Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Free Radicals Generated in Perfluorocarbon-Water (Liquid-Liquid) Interfacial Contact Electrification and Their Application in Cancer Therapy.

Electron transfer during solid-liquid contact electrification has been demonstrated to produce reactive oxygen species (ROS) such as hydroxyl radicals (•OH) and superoxide anion radicals (•O2-). Here, we show that such a process also occurs in liquid-liquid contact electrification. By preparing perfluorocarbon nanoemulsions to construct a perfluorocarbon-water "liquid-liquid" interface, we confirmed that electrons were transferred from water to perfluorocarbon in ultrasonication-induced high-frequency liquid-liquid contact to produce •OH and •O2-. The produced ROS could be applied to ablate tumors by triggering large-scale immunogenic cell death in tumor cells, promoting dendritic cell maturation and macrophage polarization, ultimately activating T cell-mediated antitumor immune response. Importantly, the raw material for producing •OH is water, so the tumor therapy is not limited by the endogenous substances (O2, H2O2, etc.) in the tumor microenvironment. This work provides new perspectives for elucidating the mechanism of generation of free radicals in liquid-liquid contact and provides an excellent tumor therapeutic modality.

Controllable Electronic Transfer Tailoring d-band Center via Cobalt-Oxygen-Bridged Ru/Fe Dual-sites for Boosted Oxygen Evolution.

Rational tailoring of the electronic structure at the defined active center of reconstructed metal (oxy)hydroxides (MOOH) during oxygen evolution reaction (OER) remains a challenge. With the guidance of density functional theory (DFT), herein a dual-site regulatory strategy is reported to tailor the d-band center of the Co site in CoOOH via the controlled electronic transfer at the Ru─O─Co─O─Fe bonding structure. Through the bridged O2- site, electrons are vastly flowed from the t2g-orbital of the Ru site to the low-spin orbital of the Co site in the Ru-O-Co coordination and further transfer from the strong electron-electron repulsion of the Co site to the Fe site by the Co-O-Fe coordination, which balancing the electronic configuration of Co sites to weaken the over-strong adsorption energy barrier of OH* and O*, respectively. Benefiting from the highly active of the Co site, the constructed (Ru2Fe2Co6)OOH provide an extremely low overpotential of 248 mV and a Tafel slope of 32.5 mV dec-1 at 10 mA cm-2 accompanied by long durability in alkaline OER, far superior over the pristine and Co-O-Fe bridged CoOOH catalysts. This work provides guidance for the rational design and in-depth analysis of the optimized role of metal dual-sites.

Directed Dual Charge Pumping Tunes the d-Orbital Configuration of Pt Cluster Boosting Hydrogen Evolution Kinetic.

Achieving high catalytic activity with a minimum amount of platinum (Pt) is crucial for accelerating the cathodic hydrogen evolution reaction (HER) in proton exchange membrane (PEM) water electrolysis, yet it remains a significant challenge. Herein, a directed dual-charge pumping strategy to tune the d-orbital electronic distribution of Pt nanoclusters for efficient HER catalysis is proposed. Theoretical analysis reveals that the ligand effect and electronic metal-support interactions (EMSI) create an effective directional electron transfer channel for the d-orbital electrons of Pt, which in turn optimizes the binding strength to H*, thereby significantly enhancing HER efficiency of the Pt site. Experimentally, this directed dual-charge pumping strategy is validated by elaborating Sb-doped SnO2 (ATO) supported Fe-doped PtSn heterostructure catalysts (Fe-PtSn/ATO). The synthesized 3%Fe-PtSn/ATO catalysts exhibit lower overpotential (requiring only 10.5 mV to reach a current density of 10 mA cm- 2), higher mass activity (28.6 times higher than commercial 20 wt.% Pt/C), and stability in the HER process in acidic media. This innovative strategy presents a promising pathway for the development of highly efficient HER catalysts with low Pt loading.

CAR T Cell Membrane Camouflaged Nanocatalyst Augments CAR T Cell Therapy Efficacy Against Solid Tumor.

