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The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.
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Fibrilação Atrial , Cálcio , Átrios do Coração , Camundongos Knockout , Miócitos Cardíacos , Fatores de Transcrição , Animais , Miócitos Cardíacos/metabolismo , Camundongos , Fibrilação Atrial/metabolismo , Fibrilação Atrial/genética , Cálcio/metabolismo , Átrios do Coração/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Sinalização do Cálcio , Potenciais de Ação , Potenciais da Membrana , MasculinoRESUMO
BACKGROUND: Intracranial aneurysm (IA) is a severe cerebrovascular disease, and effective gene therapy and drug interventions for its treatment are still lacking. Oxidative stress (OS) is closely associated with the IA, but the key regulatory genes involved are still unclear. Through multiomics analysis and experimental validation, we identified two diagnostic markers for IA associated with OS. METHODS: In this study, we first analyzed the IA dataset GSE75436 and conducted a joint analysis of oxidative stress-related genes (ORGs). Differential analysis, functional enrichment analysis, immune infiltration, WGCNA, PPI, LASSO, and other methods were used to identify IA diagnostic markers related to OS. Next, the functions of TLR4 and ALOX5 expression in IA and their potential targeted therapeutic drugs were analyzed. We also performed single-cell sequencing of patient IA and control (superficial temporal artery, STA) tissues. 23,342 cells were captured from 2 IA and 3 STA samples obtained from our center. Cell clustering and annotation were conducted using R software to observe the distribution of TLR4 and ALOX5 expression in IAs. Finally, the expression of TLR4 and ALOX5 were validated in IA patients and in an elastase-induced mouse IA model using experiments such as WB and immunofluorescence. RESULTS: Through bioinformatics analysis, we identified 16 key ORGs associated with IA pathogenesis. Further screening revealed that ALOX5 and TLR4 were highly expressed to activate a series of inflammatory responses and reduce the production of myocytes. Methotrexate (MTX) may be a potential targeted drug. Single-cell analysis revealed a notable increase in immune cells in the IA group, with ALOX5 and TLR4 primarily localized to monocytes/macrophages. Validation through patient samples and mouse models confirmed high expression of ALOX5 and TLR4 in IAs. CONCLUSIONS: Bioinformatics analysis indicated that ALOX5 and TLR4 are the most significant ORGs associated with the pathogenesis of IA. Single-cell sequencing and experiments revealed that the high expression of ALOX5 and TLR4 are closely related to IA. These two genes are promising new targets for IA therapy.
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Araquidonato 5-Lipoxigenase , Biomarcadores , Aneurisma Intracraniano , Estresse Oxidativo , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Aneurisma Intracraniano/metabolismo , Aneurisma Intracraniano/genética , Animais , Camundongos , Humanos , Estresse Oxidativo/fisiologia , Araquidonato 5-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/biossíntese , Biomarcadores/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Feminino , MultiômicaRESUMO
Reducing the average resource consumption is the central quest in discriminating non-orthogonal quantum states for a fixed admissible error rate ϵ. The globally optimal fixed local projective measurement for this task is found to be different from that for previous minimum-error discrimination tasks [S. Slussarenko et al., Phys. Rev. Lett. 118, 030502 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.030502]. To achieve the ultimate minimum average consumption, here we develop a general globally optimal adaptive strategy (GOA) by subtly using the updated posterior probability, which works under any error rate requirements and any one-way measurement restrictions, and can be solved by a convergent iterative relation. First, under the local measurement restrictions, our GOA is solved to serve as the local bound, which saves 16.6 copies (24%) compared with the previously best globally optimal fixed local projective measurement. When the more powerful two-copy collective measurements are allowed, our GOA is experimentally demonstrated to beat the local bound by 3.9 copies (6.0%). By exploiting both adaptivity and collective measurements, our Letter marks an important step toward minimum-consumption quantum state discrimination.
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Quantum measurements based on mutually unbiased bases (MUBs) play crucial roles in foundational studies and quantum information processing. It is known that there exist inequivalent MUBs, but little is known about their operational distinctions, not to say experimental demonstration. In this Letter, by virtue of a simple estimation problem, we experimentally demonstrate the operational distinctions between inequivalent triples of MUBs in dimension 4 based on high-precision photonic systems. The experimental estimation fidelities coincide well with the theoretical predictions with only 0.16% average deviation, which is 25 times less than the difference (4.1%) between the maximum estimation fidelity and the minimum estimation fidelity. Our experiments clearly demonstrate that inequivalent MUBs have different information extraction capabilities and different merits for quantum information processing.
