458 research outputs found

    When can we trust structural models derived from pair distribution function measurements?

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    The pair distribution function (PDF) is an important metric for characterising structure in complex materials, but it is well known that meaningfully different structural models can sometimes give rise to equivalent PDFs. In this paper, we discuss the use of model likelihoods as a general approach for discriminating between such homometric structure solutions. Drawing on two main case studies—one concerning the structure of a small peptide and the other amorphous calcium carbonate—we show how consideration of model likelihood can help drive robust structure solution, even in cases where the PDF is particularly information-poor. The obvious thread of these individual case studies is the potential role for machine-learning approaches to help guide structure determination from the PDF, and our paper finishes with some forward-looking discussion along these lines

    Investigation of a dual siRNA/chemotherapy delivery system for breast cancer therapy

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    Multidrug resistance (MDR) is a problem that is often associated with a poor clinical outcome in chemotherapeutic cancer treatment. MDR may potentially be overcome by utilizing synergistic approaches, such as combining siRNA gene therapy and chemotherapy to target different mechanisms of apoptosis. In this study, a strategy is presented for developing multicomponent nanomedicines using orthogonal and compatible chemistries that lead to effective nanotherapeutics. Hyperbranched polymers were used as drug carriers that contained doxorubicin (DOX), attached via a pH-sensitive hydrazone linkage, and ataxia-telangiectasia mutated (ATM) siRNA, attached via a redox-sensitive disulfide group. This nanomedicine also contained cyanine 5 (Cy5) as a diagnostic tracer as well as in-house developed bispecific antibodies that allowed targeting of the epidermal growth factor receptor (EGFR) present on tumor tissue. Highly efficient coupling of siRNA was achieved with 80% of thiol end-groups on the hyperbranched polymer coupling with siRNA. This attachment was reversible, with the majority of siRNA released in vitro under reducing conditions as desired. In cellular studies, the nanomedicine exhibited increased DNA damage and cancer cell inhibition compared to the individual treatments. Moreover, the nanomedicine has great potential to suppress the metabolism of cancer cells including both mitochondrial respiration and glycolytic activity, with enhanced efficacy observed when targeted to the cell surface protein EGFR. Our findings indicated that co-delivery of ATM siRNA and DOX serves as a more efficient therapeutic avenue in cancer treatment than delivery of the single species and offers a potential route for synergistically enhanced gene therapy

    Phonon-drag effects on thermoelectric power

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    We carry out a calculation of the phonon-drag contribution SgS_g to the thermoelectric power of bulk semiconductors and quantum well structures for the first time using the balance equation transport theory extended to the weakly nonuniform systems. Introducing wavevector and phonon-mode dependent relaxation times due to phonon-phonon interactions, the formula obtained can be used not only at low temperatures where the phonon mean free path is determined by boundary scattering, but also at high temperatures. In the linear transport limit, SgS_g is equivalent to the result obtained from the Boltzmann equation with a relaxation time approximation. The theory is applied to experiments and agreement is found between the theoretical predictions and experimental results. The role of hot-electron effects in SgS_g is discussed. The importance of the contribution of SgS_g to thermoelectric power in the hot-electron transport condition is emphasized.Comment: 8 pages, REVTEX 3.0, 7 figures avilable upon reques

    Multisite functional connectivity MRI classification of autism: ABIDE results

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    Background:: Systematic differences in functional connectivity MRI metrics have been consistently observed in autism, with predominantly decreased cortico-cortical connectivity. Previous attempts at single subject classification in high-functioning autism using whole brain point-to-point functional connectivity have yielded about 80% accurate classification of autism vs. control subjects across a wide age range. We attempted to replicate the method and results using the Autism Brain Imaging Data Exchange (ABIDE) including resting state fMRI data obtained from 964 subjects and 16 separate international sites. Methods:: For each of 964 subjects, we obtained pairwise functional connectivity measurements from a lattice of 7266 regions of interest covering the gray matter (26.4 million “connections”) after preprocessing that included motion and slice timing correction, coregistration to an anatomic image, normalization to standard space, and voxelwise removal by regression of motion parameters, soft tissue, CSF, and white matter signals. Connections were grouped into multiple bins, and a leave-one-out classifier was evaluated on connections comprising each set of bins. Age, age-squared, gender, handedness, and site were included as covariates for the classifier. Results:: Classification accuracy significantly outperformed chance but was much lower for multisite prediction than for previous single site results. As high as 60% accuracy was obtained for whole brain classification, with the best accuracy from connections involving regions of the default mode network, parahippocampaland fusiform gyri, insula, Wernicke Area, and intraparietal sulcus. The classifier score was related to symptom severity, social function, daily living skills, and verbal IQ. Classification accuracy was significantly higher for sites with longer BOLD imaging times. Conclusions:: Multisite functional connectivity classification of autism outperformed chance using a simple leave-one-out classifier, but exhibited poorer accuracy than for single site results. Attempts to use multisite classifiers will likely require improved classification algorithms, longer BOLD imaging times, and standardized acquisition parameters for possible future clinical utility

    Validation of EpiTRAQ, a transition readiness assessment tool for adolescents and young adults with epilepsy

