The application of pH-responsive hyaluronic acid-based essential oils hydrogels with enhanced anti-biofilm and wound healing.

pH could play vital role in the wound healing process due to the bacterial metabolites, which is one essential aspect of desirable wound dressings lies in being pH-responsive. This work has prepared a degradable hyaluronic acid hydrogel dressing with wound pH response-ability. The aldehyde-modified hyaluronic acid (AHA) was obtained, followed by complex mixture formation of eugenol and oregano antibacterial essential oil in the AHA-CMCS hydrogel through the Schiff base reaction with carboxymethyl chitosan (CMCS). This hydrogel composite presents pH-responsiveness, its disintegration mass in acidic environment (pH = 5.5) is 4 times that of neutral (pH = 7.2), in which the eugenol release rate increases from 37.6 % to 82.1 %. In vitro antibacterial and in vivo wound healing investigations verified that hydrogels loaded with essential oils have additional 5 times biofilm removal efficiency, and significantly accelerate wound healing. Given its excellent anti-biofilm and target-release properties, the broad application of this hydrogel in bacteria-associated wound management is anticipated.

Application of 5T glutamate chemical exchange saturation transfer imaging in brain tumors: preliminary results.

PURPOSE: Glutamate chemical exchange saturation transfer (GluCEST) is a non-invasive CEST imaging technique for detecting glutamate levels in tissues. We aimed to investigate the reproducibility of the 5T GluCEST technique in healthy volunteers and preliminarily explore its potential clinical application in patients with brain tumors. METHODS: Ten volunteers (4 males, mean age 29 years) underwent three 5T GluCEST imaging scans. The reproducibility of the three imaging GluCEST measurements was assessed using one-way repeated measures analysis of variance (ANOVA), generalized estimating equations, and linear mixed models. Twenty-eight patients with brain tumors (10 males, mean age 54 years) underwent a single GluCEST scan preoperatively, and t-tests were used to compare the differences in GluCEST values between different brain tumors. In addition, the diagnostic accuracy of GluCEST values in differentiating brain tumors was assessed using the receiver work characteristics (ROC) curve. RESULTS: The coefficients of variation of GluCEST values in healthy volunteers were less than 5% for intra-day, inter-day, and within-subjects and less than 10% for between-subjects. High-grade gliomas (HGG) had higher GluCEST values compared to low-grade gliomas (LGG) (P < 0.001). In addition, cerebellopontine angle (CPA) meningiomas had higher GluCEST values than acoustic neuromas (P < 0.001). The area under the curve (AUC) of the GluCEST value for differentiating CPA meningioma from acoustic neuroma was 0.93. CONCLUSION: 5T GluCEST images are highly reproducible in healthy brains. In addition, the 5T GluCEST technique has potential clinical applications in differentiating LGG from HGG and CPA meningiomas from acoustic neuromas.

Correlation between bone mineral density and type 2 diabetes mellitus in elderly men and postmenopausal women.

The relationship between bone mineral density and type 2 diabetes is still controversial. The aim of this study is to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in elderly men and postmenopausal women. The participants in this study included 692 postmenopausal women and older men aged ≥ 50 years, who were divided into the T2DM group and non-T2DM control group according to whether or not they had T2DM. The data of participants in the two groups were collected from the inpatient medical record system and physical examination center systems, respectively, of the Tertiary Class A Hospital. All data analysis is performed in SPSS Software. Compared with all T2DM group, the BMD and T scores of lumbar spines 1-4 (L1-L4), left femoral neck (LFN) and all left hip joints (LHJ) in the non-T2DM group were significantly lower than those in the T2DM group (P < 0.05), and the probability of major osteoporotic fracture in the next 10 years (PMOF) was significantly higher than that in T2DM group (P < 0.001). However, with the prolongation of the course of T2DM, the BMD significantly decreased, while fracture risk and the prevalence of osteoporosis significantly increased (P < 0.05). We also found that the BMD of L1-4, LFN and LHJ were negatively correlated with homeostatic model assessment-insulin resistance (HOMA-IR) (P = 0.028, P = 0.01 and P = 0.047, respectively). The results also showed that the BMD of LHJ was positively correlated with indirect bilirubin (IBIL) (P = 0.018). Although the BMD was lower in the non-T2DM group than in the T2DM group, the prolongation of the course of T2DM associated with the lower BMD. And the higher prevalence of osteoporosis and fracture risk significantly associated with the prolongation of the course of T2DM. In addition, BMD was significantly associated with insulin resistance (IR) and bilirubin levels in T2DM patients.Registration number: China Clinical Trials Registry: MR-51-23-051741; https://www.medicalresearch.org.cn/search/research/researchView?id=c0e5f868-eca9-4c68-af58-d73460c34028 .

