Correlation between musculoskeletal structure of the hand and primate locomotion: Morphometric and mechanical analysis in prehension using the cross- and triple-ratios.

Biometric ratios of the relative length of the rays in the hand have been analyzed between primate species in the light of their hand function or phylogeny. However, how relative lengths among phalanges are mechanically linked to the grasping function of primates with different locomotor behaviors remains unclear. To clarify this, we calculated cross and triple-ratios, which are related to the torque distribution, and the torque generation mode at different joint angles using the lengths of the phalanges and metacarpal bones in 52 primates belonging to 25 species. The torque exerted on the finger joint and traction force of the flexor tendons necessary for a cylindrical grip and a suspensory hand posture were calculated using the moment arm of flexor tendons measured on magnetic resonance images, and were compared among Hylobates spp., Ateles sp., and Papio hamadryas. Finally, the torques calculated from the model were validated by a mechanical study detecting the force exerted on the phalanx by pulling the digital flexor muscles during suspension in these three species. Canonical discriminant analysis of cross and triple-ratios classified primates almost in accordance with their current classification based on locomotor behavior. The traction force was markedly reduced with flexion of the MCP joint parallel to the torque in brachiating primates; this was notably lower in the terrestrial quadrupedal primates than in the arboreal primates at mild flexion. Our mechanical study supported these features in the torque and traction force generation efficiencies. Our results suggest that suspensory or terrestrial quadrupedal primates have hand structures that can exert more torque at a suspensory posture, or palmigrade and digitigrade locomotion, respectively. Furthermore, our study suggests availability of the cross and triple-ratios as one of the indicators to estimate the hand function from the skeletal structure.

Transplantation of iPS-Derived Tumor Cells with a Homozygous MHC Haplotype Induces GRP94 Antibody Production in MHC-Matched Macaques.

Immune surveillance is a critical component of the antitumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey-induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance. Cancer Res; 77(21); 6001-10. ©2017 AACR.

Fluorodopa is a Promising Fluorine-19 MRI Probe for Evaluating Striatal Dopaminergic Function in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine-19 (19 F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low-background, and cost-effective approach to evaluate dopaminergic function using non-radioactive fluorine-containing dopaminergic agents. The aim of this study was to find a potent 19 F MRI probe to evaluate dopaminergic presynaptic function in the striatum. To select candidates for 19 F MRI probes, we investigated the following eight non-radioactive fluorine-containing dopaminergic agents: fluorodopa (F-DOPA), F-tyrosine, haloperidol, GBR13069 duhydrochloride, GBR12909 duhydrochloride, 3-bis-(4-fluorophenyl) methoxytropane hydrochloride, flupenthixol, and fenfluramine. In 19 F nuclear magnetic resonance measurements, F-tyrosine and F-DOPA displayed a relatively higher signal-to-noise ratio value in brain homogenates than in others. F-DOPA, but not F-tyrosine, induced the rotational behavior in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rat model. In addition, a significantly high amount of F-DOPA accumulated in the ipsilateral striatum of hemiparkinsonian rats after the injection. We performed 19 F MRI in PC12 cells and isolated rat brain using a 7T MR scanner. Our findings suggest that F-DOPA is a promising 19 F MRI probe for evaluating dopaminergic presynaptic function in the striatum of hemiparkinsonian rats. © 2016 Wiley Periodicals, Inc.

Amyloid imaging using fluorine-19 magnetic resonance imaging ((19)F-MRI).

The formation of senile plaques followed by the deposition of amyloid-ß is the earliest pathological change in Alzheimer's disease. Thus, the detection of senile plaques remains the most important early diagnostic indicator of Alzheimer's disease. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of Alzheimer's patients using positron emission tomography (PET) or magnetic resonance imaging (MRI). Because fluorine-19 ((19)F) displays an intense nuclear magnetic resonance signal and is almost non-existent in the body, targets are detected with a higher signal-to-noise ratio using appropriate fluorinated contrast agents. The recent introduction of high-field MRI allows us to detect amyloid depositions in the brain of living mouse using (19)F-MRI. So far, at least three probes have been reported to detect amyloid deposition in the brain of transgenic mouse models of Alzheimer's disease; (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), 1,7-bis(4'-hydroxy-3'-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene3,5-dione (FMeC1, Shiga-Y5) and 6-(3',6',9',15',18',21'-heptaoxa-23',23',23'-trifluorotricosanyloxy)-2-(4'-dimethylaminostyryl)benzoxazole (XP7, Shiga-X22). This review presents the recent advances in amyloid imaging using (19)F-MRI, including our own studies.

