Advancing insights into in vivo meningeal lymphatic vessels with stereoscopic wide-field photoacoustic microscopy.

Meningeal lymphatic vessels (mLVs) play a pivotal role in regulating metabolic waste from cerebrospinal fluid (CSF). However, the current limitations in field of view and resolution of existing imaging techniques impede understanding the stereoscopic morphology and dynamic behavior of mLVs in vivo. Here, we utilized dual-contrast functional photoacoustic microscopy to achieve wide-field intravital imaging of the lymphatic system, including mLVs and glymphatic pathways. The stereoscopic photoacoustic microscopy based on opto-acoustic confocal features has a depth imaging capability of 3.75 mm, facilitating differentiation between mLVs on the meninges and glymphatic pathways within the brain parenchyma. Subsequently, using this imaging technique, we were able to visualize the dynamic drainage of mLVs and identify a peak drainage period occurring around 20-40 min after injection, along with determining the flow direction from CSF to lymph nodes. Inspiringly, in the Alzheimer's disease (AD) mouse model, we observed that AD mice exhibit a ~ 70% reduction in drainage volume of mLVs compared to wild-type mice. With the development of AD, there is be continued decline in mLVs drainage volume. This finding clearly demonstrates that the AD mouse model has impaired CSF drainage. Our study opens up a horizon for understanding the brain's drainage mechanism and dissecting mLVs-associated neurological disorders.

Financial toxicity and its risk factors among patients with cancer in China: A nationwide multisite study.

Objective: We assessed financial toxicity (FT) among Chinese patients with cancer and investigated associated risk factors guided by a multilevel conceptual framework. Methods: Applying multistage stratified sampling, we selected six tertiary and six secondary hospitals across three economically diverse provinces in China. From February to October 2022, 1208 patients with cancer participated. FT was measured using the COmprehensive Score for financial Toxicity (COST), with 28 potential risk factors identified at multilevel. Multiple regression analysis was used for risk factor identification. Results: FT prevalence was 82.6% (95% confidence interval [CI]: 80.5%, 84.8%), with high FT (COST score ≤ 18.5) observed in 40.9% of participants (95% CI: 38.1%, 43.7%). Significant risk factors included younger age at cancer diagnosis, unmarried status, low annual household income, negative impact of cancer on participants' or family caregiver's work, advanced cancer stage, longer hospital stay for cancer treatment or treatment-related side effects, high perceived stress, poor emotional/informational support, lack of social medical insurance or having urban and rural resident basic medical insurance, lack of commercial medical insurance, tertiary hospital treatment, and inadequate cost discussions with healthcare providers (all P < 0.05). Conclusions: Cancer-related FT is prevalent in China, contributing to disparities in cancer care access and health-related outcomes. The risk factors associated with cancer-related FT encompasses multilevel, including patient/family, provider/practice, and payer/policy levels. There is an urgent need for collective efforts by patients, healthcare providers, policymakers, and insurers to safeguard the financial security and well-being of individuals affected by cancer, promoting health equities in the realm of cancer care.

Expression profiles and gene set enrichment analysis of the transcriptomes from the cancer tissue, white adipose tissue and paracancer tissue with colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and is related to diet and obesity. Currently, crosstalk between lipid metabolism and CRC has been reported; however, the specific mechanism is not yet understood. In this study, we screened differentially expressed long non-coding RNAs (lncRNAs) and mRNAs from primary cancer, paracancer, and white adipose tissue of CRC patients. We screened and analyzed the genes differentially expressed between primary and paracancer tissue and between paracancer and white adipose tissue but not between primary and white adipose tissue. According to the results of the biological analysis, we speculated a lncRNA (MIR503HG) that may be involved in the crosstalk between CRC and lipid metabolism through exosome delivery. Methods: We screened differentially expressed long non-coding RNAs (lncRNAs) and mRNAs from primary cancer, paracancer, and white adipose tissue of CRC patients. We screened and analyzed the genes differentially expressed between primary and paracancer tissue and between paracancer and white adipose tissue but not between primary and white adipose tissue. Results: We speculated a lncRNA (MIR503HG) that may be involved in the crosstalk between CRC and lipid metabolism through exosome delivery. Conclusions: In this study, the findings raise the possibility of crosstalk between lipid metabolism and CRC through the exosomal delivery of lncRNAs.

