The ß2-adrenergic receptor associates with CXCR4 multimers in human cancer cells.

While the existence and functional role of class C G-protein-coupled receptors (GPCR) dimers is well established, there is still a lack of consensus regarding class A and B GPCR multimerization. This lack of consensus is largely due to the inherent challenges of demonstrating the presence of multimeric receptor complexes in a physiologically relevant cellular context. The C-X-C motif chemokine receptor 4 (CXCR4) is a class A GPCR that is a promising target of anticancer therapy. Here, we investigated the potential of CXCR4 to form multimeric complexes with other GPCRs and characterized the relative size of the complexes in a live-cell environment. Using a bimolecular fluorescence complementation (BiFC) assay, we identified the ß2 adrenergic receptor (ß2AR) as an interaction partner. To investigate the molecular scale details of CXCR4-ß2AR interactions, we used a time-resolved fluorescence spectroscopy method called pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS can resolve membrane protein density, diffusion, and multimerization state in live cells at physiological expression levels. We probed CXCR4 and ß2AR homo- and heteromultimerization in model cell lines and found that CXCR4 assembles into multimeric complexes larger than dimers in MDA-MB-231 human breast cancer cells and in HCC4006 human lung cancer cells. We also found that ß2AR associates with CXCR4 multimers in MDA-MB-231 and HCC4006 cells to a higher degree than in COS-7 and CHO cells and in a ligand-dependent manner. These results suggest that CXCR4-ß2AR heteromers are present in human cancer cells and that GPCR multimerization is significantly affected by the plasma membrane environment.

Polycrystalline SnSe with a thermoelectric figure of merit greater than the single crystal.

Thermoelectric materials generate electric energy from waste heat, with conversion efficiency governed by the dimensionless figure of merit, ZT. Single-crystal tin selenide (SnSe) was discovered to exhibit a high ZT of roughly 2.2-2.6 at 913 K, but more practical and deployable polycrystal versions of the same compound suffer from much poorer overall ZT, thereby thwarting prospects for cost-effective lead-free thermoelectrics. The poor polycrystal bulk performance is attributed to traces of tin oxides covering the surface of SnSe powders, which increases thermal conductivity, reduces electrical conductivity and thereby reduces ZT. Here, we report that hole-doped SnSe polycrystalline samples with reagents carefully purified and tin oxides removed exhibit an ZT of roughly 3.1 at 783 K. Its lattice thermal conductivity is ultralow at roughly 0.07 W m-1 K-1 at 783 K, lower than the single crystals. The path to ultrahigh thermoelectric performance in polycrystalline samples is the proper removal of the deleterious thermally conductive oxides from the surface of SnSe grains. These results could open an era of high-performance practical thermoelectrics from this high-performance material.

Effectiveness of hydraulic pressure-assisted sinus augmentation in a rabbit sinus model: a preclinical study.

OBJECTIVES: To investigate the effectiveness of hydraulic pressure-assisted sinus augmentation (SA) in a rabbit sinus model in terms of radiographical and histological healing. MATERIALS AND METHODS: Bilateral SA was performed in 12 rabbits. Each sinus was randomly assigned to either a hydraulic pressure-assisted SA (test) or a conventional SA (control) group. Healing periods of 2 and 4 weeks were applied (n = 6 for each week). Healing pattern including newly formed bone (NB) and residual bone substitute material (RM) was analyzed with microcomputed tomographically, histologically, and histomorphometrically. RESULTS: No sinus membrane perforation was detected in either group. In the microcomputed tomographic analysis, the test group exhibited higher apico-coronal spread of RM compared to the control group (p < 0.05). Particularly, the test group exhibited several masses of NB out of the cluster of RM. Histologically, the test group showed an elongated shape of the augmented space, whereas the control group generally presented a dome shape. Histomorphometrically, the total augmented area and the area of NB (1.32 ± 0.56 vs. 0.84 ± 0.40 mm2 at 2 weeks, 2.24 ± 1.09 vs. 2.22 ± 0.85 mm2 at 4 weeks) were not significantly different between the test and the control groups at both healing periods (p > 0.05). CONCLUSION: Hydraulic pressure-assisted SA led to new bone formation in the distant areas from the bony access hole, but similar histological healing pattern to conventional SA. CLINICAL RELEVANCE: Hydraulic pressure-assisted SA is a promising option for treating pneumatized posterior maxilla.

