Melittin-Phospholipase A2 Synergism Is Mediated by Liquid-Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles.

The primary constituents of honeybee venom, melittin and phospholipase A2 (PLA2), display toxin synergism in which the PLA2 activity is significantly enhanced by the presence of melittin. It has been shown previously that this is accomplished by the disruption in lipid packing, which allows PLA2 to become processive on the membrane surface. In this work, we show that melittin is capable of driving miscibility phase transition in giant unilamellar vesicles (GUVs) and that it raises the miscibility transition temperature (Tmisc) in a concentration-dependent manner. The induced phase separation enhances the processivity of PLA2, particularly at its boundaries, where a substantial difference in domain thickness creates a membrane discontinuity. The catalytic action of PLA2, in response, induces changes in the membrane, rendering it more conducive to melittin binding. This, in turn, facilitates further lipid phase separation and eventual vesicle lysis. Overall, our results show that melittin has powerful membrane-altering capabilities that activate PLA2 in various membrane contexts. More broadly, they exemplify how this biochemical system actively modulates and capitalizes on the spatial distribution of membrane lipids to efficiently achieve its objectives.

Correction: Analysis of 1-aminoisoquinoline using the signal amplification by reversible exchange hyperpolarization technique.

Correction for 'Analysis of 1-aminoisoquinoline using the signal amplification by reversible exchange hyperpolarization technique' by Hye Jin Jeong et al., Analyst, 2020, 145, 6478-6484. DOI: .

Optimization of signal amplification by reversible exchange for polarization of tridentate chelating bis[(2-pyridyl)alkyl]amine.

Signal amplification by reversible exchange (SABRE) is an effective NMR hyperpolarization technique for signal enhancement using para-hydrogen on iridium catalysts. To date, monodentate chelating nitrogen analogs have been predominantly used as substrates for SABRE because of the limited chelating sites of the Ir-catalyst with different molecular orientations. Herein, for the first time, the use of a tridentate chelating ligand (BPEA) containing pyridine moieties and a secondary amine as a SABRE substrate is demonstrated. For the optimization of the tridentate chelating ligand, alkyl chain lengths were varied with the optimization of the external magnetic field and concentrations of three different ligands. Because many chemically multidentate complexes present in nature have scarcely been studied as SABRE substrates, this optimized tridentate chelating ligand structure with the SABRE catalyst and its polarization transfer from para-hydrogen will broaden the scope of hyperpolarizable substrates and help in the investigation of chelating structures for future applications.

Organic Reaction Monitoring of a Glycine Derivative Using Signal Amplification by Reversible Exchange-Hyperpolarized Benchtop Nuclear Magnetic Resonance Spectroscopy.

Currently, signal amplification by reversible exchange (SABRE) using para-hydrogen is an attractive method of hyperpolarization for overcoming the sensitivity problems of nuclear magnetic resonance (NMR) spectroscopy. Additionally, SABRE, using the spin order of para-hydrogen, can be applied in reaction monitoring processes for organic chemistry reactions where a small amount of reactant exists. The organic reaction monitoring system created by integrating SABRE and benchtop NMR is the ideal combination for monitoring a reaction and identifying the small amounts of materials in the middle of the reaction. We used a laboratory-built setup, prepared materials by synthesis, and showed that the products obtained by esterification of glycine were also active in SABRE. The products, which were synthesized esterified glycine with nicotinoyl chloride hydrochloride, were observed with a reaction monitoring system. The maximum SABRE enhancement among them (approximately 147-fold) validated the use of this method. This study is the first example of the monitoring of this organic reaction by SABRE and benchtop NMR. It will open new possibilities for applying this system to many other organic reactions and also provide more fruitful future applications such as drug discovery and mechanism study.

Analysis of 1-aminoisoquinoline using the signal amplification by reversible exchange hyperpolarization technique.