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PURPOSE: Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated mannosylated dextran derivative (Al[18F]F-NOTA-D10CM) is a new tracer for PET imaging. We report here on in vitro and in vivo validation of the tracer's ability to target the macrophage mannose receptor CD206. METHODS: First, the uptake of intravenously (i.v.) administered Al[18F]F-NOTA-D10CM was compared between wild-type (WT) and CD206-/- knockout (KO) mice. C57BL/6N mice were injected with complete Freund's adjuvant (CFA) in the left hind leg and the uptake of Al[18F]F-NOTA-D10CM after i.v. or intradermal (i.d.) injection was studied at 5 and 14 days after CFA induction of inflammation. Healthy C57BL/6N mice were studied as controls. Mice underwent PET/CT on consecutive days with [18F]FDG, i.v. Al[18F]F-NOTA-D10CM, and i.d. Al[18F]F-NOTA-D10CM. After the last imaging, Al[18F]F-NOTA-D10CM was i.v. injected for an ex vivo biodistribution study and autoradiography of inflamed tissues. Blood plasma samples were analyzed using high-performance liquid chromatography. To evaluate the specificity of Al[18F]F-NOTA-D10CM binding, an in vitro competitive displacement study was performed on inflamed tissue sections using autoradiography. CD206 expression was assessed by immunohistochemical staining. RESULTS: Compared with WT mice, the uptake of Al[18F]F-NOTA-D10CM was significantly lower in several CD206-/- KO mice tissues, including liver (SUV 8.21 ± 2.51 vs. 1.06 ± 0.16, P < 0.001) and bone marrow (SUV 1.63 ± 0.37 vs. 0.22 ± 0.05, P < 0.0001). The uptake of i.v. injected Al[18F]F-NOTA-D10CM was significantly higher in inflamed ankle joint (SUV 0.48 ± 0.13 vs. 0.18 ± 0.05, P < 0.0001) and inflamed foot pad skin (SUV 0.41 ± 0.10 vs. 0.04 ± 0.01, P < 0.0001) than in the corresponding tissues in healthy mice. The i.d.-injected Al[18F]F-NOTA-D10CM revealed differences between CFA-induced lymph node activation and lymph nodes in healthy mice. Ex vivo γ-counting, autoradiography, and immunohistochemistry supported the results, and a decrease of ~ 80% in the binding of Al[18F]F-NOTA-D10CM in the displacement study with excess NOTA-D10CM confirmed that tracer binding was specific. At 60 min after i.v. injection, an average 96.70% of plasma radioactivity was derived from intact Al[18F]F-NOTA-D10CM, indicating good in vivo stability. The uptake of Al[18F]F-NOTA-D10CM into inflamed tissues was positively associated with the area percentage of CD206-positive staining. CONCLUSION: The uptake of mannosylated dextran derivative Al[18F]F-NOTA-D10CM correlated with CD206 expression and the tracer appears promising for inflammation imaging.
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Dextranos , Radioisótopos de Flúor , Lectinas Tipo C , Receptor de Manose , Lectinas de Ligação a Manose , Receptores de Superfície Celular , Animais , Camundongos , Lectinas Tipo C/metabolismo , Receptores de Superfície Celular/metabolismo , Lectinas de Ligação a Manose/metabolismo , Distribuição Tecidual , Dextranos/química , Manose/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Camundongos Endogâmicos C57BL , Macrófagos/metabolismo , Marcação por Isótopo , Compostos Heterocíclicos com 1 AnelRESUMO
Visible-light-mediated [2+2] photocycloaddition reaction can be considered an ideal solution due to its green and sustainable properties, and is one of the most efficient methods to synthesize four-membered ring motifs. Although research on the [2+2] photocycloaddition of alkynes is challenging because of the diminished reactivity of alkynes, and the more significant ring strain of the products, remarkable achievements have been made in this field. In this article, we highlight the recent advances in visible-light-mediated [2+2] photocycloaddition reactions of alkynes, with focus on the reaction mechanism and the late-stage synthetic applications. Advances in obtaining cyclobutenes, azetines, and oxetene active intermediates continue to be breakthroughs in this fascinating field of research.