ZNF746/PARIS promotes the occurrence of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer to cause liver cancer related deaths worldwide. Zinc finger protein 746 (ZNF746), initially identified as a Parkin-interacting substrate (PARIS), acts as a transcriptional repressor of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in Parkinson's disease. As recent studies reported that PARIS is associated with cancer onset, we investigated whether PARIS is associated with HCC. We found an increase in insoluble parkin and PARIS accumulation in the liver of diethylnitrosamine (DEN)-injected mice, leading to the downregulation of PGC-1α and nuclear respiratory factor 1 (NRF1). Interestingly, the occurrence of DEN-induced tumors was significantly alleviated in the livers of DEN-injected PARIS knockout mice compared to DEN-injected wild-type mice, suggesting that PARIS is involved in DEN-induced hepatocellular tumorigenesis. Moreover, H2O2-treated Chang liver cells showed accumulation of PARIS and downregulation of PGC-1α and NRF1. Thus, these results suggest that PARIS upregulation by oncogenic stresses can promote cancer progression by suppressing the transcriptional level of PGC-1α, and the modulation of PARIS can be a promising therapeutic target for HCC.

FOPR test: a virtual reality-based technique to assess field of perception and field of regard in hemispatial neglect.

BACKGROUND: We previously proposed a novel virtual reality-based method to assess human field of perception (FOP) and field of regard (FOR), termed the FOPR test. This study assessed the diagnostic validity of the FOPR test for hemispatial neglect (HSN). METHODS: We included 19 stroke patients with a lesion in the right hemisphere and with HSN (HSN+SS), 22 stroke patients with a lesion in the right hemisphere and without HSN (HSN-SS), and 22 healthy controls aged 19-65 years. The success rate (SR) and response time (RT) in the FOPR test for both FOP and FOR were assessed (FOP-SR, FOR-SR, FOP-RT, and FOR-RT, respectively). Using a Bland-Altman plot, agreements between the FOPR test and conventional tests were confirmed, and the FOPR test accuracy was verified using the support vector machine (SVM). Measured values were analysed using ANOVA and Kruskall-Wallis tests for group comparison. RESULTS: The Bland-Altman plot showed good agreement between FOPR test and conventional tests; individuals within 95% agreement limits were within the range of 94.8-100.0%. The SVM classification accuracy, using FOP and FOR variables from the left hemispace, ranged from 83.3 to 100.0% in a binary classification (HSN vs non-HSN). The FOPR test demonstrated differences in SR and RT for both FOP and FOR across the groups. CONCLUSION: The FOPR test was valid for the HSN diagnosis and provided quantitative and intuitive information regarding visuospatial function. Furthermore, it might enhance our understanding of visuospatial function including HSN by applying the time relative component and concepts of perception and exploration, FOP and FOR. TRIAL REGISTRATION: NCT03463122. Registered 13 March 2018, retrospectively registered.

α-Synuclein A53T Binds to Transcriptional Adapter 2-Alpha and Blocks Histone H3 Acetylation.

α-Synuclein (α-syn) is a hallmark amyloidogenic protein component of Lewy bodies in dopaminergic neurons affected by Parkinson's disease (PD). Despite the multi-faceted gene regulation of α-syn in the nucleus, the mechanism underlying α-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, we identified transcriptional adapter 2-alpha (TADA2a) as a novel binding partner of α-syn using the BioID system. TADA2a is a component of the p300/CBP-associated factor and is related to histone H3/H4 acetylation. We found that α-syn A53T was more preferentially localized in the nucleus than the α-syn wild-type (WT), leading to a stronger disturbance of TADA2a. Indeed, α-syn A53T significantly reduced the level of histone H3 acetylation in SH-SY5Y cells; its reduction was also evident in the striatum (STR) and substantia nigra (SN) of mice that were stereotaxically injected with α-syn preformed fibrils (PFFs). Interestingly, α-syn PFF injection resulted in a decrease in TADA2a in the STR and SN of α-syn PFF-injected mice. Furthermore, the levels of TADA2a and acetylated histone H3 were significantly decreased in the SN of patients with PD. Therefore, histone modification through α-syn A53T-TADA2a interaction may be associated with α-syn-mediated neurotoxicity in PD pathology.