Signal amplification by reversible exchange (SABRE), a parahydrogen-based hyperpolarization technique, is valuable in detecting low concentrations of chemical compounds, which facilitates the understanding of their functions at the molecular level as well as their applicability in nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). SABRE of 1-aminoisoquinoline (1-AIQ) is significant because isoquinoline derivatives are the fundamental structures in compounds with notable biological activity and are basic organic building blocks. Through this study, we explain how SABRE is applied to hyperpolarize 1-AIQ for diverse solvent systems such as deuterated and non-deuterated solvents. We observed the amplification of individual protons of 1-AIQ at various magnetic fields. Further, we describe the polarization transfer mechanism of 1-AIQ compared to pyridine using density functional theory (DFT) calculations. This hyperpolarization technique, including the polarization transfer mechanism investigation on 1-AIQ, will provide a firm basis for the future application of the hyperpolarization study on various bio-friendly materials.

Prediction of Binding Stability of Pu(IV) and PuO2(VI) by Nitrogen Tridentate Ligands in Aqueous Solution.

Plutonium has potential applications in energy production in well-controlled nuclear reactors. Since nuclear power plants have great merit as environmentally friendly energy sources with a recyclable system, a recycling system for extracting Pu from spent fuels using suitable extractants has been proposed. Pu leakage is a potential environmental hazard, hence the need for chemical sensor development. Both extractants and chemical sensors involve metal-ligand interactions and to develop efficient extractants and chemical sensors, structural information about Pu ligands must be obtained by quantum calculations. Herein, six representative nitrogen tridentate ligands were introduced, and their binding stabilities were evaluated. The tridentate L6, which contains tri-pyridine chelate with benzene connectors, showed the highest binding energies for Pu(IV) and PuO2(VI) in water. Analysis based on the quantum theory of atoms in molecular analysis, including natural population analysis and electron density studies, provided insight into the bonding characteristics for each structure. We propose that differences in ionic bonding characteristics account for the Pu-ligand stability differences. These results form a basis for designing novel extractants and organic Pu sensors.

Hyperpolarization of Nitrile Compounds Using Signal Amplification by Reversible Exchange.

Signal Amplification by Reversible Exchange (SABRE), a hyperpolarization technique, has been harnessed as a powerful tool to achieve useful hyperpolarized materials by polarization transfer from parahydrogen. In this study, we systemically applied SABRE to a series of nitrile compounds, which have been rarely investigated. By performing SABRE in various magnetic fields and concentrations on nitrile compounds, we unveiled its hyperpolarization properties to maximize the spin polarization and its transfer to the next spins. Through this sequential study, we obtained a ~130-fold enhancement for several nitrile compounds, which is the highest number ever reported for the nitrile compounds. Our study revealed that the spin polarization on hydrogens decreases with longer distances from the nitrile group, and its maximum polarization is found to be approximately 70 G with 5 µL of substrates in all structures. Interestingly, more branched structures in the ligand showed less effective polarization transfer mechanisms than the structural isomers of butyronitrile and isobutyronitrile. These first systematic SABRE studies on a series of nitrile compounds will provide new opportunities for further research on the hyperpolarization of various useful nitrile materials.

[18F]-THK5351 PET Imaging in Patients With Semantic Variant Primary Progressive Aphasia.

BACKGROUND: Semantic variant primary progressive aphasia (svPPA) has been associated with a variety of proteinopathies, mainly transactive response DNA-binding protein, but also with tau and ß-amyloid. Recently selective tau tracers for positron emission tomography (PET) have been developed to determine the presence of cerebral tau deposits in vivo. Here, we investigated the topographical distribution of THK5351 in svPPA patients. MATERIALS AND METHODS: Five svPPA patients, 14 Alzheimer's disease patients, and 15 age-matched normal controls underwent [F]-THK5351 PET scans, magnetic resonance imaging, and detailed neuropsychological tests. [F]-fluorodeoxyglucose PET was obtained in 3 svPPA patients, whereas the remaining 2 underwent amyloid PET using [F]-flutemetamol. Tau distribution among the 3 groups was compared using regions of interest-based and voxel-based statistical analyses. RESULTS: In svPPA patients, [F]-THK5351 retention was elevated in the anteroinferior and lateral temporal cortices compared with the normal controls group (left>right), and in the left inferior and temporal polar region compared with Alzheimer's disease patients. [F]-THK5351 retention inversely correlated with glucose metabolism, whereas regional THK retention correlated with clinical severity. [F]-flutemetamol scans were negative for ß-amyloid. CONCLUSIONS: These findings show that [F]-THK5351 retention may be detected in cortical regions correlating with svPPA pathology.