Unraveling Key m6A Modification Regulators Signatures in Postmenopausal Osteoporosis through Bioinformatics and Experimental Verification.

OBJECTIVE: Bone marrow mesenchymal stem cells (BMSCs) show significant potential for osteogenic differentiation. However, the underlying mechanisms of osteogenic capability in osteoporosis-derived BMSCs (OP-BMSCs) remain unclear. This study aims to explore the impact of YTHDF3 (YTH N6-methyladenosine RNA binding protein 3) on the osteogenic traits of OP-BMSCs and identify potential therapeutic targets to boost their bone formation ability. METHODS: We examined microarray datasets (GSE35956 and GSE35958) from the Gene Expression Omnibus (GEO) to identify potential m6A regulators in osteoporosis (OP). Employing differential, protein interaction, and machine learning analyses, we pinpointed critical hub genes linked to OP. We further probed the relationship between these genes and OP using single-cell analysis, immune infiltration assessment, and Mendelian randomization. Our in vivo and in vitro experiments validated the expression and functionality of the key hub gene. RESULTS: Differential analysis revealed seven key hub genes related to OP, with YTHDF3 as a central player, supported by protein interaction analysis and machine learning methodologies. Subsequent single-cell, immune infiltration, and Mendelian randomization studies consistently validated YTHDF3's significant link to osteoporosis. YTHDF3 levels are significantly reduced in femoral head tissue from postmenopausal osteoporosis (PMOP) patients and femoral bone tissue from PMOP mice. Additionally, silencing YTHDF3 in OP-BMSCs substantially impedes their proliferation and differentiation. CONCLUSION: YTHDF3 may be implicated in the pathogenesis of OP by regulating the proliferation and osteogenic differentiation of OP-BMSCs.

Apple E3 ligase MdPUB23 mediates ubiquitin-dependent degradation of MdABI5 to delay ABA-triggered leaf senescence.

ABSCISIC ACID-INSENSITIVE5 (ABI5) is a core regulatory factor that mediates the ABA signaling response and leaf senescence. However, the molecular mechanism underlying the synergistic regulation of leaf senescence by ABI5 with interacting partners and the homeostasis of ABI5 in the ABA signaling response remain to be further investigated. In this study, we found that the accelerated effect of MdABI5 on leaf senescence is partly dependent on MdbHLH93, an activator of leaf senescence in apple. MdABI5 directly interacted with MdbHLH93 and improved the transcriptional activation of the senescence-associated gene MdSAG18 by MdbHLH93. MdPUB23, a U-box E3 ubiquitin ligase, physically interacted with MdABI5 and delayed ABA-triggered leaf senescence. Genetic and biochemical analyses suggest that MdPUB23 inhibited MdABI5-promoted leaf premature senescence by targeting MdABI5 for ubiquitin-dependent degradation. In conclusion, our results verify that MdABI5 accelerates leaf senescence through the MdABI5-MdbHLH93-MdSAG18 regulatory module, and MdPUB23 is responsible for the dynamic regulation of ABA-triggered leaf senescence by modulating the homeostasis of MdABI5.

Hydrogen Embrittlement of 27Cr-4Mo-2Ni Super Ferritic Stainless Steel.