Germanium-Vacancy Single Color Centers in Diamond.

Atomic-sized fluorescent defects in diamond are widely recognized as a promising solid state platform for quantum cryptography and quantum information processing. For these applications, single photon sources with a high intensity and reproducible fabrication methods are required. In this study, we report a novel color center in diamond, composed of a germanium (Ge) and a vacancy (V) and named the GeV center, which has a sharp and strong photoluminescence band with a zero-phonon line at 602 nm at room temperature. We demonstrate this new color center works as a single photon source. Both ion implantation and chemical vapor deposition techniques enabled fabrication of GeV centers in diamond. A first-principles calculation revealed the atomic crystal structure and energy levels of the GeV center.

Arsenic trioxide sensitizes glioblastoma to a myc inhibitor.

Glioblastoma multiforme (GBM) is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC) of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs) than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.

Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus.

Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus.

A polymer-based magnetic resonance tracer for visualization of solid tumors by 13C spectroscopic imaging.

Morphological imaging precedes lesion-specific visualization in magnetic resonance imaging (MRI) because of the superior ability of this technique to depict tissue morphology with excellent spatial and temporal resolutions. To achieve lesion-specific visualization of tumors by MRI, we investigated the availability of a novel polymer-based tracer. Although the 13C nucleus is a candidate for a detection nucleus because of its low background signal in the body, the low magnetic resonance sensitivity of the nucleus needs to be resolved before developing a 13C-based tracer. In order to overcome this problem, we enriched polyethylene glycol (PEG), a biocompatible polymer, with 13C atoms. 13C-PEG40,000 (13C-PEG with an average molecular weight of 40 kDa) emitted a single 13C signal with a high signal-to-noise ratio due to its ability to maintain signal sharpness, as was confirmed by in vivo investigation, and displayed a chemical shift sufficiently distinct from that of endogenous fat. 13C-PEG40,000 intravenously injected into mice showed long retention in circulation, leading to its effective accumulation in tumors reflecting the well-known phenomenon that macromolecules accumulate in tumors because of leaky tumor capillaries. These properties of 13C-PEG40,000 allowed visualization of tumors in mice by 13C spectroscopic imaging. These findings suggest that a technique based on 13C-PEG is a promising strategy for tumor detection.

Preferred features of a fluorine-19 MRI probe for amyloid detection in the brain.

Fluorine-19 magnetic resonance imaging (19F MRI) could be a promising approach for imaging amyloid deposition in the brain. However, the required features of a 19F MRI probe for amyloid detection remain unclear. In the present study, we investigated a series of compounds as potent 19F probes that could prevent the reduction in MR signal when bound to amyloid plaques in the brain. Each compound consists of styrylbenzoxazole as a core structure linked by a different length of polyethylene glycol (PEG) chain to one of three types of fluorine-labeled group: a trifluoroethoxy group, a hexafluoroisopropoxy group, or a 3',5'-bis(trifluoromethyl)benzylamino group. Among these compounds, 6-(3',6',9',15',18',21'-heptaoxa-23',23',23'-trifluoro tricosanyloxy)-2-(4'-dimethylaminostyryl)benzoxazole [compound 3b (m = 6)], which has a trifluoroethoxy group with seven ethylene glycol groups in the PEG chain, showed significant 19F MR signals in the brains of AßPPswe/PS1dE9 double-transgenic mice, but not wild-type mice. This suggested that compound 3b (m = 6) could be a useful 19F MRI probe for amyloid detection. Furthermore, this study identified the most effective length of PEG chain between the fluorine-labeled group and the core structure to ensure a strong MR signal when the probe is bound to amyloid plaques.

