Background-free dual-mode optical and 13C magnetic resonance imaging in diamond particles.

Multimodal imaging-the ability to acquire images of an object through more than one imaging mode simultaneously-has opened additional perspectives in areas ranging from astronomy to medicine. In this paper, we report progress toward combining optical and magnetic resonance (MR) imaging in such a "dual" imaging mode. They are attractive in combination because they offer complementary advantages of resolution and speed, especially in the context of imaging in scattering environments. Our approach relies on a specific material platform, microdiamond particles hosting nitrogen vacancy (NV) defect centers that fluoresce brightly under optical excitation and simultaneously "hyperpolarize" lattice [Formula: see text] nuclei, making them bright under MR imaging. We highlight advantages of dual-mode optical and MR imaging in allowing background-free particle imaging and describe regimes in which either mode can enhance the other. Leveraging the fact that the two imaging modes proceed in Fourier-reciprocal domains (real and k-space), we propose a sampling protocol that accelerates image reconstruction in sparse-imaging scenarios. Our work suggests interesting possibilities for the simultaneous optical and low-field MR imaging of targeted diamond nanoparticles.

Direct Crystallization of Diamine Radical Cations: Carbon-Nitrogen Bond Formation from the Reaction of Triphenylamine with TiCl4 , TiBr4 , or SnCl4 versus Carbon-Carbon Bond Formation with SbCl5.

Direct synthesis of diamine radical cations in crystalline form proceeding through oxidation of triphenylamine followed by the formation of a new C-N bond is reported. Although the oxidative coupling of triphenylamine is well studied, diamine products are rarely captured in their radical cation state. The neutral diamine most frequently obtained from this reaction pathway is N,N,N',N'-tetraphenylbenzidine. Herein, the capture of radical cations of diamines in crystalline form in one step starting with neutral triphenylamine was demonstrated, and the formation of two products (the radical cations of N,N,N',N'-tetraphenyl-1,4-benzenediamine or N,N,N',N'-tetraphenylbenzidine) depending on the oxidizing agent used was observed. The radical species are characterized by single-crystal X-Ray diffraction, electron paramagnetic resonance spectroscopy, and optical spectroscopy.

Imaging Sequences for Hyperpolarized Solids.

Hyperpolarization is one of the approaches to enhance Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) signal by increasing the population difference between the nuclear spin states. Imaging hyperpolarized solids opens up extensive possibilities, yet is challenging to perform. The highly populated state is normally not replenishable to the initial polarization level by spin-lattice relaxation, which regular MRI sequences rely on. This makes it necessary to carefully "budget" the polarization to optimize the image quality. In this paper, we present a theoretical framework to address such challenge under the assumption of either variable flip angles or a constant flip angle. In addition, we analyze the gradient arrangement to perform fast imaging to overcome intrinsic short decoherence in solids. Hyperpolarized diamonds imaging is demonstrated as a prototypical platform to test the theory.

Characterizing blood-brain barrier perturbations after exposure to human triglyceride-rich lipoprotein lipolysis products using MRI in a rat model.

PURPOSE: Previous studies indicated hyperlipidemia may be a risk factor for Alzheimer's disease, but the contributions of postprandial triglyceride-rich lipoprotein (TGRL) are not known. In this study, changes in blood-brain barrier diffusional transport following exposure to human TGRL lipolysis products were studied using MRI in a rat model. METHODS: Male Sprague-Dawley rats (∼180-250 g) received an i.v. injection of lipoprotein lipase (LpL)-hydrolyzed TGRL (n = 8, plasma concentration ≈ 150 mg human TGRL/dL). Controls received i.v. injection of either saline (n = 6) or LpL only (n = 6). The (1) H longitudinal relaxation rate R1 = 1/T1 was measured over 18 min using a rapid-acquired refocus-echo (RARE) sequence after each of three injections of the contrast agent Gd-DTPA. Patlak plots were generated for each pixel yielding blood-to-brain transfer coefficients, Ki , chosen for best fit to impermeable, uni-directional influx or bi-directional flux models using the F-test. RESULTS: Analysis from a 2-mm slice, 2-mm rostral to the bregma showed a 275% increase of mean Ki during the first 20 min after infusion of human TGRL lipolysis product that differed significantly compared with saline and LpL controls. This difference disappeared by 40 min mark. CONCLUSION: These results suggest human TGRL lipolysis products can lead to a transient increase in rat BBB permeability. Magn Reson Med 76:1246-1251, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Click chemistry generated model DNA-peptide heteroconjugates as tools for mass spectrometry.