The immunosuppressive tumor microenvironment (TME) reduces the chimeric antigen receptor (CAR) T-cell therapy against solid tumors. Here, a CAR T cell membrane-camouflaged nanocatalyst (ACSP@TCM) is prepared to augment CAR T cell therapy efficacy against solid tumors. ACSP@TCM is prepared by encapsulating core/shell Au/Cu2- xSe and 3-bromopyruvate with a CAR T cell membrane. It is demonstrated that the CAR T cell membrane camouflaging has much better-targeting effect than the homologous tumors cell membrane camouflaging. ACSP@TCM has an appealing synergistic chemodynamic/photothermal therapy (CDT/PTT) effect that can induce the immunogenic cell death (ICD) of NALM 6 cells. Moreover, 3-bromopyruvate can inhibit the efflux of lactic acid by inhibiting the glycolysis process, regulating the acidity of TME, and providing a more favorable environment for the survival of CAR T cells. In addition, the photoacoustic (PA) imaging and computed tomography (CT) imaging performance can guide the ACSP@TCM-mediated tumor therapy. The results demonstrated that the ACSP@TCM significantly enhanced the CAR T cell therapy efficacy against NALM 6 solid tumor mass, and completely eliminated tumors. This work provides an effective tumor strategy for CAR T cell therapy in solid tumors.

Identification of Embryonic Chicken Proteases Activating Newcastle Disease Virus and Their Roles in the Pathogenicity of Virus Used as In Ovo Vaccine.

In ovo vaccination is an attractive immunization approach for chickens. However, most live Newcastle disease virus (NDV) vaccine strains used safely after hatching are unsafe as in ovo vaccines due to their high pathogenicity for chicken embryos. The mechanism for viral pathogenicity in chicken embryos is poorly understood. Our previous studies reported that NDV strain TS09-C was a safe in ovo vaccine, and the F protein cleavage site (FCS) containing three basic amino acids (3B-FCS) was the crucial determinant of the attenuation of TS09-C in chicken embryos. Here, five trypsin-like proteases that activated NDV in chicken embryos were identified. The F protein with 3B-FCS was sensitive to the proteases Tmprss4, Tmprss9, and F7, was present in fewer tissue cells of chicken embryos, which limited the viral tropism, and was responsible for the attenuation of NDV with 3B-FCS, while the F protein with FCS containing two basic amino acids could be cleaved not only by Tmprss4, Tmprss9, and F7 but also by Prss23 and Cfd, was present in most tissue cells, and thereby was responsible for broad tissue tropism and high pathogenicity of virus in chicken embryos. Furthermore, when mixed with the protease inhibitors aprotinin and camostat, NDV with 2B-FCS exhibited greatly weakened pathogenicity in chicken embryos. Thus, our results extend the understanding of the molecular mechanism of NDV pathogenicity in chicken embryos and provide a novel molecular target for the rational design of in ovo vaccines, ensuring uniform and effective vaccine delivery and earlier induction of immune protection by the time of hatching. IMPORTANCE As an attractive immunization approach for chickens, in ovo vaccination can induce a considerable degree of protection by the time of hatching, provide support in closing the window in which birds are susceptible to infection, facilitate fast and uniform vaccine delivery, and reduce labor costs by the use of mechanized injectors. The commercial live Newcastle disease virus (NDV) vaccine strains are not safe for in ovo vaccination and cause the death of chicken embryos. The mechanism for viral pathogenicity in chicken embryos is poorly understood. In the present study, we identified five trypsin-like proteases that activate NDV in chicken embryos and elucidated their roles in the tissue tropism and pathogenicity of NDV used as in ovo vaccine. Finally, we revealed the molecular basis for the pathogenicity of NDV in chicken embryos and provided a novel strategy for the rational design of in ovo ND vaccines.

Limited disassembly of cytoplasmic hepatitis B virus nucleocapsids restricts viral infection in murine hepatic cells.

