Effect of Lingual Nerve Block and Localised Somatosensory Abnormalities in Patients With Burning Mouth Syndrome-A Randomised Crossover Double-Blind Trial.

AIMS: To investigate the effect of a lingual nerve block on spontaneous pain in patients with burning mouth syndrome (BMS) and to estimate associated somatosensory abnormalities by quantitative sensory testing (QST). PROTOCOL AND METHODS: A standardised QST battery including cold detection threshold (CDT), warmth detection threshold (WDT), thermal sensory limen (TSL), paradoxical heat sensation (PHS), cold pain threshold (CPT), heat pain threshold (HPT), mechanical pain threshold (MPT), wind-up ratio (WUR) and pressure pain threshold (PPT) was performed at the oral mucosa of the most painful site and intraoral control site in 20 BMS patients, and at the tongue and cheek mucosa in 22 age- and gender-matched healthy controls. The effect of a lingual nerve block on spontaneous burning pain reported by the BMS patients on a 0-10 cm visual analogue scale (VAS) was investigated in a randomised double-blind crossover design using (1 mL) lidocaine (lido) or saline (sal) with an interval of 1 week. The BMS patients were grouped into 'central' and 'peripheral' mechanisms based on the effect of the lingual nerve injections. For each BMS patient, Z-scores and Loss/Gain scores were computed. Differences among groups and sites were analysed using a two-way ANOVA. Differences within group were assessed by paired t-test. RESULTS: The 20 BMS patients were characterised on the basis of VAS changes (ΔLido-ΔSal) as a peripheral BMS subgroup (n = 9) with pain relief more than 1 cm on the VAS and a central BMS subgroup (n = 11) with pain relief less than 1 cm. BMS patients (n = 20) had lower sensitivity to thermal stimuli (i.e., CDT, WDT, TSL, CPT, HPT and PPT) and higher sensitivity to mechanical stimuli (i.e., PPT) compared with controls (p ≤ 0.007). Based on Loss/Gain coding, L1G0 (loss of thermal somatosensory function with no somatosensory gain, 55.0%) was the most frequent coding in the BMS group, which was higher than 11.4% in the control group (p < 0.001). Surprisingly, there was no significant difference between the peripheral and central BMS subgroups with regard to the Z-scores of any of the nine QST parameters (p > 0.097). CONCLUSIONS: The results of the lingual nerve blocks demonstrated two distinct phenotypes with either peripheral or central mechanisms but no direct impact on somatosensory function. Overall, somatosensory function in BMS patients seems abnormal in the painful areas compared to matched controls with a conspicuous loss of thermosensory function.

Conditioned Pain Modulation Differences in Central and Peripheral Burning Mouth Syndrome (BMS) Patients.

AIM: To evaluate conditioned pain modulation (CPM) in burning mouth syndrome (BMS) patients with different pain mechanisms. MATERIALS AND METHODS: Twenty BMS patients (52.0 ± 6.8 years, 17 women and 3 men) and age- and gender-matched 22 healthy controls were enrolled in this randomised controlled trial. The patients received an active lingual nerve block (lidocaine) and a placebo injection (saline) randomly with an interval of 1 week in a double-blinded manner. Patients evaluated their pain intensity on a 0- to 10-cm visual analogue scale (VAS) before and after each injection, with or without CPM. Based on the anaesthesia effect, BMS patients were divided into two groups with presumed different pain mechanisms; a 'central subgroup (n = 11)' with pain relief less than 1 cm and 'peripheral subgroup (n = 9)' with pain relief more than 1 cm on the VAS. Mechanical pain threshold (MPT) and wind-up ratio (WUR) were investigated at two oral mucosa regions: the region with most intense symptoms and a control region for the patient group; tongue and buccal region for the control group. CPM was induced by immersing the left hand into cold water. A moderate level of pain (around five on the VAS) was obtained by adjusting the water temperature. MPT and WUR were measured twice for all the participants with and without CPM, which was analysed and presented as relative change in MPT and WUR. Differences between groups were analysed using two-way ANOVA. Differences within group between tests were assessed by paired t-test. RESULTS: At baseline, there were no significant group differences for MPT or WUR between BMS patients and healthy controls (p ≥ 0.156). The mean bath temperature to evoke moderate pain for the BMS group was significantly lower than that for the healthy control group (8.9°C vs. 11.9°C, p = 0.003). The CPM evoked an inhibitory modulation in 18.2%-44.4% of BMS patients, while for the healthy group, the ratio was 68.2%-81.8%. Central BMS patients had smaller CPM effects than healthy participants at the painful site and control site, which indicated a decreased CPM function (p ≤ 0.034). Peripheral BMS patients had lower CPM effects than healthy participants only at the painful site (p = 0.037). CONCLUSIONS: The present findings documented impairment of central nociceptive inhibition processing in BMS patients which was more extensive in central BMS than peripheral BMS. These findings add to the suggestion that BMS may a heterogeneous pain condition with at least two different phenotypes.