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Fatty acid binding protein 3 (FABP3) is expressed both in tumor cells and in the tumor vasculature, making it a potential target for medical imaging and therapy. In this study, we aimed to radiolabel a CooP peptide with a free amino and thiol group, and evaluate the radiolabeled product [18F]FNA-N-CooP for imaging FABP3 expression in breast cancer brain metastases by positron emission tomography. [18F]FNA-N-CooP was prepared by highly chemoselective N-acylation and characterized using different chemical approaches. We validated its binding to the target using in vitro tissue section autoradiography and performed stability tests in vitro and in vivo. [18F]FNA-N-CooP was successfully synthesized in 16.8% decay-corrected radiochemical yield with high radiochemical purity (98.5%). It exhibited heterogeneous binding on brain metastasis tissue sections from a patient with breast cancer, with foci of radioactivity binding corresponding to FABP3 positivity. Furthermore, the tracer binding was reduced by 55% in the presence of nonradioactive FNA-N-CooP a blocker, indicating specific tracer binding and that FABP3 is a viable target for [18F]FNA-N-CooP. Favorably, the tracer did not bind to necrotic tumor tissue. However, [18F]FNA-N-CooP displayed limited stability both in vitro in mouse plasma or human serum and in vivo in mouse, therefore further studies are needed to improve the stability [18F]FNA-N-CooP to be used for in vivo applications.
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Neoplasias Encefálicas , Neoplasias da Mama , Proteína 3 Ligante de Ácido Graxo , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Humanos , Feminino , Camundongos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Proteína 3 Ligante de Ácido Graxo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Radioisótopos de Flúor/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Linhagem Celular Tumoral , Peptídeos/química , Distribuição Tecidual , Compostos de Sulfidrila/química , Camundongos NusRESUMO
We report the first total synthesis of scleropentaside D, a unique C-glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C-acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.
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Taninos Hidrolisáveis , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/síntese química , Estrutura Molecular , Glicosídeos/química , Glicosídeos/síntese química , Glicosídeos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , CatáliseRESUMO
Cryopreservation causes higher reactive oxygen species (ROS) concentrations, leading to oxidative stress and lipid peroxidation damaging sperm, and using antioxidants can improve semen quality after freeze-thaw. Natural astaxanthin (ASTA) can be inserted into cell membranes and its antioxidant properties are stronger than other antioxidants. We aimed to investigate the effects of ASTA supplementation in the Beltsville Poultry Semen Extender (BPSE) on post-thaw rooster semen quality and to explore the potential mechanism of rooster semen quality change. The qualifying semen ejaculates collected from 30 adult male Jinghong No. 1 laying hen breeder roosters (65 wk old) were pooled, divided into four aliquots, and diluted with BPSE having different levels of ASTA (0, 0.5, 1, or 2 µg/mL). Treated semen was cryopreserved and kept in liquid nitrogen. The entire experiment was replicated three times independently. Sperm viability, motility, curvilinear velocity, amplitude of lateral head displacement, straightness, plasma membrane integrity, and acrosome integrity were observed to be highest (P < 0.05) with 1 µg/mL ASTA at freeze-thawing. Higher (P < 0.05) antioxidant enzyme (CAT-like, SOD) activities and free radical (·OH, O2.-) scavenging ability, less ROS and malondialdehyde (MDA) concentrations were recorded with the addition of appropriate concentrations of ASTA compared to control. In addition, the levels of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), and lactate dehydrogenase (LDH) in the 1 µg/mL ASTA group improved compared to the control group, and decreased the amount of AIF protein level but increased the Bcl-2 protein level (P < 0:05). Collectively, these results demonstrate that adding ASTA in the BPSE promoted rooster freeze-thaw sperm quality, which may be related to reducing ROS levels, protecting the antioxidant defense system, preventing lipid peroxidation, improving mitochondrial structural and functional integrity, and inhibiting sperm apoptosis.
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BACKGROUND: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and primary amine oxidase, and Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',Nâ³,Nâ´-tetra-acetic acid conjugated sialic acid-binding immunoglobulin-like lectin 9 motif containing peptide ([68Ga]Ga-DOTA-Siglec-9) is a positron emission tomography (PET) tracer targeting VAP-1. We evaluated the feasibility of PET imaging with [68Ga]Ga-DOTA-Siglec-9 for the detection of myocardial lesions in rats with autoimmune myocarditis. METHODS: Rats (n = 9) were immunized twice with porcine cardiac myosin in complete Freund's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. On day 21, in vivo PET/computed tomography (CT) imaging with [68Ga]Ga-DOTA-Siglec-9 was performed, followed by ex vivo autoradiography, histology, and immunohistochemistry of tissue sections. In addition, myocardial samples from three patients with cardiac sarcoidosis were studied. RESULTS: [68Ga]Ga-DOTA-Siglec-9 PET/CT images of immunized rats showed higher uptake in myocardial lesions than in myocardium outside lesions (SUVmean, 0.5 ± 0.1 vs 0.3 ± 0.1; P = .003) or control rats (SUVmean, 0.2 ± 0.03; P < .0001), which was confirmed by ex vivo autoradiography of tissue sections. Immunohistochemistry showed VAP-1-positive staining in lesions of rats with myocarditis and in patients with cardiac sarcoidosis. CONCLUSION: VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 PET is a potential novel technique for the detection of myocardial lesions.