BACKGROUND AND AIMS: Murine hepatic cells cannot support hepatitis B virus (HBV) infection even with supplemental expression of viral receptor, human sodium taurocholate cotransporting polypeptide (hNTCP). However, the specific restricted step remains elusive. In this study, we aimed to dissect HBV infection process in murine hepatic cells. APPROACH AND RESULTS: Cells expressing hNTCP were inoculated with HBV or hepatitis delta virus (HDV). HBV pregenomic RNA (pgRNA), covalently closed circular DNA (cccDNA), and different relaxed circular DNA (rcDNA) intermediates were produced in vitro . The repair process from rcDNA to cccDNA was assayed by in vitro repair experiments and in mouse with hydrodynamic injection. Southern blotting and in situ hybridization were used to detect HBV DNA. HBV, but not its satellite virus HDV, was restricted from productive infection in murine hepatic cells expressing hNTCP. Transfection of HBV pgRNA could establish HBV replication in human, but not in murine, hepatic cells. HBV replication-competent plasmid, cccDNA, and recombinant cccDNA could support HBV transcription in murine hepatic cells. Different rcDNA intermediates could be repaired to form cccDNA both in vitro and in vivo . In addition, rcDNA could be detected in the nucleus of murine hepatic cells, but cccDNA could not be formed. Interestingly, nuclease sensitivity assay showed that the protein-linked rcDNA isolated from cytoplasm was completely nuclease resistant in murine, but not in human, hepatic cells. CONCLUSIONS: Our results imply that the disassembly of cytoplasmic HBV nucleocapsids is restricted in murine hepatic cells. Overcoming this limitation may help to establish an HBV infection mouse model.

Deep Learning for Discrimination of Hypertrophic Cardiomyopathy and Hypertensive Heart Disease on MRI Native T1 Maps.

BACKGROUND: Native T1 and radiomics were used for hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) differentiation previously. The current problem is that global native T1 remains modest discrimination performance and radiomics requires feature extraction beforehand. Deep learning (DL) is a promising technique in differential diagnosis. However, its feasibility for discriminating HCM and HHD has not been investigated. PURPOSE: To examine the feasibility of DL in differentiating HCM and HHD based on T1 images and compare its diagnostic performance with other methods. STUDY TYPE: Retrospective. POPULATION: 128 HCM patients (men, 75; age, 50 years ± 16) and 59 HHD patients (men, 40; age, 45 years ± 17). FIELD STRENGTH/SEQUENCE: 3.0T; Balanced steady-state free precession, phase-sensitive inversion recovery (PSIR) and multislice native T1 mapping. ASSESSMENT: Compare HCM and HHD patients baseline data. Myocardial T1 values were extracted from native T1 images. Radiomics was implemented through feature extraction and Extra Trees Classifier. The DL network is ResNet32. Different input including myocardial ring (DL-myo), myocardial ring bounding box (DL-box) and the surrounding tissue without myocardial ring (DL-nomyo) were tested. We evaluate diagnostic performance through AUC of ROC curve. STATISTICAL TESTS: Accuracy, sensitivity, specificity, ROC, and AUC were calculated. Independent t test, Mann-Whitney U-test and Chi-square test were adopted for HCM and HHD comparison. P < 0.05 was considered statistically significant. RESULTS: DL-myo, DL-box, and DL-nomyo models showed an AUC (95% confidential interval) of 0.830 (0.702-0.959), 0.766 (0.617-0.915), 0.795 (0.654-0.936) in the testing set. AUC of native T1 and radiomics were 0.545 (0.352-0.738) and 0.800 (0.655-0.944) in the testing set. DATA CONCLUSION: The DL method based on T1 mapping seems capable of discriminating HCM and HHD. Considering diagnostic performance, the DL network outperformed the native T1 method. Compared with radiomics, DL won an advantage for its high specificity and automated working mode. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

MitoTNT: Mitochondrial Temporal Network Tracking for 4D live-cell fluorescence microscopy data.