A comparison of the effects and usability of two exoskeletal robots with and without robotic actuation for upper extremity rehabilitation among patients with stroke: a single-blinded randomised controlled pilot study.

BACKGROUND: Robotic rehabilitation of stroke survivors with upper extremity dysfunction may yield different outcomes depending on the robot type. Considering that excessive dependence on assistive force by robotic actuators may interfere with the patient's active learning and participation, we hypothesised that the use of an active-assistive robot with robotic actuators does not lead to a more meaningful difference with respect to upper extremity rehabilitation than the use of a passive robot without robotic actuators. Accordingly, we aimed to evaluate the differences in the clinical and kinematic outcomes between active-assistive and passive robotic rehabilitation among stroke survivors. METHODS: In this single-blinded randomised controlled pilot trial, we assigned 20 stroke survivors with upper extremity dysfunction (Medical Research Council scale score, 3 or 4) to the active-assistive robotic intervention (ACT) and passive robotic intervention (PSV) groups in a 1:1 ratio and administered 20 sessions of 30-min robotic intervention (5 days/week, 4 weeks). The primary (Wolf Motor Function Test [WMFT]-score and -time: measures activity), and secondary (Fugl-Meyer Assessment [FMA] and Stroke Impact Scale [SIS] scores: measure impairment and participation, respectively; kinematic outcomes) outcome measures were determined at baseline, after 2 and 4 weeks of the intervention, and 4 weeks after the end of the intervention. Furthermore, we evaluated the usability of the robots through interviews with patients, therapists, and physiatrists. RESULTS: In both the groups, the WMFT-score and -time improved over the course of the intervention. Time had a significant effect on the WMFT-score and -time, FMA-UE, FMA-prox, and SIS-strength; group × time interaction had a significant effect on SIS-function and SIS-social participation (all, p < 0.05). The PSV group showed better improvement in participation and smoothness than the ACT group. In contrast, the ACT group exhibited better improvement in mean speed. CONCLUSIONS: There were no differences between the two groups regarding the impairment and activity domains. However, the PSV robots were more beneficial than ACT robots regarding participation and smoothness. Considering the high cost and complexity of ACT robots, PSV robots might be more suitable for rehabilitation in stroke survivors capable of voluntary movement. Trial registration The trial was registered retrospectively on 14 March 2018 at ClinicalTrials.gov (NCT03465267).

Fabrication of Atom Probe Tomography Specimens from Nanoparticles Using a Fusible Bi-In-Sn Alloy as an Embedding Medium.

We propose a new method for preparing atom probe tomography specimens from nanoparticles using a fusible bismuth-indium-tin alloy as an embedding medium. Iron nanoparticles synthesized by the sodium borohydride reduction method were chosen as a model system. The as-synthesized iron nanoparticles were embedded within the fusible alloy using focused ion beam milling and ion-milled to needle-shaped atom probe specimens under cryogenic conditions. An atom probe analysis revealed boron atoms in a detected iron nanoparticle, indicating that boron from the sodium borohydride reductant was incorporated into the nanoparticle during its synthesis.

Effects of virtual reality-based planar motion exercises on upper extremity function, range of motion, and health-related quality of life: a multicenter, single-blinded, randomized, controlled pilot study.