Mapping of cerebral metabolic rate of oxygen using DSC and BOLD MR imaging: a preliminary study.

Imaging of cerebral oxygen metabolism is useful for selecting and monitoring therapy, matching patients with interventions, and optimizing outcomes while reducing the incidence of hemorrhagic changes. We aimed to measure oxygen metabolism using magnetic resonance (MR) imaging. Because the magnetic susceptibility of hemoglobin varies with its redox status, the regional oxygen saturation should be measurable by MR imaging. We derived equations based on the blood oxygenation level-dependent (BOLD) theory and evaluated their validity in patients with chronic cerebral ischemia. From changes in BOLD signal, cerebral blood flow (CBF), and cerebral blood volume (CBV) after loading of acetazolamide or breath-holding, we calculated the cerebral metabolic rate of oxygen (CMRO(2)) pixel by pixel and compared the results to those of positron emission tomography (PET) examination. The correlation coefficient between the 2 modalities was between 0.70 and 0.75 in 4 patients, suggesting the applicability of BOLD-contrast MR imaging, but ranged from 0.39 to 0.47 in assessment of oxygen extraction fraction (OEF). BOLD contrast MR imaging tended to overestimate the region of decreased OEF. Some technical challenges remain for improving the sensitivity of delta BOLD, selective measurement of venous blood volume, and shortening of examination time.

The profile of hippocampal metabolites differs between Alzheimer's disease and subcortical ischemic vascular dementia, as measured by proton magnetic resonance spectroscopy.

Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD) have overlapping pathologies and risk factors, but their underlying neurodegenerative mechanisms are basically different. We performed magnetic resonance spectroscopy (MRS) to study metabolite differences between the two diseases in vivo. The subjects were 31 patients with SIVD and 99 with AD. Additionally, 45 elderly subjects were recruited as controls. We measured N-acetylaspartate (NAA), glutamine and glutamate (Glx), and myoinositol (mIns) concentration quantitatively using a 1.5-T MR scanner. N-acetylaspartate and Glx concentrations decreased in the hippocampus and cingulate/precuneal cortices (PCC) in both AD and SIVD patients, and the NAA decrease in the hippocampus was more prominent in AD than in SIVD. Interestingly, the pattern of mIns concentration changes differed between the two disorders; mIns was increased in AD but not increased in SIVD. If one differentiates between AD and SIVD by the mIns concentration in the hippocampus, the area under the receiver operating characteristic curve was 0.95, suggesting a high potential for discrimination. Our results suggest that proton MRS can provide useful information to differentiate between AD and SIVD. The difference of mIns concentrations in the hippocampus and PCC seems to reflect the different neurodegenerative mechanisms of the two disorders.

A simple way to acquire T(1)-weighted MR images of rat liver with respiratory triggering.

To acquire high-resolution T(1)-weighted images of the liver in rats, for which breath-holding cannot be ensured, respiratory triggering is essential. At the respiratory rate of 30-60 times/min in rats, however, T(1)-weighted images cannot be obtained with simple triggering. As a simple solution to this, we applied multiple repeated acquisitions with one trigger signal. With this technique, sufficient T(1) contrast could be easily achieved in rat liver enhanced by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid infusion.

Morphometric characterization of Binswanger's disease: comparison with Alzheimer's disease.

BACKGROUND AND PURPOSE: Dementia due to hypertensive vascular disease is a potential target to treat prophylactively before it progresses insidiously. Binswanger's disease (BD) is a type of subcortical vascular dementia, but its clinical features and pathophysiology are still obscure. We therefore tried to find a topographic distribution of brain atrophy in BD by morphometric analysis. METHODS: Twenty patients with BD, 50 patients with AD, and 80 elderly controls were recruited. We contrasted the gray matter atrophy of BD to that of AD to identify a pathognomic pattern using magnetic resonance imaging. We used DARTEL (diffeomorphic anatomical registration through exponential Lie algebra) for voxel-based morphometry, expecting that its sophisticated algorithm would work well to deal with the subjects with brain atrophy. RESULTS: Atrophy of cortices was predominant in the posterior cortices in AD but was in the anterior cortices in BD. Atrophy of amygdala and hippocampus was similar in each disease. In contrast, thalamus, caudate nucleus, insula, anterior cingulate cortex, and frontal cortices were significantly more atrophied in BD than in AD (z-score >3). CONCLUSIONS: We demonstrated topographic patterns of brain atrophy in BD. Since affected regions of BD match with the anatomical connections of frontal-subcortical circuits, it seems reasonable to suppose that BD pathology is the result of hypertensive vascular disease and subsequent regression from the white matter injuries.