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    ObjectiveTo design and validate a transition readiness assessment tool for adolescents and young adults with epilepsy and without intellectual disability.MethodsWe adapted a general transition readiness assessment tool (TRAQ) to add epilepsy‐relevant items based on concepts in current epilepsy quality measures. The adapted tool, EpiTRAQ, maintained the original structure and scoring system. Concurrent with clinical implementation in pediatric and adult epilepsy clinics at an academic medical center, we assessed the validity and reliability of this adapted tool for patients 16‐26 years of age. This process included initial validation with 302 patients who completed EpiTRAQ between October 2017 and May 2018; repeat validation with 381 patients who completed EpiTRAQ between June 2018 and September 2019; and retest reliability among 153 patients with more than one completed EpiTRAQ.ResultsMean scores were comparable between initial and repeat validation populations (absolute value differences between 0.05 and 0.1); internal consistency ranged from good to high. For both the initial and repeat validation, mean scores and internal consistency demonstrated high comparability to the original TRAQ validation results. Upon retest, few patients rated themselves with a lower score, while the majority rated themselves with higher scores.SignificanceEpiTRAQ is a valid and reliable tool for assessing transition readiness in adolescents and young adults with epilepsy and without intellectual disability.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162789/2/epi412427_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162789/1/epi412427.pd

    Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility

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    Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymerization-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated l-asparaginase (clinically used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodology as an attractive alternative to the covalent PEGylation of enzymes

    Phonon drag thermopower and weak localization

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    Previous experimental work on a two-dimensional (2D) electron gas in a Si-on-sapphire device led to the conclusion that both conductivity and phonon drag thermopower SgS^g are affected to the same relative extent by weak localization. The present paper presents further experimental and theoretical results on these transport coefficients for two very low mobility 2D electron gases in ή−\delta-doped GaAs/Gax_xAl1−x_{1-x}As quantum wells. The experiments were carried out in the temperature range 3-7K where phonon drag dominates the thermopower and, contrary to the previous work, the changes observed in the thermopower due to weak localization were found to be an order of magnitude less than those in the conductivity. A theoretical framework for phonon drag thermopower in 2D and 3D semiconductors is presented which accounts for this insensitivity of SgS^g to weak localization. It also provides transparent physical explanations of many previous experimental and theoretical results.Comment: 19 page Revtex file, 3 Postscript figur

    Secondary ion mass spectrometry

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    Secondary ion mass spectrometry (SIMS) is a technique for chemical analysis and imaging of solid materials, with applications in many areas of science and technology. It involves bombarding a sample surface under high vacuum with energetic primary ions. The ejected secondary ions undergo mass-to-charge ratio (m/z) analysis and are detected. The resulting mass spectrum contains detailed surface chemical information with sub-monolayer sensitivity. Different experimental configurations provide chemically resolved depth distribution and 2D or 3D images. SIMS is complementary to other surface analysis techniques, such as X-ray photoelectron spectroscopy; chemical imaging techniques, for example, vibrational microspectroscopy methods such as Fourier transform infrared spectroscopy and Raman spectroscopy; and other mass spectrometry imaging techniques, including desorption electrospray ionization and matrix-assisted laser desorption ionization. Features of SIMS include high spatial resolution, high depth resolution and broad chemical sensitivity to all elements, isotopes and molecules up to several thousand mass units. This Primer describes the operating principles of SIMS and outlines how the instrument geometry and operational parameters enable different modes of operation and information to be obtained. Applications, including materials science, surface science, electronic devices, geosciences and life sciences, are explored, finishing with an outlook for the technique

    Characterization of the Biodistribution of a Silica Vesicle Nanovaccine Carrying a Rhipicephalus (Boophilus) microplus Protective Antigen With in vivo Live Animal Imaging

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    Development of veterinary subunit vaccines comes with a spectrum of challenges, such as the choice of adjuvant, antigen delivery vehicle, and optimization of dosing strategy. Over the years, our laboratory has largely focused on investigating silica vesicles (SVs) for developing effective veterinary vaccines for multiple targets. Rhipicephalus microplus (cattle tick) are known to have a high impact on cattle health and the livestock industry in the tropical and subtropical regions. Development of vaccine using Bm86 antigen against R. microplus has emerged as an attractive alternative to control ticks. In this study, we have investigated the biodistribution of SV in a live animal model, as well as further explored the SV ability for vaccine development. Rhodamine-labeled SV-140-C18 (Rho-SV-140-C18) vesicles were used to adsorb the Cy5-labeled R. microplus Bm86 antigen (Cy5-Bm86) to enable detection and characterization of the biodistribution of SV as well as antigen in vivo in a small animal model for up to 28 days using optical fluorescence imaging. We tracked the in vivo biodistribution of SVs and Bm86 antigen at different timepoints (days 3, 8, 13, and 28) in BALB/c mice. The biodistribution analysis by live imaging as well as by measuring the fluorescent intensity of harvested organs over the duration of the experiment (28 days) showed greater accumulation of SVs at the site of injection. The Bm86 antigen biodistribution was traced in lymph nodes, kidney, and liver, contributing to our understanding how this delivery platform successfully elicits antibody responses in the groups administered antigen in combination with SV. Selected tissues (skin, lymph nodes, spleen, kidney, liver, and lungs) were examined for any cellular abnormalities by histological analysis. No adverse effect or any other abnormalities were observed in the tissues
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