Mitochondria form a network in the cell that rapidly changes through fission, fusion, and motility. Dysregulation of this four-dimensional (4D: x,y,z,time) network is implicated in numerous diseases ranging from cancer to neurodegeneration. While lattice light-sheet microscopy has recently made it possible to image mitochondria in 4D, quantitative analysis methods for the resulting datasets have been lacking. Here we present MitoTNT, the first-in-class software for Mitochondrial Temporal Network Tracking in 4D live-cell fluorescence microscopy data. MitoTNT uses spatial proximity and network topology to compute an optimal tracking assignment. To validate the accuracy of tracking, we created a reaction-diffusion simulation to model mitochondrial network motion and remodeling events. We found that our tracking is >90% accurate for ground-truth simulations and agrees well with published motility results for experimental data. We used MitoTNT to quantify 4D mitochondrial networks from human induced pluripotent stem cells. First, we characterized sub-fragment motility and analyzed network branch motion patterns. We revealed that the skeleton node motion is correlated along branch nodes and is uncorrelated in time. Second, we identified fission and fusion events with high spatiotemporal resolution. We found that mitochondrial skeleton nodes near the fission/fusion sites move nearly twice as fast as random skeleton nodes and that microtubules play a role in mediating selective fission/fusion. Finally, we developed graph-based transport simulations that model how material would distribute on experimentally measured mitochondrial temporal networks. We showed that pharmacological perturbations increase network reachability but decrease network resilience through a combination of altered mitochondrial fission/fusion dynamics and motility. MitoTNT's easy-to-use tracking module, interactive 4D visualization capability, and powerful post-tracking analyses aim at making temporal network tracking accessible to the wider mitochondria research community.

Serratia plymuthica HK9-3 enhances tomato resistance against Phytophthora capsici by modulating antioxidant defense systems and rhizosphere micro-ecological condition.

Tomatoes are frequently challenged by various pathogens, among which Phytophthora capsici (P. capsici) is a destructive soil-borne pathogen that seriously threatens the safe production of tomatoes. Plant growth-promoting rhizobacteria (PGPR) positively induced plant resistance against multiple pathogens. However, little is known about the role and regulatory mechanism of PGPR in tomato resistance to P. capsici. Here, we identified a new strain Serratia plymuthica (S. plymuthica), HK9-3, which has a significant antibacterial effect on P. capsici infection. Meanwhile, stable colonization in roots by HK9-3, even under P. capsici infection, improved tomato growth parameters, root system architecture, photosynthetic capacity, and boosted biomass. Importantly, HK9-3 colonization significantly alleviated the damage caused by P. capsici infection through enhancing ROS scavenger ability and inducing antioxidant defense system and pathogenesis-related (PR) proteins in leaves, as evidenced by elevating the activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), and chitinase, ß-1,3-glucanase, and increasing the transcripts of POD, SOD, CAT, APX1, PAL1, PAL2, PAL5, PPO2, CHI17 and ß-1,3-glucanase genes. Notably, HK9-3 colonization not only effectively improved soil microecology and soil fertility, but also significantly enhanced fruit yield by 44.6% and improved quality. Our study presents HK9-3 as a promising and effective solution for controlling P. capsici infection in tomato cultivation while simultaneously promoting plant growth and increasing yield, which may have implications for P. capsici control in vegetable production.

Optimizing Intermediate Adsorption on Pt Sites via Triple-Phase Interface Electronic Exchange for Methanol Oxidation.

For the most commonly applied platinum-based catalysts of direct methanol fuel cells, the adsorption ability toward reaction intermediates, including CO and OH, plays a vital role in their catalytic activity and antipoisoning in anodic methanol oxidation reaction (MOR). Herein, guided by a theoretical mechanism study, a favorable modulation of the electronic structure and intermediate adsorption energetics for Pt active sites is achieved by constructing the triple-phase interfacial structure between tin oxide (SnO2), platinum (Pt), and nitrogen-doped graphene (NG). From the strong electronic exchange at the triple-phase interface, the adsorption ability toward MOR reaction intermediates on Pt sites could be efficiently optimized, which not only inhibits the adsorption of CO* on active sites but also facilitates the adsorption of OH* to strip the poisoning species from the catalyst surface. Accordingly, the resulting catalyst delivers excellent catalytic activity and antipoisoning ability for MOR catalysis. The mass activity reaches 1098 mA mg-1Pt, 3.23 times of commercial Pt/C. Meanwhile, the initial potentials and main peak for CO oxidation are also located at a much lower potential (0.51 and 0.74 V) against commercial Pt/C (0.83 and 0.89 V).