An MR comparison study of cardiogenic and noncardiogenic pulmonary edema in animal models.

PURPOSE: To apply magnetic resonance (MR) imaging to differential diagnosis of cardiogenic pulmonary edema (CPE) and noncardiogenic pulmonary edema (NCPE). MATERIALS AND METHODS: In the CPE group, MR measurements were performed on 5 rats just before and 3 h after administration of 21 ± 2% body weight of normal saline. In the NCPE group, measurements were similarly performed on 5 animals just before and 48 h after 0.75 mg/body of lipopolysaccharide intratracheal administration. Animals were killed for bronchoalveolar lavage fluid (BALF) or pathological analysis after MR measurements. RESULTS: The relation between signal intensity and the T(2)* value of MR imaging was different in the two groups. The T(2)* in the NCPE group was significantly longer than that in the CPE group at the same signal intensity level. The lactate levels measured by in vivo MR spectroscopy did not show a difference between the CPE and NCPE groups, although the lactate BALF levels of the two groups were significantly different. CONCLUSION: The relation between signal intensity and T(2)* value was useful for the differentiation between these two pulmonary diseases. The measurable lactate level in pulmonary lesions suggests the applicability of MR spectroscopy to pulmonary disease.

Combination of two fat saturation pulses improves detectability of glucose signals in carbon-13 MR spectroscopy.

In order to improve the fat suppression performance of in vivo (13)C-MRS operating at 3.0 Tesla, a phantom model study was conducted using a combination of two fat suppression techniques; a set of pulses for frequency (chemical shift) selective suppression (CHESS), and spatial saturation (SAT). By optimizing the slab thickness for SAT and the irradiation bandwidth for CHESS, the signals of the -(13)CH(3) peak at 49 ppm and the -(13)CH(2)- peak at 26 ppm simulating fat components were suppressed to 5% and 19%, respectively. Combination of these two fat suppression pulses achieved a 53% increase of the height ratio of the glucose C1ß peak compared with the sum of all other peaks, indicating better sensitivity for glucose signal detection. This method will be applicable for in vivo (13)C-MRS by additional adjustment with the in vivo relaxation times of the metabolites.

Clinical features of myocardial triglyceride in different types of cardiomyopathy assessed by proton magnetic resonance spectroscopy: comparison with myocardial creatine.

BACKGROUND: Myocardial lipid overstorage may produce cardiomyopathy, leading to dysfunction, but advanced heart failure may cause lipolysis via sympathetic nerve activation. In the failing heart, the creatine kinase system may also be impaired. The aims of this study were to assess myocardial triglyceride (TG) and creatine (CR) in different types of cardiomyopathy and to investigate whether they are related to the severity of cardiac dysfunction. METHODS AND RESULTS: In patients with hypertrophic cardiomyopathy (HCM, n = 8), dilated cardiomyopathy (DCM, n = 12) or ischemic cardiomyopathy (ICM, n = 10), and normal subjects (NML, n = 22), myocardial TG and CR were evaluated using proton magnetic resonance spectroscopy. To assess cardiac sympathetic nerve activity, myocardial MIBG (a radioactive guanethidine analog) uptake was measured in DCM. Myocardial TG was significantly lower in hypertrophic cardiomyopathy (HCM) (1.92 ± 0.99 µmol/g), but higher in ICM (7.59 ± 4.36 µmol/g) than in NML hearts (4.05 ± 1.94 µmol/g). There was no significant difference in TG between DCM (4.84 ± 6.45 µmol/g) and NML. Myocardial CR in HCM (20.4 ± 8.4 µmol/g), DCM (14.8 ± 4.8 µmol/g), and ICM (19.4 ± 6.3 µmol/g) was significantly lower than that in NML hearts (27.1 ± 4.3 µmol/g). Overall, myocardial CR correlated positively with the severity of heart failure estimated by ejection fraction or myocardial BMIPP (a radioactive fatty acid analog) uptake, but TG did not. In DCM, myocardial TG correlated with body mass index, but not with MIBG uptake. CONCLUSIONS: Myocardial TG may be related to the specific cause of disease rather than the severity of cardiac dysfunction. In contrast, myocardial CR reflects the severity of heart failure despite different pathoetiologic mechanisms of dysfunction. In DCM, myocardial TG may be affected by an overweight state rather than cardiac sympathetic nerve dysfunction. Thus, myocardial CR has a closer relationship to heart failure severity than does myocardial TG.