Transcription factor EB, a promising therapeutic target in cardiovascular disease.

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality around the world. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis and autophagy. Emerging studies revealed that TFEB also mediates cellular adaptation responses to various stimuli, such as mitochondrial dysfunction, pathogen infection and metabolic toxin. Based on its significant capability to modulate the autophagy-lysosome process (ALP), TFEB plays a critical role in the development of CVD. In this review, we briefly summarize that TFEB regulates cardiac dysfunction mainly through ameliorating lysosomal and mitochondrial dysfunction and reducing inflammation.

How to apply ex-vivo split liver transplantation safely and feasibly: A three-step approach.

BACKGROUND: Given the current organ shortage crisis, split liver transplantation (SLT) has emerged as a promising alternative for select end-stage liver disease patients. AIM: To introduce an ex-vivo liver graft splitting approach and evaluate its safety and feasibility in SLT. METHODS: A retrospective analysis was conducted on the liver transplantation data from cases performed at our center between April 1, 2022, and May 31, 2023. The study included 25 SLT cases and 81 whole liver transplantation (WLT) cases. Total ex-vivo liver splitting was employed for SLT graft procurement in three steps. Patient outcomes were determined, including liver function parameters, postoperative complications, and perioperative mortality. Group comparisons for categorical variables were performed using the χ²-test. RESULTS: In the study, postoperative complications in the 25 SLT cases included hepatic artery thrombosis (n = 1) and pulmonary infections (n = 3), with no perioperative mortality. In contrast, among the 81 patients who underwent WLT, complications included perioperative mortality (n = 1), postoperative pulmonary infections (n = 8), abdominal infection (n = 1), hepatic artery thromboses (n = 3), portal vein thrombosis (n = 1), and intra-abdominal bleeding (n = 5). Comparative analysis demonstrated significant differences in alanine aminotransferase (176.0 vs 73.5, P = 0.000) and aspartate aminotransferase (AST) (42.0 vs 29.0, P = 0.004) at 1 wk postoperatively, and in total bilirubin (11.8 vs 20.8, P = 0.003) and AST (41.5 vs 26.0, P = 0.014) at 2 wk postoperatively. However, the overall incidence of complications was comparable between the two groups (P > 0.05). CONCLUSION: Our findings suggest that the total ex-vivo liver graft splitting technique is a safe and feasible approach, especially under the expertise of an experienced transplant center. The approach developed by our center can serve as a valuable reference for other transplantation centers.

Targeted Modulation of Redox and Immune Homeostasis in Acute Lung Injury Using a Thioether-Functionalized Dendrimer.