UV cross-linking of nucleic acids to proteins in combination with mass spectrometry is a powerful technique to identify proteins, peptides, and the amino acids involved in intermolecular interactions within nucleic acid-protein complexes. However, the mass spectrometric identification of cross-linked nucleic acid-protein heteroconjugates in complex mixtures and MS/MS characterization of the specific sites of cross-linking is extremely challenging. As a tool for the optimization of sample preparation, ionization, fragmentation, and detection by mass spectrometry, novel synthetic DNA-peptide heteroconjugates were generated to act as mimics of UV cross-linked heteroconjugates. Click chemistry was employed to cross-link peptides to DNA oligonucleotides. These heteroconjugates were fully characterized by high resolution FTICR mass spectrometry and by collision-induced dissociation (CID) following nuclease P1 digestion of the DNA moiety to a single nucleotide monophosphate. This allowed the exact site of the cross-linking within the peptide to be unambiguously assigned. These synthetic DNA-peptide heteroconjugates have the potential to be of use for a variety of applications that involve DNA-peptide heteroconjugates.

MRI measurement of blood-brain barrier transport with a rapid acquisition refocused echo (RARE) method.

Dynamic Contrast Enhanced (DCE) MRI is increasingly being used to assess changes in capillary permeability. Most quantitative techniques used to measure capillary permeability are based on the Fick equation that requires measurement of signal reflecting both plasma and tissue concentrations of the solute being tested. To date, most Magnetic Resonance Imaging (MRI) methods for acquiring appropriate data quickly rely on gradient recalled echo (GRE) type acquisitions, which work well in clinical low field settings. However, acquiring this type of data on high field small animal preclinical MRIs is problematic due to geometrical distortions from susceptibility mismatch. This problem can be exacerbated when using small animal models to measure blood brain barrier (BBB) permeability, where precise sampling from the superior sagittal sinus (SSS) is commonly used to determine the plasma concentration of the contrast agent. Here we present results demonstrating that a standard saturation recovery rapid acquisition refocused echo (RARE) method is capable of acquiring T1 maps with good spatial and temporal resolution for Patlak analysis (Patlak, 1983) to assess changes in BBB Gd-DTPA permeability following middle cerebral artery occlusion with reperfusion in the rat. This method limits known problems with magnetic susceptibility mismatch and may thus allow greater accuracy in BBB permeability measurement in small animals.

Photoluminescent carbon dots from 1,4-addition polymers.

Photoluminescent carbon dots were synthesised directly by thermopyrolysis of 1,4-addition polymers, allowing precise control of their properties. The effect of polymer composition on the properties of the carbon dots was investigated by TEM, IR, XPS, elemental analysis and fluorescence analysis, with carbon dots synthesised from nitrogen-containing polymers showing the highest fluorescence. The carbon dots with high nitrogen content were observed to have strong fluorescence in the visible region, and culture with cells showed that the carbon dots were non-cytotoxic and readily taken up by three different cell lines.

A high-pressure NMR probe for aqueous geochemistry.

A non-magnetic piston-cylinder pressure cell is presented for solution-state NMR spectroscopy at geochemical pressures. The probe has been calibrated up to 20 kbar using in situ ruby fluorescence and allows for the measurement of pressure dependencies of a wide variety of NMR-active nuclei with as little as 10 µL of sample in a microcoil. Initial (11)B NMR spectroscopy of the H3BO3-catechol equilibria reveals a large pressure-driven exchange rate and a negative pressure-dependent activation volume, reflecting increased solvation and electrostriction upon boron-catecholate formation. The inexpensive probe design doubles the current pressure range available for solution NMR spectroscopy and is particularly important to advance the field of aqueous geochemistry.

Speciation of Phosphorus in Pet Foods by Solid-State 31P-MAS-NMR Spectroscopy.