Impact of midfoot and Hindfoot involvement on functional disability in Korean patients with rheumatoid arthritis.

BACKGROUND: Foot involvement in rheumatoid arthritis (RA) patients has been reported to severely affect functional capacity and quality of life. We aimed to determine the impact of midfoot and hindfoot involvement on functional disability in Korean patients with RA. METHODS: We evaluated the RA involvement and deformity of three regions of the foot (forefoot, midfoot and hindfoot) and ankle using conventional radiography in Korean patients with RA. We compared the clinical features between RA patients with and without foot or ankle involvement. Using multivariable logistic regression analyses, the impact of midfoot or hindfoot involvement on functional disability in RA patients was evaluated. RESULTS: Overall, 120 patients with a median age of 48.0 [interquartile range (IQR), 37-56] years and median disease duration of 58.0 (IQR, 10-89) months were included. The prevalence of foot or ankle RA involvement was 74 (61.7%). The number of patients with forefoot, midfoot, hindfoot and ankle involvement was 32 (43.2%), 24 (32.4%), 46 (62.2%) and 4 (5.4%), respectively. Compared to patients without foot or ankle involvement those with such involvement had greater disease activity and functional disability, more of them were treated with biologic agents, and they had a lower health-related quality of life. After adjusting for potential confounders, hindfoot involvement was associated with a higher degree of functional disability. However, walking difficulty was more associated with midfoot involvement rather than with involvement in other regions. CONCLUSIONS: In Korean patients with RA, hindfoot involvement is associated with functional disability and midfoot involvement affects walking.

Cerebellar Development in Preterm Infants at Term-Equivalent Age Is Impaired after Low-Grade Intraventricular Hemorrhage.

OBJECTIVES: To investigate cerebellar development in preterm infants at term-equivalent age compared with healthy full-term infants and to examine the effect of a low-grade intraventricular hemorrhage (IVH) on cerebellar development. STUDY DESIGN: This study used 3T magnetic resonance and diffusion tensor imaging (DTI) at 36-41 weeks' postmenstrual age (PMA) in 72 preterm infants without severe brain injury and 16 full-term infants. Cerebellar volumes and DTI parameters of the cerebellar peduncles including fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity, and radial diffusivities were measured. Clinical variables that may affect brain development were collected. RESULTS: Compared with full-term infants, preterm infants showed smaller cerebellar volumes and a lower FA, greater ADC, and increased radial diffusivities in the cerebellar peduncles (all P < .05). This cerebellar impairment was associated significantly with PMA and IVH grade 2 but was independent of gestational age at birth. When we adjusted for clinical variables, an IVH grade 2 was related with 1.73 cm(3) reduction in cerebellar volumes and altered DTI parameters in the cerebellar peduncles, including decreased FA and increased radial diffusivities in the superior cerebellar peduncle and increases in ADC, axial diffusivity, and radial diffusivities of the middle cerebellar peduncle (all P < .05). Cerebellar hemispheric volumes were associated with both ipsilateral and contralateral IVH grade 2. CONCLUSION: Preterm infants without severe brain abnormalities showed impaired cerebellar development at term-equivalent age after we controlled for PMA at the time of the scan, and this is associated with IVH grade 2. These findings suggest that even a low-grade IVH has potential harmful effects on cerebellar development.

Loss of Nigral Hyperintensity on 3 Tesla MRI of Parkinsonism: Comparison With (123) I-FP-CIT SPECT.