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It is characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions and immune homeostasis in the lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG is developed, to scavenge both proinflammatory cytokines and reactive oxygen species (ROS) and restore homeostasis during ALI treatment. The dendrimers are synthesized using an efficient and orthogonal thiol-ene "click" chemistry approach that involves incorporating thioether moieties within the dendritic architectures to neutralize the ROS. The ROS scavenging of Sr-G4-PEG manifests in its capacity to sequester proinflammatory cytokines. The synergistic effects of scavenging ROS and sequestering inflammatory cytokines by Sr-G4-PEG contribute to redox remodeling and immune homeostasis, along with the modulation of the NLRP3-pyroptosis pathway. Treatment with Sr-G4-PEG enhances the therapeutic efficacy of ALIs by alleviating alveolar bleeding, reducing inflammatory cell infiltration, and suppressing the release of inflammatory cytokines. These results suggest that Sr-G4-PEG is a potent nanotechnological candidate for remodeling redox and immune homeostasis in the treatment of ALIs, demonstrating the great potential of dendrimer-based nanomedicine for the treatment of respiratory pathologies.

Effectivity and safety of trifocal intraocular lenses and capsular tension rings implantation for cataract patients with axial high myopia.

AIM: To assess effectivity and safety of trifocal intraocular lenses (IOLs) and capsular tension rings in treating cataract patients with axial high myopia. METHODS: A prospective nonrandomized controlled clinical trial was conducted. Totally 98 eyes (74 patients) who underwent femtosecond laser-assisted cataract surgery (FLACS) with trifocal IOLs were enrolled in the study and followed up for 2y after surgery: 46 eyes (33 patients) with capsular tension ring implantation in the long axial lengths (AL) group (260.05). The dysfunctional lens index and total modulation transfer function (MTF) average height were similar between the two groups. The postoperative internal coma aberrations in the axial high myopia eyes were significantly higher than that in the normal AL group (P<0.05). The total satisfaction score in the long AL group (91.32±2.76) was slightly higher than that in the normal AL group (90.36±3.47), but there was no difference (P=0.136). A statistically negative correlation was found between corrected distance visual acuity (CDVA) and dysfunctional lens index (r=-0.382, P=0.009), and between CDVA and the total MTF average height (r=-0.374, P=0.01). But there was no significant correlation between CDVA and total satisfaction score (r=0.059, P=0.696). Postoperative complications mainly presented as posterior capsular opacity (PCO), retinal detachment and cystoid macular edema. There was no difference in the incidence of fundus disease (6.5% vs 3.8%, P=0.663) or PCO (17.4% vs 7.7%, P=0.217) between the two groups at two years. CONCLUSION: The utilization of trifocal IOL and capsular tension ring implantation is beneficial for cataract patients with axial high myopia undergoing FLACS. This approach not only ensures excellent subjective feelings and objective visual quality, but also does not increase the incidence of postoperative complications.

Dexamethasone protects against asthma via regulating Hif-1α-glycolysis-lactate axis and protein lactylation.

PURPOSE: Asthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation. METHODS: Ovalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed. RESULTS: DEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX. CONCLUSION: Our present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.

Melatonin regulates circadian clock proteins expression in allergic airway inflammation.

Asthma demonstrates a strong circadian rhythm with disrupted molecular clock. Melatonin which can directly regulate circadian rhythm has been reported to alleviate asthma, but whether this effect is related to its regulation on circadian clock has not yet been known. Here, female C57BL/6 mice were challenged with ovalbumin (OVA) to establish allergic airway inflammation, and were treated with melatonin or Luzindole to investigate whether the expressions of circadian clock proteins were changed in response to OVA and were affected by exogenous/endogenous melatonin. Airway inflammation, mucus secretion, protein expressions of circadian proteins (Bmal1, Per1, Clock, Timeless, Cry1 and Cry2), melatonin biosynthetase (ASMT, AANAT) and melatonin receptor (Mel-1A/B-R) were analyzed accordingly. The results showed that in the successfully established allergic airway inflammation model, inflammatory cells infiltration, expressions of circadian clock proteins in the lung tissues of OVA-challenged mice were all notably up-regulated as compared to that of the vehicle mice. Meanwhile, the protein expression of ASMT and the level of melatonin in the lung tissues were reduced in allergic mice, while the expression of melatonin receptor Mel-1A/B-R was markedly increased. After addition of exogenous melatonin, the OVA-induced airway inflammation was pronouncedly ameliorated, while simultaneously the OVA-induced expressions of Per1 and Clock were further increased. However, a melatonin receptor antagonist Luzindole further augmented the OVA-induced airway inflammation, accompanied with remarkably decreased expressions of Per1, Bmal1, Cry1 and Cry2 but notably increased expression of Timeless. Collectively, our results demonstrated that the expression of circadian clock proteins was increased in the lungs during allergic airway inflammation, and Per1 was a clock protein that can be regulated by both exogenous and endogenous melatonin, suggesting Per1 may be an important potential circadian clock target for melatonin as a negative regulatory factor against Th2-type airway inflammation.