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.

Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.

Facile synthesis of 2-vinylindolines via a phosphine-mediated α-umpolung/Wittig olefination/cyclization cascade process.

A novel phosphine-mediated α-umpolung/Wittig olefination/cyclization cascade process between o-aminobenzaldehydes and Morita-Baylis-Hillman (MBH) carbonates has been ingeniously developed. This protocol serves as a practical tool for the facile synthesis of a broad range of 2-vinylindolines in moderate to good yields under mild reaction conditions. The applicability of this method was demonstrated with gram-scale reaction and various transformations of the corresponding product.

Mechanisms of gastrointestinal toxicity in neuromyelitis optica spectrum disorder patients treated with mycophenolate mofetil: insights from a mouse model and human study.

Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial ß-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The ß-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF. IMPORTANCE: Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.

Oral oxytocin blurs sex differences in amygdala responses to emotional scenes.

BACKGROUND: The sex differences were co-shaped by innate biological differences and social environment, and were frequently observed in human emotional neural responses. Oral administration of oxytocin, as an alternative and noninvasive intake method, has been demonstrated to produce sex-dependent effects on emotional face processing. However, it is unclear whether oral oxytocin produces similar sex-dependent effects on processing continuous emotional scenes. METHODS: Current randomized, double-blind, placebo-controlled neuro-psychopharmacological fMRI experiment was conducted in 147 healthy participants (oxytocin=74, male/female=37/37; placebo=73, male/female=36/37) to examine the oral oxytocin effect on plasma oxytocin concentrations and neural response to emotional scenes in both sexes. RESULTS: At the neuroendocrine level, females showed lower endogenous oxytocin concentrations than males, but oral oxytocin equally increased the oxytocin concentrations in both sexes. Regarding neural activity, emotional scenes evoked opposite valence-independent effects on right amygdala activation (females>males) and its functional connectivity with the insula (males>females) in two sexes in the placebo group. This sex difference were either attenuated (amygdala response) or even completely eliminated (amygdala-insula functional connectivity) in the oxytocin group. The multivariate pattern analysis confirmed these findings by developing an accurate sex-predictive neural pattern that including the amygdala and the insula under the placebo but not oxytocin condition. CONCLUSION: Present study suggests a pronounced sex-difference in neural responses to emotional scenes which is abolished by oral oxytocin, with it having opposite modulatory effects in two sexes. Possibly this may reflect oral OXT enhancing emotional regulation to continuous emotional stimuli in both sexes by facilitating appropriate changes in sex-specific amygdala-insula circuitry.

Distinct glutamatergic projections of the posteroventral medial amygdala play different roles in arousal and anxiety.

Sleep disturbance usually accompanies anxiety disorders and exacerbates their incidence rates. The precise circuit mechanisms remain poorly understood. Here, we found that glutamatergic neurons in the posteroventral medial amygdala (MePVGlu) are involved in arousal and anxiety-like behaviors. Excitation of MePVGlu neurons not only promoted wakefulness but also increased anxiety-like behaviors. Different projections of MePVGlu neurons played various roles in regulating anxiety-like behaviors and sleep-wakefulness. MePVGlu neurons promoted wakefulness through the MePVGlu-posteromedial cortical amygdaloid area (PMCo) pathway and the MePVGlu-bed nucleus of the stria terminals (BNST) pathway. In contrast, MePVGlu neurons increased anxiety-like behaviors through the MePVGlu-ventromedial hypothalamus (VMH) pathway. Chronic sleep disturbance increased anxiety levels and reduced reparative sleep, accompanied by the enhanced excitability of MePVGlu-PMCo and MePVGlu-VMH circuits but suppressed responses of glutamatergic neurons in the BNST. Inhibition of the MePVGlu neurons could rescue chronic sleep deprivation-induced phenotypes. Our findings provide important circuit mechanisms for chronic sleep disturbance-induced hyperarousal response and obsessive anxiety-like behavior, and are expected to provide a promising strategy for treating sleep-related psychiatric disorders and insomnia.