Polydopamine-mediated immobilization of BMP-2 onto electrospun nanofibers enhances bone regeneration.

Dealing with bone defects is a significant challenge to global health. Electrospinning in bone tissue engineering has emerged as a solution to this problem. In this study, we designed a PVDF-b-PTFE block copolymer by incorporating TFE, which induced a phase shift in PVDF fromαtoß, thereby enhancing the piezoelectric effect. Utilizing the electrospinning process, we not only converted the material into a film with a significant surface area and high porosity but also intensified the piezoelectric effect. Then we used polydopamine to immobilize BMP-2 onto PVDF-b-PTFE electrospun nanofibrous membranes, achieving a controlled release of BMP-2. The scaffold's characters were examined using SEM and XRD. To assess its osteogenic effectsin vitro, we monitored the proliferation of MC3T3-E1 cells on the fibers, conducted ARS staining, and measured the expression of osteogenic genes.In vivo, bone regeneration effects were analyzed through micro-CT scanning and HE staining. ELISA assays confirmed that the sustained release of BMP-2 can be maintained for at least 28 d. SEM images and CCK-8 results demonstrated enhanced cell viability and improved adhesion in the experimental group. Furthermore, the experimental group exhibited more calcium nodules and higher expression levels of osteogenic genes, including COL-I, OCN, and RUNX2. HE staining and micro-CT scans revealed enhanced bone tissue regeneration in the defective area of the PDB group. Through extensive experimentation, we evaluated the scaffold's effectiveness in augmenting osteoblast proliferation and differentiation. This study emphasized the potential of piezoelectric PVDF-b-PTFE nanofibrous membranes with controlled BMP-2 release as a promising approach for bone tissue engineering, providing a viable solution for addressing bone defects.

Spray vaccination with a Newcastle disease virus (NDV)-vectored infectious laryngotracheitis (ILT) vaccine protects commercial chickens from ILT in the presence of maternally-derived antibodies.

Infectious laryngotracheitis (ILT) poses a significant threat to the poultry industry, and vaccines play an important role in protection. However, due to the increasing scale of poultry production, there is an urgent need to develop vaccines that are suitable for convenient immunization methods such as spraying. Previous studies have shown that Newcastle disease virus (NDV)-ILT vaccines administered via intranasal and intraocular routes to commercial chickens carrying maternally-derived antibodies (MDAs) are still protective against ILT. In this study, a recombinant NDV (rNDV) was generated to express infectious laryngotracheitis virus (ILTV) glycoprotein B (gB), named rLS-gB, based on a full-length cDNA clone of the LaSota strain. The protective effect of different doses of rLS-gB administered by spray vaccination to commercial chickens at 1 d of age (doa) was evaluated. The chickens were exposed to 160-µm aerosol particles for 10 min for spray vaccination, and no adverse reactions were observed after vaccination. Despite the presence of anti-NDV MDAs and anti-ILTV MDAs in chickens, the ILTV- and NDV-specific antibody titres were significantly greater in the vaccinated groups than in the unvaccinated group. After challenge with a virulent ILTV strain, no clinical signs were observed in the 107 EID50/ml group compared to the other groups. Furthermore, vaccination with 107 EID50/ml rLS-gB significantly reduced the ILTV viral load and ameliorated gross and microscopic lesions in the trachea of chickens. Overall, these results suggested that rLS-gB is a safe and efficient candidate spray vaccine for ILT and is especially suitable for scaled chicken farms.

Braden score can independently predict 90-day mortality in critically ill patients with dementia.