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Miocardite , Sarcoidose , Humanos , Ratos , Animais , Suínos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Gálio/química , Miocardite/diagnóstico por imagem , Adjuvante de Freund , Tomografia Computadorizada por Raios X , Tomografia por Emissão de Pósitrons/métodos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/químicaRESUMO
Coherence and entanglement are both the fundamental properties which quantify the degree of nonclassicality possessed in a quantum state. Recently coherence and entanglement are considered as a dynamical resource where the nonclassicality is strongly related to the amount of the static resources which can be generated in a quantum process. In [Phys. Rev. Lett.125, 130401 (2020)10.1103/PhysRevLett.125.130401], for the first time, the authors study the interconvertability of these two kinds of dynamical resources. Here, we demonstrate this resource conversion in an all optical setup, and successfully observe the dynamical resource conversion. The experimental observation prove the ability of manipulating dynamical resource within current quantum photonic technologies.
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Verifying the correct functioning of quantum gates is a crucial step toward reliable quantum information processing, but it becomes an overwhelming challenge as the system size grows due to the dimensionality curse. Recent theoretical breakthroughs show that it is possible to verify various important quantum gates with the optimal sample complexity of O(1/ε) using local operations only, where ε is the estimation precision. In this Letter, we propose a variant of quantum gate verification (QGV) that is robust to practical gate imperfections and experimentally realize efficient QGV on a 2-qubit controlled-not gate and a 3-qubit Toffoli gate using only local state preparations and measurements. The experimental results show that, by using only 1600 and 2600 measurements on average, we can verify with 95% confidence level that the implemented controlled-not gate and Toffoli gate have fidelities of at least 99% and 97%, respectively. Demonstrating the superior low sample complexity and experimental feasibility of QGV, our work promises a solution to the dimensionality curse in verifying large quantum devices in the quantum era.
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Inspired by Roush's pioneering work on rare sugars, we have developed a scalable, stereoselective, de novo synthesis of orthogonally protected C2-fluoro digitoxose and cymarose, utilizing Sharpless kinetic resolution and organocatalytic fluorination as key steps. The utility of this strategy is demonstrated by the synthesis of a fluorinated analogue of digoxin, which indicates the fluorine on the sugar ring may have a significant impact on biological activity.
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Digoxina , Flúor , Halogenação , Hexoses , EstereoisomerismoRESUMO
We have developed an improved cyanide-free strategy for the synthesis of glycosyl carboxylic acids, employing stereoselective C-vinyl glycosylation and oxidative cleavage of C-vinyl glycosides as key steps. Compared to our previous work, the amount of NaIO4 required for the oxidative cleavage step is reduced significantly from 18 equivalents to 4.5 equivalents. This modification not only is advantageous in terms of operation and costs but also avoids the over-oxidation problem, thus greatly expanding the substrate scope, which is evidenced by the fact that 10 out of 21 glycosyl carboxylic acids synthesized are undocumented. With differently O5-protected furanosyl acids in hand, we demonstrate that an electron-rich protecting group is beneficial for the decarboxylative arylation of furanosyl carboxylic acids. This represents a rare example of protecting groups affecting the reaction efficiency in radical C-glycosylation. As C-vinyl glycosides can be prepared stereoselectively and the oxidative step is stereoretentive, the approach provides an effective means to access 1,2-trans or 1,2-cis glycosyl acids, which would be a valuable alternative to the cyanide-based synthesis of glycosyl carboxylic acids.