The effect of hydrogen content on the deformation and fracture behavior of 27Cr-4Mo-2Ni super ferritic stainless steel (SFSS) was investigated in this study. It was shown that the plasticity and yield strength of SFSS were very susceptible to hydrogen content. The introduction of hydrogen led to a significant decrease in elongation and a concurrent increase in yield strength. Nevertheless, a critical threshold was identified in the elongation reduction, after which the elongation remained approximately constant even with more hydrogen introduced, while the yield strength exhibited a monotonic increase with increasing hydrogen content within the experimental range, attributed to the pinning effect of the hydrogen Cottrell atmosphere on dislocations. Furthermore, the hydrogen-charged SFSS shows an apparent drop in flow stress after upper yielding and a reduced work hardening rate during the subsequent plastic deformation. The more hydrogen is charged, the more the flow stress drops, and the lower the work hardening rate becomes.

Size, distribution, and vulnerability of the global soil inorganic carbon.

Global estimates of the size, distribution, and vulnerability of soil inorganic carbon (SIC) remain largely unquantified. By compiling 223,593 field-based measurements and developing machine-learning models, we report that global soils store 2305 ± 636 (±1 SD) billion tonnes of carbon as SIC over the top 2-meter depth. Under future scenarios, soil acidification associated with nitrogen additions to terrestrial ecosystems will reduce global SIC (0.3 meters) up to 23 billion tonnes of carbon over the next 30 years, with India and China being the most affected. Our synthesis of present-day land-water carbon inventories and inland-water carbonate chemistry reveals that at least 1.13 ± 0.33 billion tonnes of inorganic carbon is lost to inland-waters through soils annually, resulting in large but overlooked impacts on atmospheric and hydrospheric carbon dynamics.

Sodium Silicate/Urea/Melamine Ternary Synergistic Waterborne Acrylic Acid Flame-Retardant Coating and Its Flame-Retardant Mechanism.

Waterborne acrylic coatings, the largest market share of predominant environmentally friendly coatings, face limitations in their extensive application due to their flammability. The flame-retardant properties of the coatings could be significantly enhanced by incorporate inorganic flame retardants. However, inorganic flame retardants tend to aggregate and unevenly disperse in waterborne acrylic coatings, causing a substantial decrease in flame retardancy. In this work, sodium silicate was utilized as a flame retardant, with urea and melamine serving as modifiers and synergistic agents. This combination resulted in the preparation of a sodium silicate/urea/melamine ternary synergistic waterborne acrylic flame-retardant coating. This coating was applied to the surface of poplar veneer to create flame-retardant poplar veneer. Subsequently, various instruments, including a scanning electron microscope (SEM), a limiting oxygen index meter (LOI), a thermogravimetric analyzer (TG), and a cone calorimeter (CONE), were employed to investigate the relevant properties and mechanisms of both the flame-retardant coating and poplar veneer. The results demonstrated that the sodium silicate/urea/melamine ternary synergistic flame retardant did not exhibit aggregation and could be uniformly dispersed in waterborne acrylic coatings. The physical and mechanical properties of the ternary synergistic flame-retardant poplar veneer coating were satisfactory. Melamine and urea, acting as modifiers, not only greatly enhanced the dispersibility of sodium silicate in waterborne acrylic coatings, but also assisted in the formation of a silicon-containing char layer through the generation of nitrogen, achieving ternary synergistic flame retardancy. In conclusion, this work explores a novel method to efficiently and uniformly disperse inorganic flame retardants in organic coatings. It significantly improves the dispersibility and uniformity of inorganic flame retardants in organic polymers, thereby substantially enhancing the flame-retardant performance of coatings. This work provides a theoretical basis for the research and application of new flame-retardant coatings in the field of chemistry and materials.

Factors associated with burnout among frontline nurses in the post-COVID-19 epidemic era: a multicenter cross-sectional study.