Preparation for highly sensitive MRI contrast agents using core/shell type nanoparticles consisting of multiple SPIO cores with thin silica coating.

We describe here the facile and robust preparation methods for the multiple-SPIO-containing silica-coated core/shell type nanoparticles which can serve as a highly sensitive MRI contrast agent. The imidazolium-tethered core/shell type particles were synthesized, and the centrifugal selection for the multiple-SPIO-containing particles and the etching process to fabricate thin silica layers were carried out to improve the proton relaxivity of water tissue. We found that the synthetic particles can provide approximately 7-fold clearer contrasts than that of the particles before treatments. In addition, the particles can show good dispersibility at least for 1 week in aqueous media.

Simple PEG conjugation of SPIO via an Au-S bond improves its tumor targeting potency as a novel MR tumor imaging agent.

Gold/iron oxide magnetic nanoparticles are hybrid nanoparticles containing a core of magnetic iron oxide and surface colloidal gold, which allows for various biomaterials to be immobilized on the surface of the iron oxide nanoparticles via colloidal gold. Here, we developed a novel magnetic resonance (MR) imaging agent to broaden the MR tumor-imaging spectrum of superparamagnetic iron oxide nanoparticles (SPIO), e.g., Feridex(), a clinical MR imaging agent for diagnosing liver cancer. Au/Feridex was synthesized by electron beam irradiation, and thiol-modified poly(ethylene glycol) (PEG-SH) was easily conjugated to its surface via an Au-S bond without the need for any chemical reactions. PEG conjugation of Au/Feridex enhanced its accumulation in Meth-A tumor tissue and decreased its accumulation in normal liver tissue. In addition, MRI using PEG-Au/Feridex, in contrast to MRI using unmodified Au/Feridex and Feridex, detected B16BL6 and Meth-A tumor tissues in vivo. This finding indicates that PEG-Au/Feridex is useful for diagnosing various types of tumors. In addition, because the synthesis of PEG-Au/Feridex is simple and high yields are easily produced, PEG-modified SPIO for tumor diagnosis can be prepared on an industrial scale with low cost.

Relationship between the tautomeric structures of curcumin derivatives and their Abeta-binding activities in the context of therapies for Alzheimer's disease.

Curcumin, which can exist in an equilibrium between keto and enol tautomers, binds to beta-amyloid (Abeta) fibrils/aggregates. The aim of this study was to assess the relationship between the tautomeric structures of curcumin derivatives and their Abeta-binding activities. Curcumin derivatives with keto-enol tautomerism showed high levels of binding to Abeta aggregates but not to Abeta monomers. The binding activity of the keto form analogue of curcumin to Abeta aggregates was found to be much weaker than that of curcumin derivatives with keto-enol tautomerism. The color of a curcumin derivative with keto-enol tautomerism, which was substituted at the C-4 position, changed from yellow to orange within 30 min of being combined with Abeta aggregates in physiological buffer. This resulted from a remarkable increase in the enol form with extended conjugation of double bonds upon binding. These findings suggest that curcumin derivatives exist predominantly in the enol form during binding to Abeta aggregates, and that the enolization of curcumin derivatives is crucial for binding to Abeta aggregates. The keto-enol tautomerism of curcumin derivatives may be a novel target for the design of amyloid-binding agents that can be used both for therapy and for amyloid detection in Alzheimer's disease.