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Ácidos Carboxílicos , Glicosídeos , Glicosilação , Estresse Oxidativo , EstereoisomerismoRESUMO
The COVID-19 pandemic has triggered the dramatical development and prosperity of online games, while worldwide people are suffering from it. Considering the high prevalence, serious impacts, and huge development potential of internet gaming disorder (IGD), it is extremely necessary to develop a protective model to prevent and intervene with it among young people. Based on the developmental assets theory, the present study adopted a two-wave longitudinal design to evaluate the cumulative effects of developmental assets on IGD, as well as the underlying mechanisms during this specific period. Data were collected from a sample of 1023 adolescents in Hubei province, Central China through self-report questionnaires. The results indicated that (1) developmental assets were negatively associated with adolescents' IGD concurrently and longitudinally; (2) the overall developmental assets had cumulative effects in linear patterns on adolescents' IGD, concurrently and longitudinally; and (3) internal developmental assets mediated the relationship between external developmental assets and adolescents' IGD longitudinally. Theoretically, the present study supports the developmental assets theory and expands the literature about developmental assets and IGD in younger generations. Practically, the present study provides guidance for prevention and intervention of IGD among adolescents during and after the COVID-19 pandemic. Comprehensive measures should be taken to assist in developing positive internal and external resources to promote youth thriving.
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The outbreak of COVID-19 has brought many challenges to youth development. During this specific period, adolescents have suffered from numerous behavioral problems, which will lead to more maladaptive consequences. It is necessary to explore several protective factors to prevent or reduce the occurrence of problem behaviors in adolescence. The current study combined school resources and self-control to evaluate the multiple protective effects on adolescents' problematic behaviors in a two-wave longitudinal study. A sample of 789 Chinese adolescents (Mage = 14.00 years, SD = 2.05, 418 boys) were recruited via the random cluster sampling method to participate in the survey. The results confirmed the assumptions about the multiple protective effects of school resources and self-control on adolescents' problem behaviors. Specifically, school resources could negatively predict IGD and victimization, and self-control mediated these associations. Moreover, one problematic behavior could also mediate the associations between self-control and another problematic behavior. This is the first study to focus on the multiple protective effects of positive factors on adolescents' problem behaviors during the post-pandemic period, which has made several contributions to the literature and practice.
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Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.
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Aterosclerose/metabolismo , Diabetes Mellitus Experimental/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Acetatos/farmacocinética , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Exenatida/farmacocinética , Feminino , Radioisótopos de Gálio/farmacocinética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons/métodos , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMO
BACKGROUND: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-ß (FR-ß), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-ß is expressed in the brain of patients with MS. METHODS: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-ß expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. RESULTS: Immunofluorescence and histological analyses revealed significant reductions in FR-ß expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-ß positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. CONCLUSIONS: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-ß-positive cells in chronically active plaques, which suggests that these results may have translational relevance.
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Aminopterina/farmacologia , Encefalomielite Autoimune Experimental/patologia , Receptor 2 de Folato/metabolismo , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/farmacologia , Animais , Humanos , Esclerose Múltipla/metabolismo , Ratos , Ratos Endogâmicos LewRESUMO
Wave-particle duality is one of the basic features of quantum mechanics, giving rise to the use of complex numbers in describing states of quantum systems and their dynamics and interaction. Since the inception of quantum theory, it has been debated whether complex numbers are essential or whether an alternative consistent formulation is possible using real numbers only. Here, we attack this long-standing problem theoretically and experimentally, using the powerful tools of quantum resource theories. We show that, under reasonable assumptions, quantum states are easier to create and manipulate if they only have real elements. This gives an operational meaning to the resource theory of imaginarity. We identify and answer several important questions, which include the state-conversion problem for all qubit states and all pure states of any dimension and the approximate imaginarity distillation for all quantum states. As an application, we show that imaginarity plays a crucial role in state discrimination, that is, there exist real quantum states that can be perfectly distinguished via local operations and classical communication but that cannot be distinguished with any nonzero probability if one of the parties has no access to imaginarity. We confirm this phenomenon experimentally with linear optics, discriminating different two-photon quantum states by local projective measurements. Our results prove that complex numbers are an indispensable part of quantum mechanics.
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We investigate whether paradigmatic measurements for quantum state tomography, namely mutually unbiased bases and symmetric informationally complete measurements, can be employed to certify quantum correlations. For this purpose, we identify a simple and noise-robust correlation witness for entanglement detection, steering, and nonlocality that can be evaluated based on the outcome statistics obtained in the tomography experiment. This allows us to perform state tomography on entangled qutrits, a test of Einstein-Podolsky-Rosen steering and a Bell inequality test, all within a single experiment. We also investigate the trade-off between quantum correlations and subsets of tomographically complete measurements as well as the quantification of entanglement in the different scenarios. Finally, we perform a photonics experiment in which we demonstrate quantum correlations under these flexible assumptions, namely with both parties trusted, one party untrusted and both parties untrusted.