Down-regulation of Lon protease 1 lysine crotonylation aggravates mitochondrial dysfunction in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent reproductive endocrine disorder, with metabolic abnormalities and ovulation disorders. The post-translational modifications (PTMs) are functionally relevant and strengthen the link between metabolism and cellular functions. Lysine crotonylation is a newly identified PTM, the function of which in PCOS has not yet been reported. To explore the molecular mechanisms of crotonylation involved in the abnormalities of metabolic homeostasis and oocyte maturation in PCOS, by using liquid chromatography-tandem mass spectrometry analysis, we constructed a comprehensive map of crotonylation modifications in ovarian tissue of PCOS-like mouse model established by dehydroepiandrosterone induction. The crotonylation levels of proteins involved in metabolic processes were significantly decreased in PCOS ovaries compared to control samples. Further investigation showed that decrotonylation of Lon protease 1 (LONP1) at lysine 390 was associated with mitochondrial dysfunction in PCOS. Moreover, LONP1 crotonylation levels in PCOS were correlated with ovarian tissue oxidative stress levels, androgen levels, and oocyte development. Consistently, down-regulation of LONP1 and LONP1 crotonylation levels were also observed in the blood samples of PCOS patients. Collectively, our study revealed a mechanism by which the decrotonylation of LONP1 may attenuate its activity and alter follicular microenvironment to affect oocyte maturation in PCOS.

Prognostic implications of left ventricular hypertrophy defined by the thresholds from the international and Chinese guidelines.

To compare the predictive value of mortality between left ventricular hypertrophy (LVH) defined by Chinese thresholds and defined by international guidelines in hypertension individuals and investigate better indexation methods for LVH in Chinese population. We included 2454 community hypertensive patients with Left ventricular mass (LVM) and relative wall thickness. LVM was indexed to body surface area (BSA), height2 7 and height 1 7 . The outcomes were all-cause and cardiovascular mortality. Cox proportional hazards models were used to explore the association between LVH and the outcomes. C-statistics and time-dependent receiver operating characteristic curve (ROC) was used to evaluate the value of those indicators. During a median follow-up of 49 months (interquartile range 2-54 months), 174 participants (7.1%) died from any cause (n = 174), with 71 died of cardiovascular disease. LVM/BSA defined by the Chinese thresholds was significantly associated with cardiovascular mortality (HR: 1.63; 95%CI: 1.00-2.64). LVM/BSA was significantly associated with all-cause mortality using Chinese thresholds (HR: 1.56; 95%CI: 1.14-2.14) and using Guideline thresholds (HR: 1.52; 95%CI: 1.08-2.15). LVM/Height1.7 was significantly associated with all-cause mortality using Chinese thresholds (HR: 1.60; 95%CI: 1.17-2.20) and using Guideline thresholds (HR: 1.54; 95%CI: 1.04-2.27). LVM/Height2.7 was not significantly associated with all-cause mortality. C-statistics indicated that LVM/BSA and LVM/Height1.7 by Chinese thresholds had better predictive ability for mortality. Time-ROC indicated that only LVM/Height1.7 defined by Chinese threshold had incremental value for predicting mortality. We found that in community hypertensive populations, race-specific thresholds should be used to classify LV hypertrophy related to mortality risk stratification. LVM/BSA and LVM/Height1.7 are acceptable normalization method in Chinese hypertension.

