3T磁共振直肠小视野APT成像

目的 化学交换饱和转移（CEST）成像技术已成为诊断与脑部和全身疾病代谢相关变化的有用工具,通过计算与水分子相邻化合物的可交换质子的含量进行定量分析。具体而言,酰胺质子转移（APT）CEST技术通过比较可交换的内源性蛋白质或肽的含量变化来区分正常组织与脑卒中和脑肿瘤组织。在体内的小器官病变诊断中,小视野（rFOV）成像技术已被广泛应用,本研究旨在应用rFOV成像技术来识别直肠中的CEST信号,探讨rFOV成像技术在直肠疾病临床诊断中的潜在效用,并为直肠疾病的放化疗提供代谢影像信息。方法 使用3.0T磁共振成像扫描仪对11名健康志愿者进行了横断面全视野（Full_FOV）和rFOV CEST成像。设置的分辨率分别为2.5×2.5×6 mm³和1.5×1.5×6 mm³。采用了0.7 μT和2 μT两种预饱和脉冲。rFOV成像采用了ZOOM成像方法。对于2 μT的饱和脉冲,采用了±3.5 ppm的MTRasym方法进行定量分析,而对于0.7 μT的饱和脉冲,则采用Lorentzian Difference的方法来量化CEST的对比度图和曲线。结果 相较于Full_FOV成像,rFOV方法可以在保持较好对比度的同时将扫描时间减半。与Full_FOV方法相比,rFOV成像方法可以得出与Full_FOV方法几乎相同的Z谱和MTRasym曲线。此外,以大约3 min的时间可以实现1.5 mm×1.5 mm分辨率的rFOV成像。这种rFOV成像方法可以更好地显示出整个直肠的解剖细节,包括CEST成像对比图及定量分析曲线。结论 CEST MRI在直肠疾病诊断方面具有较高价值,采用rFOV技术可以提供更高的空间和时间分辨率。由于其在直肠疾病诊断方面的潜力,CEST MRI可以作为临床诊断直肠疾病的首选。     

Dimerization of Cadherin-11 involves multi-site coupled unfolding and strand swapping

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Determination of water permeability of paramagnetic liposomes of interest in MRI field

The water permeability of various liposome membranes has been determined at 298 K by measuring the NMR longitudinal water proton relaxation rate of vesicles encapsulating the clinically approved Gd-HPDO3A complex (HPDO3A = 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). Two basic formulations based on DPPC (dipalmitoylphosphatidylcholine) and POPC (palmitoyl-oleylphosphatidylcholine) phospholipids were selected and investigated. Furthermore, the permeability changes caused by the membrane incorporation of amphiphiles like cholesterol and/or metal complexes of interest for designing improved liposome-based MRI contrast agents, were also investigated. The incorporation of cholesterol and metal complexes bearing C18 saturated chains in POPC-based liposomes reduces the water diffusivity across the membrane bilayer. On the contrary, the incorporation of a macrocyclic metal complex bearing four C12 alkylic chains, one for each coordination arm of the ligand, considerably enhances the water permeability in DPPC-based liposomes. Finally, it is reported that the permeability of POPC-based bilayer is increased when the liposomes are subjected to an osmotic stress.     

Hyperpolarized MRI,functional MRI,MR spectroscopy and CEST to provide metabolic information in vivo

Access to metabolic information in vivo using magnetic resonance (MR) technologies has generally been the niche of MR spectroscopy (MRS) and spectroscopic imaging (MRSI). Metabolic fluxes can be studied using the infusion of substrates labeled with magnetic isotopes, with the use of hyperpolarization especially powerful. Unfortunately, these promising methods are not yet accepted clinically, where fast, simple, and reliable measurement and diagnosis are key. Recent advances in functional MRI and chemical exchange saturation transfer (CEST) MRI allow the use of water imaging to study oxygen metabolism and tissue metabolite levels. These, together with the use of novel data analysis approaches such as machine learning for all of these metabolic MR approaches, are increasing the likelihood of their clinical translation.     