BACKGROUND: Dementia is a significant cause of death in the older population and is becoming an important public health issue as the population ages and the prevalence of dementia increases. The Braden score is one of the most commonly used clinical tools to assess the risk of skin pressure injury in patients, and some studies have reported that it may reflect the state of frailty of patients. The present study attempted to explore the association between Braden score and 90-day mortality, pressure injury, and aspiration pneumonia in older patients with dementia in the intensive care unit (ICU). METHODS: The study involved extracting crucial data from the Medical Information Market for Intensive Care IV (MIMIC-IV) database using Structured Query Language, with a license certificate obtained after completing the necessary training and examination available on the MIMIC-IV website. A retrospective analysis was performed on older patients with dementia, aged 65 or older, who were first admitted to the ICU. Ninth and tenth revision International Classification of Diseases codes were used to identify patients with dementia. The primary outcome was 90-day mortality. Cox proportional hazards models were used to determine the association between Braden score and death, and hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Propensity score matching and E-value assessments were employed for sensitivity analysis. RESULTS: A total of 2892 patients with a median age of approximately 85 years (interquartile range 78.74-89.59) were included, of whom 1625 were female (56.2%). Patients had a median Braden score of 14 (interquartile range 12-15) at ICU admission. Braden score at ICU admission was inversely associated with 90-day mortality risk after adjustment for demographics, severity of illness, treatment and medications, delirium, and sepsis (adjusted HR: 0.92, 95% CI: 0.87-0.98, p = 0.006). Patients were divided into two groups with a cut-off value of 15: high-risk group and low-risk group. Compared to the low-risk group (Braden score >15), the risk of 90-day mortality was significantly increased in the high-risk group (Braden score ≤15) (adjusted HR: 1.52, 95% CI: 1.10-2.09, p = 0.011, E-value: 2.01), the risk of pressure injury (adjusted OR: 2.62, 95% CI: 2.02-3.43, E-value: 2.62) and aspiration pneumonia (adjusted OR: 2.55, 95% CI: 1.84-3.61, E-value: 2.57) was also significantly higher. CONCLUSIONS: The Braden score may be a quick and simple screening tool to identify the risk of adverse outcomes in critically ill older adults with dementia.

Does ICU admission dysphagia independently contribute to delirium risk in ischemic stroke patients? Results from a cohort study.

BACKGROUND: Delirium is prevalent in ischemic stroke patients, particularly those in the intensive care unit (ICU), and it poses a significant burden on patients and caregivers, leading to increased mortality rates, prolonged hospital stays, and impaired cognitive function. Dysphagia, a common symptom in critically ill patients with ischemic stroke, further complicates their condition. However, the association between dysphagia and delirium in this context remains unclear. The objective of this study was to investigate the correlation between dysphagia and delirium in ICU patients with ischemic stroke. METHODS: A retrospective analysis was conducted on adult patients diagnosed with ischemic stroke at a medical center in Boston. Ischemic stroke cases were identified using the ninth and tenth revisions of the International Classification of Diseases. Dysphagia was defined as a positive bedside swallowing screen performed by medical staff on the day of ICU admission, while delirium was assessed using the ICU Confusion Assessment Method and review of nursing notes. Logistic regression models were used to explore the association between dysphagia and delirium. Causal mediation analysis was employed to identify potential mediating variables. RESULTS: The study comprised 1838 participants, with a median age of approximately 70 years, and 50.5% were female. Among the total study population, the prevalence of delirium was 43.4%, with a higher prevalence observed in the dysphagia group (60.7% vs. 40.8%, p < 0.001) compared to the non-dysphagia group. After adjusting for confounding factors including age, sex, race, dementia, depression, sedative medications, history of falls, visual or hearing deficit, sequential organ failure score, and Glasgow coma score, multifactorial logistic regression analysis demonstrated a significant association between dysphagia and an increased likelihood of delirium (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 1.07-2.05; p = 0.018; E-value = 1.73). Causal mediation analysis revealed that serum albumin levels partially mediated the association between dysphagia and delirium in critically ill patients with ischemic stroke (average causal mediated effect [ACME]: 0.02, 95% CI: 0.01 to 0.03; p < 0.001). CONCLUSION: ICU admission dysphagia may independently contribute to the risk of delirium in patients with ischemic stroke. Early identification and intervention in ischemic stroke patients with dysphagia may help mitigate the risk of delirium and improve patient prognosis.