Supplementation of the Combination of Quercetin and Vitamin E Alleviates the Effects of Heat Stress on the Uterine Function and Hormone Synthesis in Laying Hens.

Chickens are sensitive to heat stress because their capacity to dissipate body heat is low. Hence, in chickens, excessive ambient temperature negatively influences their reproductive performance and health. Heat stress induces inflammation and oxidative stress, thereby rendering many reproductive organs dysfunctional. In this study, we evaluated the effects of the supplementation of dietary quercetin and vitamin E on the uterine function, eggshell quality via estrogen concentration, calcium metabolism, and antioxidant status of the uterus of laying hens under heat stress. The ambient temperature transformation was set at 34 ± 2 °C for 8 h/d (9:00 am-5:00 pm), which was followed by 22 °C to 28 °C for 16 h/d. Throughout the experiment, the relative humidity in the chicken's pen was at 50 to 65%. A total of 400 Tianfu breeder hens (120-days-old) were randomly divided into four dietary experimental groups, including basal diet (Control); basal diet + 0.4 g/kg quercetin; basal diet + 0.2 g/kg vitamin E; and basal diet + the combination of quercetin (0.4 g/kg) and vitamin E (0.2 g/kg). The results show that the combination of quercetin and vitamin E significantly increased the serum alkaline phosphatase levels and the antioxidant status of the uterus (p < 0.05). In addition, the combination of quercetin and vitamin E significantly increased the concentrations of serum estrogen and progesterone, as well as elevated the expression of hypothalamic gonadotropin-releasing hormone-1 and follicular cytochrome P450 family 19 subfamily A member-1 (p < 0.05). We also found that the calcium levels of the serum and uterus were significantly increased by the synergistic effects of quercetin and vitamin E (p < 0.05), and they also increased the expression of Ca2+-ATPase and the mRNA expression of calcium-binding-related genes in the uterus (p < 0.05). These results are consistent with the increased eggshell quality of the laying hens under heat stress. Further, the combination of quercetin and vitamin E significantly increased the uterine morphological characteristics, such as the height of the uterine mucosal fold and the length of the uterine mucosa villus of the heat-stressed laying hens. These results collectively improve the uterine function, serum and uterine calcium concentration, eggshell strength, and eggshell thickness (p < 0.05) in heat-stressed laying hens. Taken together, we demonstrated in the present study that supplementing the combination of dietary quercetin and vitamin E alleviated the effects of heat stress and improved calcium metabolism, hormone synthesis, and uterine function in the heat-stressed laying hens. Thus, the supplementation of the combination of quercetin and vitamin E alleviates oxidative stress in the eggshell gland of heat-stressed laying hens, thereby promoting calcium concentration in the serum and eggshell gland, etc., in laying hens. Hence, the combination of quercetin and vitamin E promotes the reproductive performance of the laying hens under heat stress and can also be used as a potent anti-stressor in laying hens.

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

Integrin activating molecule-talin1 promotes skin fibrosis in systemic sclerosis.

Background: Integrin-dependent cell adhesion and migration play important roles in systemic sclerosis (SSc). The roles of integrin activating molecules including talins and kindlins, however, are unclear in SSc. Objectives: We aimed to explore the function of integrin activating molecules in SSc. Methods: Transcriptome analysis of skin datasets of SSc patients was performed to explore the function of integrin-activating molecules including talin1, talin2, kindlin1, kindlin2 and kindlin3 in SSc. Expression of talin1 in skin tissue was assessed by multiplex immunohistochemistry staining. Levels of talin1 in serum were determined by ELISA. The effects of talin1 inhibition were analyzed in human dermal fibroblasts by real-time PCR, western blot and flow cytometry. Results: We identified that talin1 appeared to be the primary integrin activating molecule involved in skin fibrosis of SSc. Talin1 was significantly upregulated and positively correlates with the modified Rodnan skin thickness score (mRSS) and the expression of pro-fibrotic biomarkers in the skin lesions of SSc patients. Further analyses revealed that talin1 is predominantly expressed in the dermal fibroblasts of SSc skin and promotes fibroblast activation and collagen production. Additionally, talin1 primarily exerts its effects through integrin ß1 and ß5 in SSc. Conclusions: Overexpressed talin1 is participated in skin fibrosis of SSc, and talin1 appears to be a potential new therapeutic target for SSc.

