Positron emission tomography (PET) and magnetic resonance imaging (MRI) are widely used in vivo imaging technologies with both clinical and biomedical research applications. The strengths of MRI include high-resolution, high-contrast morphologic imaging of soft tissues; the ability to image physiologic parameters such as diffusion and changes in oxygenation level resulting from neuronal stimulation; and the measurement of metabolites using chemical shift imaging. PET images the distribution of biologically targeted radiotracers with high sensitivity, but images generally lack anatomic context and are of lower spatial resolution. Integration of these technologies permits the acquisition of temporally correlated data showing the distribution of PET radiotracers and MRI contrast agents or MR-detectable metabolites, with registration to the underlying anatomy. An MRI-compatible PET scanner has been built for biomedical research applications that allows data from both modalities to be acquired simultaneously. Experiments demonstrate no effect of the MRI system on the spatial resolution of the PET system and <10% reduction in the fraction of radioactive decay events detected by the PET scanner inside the MRI. The signal-to-noise ratio and uniformity of the MR images, with the exception of one particular pulse sequence, were little affected by the presence of the PET scanner. In vivo simultaneous PET and MRI studies were performed in mice. Proof-of-principle in vivo MR spectroscopy and functional MRI experiments were also demonstrated with the combined scanner. molecular imaging ͉ small animal imaging ͉ multimodality imaging P ositron emission tomography (PET) noninvasively images the distribution in vivo of biomolecules (small molecules, peptides, antibodies, and nanoparticles) labeled with radionuclides that undergo positron decay and produce back-to-back 511-keV annihilation photons (1). Because of the high sensitivity of radioactive assays, PET can measure picomolar concentrations of labeled biomolecules. A wide variety of molecular targets and pathways have been imaged by using PET radiotracers (2, 3), with the avid accumulation of the radiotracer [ 18 F]-2-fluoro-2-deoxy-D-gluocse (FDG) in malignant tumors being just one example that has widespread applications in the clinic and in the study of therapeutic strategies for tumor treatment in animal models. However, the spatial resolution of PET is limited by physical factors associated with positron physics and by the difficulty of acquiring sufficient counting statistics. Furthermore, PET images often lack definitive anatomic information, making interpretation of the precise location of radiotracer accumulation difficult.Magnetic resonance imaging (MRI) can provide high-spatialresolution anatomic images with exquisite soft-tissue contrast by exploiting the differences in relaxation times of protons in different biochemical environments (4, 5). The combination of high spatial resolution and contrast allows the anatomic consequences (e.g., tumor growth, brain atroph...

Rationale: Clinical benefits of reperfusion after myocardial infarction are offset by maladaptive innate immune cell function, and therapeutic interventions are lacking. Objective : We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion. Methods and Results: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage Mertk deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial ischemia reperfusion. More notably, Mertk(CR ) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCII LO CCR2 − (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-β. Mertk deficiency compromised the accumulation of MHCII LO phagocytes, and this was rescued in Mertk(CR ) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced soluble MER levels post-ischemia reperfusion. Conclusions: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCII LO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.

Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury, SNI). We observed inter-related changes: 1) In resting-state fMRI, functional connectivity of the NAc to dorsal striatum and cortex was reduced 28 days (but not 5 days) after SNI; 2) contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28 days after SNI; 3) In SNI (but not sham) covariance of gene expression was upregulated at 5 days and settled to a new state at 28 days; and 4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior.

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.

We report a detailed 1 H NMR study on the spin dynamics of single molecule magnets as a function of temperature and external magnetic field. A gradual loss of the 1 H NMR signal intensity ͑wipeout effect͒ is observed on decreasing the temperature for all the investigated ferromagnetic clusters. This effect is accompanied by a simultaneous enhancement of the spin-spin and spin-lattice relaxation rate T 2 −1 and T 1 −1 , respectively. The complications entered in the interpretation of the signal loss by the wipeout effect are overcome, and the information about the spin dynamics is retrieved, by implementing a simple and intuitive model that captures the main physical characteristics of the problem and reveals a universal behavior of the spin dynamics for all the clusters. According to our analysis the origin of the wipeout effect as well as the enhancement of the relaxation rates T 1 −1 and T 2 −1 in the FM clusters is related to a decrease of the lifetime broadening parameter of the magnetic energy levels, down to the range of the 1 H Larmor frequency. The temperature dependence of the lifetime broadening can be described at intermediate temperatures by a power law dependence on T similar to that observed in antifferomagnetic rings ͓S. H. Baek et al., Phys. Rev. B 70, 134434 ͑2004͔͒.

Functional magnetic resonance imaging (fMRI) in rodents holds great promise for advancing our knowledge about human brain function. However, the use of anesthetics to immobilize rodents during fMRI experiments has restricted the type of questions that can be addressed using this technique. Here we describe an innovative procedure to train rats to be constrained without the need of any anesthesia during the whole procedure. We show that with 8–10 days of acclimation rats can be conscious and remain still during fMRI experiments under minimal stress. In addition, we provide fMRI results of conscious rodents in a variety of commonly used fMRI experimental paradigms, and we demonstrate the improved quality of these scans by comparing results when the same rodents were scanned under anesthesia. We confirm that the awake scanning procedure permits an improved evaluation of brain networks and brain response to external stimuli with minimal movement artifact. The present study further advances the field of fMRI in awake rodents, which provide more direct, forward and reverse, translational opportunities regarding brain functional correspondences between human and rodent research.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through noninvasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients. We consistently observed demyelinated lesions and focal inflammatory changes of the CNS in both mouse models but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP.

Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nano-ablation and nano-embolization. Nano-ablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nano-embolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intra-tumoral DOX-SPIO uptake, with limited off-target delivery in tumor bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.