Solid-state magic angle spinning 31P NMR spectroscopy is used to identify and quantify phosphorus-containing species in pet foods. The measurement is challenging due to the long spin-lattice relaxation times (T1s). Data acquisition times are shortened by acquiring data with a tip angle smaller than 90° and shortening the repetition time. However, the spin-lattice relaxation times (T1s) of the different 31P compounds are quite different, necessitating a separate measurement for each compound in the pet food. Knowledge of T1 is used to calculate the relative amount of 31P in the samples. Samples of known concentration are also measured, enabling the quantitative measurement of total phosphorus content.

Aß efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.

Impairment of vascular pathways of cerebral ß-amyloid (Aß) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aß clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aß within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aß co-deposits. LRP1-mediated Aß transport across the blood-brain barrier and Aß clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aß deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aß pathology.

Magnetic resonance thermal imaging combined with SMASH navigators in the presence of motion.

This study develops and tests an MR thermometry method combined with SMASH navigators in phantom experiments mimicking human liver motion with the purpose of detecting and correcting motion artifacts in thermal MR images. Experimental data were acquired on a 3T MRI scanner. Motion artifacts of mobile phantoms mimicking human liver motion were detected and corrected using the SMASH navigators and then MR temperature maps were obtained using a proton resonant frequency (PRF) shift method with complex image subtraction. Temperature acquired by MR thermal imaging was compared to that measured via thermocouples. MR thermal imaging combined with the SMASH navigator technique resulted in accurate temperature maps of the mobile phantoms compared to temperatures measured using the thermocouples. The differences between the obtained and measured temperatures varied from 8.2°C to 14.2°C and 2.2°C to 4.9°C without and with motion correction, respectively. Motion correction improved the temperature acquired by MR thermal imaging by > 55%. The combination of the MR thermal imaging and SMASH navigator technique will enable monitoring and controlling heat distribution and temperature change in tissues during thermal therapies and will be a very important tool for cancer treatment in mobile organs.

Two-way magnetic resonance tuning and enhanced subtraction imaging for non-invasive and quantitative biological imaging.

Distance-dependent magnetic resonance tuning (MRET) technology enables the sensing and quantitative imaging of biological targets in vivo, with the advantage of deep tissue penetration and fewer interactions with the surroundings as compared with those of fluorescence-based Förster resonance energy transfer. However, applications of MRET technology in vivo are currently limited by the moderate contrast enhancement and stability of T1-based MRET probes. Here we report a new two-way magnetic resonance tuning (TMRET) nanoprobe with dually activatable T1 and T2 magnetic resonance signals that is coupled with dual-contrast enhanced subtraction imaging. This integrated platform achieves a substantially improved contrast enhancement with minimal background signal and can be used to quantitatively image molecular targets in tumours and to sensitively detect very small intracranial brain tumours in patient-derived xenograft models. The high tumour-to-normal tissue ratio offered by TMRET in combination with dual-contrast enhanced subtraction imaging provides new opportunities for molecular diagnostics and image-guided biomedical applications.

IDENTIFICATION OF CONOIDIN A AS A COVALENT INHIBITOR OF PEROXIREDOXIN II.

Conoidin A (1) is an inhibitor of host cell invasion by the protozoan parasite Toxoplasma gondii. In the course of studies aimed at identifying potential targets of this compound, we determined that it binds to the T. gondii enzyme peroxiredoxin II (TgPrxII). Peroxiredoxins are a widely conserved family of enzymes that function in antioxidant defense and signal transduction, and changes in PrxII expression are associated with a variety of human diseases, including cancer. Disruption of the TgPrxII gene by homologous recombination had no effect on the sensitivity of the parasites to 1, suggesting that TgPrxII is not the invasion-relevant target of 1. However, we showed that 1 binds covalently to the peroxidatic cysteine of TgPrxII, inhibiting its enzymatic activity in vitro. Studies with human epithelial cells showed that 1 also inhibits hyperoxidation of human PrxII. These data identify Conoidin A as a novel inhibitor of this important class of antioxidant and redox signaling enzymes.

Electrically Elicited Quadriceps Muscle Torque: A Comparison of 3 Waveforms.