BACKGROUND: Virtual reality (VR)-based rehabilitation is considered a beneficial therapeutic option for stroke rehabilitation. This pilot study assessed the clinical feasibility of a newly developed VR-based planar motion exercise apparatus (Rapael Smart Board™ [SB]; Neofect Inc., Yong-in, Korea) for the upper extremities as an intervention and assessment tool. METHODS: This single-blinded, randomized, controlled trial included 26 stroke survivors. Patients were randomized to the intervention group (SB group) or control (CON) group. During one session, patients in the SB group completed 30 min of intervention using the SB and an additional 30 min of standard occupational therapy; however, those in the CON group completed the same amount of conventional occupational therapy. The primary outcome was the change in the Fugl-Meyer assessment (FMA) score, and the secondary outcomes were changes in the Wolf motor function test (WMFT) score, active range of motion (AROM) of the proximal upper extremities, modified Barthel index (MBI), and Stroke Impact Scale (SIS) score. A within-group analysis was performed using the Wilcoxon signed-rank test, and a between-group analysis was performed using a repeated measures analysis of covariance. Additionally, correlations between SB assessment data and clinical scale scores were analyzed by repeated measures correlation. Assessments were performed three times (baseline, immediately after intervention, and 1 month after intervention). RESULTS: All functional outcome measures (FMA, WMFT, and MBI) showed significant improvements (p < 0.05) in the SB and CON groups. AROM showed greater improvements in the SB group, especially regarding shoulder abduction and internal rotation. There was a significant effect of time × group interactions for the SIS overall score (p = 0.038). Some parameters of the SB assessment, such as the explored area ratio, mean reaching distance, and smoothness, were significantly associated with clinical upper limb functional measurements with moderate correlation coefficients. CONCLUSIONS: The SB was available for improving upper limb function and health-related quality of life and useful for assessing upper limb ability in stroke survivors. TRIAL REGISTRATION: The study was registered with the clinical research information service (CRIS) ( KCT0003783 , registered 15 April 2019; retrospectively registered).

PARIS reprograms glucose metabolism by HIF-1α induction in dopaminergic neurodegeneration.

Our previous study found that PARIS (ZNF746) transcriptionally suppressed transketolase (TKT), a key enzyme in pentose phosphate pathway (PPP) in the substantia nigra (SN) of AAV-PARIS injected mice. In this study, we revealed that PARIS overexpression reprogrammed glucose metabolic pathway, leading to the increment of glycolytic proteins along with TKT reduction in the SN of AAV-PARIS injected mice. Knock-down of TKT in differentiated SH-SY5Y cells led to an increase of glycolytic enzymes and decrease of PPP-related enzymes whereas overexpression of TKT restored PARIS-mediated glucose metabolic shift, suggesting that glucose metabolic alteration by PARIS is TKT-dependent. Inhibition of PPP by either PARIS overexpression or TKT knock-down elevated the level of H2O2, and diminished NADPH and GSH levels, ultimately triggering the induction of HIF-1α, a master activator of glycolysis. In addition, TKT inhibition by stereotaxic injection of oxythiamine demonstrated slight decrement of dopaminergic neurons (DNs) in SN but not cortical neurons in the cortex, suggesting that TKT might be a survival factor of DNs. In differentiated SH-SY5Y, cell toxicity by GFP-PARIS was partially restored by introduction of Flag-TKT and siRNA-HIF-1α. We also observed the increase of HIF-1α and glycolytic hexokinase 2 in the SN of Parkinson's disease patients. Taken together, these results suggest that PARIS accumulation might distort the balance of glucose metabolism, providing clues for understanding mechanism underlying selective DNs death by PARIS.

Virtual Reality Rehabilitation With Functional Electrical Stimulation Improves Upper Extremity Function in Patients With Chronic Stroke: A Pilot Randomized Controlled Study.