Descending serotonergic modulation from rostral ventromedial medulla to spinal trigeminal nucleus is involved in experimental occlusal interference-induced chronic orofacial hyperalgesia.

BACKGROUND: Dental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI). METHODS: Expressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM. RESULTS: Upregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats. CONCLUSIONS: These results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI.

Dynamic three-sided matching model for personnel-robot-position matching problem in intelligent environments.

In recent years, intelligent robots have facilitated intelligent production, and a new type of problem (personnel-robot-position matching (PRPM)) has been encountered in personnel-position matching (PPM). In this study, a dynamic three-sided matching model is proposed to solve the PRPM problem in an intelligent production line based on man-machine collaboration. The first issue considered is setting the dynamic reference point, which is addressed in the information evaluation phase by proposing a method for setting the dynamic reference point based on the prospect theory. Another important issue involves multistage preference information integration, wherein a probability density function and a value function are introduced. Considering the attenuation of preference information in a time series, the attenuation index model is introduced to calculate the satisfaction matrix. Furthermore, a dynamic three-sided matching model is established. Additionally, a multi-objective decision-making model is established to optimize the matching of multiple sides (personnel, intelligent robots, and positions). Subsequently, the model is transformed into a single objective model using the triangular balance principle, which is introduced to obtain the final optimisation results in this modelling process. A case study is presented to illustrate the practicality of the dynamic three-sided matching model in intelligent environments. The results indicate that this model can solve the PRPM problem in an intelligent production line.

TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.

As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2-/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2-/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2-/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2-/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2-/- mice abolished while transfer of TLR2-/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.

Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation.

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1-/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity.

Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.

Stiff matrix induced srGAP2 tension gradients control migration direction in triple-negative breast cancer.

Rationale: Cells migrating through interstitial matrix enables stiffening of the tumor micro-environment. To overcome the stiff resistance of extracellular matrix, aggressive cells require the extracellular mechanosensory activation and intracellular tension response. Mechanotransduction linker srGAP2 can synergistically control the mechanical-biochemical process of malignant cell migration. Methods: To mimic the tumor micro-environment containing abundant collagen fibers and moving durotaxis of triple-negative breast cancer cells, the stiff-directed matrix was established. The newly designed srGAP2 tension probe was used to real-time supervise srGAP2 tension in living cells. The phosphorylation sites responsible for srGAP2 tension were identified by phosphorylated mutagenesis. Transwell assays and Xenograft mouse model were performed to evaluate TNBC cells invasiveness in vitro and in vivo. Fluorescence staining and membrane protein isolation were used to detect protein localization. Results: The present study shows srGAP2 serves as a linker to transmit the mechanical signals among cytoskeleton and membrane. SrGAP2 exhibits tension gradients among different parts in the stiff-directionally migrating triple-negative breast cancer cells. Cells showing the polarized tension that increased in the leading edge move faster, particularly guided by the stiff interstitial matrix. The srGAP2 tension-directed cell migration results from the upstream events of PKCα-mediated phosphorylation at Ser206 in the F-bar domain of srGAP2. In addition, Syndecan-4 (SDC4), a transmembrane mechanoreceptor protein, drives PKCα regional recruit on the area of membrane trending deformation, which requires the distinct extent of extracellular mechanics. Conclusion: SDC4-PKCα polarized distribution leads to the intracellular tension gradient of srGAP2, presenting the extra- and intracellular physiochemical integration and essential for persistent cell migration in stiff matrix and caner progression. Targeting the srGAP2-related physicochemical signaling could be developed into the therapeutic strategies of inhibiting breast cancer cell invasion and durotaxis.

Myocardial extracellular volume fraction quantification based on T1 mapping at 3 T: quality optimization by contour-based registration and segmental analysis.