BACKGROUND: The aim of this study was to investigate whether 3 Tesla susceptibility-weighted imaging can detect the alteration of substantia nigra hyperintensity in Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) and to assess the concordance between the loss of nigral hyperintensity on 3 Tesla susceptibility-weighted imaging and the nigrostriatal dopaminergic degeneration indicated by (123) I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computerized tomography. METHODS: Consecutive subjects with suspected parkinsonism were included, and clinical diagnosis was solidified during clinical follow-up. Two blinded neuroradiologists interpreted the nigral hyperintensity on susceptibility-weighted imaging. The performance of susceptibility-weighted imaging for detection of nigral hyperintensity loss was estimated on the basis of the clinical diagnosis and compared with single photon emission computerized tomography results. RESULTS: The study included 210 subjects (126 PD, 11 MSA, 11 PSP patients, 26 healthy controls, 36 disease controls). The presence or absence of nigral hyperintensity was accurately visualized in 112 PD, 7 MSA, and 11 PSP patients and 53 controls. We identified 16 false-negative cases and 11 false-positive cases. The sensitivity and specificity of susceptibility-weighted imaging were 88.8% and 83.6%, respectively. The concordance rate between susceptibility-weighted imaging and single photon emission computerized tomography was 86.2%. CONCLUSIONS: The loss of nigral hyperintensity on susceptibility-weighted imaging suggested nigrostriatal dopaminergic degeneration in a large portion of patients with parkinsonism, which was indicated by (123) I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computerized tomography. In consideration of false-negative and -positive cases, well-designed imaging protocols should be introduced to improve the performance of nigral hyperintensity imaging. © 2016 International Parkinson and Movement Disorder Society.

Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus.

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.

Role of the spleen in liver regeneration in relation to transforming growth factor-ß1 and hepatocyte growth factor.

BACKGROUND: Optimizing the hepatic regenerative capacity is an immediate priority after partial hepatectomy (PH). Recent reports have indicated improvement in liver regeneration after splenectomy, raising interest on the role of the spleen in liver regeneration. However, little is known about the exact mechanism underlying these effects. MATERIALS AND METHODS: Eight-week-old male Sprague-Dawley rats randomly underwent either 70% PH only (PH, n = 25) or 70% PH combined with splenectomy (PHS, n = 25). The specimens, including liver and/or spleen tissues and sera, were collected and evaluated using immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and serum biochemical analyses. RESULTS: PH induced higher transforming growth factor (TGF)-ß1 expression in the liver up to 72 h after PH. The PHS group showed significantly higher numbers of proliferating cell nuclear antigen-positive cells, reflecting higher liver regeneration and lower amounts of liver enzymes compared with the PH group. Splenectomy after PH resulted in increased and decreased serum concentrations of hepatocyte growth factor (HGF) and TGF-ß1 in the portal vein, respectively. Moreover, the PHS group demonstrated downregulation of TGF-ß1 and its receptor TGF-ß-RII and upregulation of HGF and its receptor c-Met in the liver. CONCLUSIONS: The spleen seemed to exhibit an inhibitory effect on liver regeneration by upregulating TGF-ß1 and its receptor TGF-ß-RII and downregulating HGF and its receptor c-Met in the liver. Therefore, splenectomy can be considered an option for improving liver regeneration in selected patients with reduced regenerative capacity of the liver.

Flavokawains B and C, melanogenesis inhibitors, isolated from the root of Piper methysticum and synthesis of analogs.

The ethanolic extract of the root of Piper methysticum was found to inhibit melanogenesis in MSH-activated B16 melanoma cells. Flavokawains B and C were isolated from this extract based on their anti-melanogenesis activity and found to inhibit melanogenesis with IC50 values of 7.7µM and 6.9µM, respectively. Flavokawain analogs were synthesized through a Claisen-Schmidt condensation of their corresponding acetophenones and benzaldehydes and were evaluated in terms of their tyrosinase inhibitory and anti-melanogenesis activities. Compound 1b was the most potent of these with an IC50 value of 2.3µM in melanogenesis inhibition assays using MSH-activated B16 melanoma cells.