Study Design A controlled laboratory study, with a single-blind, block-randomization crossover design. Objectives To compare the electrically elicited knee extensor torque produced by 3 clinically available waveforms: 2500-Hz burst-modulated alternating current (BMAC), 1000-Hz BMAC, and 1000-Hz burst-modulated biphasic square-wave pulsed current (BMBPC). Background Neuromuscular electrical stimulation (NMES) is the therapeutic use of electrical current to strengthen muscle. Muscle torque produced by NMES is limited by discomfort. Methods The knee extensor maximal volitional isometric torque (KEMVIT) of 33 able-bodied participants (18 female) was measured and used to normalize the electrically elicited knee extensor torque to produce a percent of KEMVIT (%KEMVIT). Electrically elicited isometric knee extensor torque was measured in response to each of the waveforms at the participants' maximum tolerance. Results The average maximum tolerated stimulation produced 32.0 ± 16.7 %KEMVIT with 2500-Hz BMAC, 38.2 ± 18.4 %KEMVIT with 1000-Hz BMAC, and 42.2 ± 17.1 %KEMVIT with 1000-Hz BMBPC. Tukey honest significant difference (HSD) post hoc testing revealed a statistically significant difference between 2500-Hz BMAC and 1000-Hz BMAC (P = .046), and between 2500-Hz BMAC and 1000-Hz BMBPC (P<.001). No statistically significant difference was found between 1000-Hz BMAC and 1000-Hz BMBPC (P = .267). Conclusion For eliciting maximum knee extensor muscle torque, 1000-Hz BMBPC and 1000-Hz BMAC were similarly effective, and 2500-Hz BMAC was less effective. J Orthop Sports Phys Ther 2018;48(3):217-224. Epub 19 Dec 2017. doi:10.2519/jospt.2018.7601.

EPR and Structural Characterization of Water-Soluble Mn2+-Doped Si Nanoparticles.

Water-soluble poly(allylamine) Mn2+-doped Si (SiMn) nanoparticles (NPs) were prepared and show promise for biologically related applications. The nanoparticles show both strong photoluminescence and good magnetic resonance contrast imaging. The morphology and average diameter were obtained through transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM); spherical crystalline Si NPs with an average diameter of 4.2 ± 0.7 nm were observed. The doping maximum obtained through this process was an average concentration of 0.4 ± 0.3% Mn per mole of Si. The water-soluble SiMn NPs showed a strong photoluminescence with a quantum yield up to 13%. The SiMn NPs had significant T1 contrast with an r1 relaxivity of 11.1 ± 1.5 mM-1 s-1 and r2 relaxivity of 32.7 ± 4.7 mM-1 s-1 where the concentration is in mM of Mn2+. Dextran-coated poly(allylamine) SiMn NPs produced NPs with T1 and T2 contrast with a r1 relaxivity of 27.1 ± 2.8 mM-1 s-1 and r2 relaxivity of 1078.5 ± 1.9 mM-1 s-1. X-band electron paramagnetic resonance spectra are fit with a two-site model demonstrating that there are two types of Mn2+ in these NP's. The fits yield hyperfine splittings (A) of 265 and 238 MHz with significant zero field splitting (D and E terms). This is consistent with Mn in sites of symmetry lower than tetrahedral due to the small size of the NP's.

A Metal-Free Method for Producing MRI Contrast at Amyloid-ß.

Alzheimer's disease (AD) is characterized by depositions of the amyloid-ß (Aß) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aß in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aß has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aß. The molecule is comprised of a  fluorene (a molecule with high affinity for Aß) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.

"One-Pot" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol)-porphyrin-based Nanotheranostics.