OBJECTIVE: To compare virtual reality (VR) combined with functional electrical stimulation (FES) with cyclic FES for improving upper extremity function and health-related quality of life in patients with chronic stroke. DESIGN: A pilot, randomized, single-blind, controlled trial. SETTING: Stroke rehabilitation inpatient unit. PARTICIPANTS: Participants (N=48) with hemiplegia secondary to a unilateral stroke for >3 months and with a hemiplegic wrist extensor Medical Research Council scale score ranging from 1 to 3. INTERVENTIONS: FES was applied to the wrist extensors and finger extensors. A VR-based wearable rehabilitation device was used combined with FES and virtual activity-based training for the intervention group. The control group received cyclic FES only. Both groups completed 20 sessions over a 4-week period. MAIN OUTCOME MEASURES: Primary outcome measures were changes in Fugl-Meyer Assessment-Upper Extremity and Wolf Motor Function Test scores. Secondary outcome measures were changes in Box and Block Test, Jebsen-Taylor Hand Function Test, and Stroke Impact Scale scores. Assessments were performed at baseline (t0) and at 2 weeks (t1), 4 weeks (t4), and 8 weeks (t8). Between-group comparisons were evaluated using a repeated-measures analysis of variance. RESULTS: Forty-one participants were included in the analysis. Compared with FES alone, VR-FES produced a substantial increase in Fugl-Meyer Assessment-distal score (P=.011) and marginal improvement in Jebsen-Taylor Hand Function Test-gross score (P=.057). VR-FES produced greater, although nonsignificant, improvements in all other outcome measures, except in the Stroke Impact Scale-activities of daily living/instrumental activities of daily living score. CONCLUSIONS: FES with VR-based rehabilitation may be more effective than cyclic FES in improving distal upper extremity gross motor performance poststroke.

Effects of virtual reality-based rehabilitation on distal upper extremity function and health-related quality of life: a single-blinded, randomized controlled trial.

BACKGROUND: Virtual reality (VR)-based rehabilitation has been reported to have beneficial effects on upper extremity function in stroke survivors; however, there is limited information about its effects on distal upper extremity function and health-related quality of life (HRQoL). The purpose of the present study was to examine the effects of VR-based rehabilitation combined with standard occupational therapy on distal upper extremity function and HRQoL, and compare the findings to those of amount-matched conventional rehabilitation in stroke survivors. METHODS: The present study was a single-blinded, randomized controlled trial. The study included 46 stroke survivors who were randomized to a Smart Glove (SG) group or a conventional intervention (CON) group. In both groups, the interventions were targeted to the distal upper extremity and standard occupational therapy was administered. The primary outcome was the change in the Fugl-Meyer assessment (FM) scores, and the secondary outcomes were the changes in the Jebsen-Taylor hand function test (JTT), Purdue pegboard test, and Stroke Impact Scale (SIS) version 3.0 scores. The outcomes were assessed before the intervention, in the middle of the intervention, immediately after the intervention, and 1 month after the intervention. RESULTS: The improvements in the FM (FM-total, FM-prox, and FM-dist), JTT (JTT-total and JTT-gross), and SIS (composite and overall SIS, SIS-social participation, and SIS-mobility) scores were significantly greater in the SG group than in the CON group. CONCLUSIONS: VR-based rehabilitation combined with standard occupational therapy might be more effective than amount-matched conventional rehabilitation for improving distal upper extremity function and HRQoL. TRIAL REGISTRATION: This study is registered under the title "Effects of Novel Game Rehabilitation System on Upper Extremity Function of Patients With Stroke" and can be located in https://clinicaltrials.gov with the study identifier NCT02029651 .

Extrinsic hydrophobicity-controlled silver nanoparticles as efficient and stable catalysts for CO2 electrolysis.

To realize economically feasible electrochemical CO2 conversion, achieving a high partial current density for value-added products is particularly vital. However, acceleration of the hydrogen evolution reaction due to cathode flooding in a high-current-density region makes this challenging. Herein, we find that partially ligand-derived Ag nanoparticles (Ag-NPs) could prevent electrolyte flooding while maintaining catalytic activity for CO2 electroreduction. This results in a high Faradaic efficiency for CO (>90%) and high partial current density (298.39 mA cm‒2), even under harsh stability test conditions (3.4 V). The suppressed splitting/detachment of Ag particles, due to the lipid ligand, enhance the uniform hydrophobicity retention of the Ag-NP electrode at high cathodic overpotentials and prevent flooding and current fluctuations. The mass transfer of gaseous CO2 is maintained in the catalytic region of several hundred nanometers, with the smooth formation of a triple phase boundary, which facilitate the occurrence of CO2RR instead of HER. We analyze catalyst degradation and cathode flooding during CO2 electrolysis through identical-location transmission electron microscopy and operando synchrotron-based X-ray computed tomography. This study develops an efficient strategy for designing active and durable electrocatalysts for CO2 electrolysis.