Serial changes in knee muscle strength after anterior cruciate ligament reconstruction using hamstring tendon autografts.

PURPOSE: The purpose of this study was to evaluate serial changes in quadriceps and hamstring muscle strength over the first postoperative year in patients who underwent anterior cruciate ligament (ACL) reconstruction with an autologous hamstring tendon graft and to reveal which of these 2 muscles lost more strength and recovered more slowly after autologous hamstring ACL reconstruction. METHODS: Isokinetic muscle strength was measured preoperatively and at 6 months and 1 year postoperatively in 20 patients who underwent ACL reconstruction. The maximal torque (60°/s) and total work (180°/s) of the quadriceps and hamstring were evaluated using an isokinetic testing device. The isokinetic muscle strength and endurance of the injured legs were expressed as percentages of those of the uninjured legs at the same time point. RESULTS: Both quadriceps and hamstring muscle strength at 60°/s and endurance at 180°/s of the injured relative to the uninjured leg was 50% preoperatively. Quadriceps muscle strength and endurance of the injured leg increased to 70% at 6 months and 80% at 1 year postoperatively, whereas hamstring muscle strength and endurance increased to 80% at 6 months and 80% at 1 year. CONCLUSIONS: Knee muscle strength recovered progressively after ACL reconstruction using autologous hamstring tendons but did not fully recover, being about 80% that of the uninjured leg even 1 year after surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Quadriceps Strength and Endurance After Posterior Cruciate Ligament Tears Versus Matched Group With Anterior Cruciate Ligament Tears.

PURPOSE: This study was designed to compare the preoperative strengths and endurances of the quadriceps and hamstring muscles in patients with anterior cruciate ligament (ACL) versus posterior cruciate ligament (PCL) tears. METHODS: Quadriceps and hamstring muscle strength and endurance were compared between 20 prospectively enrolled patients with isolated PCL tears and a retrospective, matched control group of 20 patients with isolated ACL tears. The maximal torque (60°/s) and total work (180°/s) of the quadriceps and hamstring were evaluated with an isokinetic testing device. RESULTS: Total work (1,094.4 ± 505.8 J v 797.5 ± 332.7 J, P = .035) and peak torque (129.9 ± 56.2 N ∙ m v 98.2 ± 37.4 N ∙ m, P = .046) of the quadriceps muscle on the involved side were higher in the PCL tear group than in the ACL tear group. However, there were no significant differences between the PCL tear group and ACL tear group in hamstring muscle strength (45.8 ± 42.3 N ∙ m and 46.0 ± 24.4 N ∙ m, respectively; P = .940) and endurance (429.3 ± 238.9 J and 382.4 ± 256.1 J, respectively; P = .574) on the involved side. CONCLUSIONS: The strength and endurance of the quadriceps muscle of the injured limb were greater after PCL tears than after ACL tears. However, there were no significant between-group differences in hamstring muscle strength and endurance on the involved side. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Hepatoprotective effects of paeonol by suppressing hepatic stellate cell activation via inhibition of SMAD2/3 and STAT3 pathways.

Hepatic stellate cell (HSC) activation is a key event in extracellular matrix accumulation, causing hepatic fibrosis. Therefore, identifying chemicals that inhibit HSC activation is an important therapeutic strategy for hepatic fibrosis. The aim of this study was to investigate the therapeutic effects of paeonol on HSC activation. In LX-2 cells, paeonol inhibited the expression of collagen and decreased the expression of HSC activation markers. In mice with thioacetamide-induced liver fibrosis, paeonol treatment decreased the serum levels of aspartate aminotransferase and alanine transaminase and mRNA expression of α-smooth muscle actin, platelet-derived growth factor-ß, and connective-tissue growth factor. Investigation of the underlying molecular mechanism of paeonol showed that paeonol inhibits the SMAD2/3 and STAT3 signaling pathways that are important for HSC activation. On the basis of these results, paeonol should be investigated and developed further for hepatic fibrosis treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01440-9.