Nanoparticle-based theranostic agents have emerged as a new paradigm in nanomedicine field for integration of multimodal imaging and therapeutic functions within a single platform. However, the clinical translation of these agents is severely limited by the complexity of fabrication, long-term toxicity of the materials, and unfavorable biodistributions. Here we report an extremely simple and robust approach to develop highly versatile and biocompatible theranostic poly(vinyl alcohol)-porphyrin nanoparticles (PPNs). Through a "one-pot" fabrication process, including the chelation of metal ions and encapsulation of hydrophobic drugs, monodispersenanoparticle could be formed by self-assembly of a very simple and biocompatible building block (poly(vinyl alcohol)-porphyrin conjugate). Using this approach, we could conveniently produce multifunctional PPNs that integrate optical imaging, positron emission tomography (PET), photodynamic therapy (PDT), photothermal therapy (PTT) and drug delivery functions in one formulation. PPNs exhibited unique architecture-dependent fluorescence self-quenching, as well as photodynamic- and photothermal- properties. Near-infrared fluorescence could be amplified upon PPN dissociation, providing feasibility of low-background fluorescence imaging. Doxorubicin (DOX)-loaded PPNs achieved 53 times longer half-life in blood circulation than free DOX. Upon irradiation by near infrared light at a single excitation wavelength, PPNs could be activated to release reactive oxygen species, heat and drugs simultaneously at the tumor sites in mice bearing tumor xenograft, resulting in complete eradication of tumors. Due to their organic compositions, PPNs showed no obvious cytotoxicity in mice via intravenous administration during therapeutic studies. This highly versatile and multifunctional PPN theranostic nanoplatform showed great potential for the integration of multimodal imaging and therapeutic functions towards personalized nanomedicine against cancers.

Performance test of an LSO-APD detector in a 7-T MRI scanner for simultaneous PET/MRI.

UNLABELLED: PET combined with CT has proven to be a valuable multimodality imaging device revealing both functional and anatomic information. Although PET/CT has become completely integrated into routine clinical application and also has been used in small-animal imaging, CT provides only limited soft-tissue contrast and, in preclinical studies, exposes the animal to a relatively high radiation dose. Unlike CT, MRI provides good soft-tissue contrast even without application of contrast agents and, furthermore, does not require ionizing radiation. METHODS: This project focused on combining a high-resolution PET scanner with a 7-T MRI system for animal research. Because classic PET detectors based on photomultiplier tubes cannot be used in high magnetic fields, we used a detector technology based on 10 x 10 lutetium oxyorthosilicate crystal arrays and 3 x 3 avalanche photodiode arrays. A ring of such PET detectors will ultimately be used as an insert for the 119-mm-diameter MRI bore. RESULTS: Initial measurements with 1 PET detector module in the 7-T field during application of MRI sequences were encouraging. Position profiles from the PET detectors and a first MR image of a mouse could be acquired simultaneously. CONCLUSION: Further work will concentrate on the construction of a full PET detector ring with compact, integrated electronics.

Fluorescent Formazans and Tetrazolium Salts - Towards Fluorescent Cytotoxicity Assays.

Formazan-based colorimetric cytotoxicity assays, such as the MTT assay, are typically used to assess cell viability with only metabolically active cells reducing tetrazolium salts into the formazans, which is then quantified by absorbance. Fluorescence offers several advantages compared to colorimetric assays and would enable techniques such as flow cytometry and confocal microscopy to be used for analysis. Here, fluorescent formazans 10, 11 and 12, and their corresponding tetrazolium salts 13, 16 and 24, respectively, were synthesised by incorporation of a known fluorophore backbone (coumarin, fluorescein and rhodol) with disruption of the conjugated system preventing or reducing fluorescence of the tetrazolium salts. These tetrazolium salts were successfully reduced to the fluorescent formazans with cells and offer a step forward in the development of fluorescent cytotoxicity assays.

Simultaneous PET/MRI Imaging During Mouse Cerebral Hypoxia-ischemia.

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics disturbance in affected cells. Diffusion weighted magnetic resonance imaging (MRI) identifies regions that are damaged, potentially irreversibly, by hypoxia-ischemia. Alterations in glucose utilization in the affected tissue may be detectable by positron emission tomography (PET) imaging of 2-deoxy-2-(18F)fluoro-ᴅ-glucose ([18F]FDG) uptake. Due to the rapid and variable nature of injury in this animal model, acquisition of both modes of data must be performed simultaneously in order to meaningfully correlate PET and MRI data. In addition, inter-animal variability in the hypoxic-ischemic injury due to vascular differences limits the ability to analyze multi-modal data and observe changes to a group-wise approach if data is not acquired simultaneously in individual subjects. The method presented here allows one to acquire both diffusion-weighted MRI and [18F]FDG uptake data in the same animal before, during, and after the hypoxic challenge in order to interrogate immediate physiological changes.