Role of Emerin in regulating fibroblast differentiation and migration at the substrate of stiffness coupled topology.

In hypertrophic scars, the differentiation and migration of fibroblasts are influenced by the extracellular matrix microenvironment, which includes factors such as stiffness, restraint, and tensile force. These mechanical stresses incite alterations in cell behavior, accompanied by cytoskeletal protein reorganization. However, the role of nucleo-skeletal proteins in this context remains underexplored. In this study, we use a polyacrylamide hydrogel (PAA) to simulate the mechanical stress experienced by cells in scar tissue and investigate the impact of Emerin on cell behavior. We utilize atomic force microscopy (AFM) and RNA interference technology to analyze cell differentiation, migration, and stiffness. Our findings reveal that rigid substrates and cellular restriction elevate Emerin expression and diminish differentiation. Conversely, reducing Emerin expression leads to attenuated cell differentiation, where stiffness and constraining factors exert no notable influence. Furthermore, a softening of cells and an enhanced migration rate are also markedly observed. These observations indicate that variations in nuclear skeletal proteins, prompted by diverse matrix microenvironments, play a pivotal role in the pathogenesis of hypertrophic scars (HSs). This research offers novel insights and a reference point for understanding scar fibrosis formation mechanisms and preventing fibrosis.

Learning data distribution of three-dimensional ocean sound speed fields via diffusion models.

The probability distribution of three-dimensional sound speed fields (3D SSFs) in an ocean region encapsulates vital information about their variations, serving as valuable data-driven priors for SSF inversion tasks. However, learning such a distribution is challenging due to the high dimensionality and complexity of 3D SSFs. To tackle this challenge, we propose employing the diffusion model, a cutting-edge deep generative model that has showcased remarkable performance in diverse domains, including image and audio processing. Nonetheless, applying this approach to 3D ocean SSFs encounters two primary hurdles. First, the lack of publicly available well-crafted 3D SSF datasets impedes training and evaluation. Second, 3D SSF data consist of multiple 2D layers with varying variances, which can lead to uneven denoising during the reverse process. To surmount these obstacles, we introduce a novel 3D SSF dataset called 3DSSF, specifically designed for training and evaluating deep generative models. In addition, we devise a high-capacity neural architecture for the diffusion model to effectively handle variations in 3D sound speeds. Furthermore, we employ state-of-the-art continuous-time-based optimization method and predictor-corrector scheme for high-performance training and sampling. Notably, this paper presents the first evaluation of the diffusion model's effectiveness in generating 3D SSF data. Numerical experiments validate the proposed method's strong ability to learn the underlying data distribution of 3D SSFs, and highlight its effectiveness in assisting SSF inversion tasks and subsequently characterizing the transmission loss of underwater acoustics.

Lipidomics Study of Sepsis-Induced Liver and Lung Injury under Anti-HMGB1 Intervention.

Sepsis usually leads to lethal multiorgan dysfunction including acute liver failure (ALF) and acute lung injury (ALI). This research sought to reveal the lipid alteration of anti-high mobility group box 1 (HMGB1) treatment in sepsis-induced ALF and ALI by lipidomics. The cecal ligation and puncture-induced mouse model was established and the anti-HMGB1 neutralizing antibody was administrated. The histopathological characteristics and inflammatory factors were determined to assess the efficacy of the antibody. Utraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to determine lipid metabolism profiles in the liver and lung. The underlying biomarkers were identified through multivariate statistical analysis and correlation analysis with traditional physiological indicators. The pathological and biochemical results demonstrated that anti-HMGB1 neutralizing antibodies mitigated ALF and ALI in mice. Three differential metabolites in the liver and six various metabolites in the lung were significantly reversed by anti-HMGB1 treatment, mainly involved in arachidonic acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. Additionally, we investigated several traditional signaling pathways associated with HMGB1. However, the correlation between these traditional pathways and anti-HMGB1 intervention was not significant in the current study. In conclusion, our finding provided some scientific basis for targeting HMGB1 in sepsis-induced liver and lung injury. Mass spectrometry data with identifier no. MTBLS6466 have been uploaded to MetaboLights (http://www.ebi.ac.uk/metabolights/login).