Quasi-1D Conductive Network Composites for Ultra-Sensitive Strain Sensing.

Highly performance flexible strain sensor is a crucial component for wearable devices, human-machine interfaces, and e-skins. However, the sensitivity of the strain sensor is highly limited by the strain range for large destruction of the conductive network. Here the quasi-1D conductive network (QCN) is proposed for the design of an ultra-sensitive strain sensor. The orientation of the conductive particles can effectively reduce the number of redundant percolative pathways in the conductive composites. The maximum sensitivity will reach the upper limit when the whole composite remains only "one" percolation pathway. Besides, the QCN structure can also confine the tunnel electron spread through the rigid inclusions which significantly enlarges the strain-resistance effect along the tensile direction. The strain sensor exhibits state-of-art performance including large gauge factor (862227), fast response time (24 ms), good durability (cycled 1000 times), and multi-mechanical sensing ability (compression, bending, shearing, air flow vibration, etc.). Finally, the QCN sensor can be exploited to realize the human-machine interface (HMI) application of acoustic signal recognition (instrument calibration) and spectrum restoration (voice parsing).

In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.

The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.

Large-Scale Engineerable Films Tailored with Cellulose Nanofibrils for Lighting Management and Thermal Insulation.

Fibrillated cellulose-based nanocomposites can improve energy efficiency of building envelopes, especially windows, but efficiently engineering them with a flexible ability of lighting and thermal management remains highly challenging. Herein, a scalable interfacial engineering strategy is developed to fabricate haze-tunable thermal barrier films tailored with phosphorylated cellulose nanofibrils (PCNFs). Clear films with an extremely low haze of 1.6% (glass-scale) are obtained by heat-assisted surface void packing without hydrophobization of nanocellulose. PCNF gel cakes serve here as templates for surface roughening, thereby resulting in a high haze (73.8%), and the roughened films can block heat transfer by increasing solar reflection in addition to a reduced thermal conduction. Additionally, obtained films can tune distribution of light from visible to near-infrared spectral range, enabling uniform colored lighting and inhibiting localized heating. Furthermore, an integrated simulation of lighting and cooling energy consumption in the case of office buildings shows that the film can reduce the total energy use by 19.2-38.1% under reduced lighting levels. Such a scalable and versatile engineering strategy provides an opportunity to endow nanocellulose-reinforced materials with tunable optical and thermal functionalities, moving their practical applications in green buildings forward.

Nucleotide metabolism-related host proteins RNA polymerase II subunit and uridine phosphorylase 1 interacting with porcine epidemic diarrhea virus N proteins affect viral replication.

Porcine epidemic diarrhea virus (PEDV) is a highly infectious pathogen that targets pig intestines to cause disease. It is globally widespread and causes huge economic losses to the pig industry. PEDV N protein is the protein that constitutes the core of PEDV virus particles, and most of it is expressed in the cytoplasm, and a small part can also be expressed in the nucleus. However, the role of related proteins in host nucleotide metabolic pathways in regulating PEDV replication have not been fully elucidated. In this study, PEDV-N-labeled antibodies were co-immunoprecipitated and combined with LC-MS to screen for host proteins that interact with N proteins. Bioinformatics analyses showed that the selected host proteins were mainly enriched in metabolic pathways. Moreover, co-immunoprecipitation and confocal microscopy confirmed that the second-largest subunit of RNA polymerase II (RPB2) and uridine phosphorylase 1 (UPP1) interacted with the N protein. RPB2 is the main subunit of RNA polymerase II and plays an important role in eukaryotic transcription. UPP1 is an enzyme that catalyzes reversible phosphorylation of uridine to uracil and ribo-1-phosphate to promote catabolism and bio anabolism. RPB2 overexpression significantly promoted viral replication, whereas UPP1 overexpression significantly inhibited viral replication. Studies on interactions between the PEDV N and host proteins are helpful in elucidating the pathogenesis and immune escape mechanism of PEDV.

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury.

Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/AKT/NRF2 signaling, thus blocking mitochondrial reactive oxygen species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1ß, and pro-IL-18 into their mature forms to mediate pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.