillation of 0.06 mg of Bleo in 0.1 ml of saline or saline alone. One of two different IFN-alpha preparations, IFN-alphaA/D or IFN-alpha2a in saline, or saline alone were administered by daily intraperitoneal injections starting 1 day prior to IT instillation. The treatment groups were as follows: IT Bleo and intraperitoneal saline; IT Bleo and intraperitoneal IFN-alpha2a; IT Bleo and intraperitoneal IFN-alphaA/D; IT saline and intraperitoneal IFN-alphaA/D or IFN-alpha2a; IT saline and intraperitoneal saline. The animals were sacrificed 14 days after IT instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage (BAL) fluid, by a semiquantitative morphological index of lung injury and a quantitative image analysis of cellularity and fibrosis fraction and by biochemical analysis of lung hydroxyproline content. RESULTS: In Bleo-treated mice, IFN-alpha2a treatment caused a significant rise in BAL lymphocytes and in cellularity and fibrosis fractions in lung tissue. In contrast, IFN-alphaA/D treatment had no effect on Bleo-induced lung injury. CONCLUSION: IFN-alpha may enhance Bleo-induced lung injury but this effect varies with different IFN preparations.     

Atomic interactions of neonicotinoid agonists with AChBP: molecular recognition of the distinctive electronegative pharmacophore

Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 A in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.     

Toll-like receptors and their ligands control mesenchymal stem cell functions.

Mesenchymal stem cells (MSCs) are widespread in adult organisms and may be involved in tissue maintenance and repair as well as in the regulation of hematopoiesis and immunologic responses. Thus, it is important to discover the factors controlling MSC renewal and differentiation. Here we report that adult MSCs express functional Toll-like receptors (TLRs), confirmed by the responses of MSCs to TLR ligands. Pam3Cys, a prototypic TLR-2 ligand, augmented interleukin-6 secretion by MSC, induced nuclear factor kappa B (NF-kappaB) translocation, reduced MSC basal motility, and increased MSC proliferation. The hallmark of MSC function is the capacity to differentiate into several mesodermal lineages. We show herein that Pam3Cys inhibited MSC differentiation into osteogenic, adipogenic, and chondrogenic cells while sparing their immunosuppressive effect. Our study therefore shows that a TLR ligand can antagonize MSC differentiation triggered by exogenous mediators and consequently maintains the cells in an undifferentiated and proliferating state in vitro. Moreover, MSCs derived from myeloid factor 88 (MyD88)-deficient mice lacked the capacity to differentiate effectively into osteogenic and chondrogenic cells. It appears that TLRs and their ligands can serve as regulators of MSC proliferation and differentiation and might affect the maintenance of MSC multipotency.     

Inkjet printing and UV-LED curing of photochromic dyes for functional and smart textile applications

Health concerns as a result of harmful UV-rays drive the development of UV-sensors of different kinds. In this research, a UV-responsive smart textile is produced by inkjet printing and UV-LED curing of a specifically designed photochromic ink on PET fabric. This paper focuses on tuning and characterizing the colour performance of a photochromic dye embedded in a UV-curable ink resin. The influence of industrial fabrication parameters on the crosslinking density of the UV-resin and hence on the colour kinetics is investigated. A lower crosslinking density of the UV-resin increases the kinetic switching speed of the photochromic dye molecules upon isomerization. By introducing an extended kinetic model, which defines rate constants k_colouration, k_decay and k_{decolouration}, the colour performance of photochromic textiles can be predicted. Fabrication parameters present a flexible and fast alternative to polymer conjugation to control kinetics of photochromic dyes in a resin. In particular, industrial fabrication parameters during printing and curing of the photochromic ink are used to set the colour yield, colouration/decolouration rates and the durability, which are important characteristics towards the development of a UV-sensor for smart textile applications.

Tuned performance of an inkjet-printed and UV-LED cured smart textile UV-sensor based on a photochromic dye using fabrication parameters.     

COVID19 infection in a patient with paroxysmal nocturnal hemoglobinuria: A case report

Introduction:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hemopoietic stem cell disorder characterized by the triad of hemolytic anemia, thrombosis, and impaired bone marrow function. Evidence suggests that severe outcomes in COVID19 infection are attributed to the excessive activation of the complement cascade leading to acute lung injury and associated is with an increased prothrombotic state.Patient concerns:A 27-year-old Caucasian man with PNH presented to the Emergency Department of our hospital with acute onset shortness of breath, cough and blood in urine.Diagnosis:The patient was diagnosed with acute hemolytic exacerbation of PNH complicated with moderate COVID19 pneumonia.Outcomes:The patient was initiated with an anticoagulant unfractionated heparin, dexamethasone, and cefuroxime injection. His symptoms quickly resolved, and he was discharged after 5 days.Conclusion:The complement system activation is a critical component in the sequalae of COVID19 infection. Evidence suggests that severe outcomes in COVID19 infection are attributed to the excessive activation of the complement cascade leading to acute lung injury and associated is with an increased prothrombotic state. Notably, C5a concentration was noted to be higher in patients with COVID19 infection. The use of complement inhibitors to attenuate immune mediated damage in COVID19 nevertheless represents a very interesting theoretical approach. However, careful consideration as to which patients may benefit will be required and the outcome of clinical trials needed.     

Admixed phenotype of NEDD4L associated periventricular nodular heterotopia: A case report

Rationale:Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene.Patient concerns:We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband''s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.Diagnoses:The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband''s genome that absented in any other analyzed family member, suggesting its de novo origin.Interventions and outcomes:The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.Lessons:We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.     

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

Molecular imaging allows the non-invasive assessment of membrane transporter expression and function in living subjects. Such technologies have the potential to become diagnostic and prognostic tools, allowing detection, localization, and prediction of response of tumors and their metastases to therapy. Beyond tumors, imaging can also help understand the role of transporters in adverse drug effects and drug clearance. Here, we review molecular imaging technologies that monitor transporter-mediated processes. We emphasize emerging probe substrates and potential clinical applications of imaging the function of membrane transporters in cancer.KEY WORDS: membrane transporters, molecular imaging, multidrug resistance, near infrared, optical imaging