BACKGROUND: Myocardial extracellular volume fraction (ECV) assessment can be affected by various technical and subject-related factors. PURPOSE: To evaluate the role of contour-based registration in quantification of ECV and investigate normal segment-based myocardial ECV values at 3T. MATERIAL AND METHODS: Pre- and post-contrast T1 mapping images of the left ventricular basal, mid-cavity, and apical slices were obtained in 26 healthy volunteers. ECV maps were generated using motion correction with and without contour-based registration. The image quality of all ECV maps was evaluated by a 4-point scale. Slices were dichotomized according to the occurrence of misregistration in the source data. Contour-registered ECVs and standard ECVs were compared within each subgroup using analysis of variance for repeated measurements and generalized linear mixed models. RESULTS: In all three slices, higher quality of ECV maps were found using contour-registered method than using standard method. Standard ECVs were statistically different from contour-registered ECVs in global (26.8% ± 2.8% vs. 25.8% ± 2.4%; P = 0.001), mid-cavity (25.4% ± 3.1% vs. 24.3% ± 2.5%; P = 0.016), and apical slices (28.7% ± 4.1% vs. 27.2% ± 3.4%; P = 0.010). In the misregistration subgroups, contour-registered ECVs were lower with smaller SDs (basal: 25.2% ± 1.8% vs. 26.7% ± 2.6%; P = 0.038; mid-cavity: 24.4% ± 2.3% vs. 26.8% ± 3.1%; P = 0.012; apical: 27.5% ± 3.6% vs. 29.7% ± 4.5%; P = 0.016). Apical (27.2% ± 3.4%) and basal-septal ECVs (25.6% ± 2.6%) were statistically higher than mid-cavity ECV (24.3% ± 2.5%; both P < 0.001). CONCLUSION: Contour-based registration can optimize image quality and improve the precision of ECV quantification in cases demonstrating ventricular misregistration among source images.

Insight into interfacial adsorption behavior of high-density lipoprotein hydrolysates regulated by carboxymethyl dextrin and in vitro digestibility of curcumin loaded high internal phase emulsions.

The interaction between high-density lipoprotein hydrolysate hydrolyzed by trypsin (EHT) and carboxymethyl dextrin (CMD) at pH 7.0, and in vitro digestibility of high internal phase emulsions (HIPEs) were studied. The particle size of EHT/CMD mixtures increased from 207.2 nm to 1229.6 nm with increase of the ratio of EHT to CMD from 8:1 to 1:2. The proportion of EHT adsorbed on the surface increased from 60.83 % to 80.81 %, forming thicker interfacial layer, exhibiting higher resistance to centrifugation and ionic strength. And more uniform proton density distribution and shorter relaxation time (T2) were charactered in HIPEs formed by mixtures. Rheological analysis further proved that CMD could lead to high viscosity, high elasticity, excellent oscillation performance of HIPEs. The spatial and electrostatic repulsion forces reduced the aggregation of oil droplets and promoted the formation of more mixed micelles, improving the bioaccessibility of curcumin. These findings provided theoretical strategies for lipid-soluble nutrients delivery systems.

Actual experience of the training effect of Baduanjin on patients with hemiplegic limb dysfunctions after cerebral infarction: A qualitative study.

AIM: To explore the actual experience of training effect of Baduanjin on patients with hemiplegic limb dysfunctions after cerebral infarction through semistructured interviews and promote Baduanjin training application in clinical and community settings. DESIGN: This qualitative study was conducted using the conventional content analysis approach. METHODS: Twenty-five patients with hemiplegic limb dysfunctions after cerebral infarction were recruited as participants by applying purposive sampling method between September 2017-December 2020 in the physical therapy department of a rehabilitation hospital affiliated with Fujian University of Traditional Chinese Medicine in China. Semistructured interviews were conducted after patients participated in Baduanjin training for 6 weeks. Data were analysed using qualitative content analysis method of Graneheim and Lundman. RESULTS: Three major themes were identified after analysis, namely improving functions of hemiplegic limbs, improving the condition of the entire body and the feelings of practice. The participants indicated that Baduanjin could improve the limb functions and general conditions of hemiplegic patients. Their experience in practicing Baduanjin was generally positive, and they were willing to continue practicing.