Feasibility of hemispatial neglect rehabilitation with virtual reality-based visual exploration therapy among patients with stroke: randomised controlled trial.

Background: Hemispatial neglect (HSN) was diagnosed using a virtual reality-based test (FOPR test) that explores the field of perception (FOP) and field of regard (FOR). Here, we developed virtual reality-visual exploration therapy (VR-VET) combining elements from the FOPR test and visual exploration therapy (VET) and examined its efficacy for HSN rehabilitation following stroke. Methods: Eleven participants were randomly assigned to different groups, training with VR-VET first then waiting without VR-VET training (TW), or vice versa (WT). The TW group completed 20 sessions of a VR-VET program using a head-mounted display followed by 4 weeks of waiting, while the WT group completed the opposite regimen. Clinical HSN measurements [line bisection test (LBT), star cancellation test (SCT), Catherine Bergego Scale (CBS), CBS perceptual-attentional (CBS-PA), and CBS motor-explanatory (CBS-ME)] and FOPR tests [response time (RT), success rate (SR), and head movement (HM) for both FOP and FOR] were assessed by blinded face-to-face assessments. Results: Five and six participants were allocated to the TW and WT groups, respectively, and no dropout occurred throughout the study. VR-VET considerably improved LBT scores, FOR variables (FOR-RT, FOR-SR), FOP-LEFT variables (FOP-LEFT-RT, FOP-LEFT-SR), and FOR-LEFT variables (FOR-LEFT-RT, FOR-LEFT-SR) compared to waiting without VR-VET. Additionally, VR-VET extensively improved FOP-SR, CBS, and CBS-PA, where waiting failed to make a significant change. The VR-VET made more improvements in the left hemispace than in the right hemispace in FOP-RT, FOP-SR, FOR-RT, and FOR-SR. Conclusion: The observed improvements in clinical assessments and FOPR tests represent the translatability of these improvements to real-world function and the multi-dimensional effects of VR-VET training. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03463122, identifier NCT03463122.

Novel H2S sensing mechanism derived from the formation of oligomeric sulfide capping the surface of gold nanourchins.

A gold nanourchin (AuNU) probe with a novel sensing mechanism for monitoring H2S was developed as a feasible colorimetric sensor. In this study, AuNUs that are selectively responsive to H2S were fabricated in the presence of trisodium citrate and 1,4-hydroquinone using a seed-mediated approach. Upon exposure of the AuNU solution to H2S, the hydrosulfide ions (HS-) in the solution are converted into oligomeric sulfides by 1,4-hydroquinone used as a reducing agent during the synthesis of AuNUs. The oligomeric sulfides formed in the AuNU solution upon the addition of H2S were found to coat the surface of the AuNUs, introducing a blue shift in absorption accompanied by a color change in the solution from sky blue to light green. This colorimetric alteration by the capping of oligomeric sulfides on the surface of AuNUs is unique compared to well-known color change mechanisms, such as aggregation, etching, or growth of nanoparticles. The novel H2S sensing mechanism of the AuNUs was characterized using UV-Vis spectroscopy, high-resolution transmission microscopy, X-ray photoelectron spectroscopy, surface-enhanced Raman spectroscopy, secondary ion mass spectroscopy, liquid chromatography-tandem mass spectrometry, and atom probe tomography. H2S was reliably monitored with two calibration curves comprising two sections with different slopes according to the low (0.3-15 µM) and high (15.0-300 µM) concentration range using the optimized AuNU probe, and a detection limit of 0.29 µM was obtained in tap water.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits ß-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (ß2AR). Co-treatment with CXCL12 and the ß2AR agonist epinephrine synergistically increases ß-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson's Disease Model.

Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson's disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the insoluble fraction, leading to the sequestration of PGC-1α into insoluble deposits. The mislocalization of PGC-1α in the insoluble fraction was observed in S-nitrosocysteine-treated PARIS knockout (KO) cells overexpressing PARIS WT but not S-nitrosylation deficient C265S mutant, indicating that insolubility of PGC-1α is SNO-PARIS-dependent. In the sporadic PD model, α-synuclein preformed fibrils (α-syn PFFs)-injected mice, we found an increase in PARIS, SNO-PARIS, and insoluble sequestration of PGC-1α in substantia nigra (SN), resulting in the reduction of mitochondrial DNA copy number and ATP concentration that were restored by N(ω)-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor. To assess the dopaminergic (DA) neuronal toxicity by SNO-PARIS, lentiviral PARIS WT, C265S, and S-nitrosylation mimic C265W was injected into the SN of either PBS- or α-syn PFFs-injected mice. PARIS WT and C265S caused DA neuronal death to a comparable extent, whereas C265W caused more severe DA neuronal loss in PBS-injected mice. Interestingly, there was synergistic DA loss in both lenti-PARIS WT and α-syn PFFs-injected mice, indicating that SNO-PARIS by α-syn PFFs contributes to the DA toxicity in vivo. Moreover, α-syn PFFs-mediated increment of PARIS, SNO-PARIS, DA toxicity, and behavioral deficits were completely nullified in neuronal NOS KO mice, suggesting that modulation of NO can be a therapeutic for α-syn PFFs-mediated neurodegeneration.

Naturally diffused sintering aid for highly conductive bilayer electrolytes in solid oxide cells.

Solid oxide cells (SOCs) are promising sustainable and efficient electrochemical energy conversion devices. The application of a bilayer electrolyte comprising wide electrolytic oxide and highly conductive oxide is essential to lower the operating temperatures while maintaining high performance. However, a structurally and chemically ideal bilayer has been unattainable through cost-effective conventional ceramic processes. Here, we describe a strategy of naturally diffused sintering aid allowing the fabrication of defect-free doped-zirconia/doped-ceria bilayer electrolyte with full density and reduced interdiffusion layer at lower sintering temperature owing to the supply of small but appropriate amount of sintering aid from doped zirconia to doped ceria that makes the thermal shrinkages of both layers perfectly congruent. The resulting SOCs exhibit a minimal ohmic loss of 0.09 ohm cm2 and remarkable performances in both fuel cell (power density exceeding 1.3 W cm−2) and electrolysis (current density of −1.27 A cm−2 at 1.3 V) operations at 700°C.

Clinical and Immunological Efficacy of Mangosteen and Propolis Extracted Complex in Patients with Gingivitis: A Multi-Centered Randomized Controlled Clinical Trial.

BACKGROUND: Mangosteen and propolis extracts (MAEC) have been potential therapeutic agents known to exhibit powerful antioxidant and anti-inflammatory properties. The aim of the current study was to evaluate the clinical and immunological efficacy of MAEC as well as safety and patient-reported outcomes (PROMs) on gingivitis and incipient periodontitis. METHODS: This study was performed on 104 patients diagnosed with gingivitis or incipient periodontitis. At baseline, the participants were randomly allocated to either the test group, with daily intake of a single capsule containing 194 mg of MAEC for eight weeks, or control group, with placebo. Clinical periodontal evaluation and immunological parameters from saliva and gingival sulcular fluid were assessed at baseline, four, and eight weeks. Individual PROMs were assessed by OHIP-14 questionnaires. RESULTS: There was a significant difference of modified gingival index at four and eight weeks between the test and control groups. In the test group, crevicular interleukin (IL)-6 was reduced, and the salivary matrix metalloproteinase (MMP)-9 was increased after eight weeks. PROMs were improved up to four weeks compared to placebo. CONCLUSION: Oral administration of MAEC would have a potential to reduce gingival inflammation clinically and immunologically in the patients with gingivitis and incipient periodontitis.

Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation.

Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212-PLD3 relationship is important for Purkinje cell survival.