Paramagnetic liposomes as innovative contrast agents for magnetic resonance (MR) molecular imaging applications

This article illustrates some innovative applications of liposomes loaded with paramagnetic lanthanide-based complexes in MR molecular imaging field. When a relatively high amount of a Gd(III) chelate is encapsulated in the vesicle, the nanosystem can simultaneously affect both the longitudinal (R(1)) and the transverse (R(2)) relaxation rate of the bulk H2O H-atoms, and this finding can be exploited to design improved thermosensitive liposomes whose MRI response is not longer dependent on the concentration of the probe. The observation that the liposome compartmentalization of a paramagnetic Ln(III) complex induce a significant R(2) enhancement, primarily caused by magnetic susceptibility effects, prompted us to test the potential of such agents in cell-targeting MR experiments. The results obtained indicated that these nanoprobes may have a great potential for the MR visualization of cellular targets (like the glutamine membrane transporters) overexpressing in tumor cells. Liposomes loaded with paramagnetic complexes acting as NMR shift reagents have been recently proposed as highly sensitive CEST MRI agents. The main peculiarity of CEST probes is to allow the MR visualization of different agents present in the same region of interest, and this article provides an illustrative example of the in vivo potential of liposome-based CEST agents.     

The thulium complex of 1,4,7,10-tetrakis{[N-(1H-imidazol-2-yl)carbamoyl]methyl}-1,4,7,10-tetraazacyclododecane (dotami) as a ParaCEST contrast agent

1,4,7,10-Tetrakis{[N-(1H-imidazol-2-yl)carbamoyl]methyl}-1,4,7,10-tetraazacyclododecane (dotami), a tetra(1H-imidazol-2-yl) derivative of the well-studied octadentate 1,4,7,10-tetrakis[(carbamoyl)methyl]-1,4,7,10-tetraazacyclododecane (dotam) ligand, was synthesized by reaction of 1,4,7,10-tetraazacyclododecane with N-(1H-imidazol-2-yl)chloroacetamide in high yield. Its tricationic thulium complex was isolated as a water-soluble chloride salt. The detection of the mildly acidic amide and amine protons by direct proton NMR in aqueous solution was unsuccessful, but such exchangeable protons could be detected via their chemical exchange-dependent saturation transfer (CEST) effect. The observed CEST effect was distinctly different from that found for respective dotam complexes and is, therefore, ascribed to exchangeable protons associated with the imidazole substituent.     

The Dysferlin C2A Domain Binds PI(4,5)P2 and Penetrates Membranes

Dysferlin is a large membrane protein found most prominently in striated muscle. Loss of dysferlin activity is associated with reduced exocytosis, abnormal intracellular Ca2+ and the muscle diseases limb-girdle muscular dystrophy and Miyoshi myopathy. The cytosolic region of dysferlin consists of seven C2 domains with mutations in the C2A domain at the N-terminus resulting in pathology. Despite the importance of Ca2+ and membrane binding activities of the C2A domain for dysferlin function, the mechanism of the domain remains poorly characterized. In this study we find that the C2A domain preferentially binds membranes containing PI(4,5)P2 through an interaction mediated by residues Y23, K32, K33, and R77 on the concave face of the domain. We also found that subsequent to membrane binding, the C2A domain inserts residues on the Ca2+ binding loops into the membrane. Analysis of solution NMR measurements indicate that the domain inhabits two distinct structural states, with Ca2+ shifting the population between states towards a more rigid structure with greater affinity for PI(4,5)P2. Based on our results, we propose a mechanism where Ca²⁺ converts C2A from a structurally dynamic, low PI(4,5)P2 affinity state to a high affinity state that targets dysferlin to PI(4,5)P2 enriched membranes through interaction with Tyr23, K32, K33, and R77. Binding also involves changes in lipid packing and insertion by the third Ca2+ binding loop of the C2 domain into the membrane, which would contribute to dysferlin function in exocytosis and Ca2+ regulation.     

Conformational exchange divergence along the evolutionary pathway of eosinophil-associated ribonucleases

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