Home-based supportive care in advanced cancer: systematic review.

OBJECTIVES: This study systematically reviewed the literature on the effect of home-based supportive care (HbSC) programmes on the quality of life (QoL) of patients with advanced cancer. METHODS: The research question 'Do home-based supportive care programmes for patients with advanced cancer improve their QoL?' was addressed. After registering the plan with PROSPERO (CRD42022341237), literature published from 1 January 1990 to 30 May 2023 was searched on PubMed, Embase, Cochrane database, CINAHL and Web of Science, and reviewed for inclusion based on predefined criteria. This review only included trial studies published in English. RESULTS: Of 5,276 articles identified, 17 studies were judged suitable for inclusion in this review. The components of HbSC programmes included home visits, patient and caregiver education, home nursing, psychotherapy, exercise, telephone consultation, and multidisciplinary team meetings. Nine studies reported improvements in QoL, including social functioning, emotional functioning, and subjective QoL. CONCLUSION: HbSC programmes appear to enable the improvement of the QoL of patients with advanced cancer. The area of QoL that shows improvement could vary depending on the HbSC components. More studies that address HbSC programmes are needed to select patients at the proper time and provide suitable programmes for patients to benefit most.

Seven-Tesla magnetic resonance images of the substantia nigra in Parkinson disease.

OBJECTIVE: To investigate anatomical changes in the substantia nigra (SN) of Parkinson disease (PD) patients with age-matched controls by using ultra-high field magnetic resonance imaging (MRI). METHODS: We performed 7T MRI in 10 PD and 10 age-matched control subjects. Magnetic resonance images of the SN were obtained from a 3-dimensional (3D) T(2)*-weighted gradient echo sequence. Region of interest-based 3D shape analysis was performed to quantitatively compare images from the 2 groups. RESULTS: The boundary between the SN and crus cerebri was not smooth in PD subjects. Undulation in the lateral surface of the SN appeared more intense in the side contralateral to that with the more severe symptoms, and more prominent at the rostral level of the SN than at the intermediate or caudal levels. In addition to the lateral surface, there was a striking difference in the dorsomedial aspects of the SN between PD and control subjects. In control subjects, a brighter signal region was observed along the dorsomedial surface of the lateral portion of SN, whereas in PD subjects, this region was observed as a dark region containing a hypointense signal in T(2)*-weighted images. The measurement of SN volumes, normalized to the intracranial volumes, showed higher values in PD subjects than in control subjects. INTERPRETATION: This study demonstrates that 3D 7T MRI can definitively visualize anatomical alterations occurring in the SN of PD subjects. Further pathological studies are required to elucidate the nature of these anatomical alterations.

Real-Time Reaction Monitoring of Azide-Alkyne Cycloadditions Using Benchtop NMR-Based Signal Amplification by Reversible Exchange (SABRE).

Rufinamide, possessing a triazole ring, is a new antiepileptic drug (AED) relatively well-absorbed in the lower dose range (10 mg/kg per day) and is currently being used in antiepileptic medications. Triazole derivatives can interact with various enzymes and receptors in biological systems via diverse non-covalent interactions, thus inducing versatile biological effects. Strain-promoted azide-alkyne cycloaddition (SPAAC) is a significant method for obtaining triazoles, even under physiological conditions, in the absence of a copper catalyst. To confirm the progress of chemical reactions under biological conditions, research on reaction monitoring at low concentrations is essential. This promising strategy is gaining acceptance for applications in fields such as drug development and nanoscience. We investigated the optimum Ir catalyst and magnetic field for achieving maximum proton hyperpolarization transfer in triazole derivatives. These reactions were analyzed using signal amplification by reversible exchange (SABRE) to overcome the limitations of low sensitivity in nuclear magnetic resonance spectroscopy, when monitoring copper-free click reactions in real time. Finally, a more versatile copper-catalyzed click reaction was monitored in real time, using a 60 MHz benchtop NMR system, in order to analyze the reaction mechanism.