Cancer-testis non-coding RNA LEF1-AS1 regulates the nuclear translocation of PDCD5 and suppresses its interaction with p53 signaling: a novel target for immunotherapy in esophageal squamous cell carcinoma.

Despite the improvement of current classical treatment, the prognosis of esophageal squamous cell carcinoma (ESCC) remains poor. Immunotherapy, as a new treatment method, has revolutionized the therapy of various cancer types and created more attractive for ESCC. Cancer-testis genes (CTGs), because of its characteristic expression and immunomodulation property, are considered as the ideal targets for tumor immunotherapy. However, the ESCC-specific CTGs, especially long non-coding RNA (lncRNA), has not been elucidated. In the present study, a systematic strategy was adopted to screen ESCC-specific cancer-testis lncRNA (CT-lncRNA). Collectively, 447 genes were recognized as ESCC-specific CT-lncRNAs, in particularly LEF1-AS1 showed the most aberrantly expression and clinically associated with poor outcome. Functional assays revealed that H3K27 acetylation in LEF1-AS1 promoter might give rise to the activation of LEF1-AS1 during ESCC tumorigenesis. The activated LEF1-AS1 was predominantly localized in the cytoplasm implicated in regulation of apoptosis and proliferation capacities of ESCC cells in vitro and in vivo. Further mechanistic studies unveiled that LEF1-AS1 participated in ESCC by interacting with RNA binding protein PDCD5 through weakened its nuclear translocation binding to TP53, leading to p53 degradation and disruption the transcription of downstream genes. Taken together, our findings suggest that LEF1-AS1 acts as a CT-lncRNA and might be an ideal immunotherapeutic target for clinical intervention for ESCC.

3-Bromopyruvate-Loaded Ti3C2 MXene/Cu2O Nanosheets for Photoacoustic Imaging-Guided and Hypoxia-Relieving Enhanced Photothermal/Chemodynamic Therapy.

Chemodynamic therapy (CDT) is an innovative and effective treatment that relies on the Fenton or Fenton-like reaction, in which endogenous H2O2 overproduction is converted into cytotoxic hydroxyl radicals (•OH) to suppress tumor growth. Nevertheless, the therapeutic efficiency of CDT is severely restricted by undesirable properties, such as reaction conditions and catalyst performance. Herein, a 2D Ti3C2 MXene/Cu2O nanosheet (MCP NS)-based multifunctional nanoplatform (3-BP@MCG NSs) has been constructed, in which glucose oxidase (GOx) and respiration inhibitor 3-bromopyruvate (3-BP) are sequentially embedded. In this structure, the copper-based catalyst Cu2O releases Cu+ in an acid-triggered manner in the tumor microenvironment (TME), which activates the Fenton-like reaction to catalyze the generation of •OH for CDT. The composite has excellent photothermal properties and a high-resolution photoacoustic imaging (PAI) capability in the near-infrared (NIR) region, and especially under NIR irradiation, the photothermal effect generated by the nanosheets accelerates catalysis. GOx is a natural enzyme catalyst for depleting glucose and oxygen content in cells, upregulating H2O2 levels in situ, and thereby improving the therapeutic effect of CDT. What is more, the supported 3-BP not only reduces oxygen consumption to alleviate hypoxia levels but also inhibits the glycolysis process and lowers ATP levels by suppressing hexokinase activity. As a result, 3-BP@MCG NSs optimize the unique properties of MCP NSs, GOx, and 3-BP via mutual promotion, realizing self-enhanced PTT/CDT synergistic therapy. This work establishes an emerging strategy for highly efficient PAI-guided integrated treatment and provides a proof of concept for the cooperation of hypoxia relief and in situ H2O2 and NIR synergistic enhancement to improve therapeutic efficiency.