BACKGROUND: The COVID-19 pandemic has significantly increased the risk of burnout among frontline nurses. However, the prevalence of burnout and its associated factors in the post-pandemic era remain unclear. This research aims to investigate burnout prevalence among frontline nurses in the post-pandemic period and pinpoint associated determinants in China. METHODS: From April to July 2023, a cross-sectional study was carried out across multiple centers, focusing on frontline nurses who had been actively involved in the COVID-19 pandemic. The data collection was done via an online platform. The Maslach Burnout Inventory-Human Services Survey was utilized to evaluate symptoms of burnout. A multivariable logistic regression analysis was used to pinpoint factors associated with burnout. RESULTS: Of the 2210 frontline nurses who participated, 75.38% scored over the cut-off for burnout. Multivariable logistic regression revealed that factors like being female [odds ratio (OR) = 0.41, 95%CI = 0.29-0.58] and exercising 1-2 times weekly[OR = 0.53, 95%CI = 0.42-0.67] were protective factors against burnout. Conversely, having 10 or more night shifts per month[OR = 1.99, 95%CI = 1.39-2.84], holding a master's degree or higher[OR = 2.86, 95% CI = 1.59-5.15], poor health status[OR = 2.43, 95% CI = 1.93-3.08] and [OR = 2.82, 95%CI = 1.80-4.43], under virus infection[OR = 7.12, 95%CI = 2.10-24.17], and elevated work-related stress[OR = 1.53, 95% CI = 1.17-2.00] were all associated with an elevated risk of burnout. CONCLUSION: Our findings indicate that post-pandemic burnout among frontline nurses is influenced by several factors, including gender, monthly night shift frequency, academic qualifications, weekly exercise frequency, health condition, and viral infection history. These insights can inform interventions aimed at safeguarding the mental well-being of frontline nurses in the post-pandemic period.

Auricular acupressure combined with Tongtian oral liquid for acute attacks of migraine without aura: a single-center, retrospective study.

OBJECTIVE: To observe the effect of auricular acupressure combined with Tongtian Oral Liquid for immediate pain relief in patients with acute migraine without aura, and to analyze the risk factors that affect the number of acute attacks of migraine without aura. METHODS: This retrospective study analyzed data of 180 patients diagnosed with acute migraine without aura who were admitted to Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine). The patients were divided into an intervention group 1 (n=60), an intervention group 2 (n=60), and a control group (n=60) according to different treatment methods. The intervention group 1 received auricular acupressure + Tongtian oral liquid, the intervention group 2 received Jing point bloodletting + Tongtian oral liquid, and the control group received ibuprofen + flunarizine. Before treatment, 60 minutes and 120 minutes after treatment, the visual analogue scale (VAS) and the short-form McGill pain questionnaire (SF-MPQ) were used to score the pain in the three groups to evaluate the efficacy of immediate analgesia. Symptoms including fatigue, drowsiness, nausea, and vomiting after 2 hours of treatment were observed. The amount of ibuprofen used within 24 hours was calculated. The drug treatment was continued for one month. The frequency of migraine attacks was compared among the three groups. The relevant factors affecting the number of migraine attacks were analyzed. RESULTS: The VAS and SF-MPQ scores of the three groups were all decreased 120 minutes after treatment as compared with those before treatment (P<0.01). The decline rate in the intervention group 1 > that in intervention group 2 > that in control group (P<0.01). The immediate analgesic efficiency at 60 minutes, intervention group 1 > intervention group 2 > control group (100% vs. 76.67% vs. 56.67%, P<0.001). After 2 hours of treatment, more cases of fatigue and lethargy occurred in the control group (P<0.05). There was no significant difference in nausea and vomiting among the three groups (P>0.05). The 24-hour ibuprofen dosage and headache recurrence ratio, control group > intervention group 2 > intervention group 1 (P<0.05). The number of headache attacks within 30 days was significantly higher in the control group than in the intervention groups (P=0.012). There was no significant statistical difference between the two intervention groups (P=0.568). Regression analysis found that age (OR=1.036, 1.006-1.068), body mass index (OR=1.101, 1.008-1.201), hypertension (OR=2.879, 1.187-6.986), chronic gastritis (OR=2.839, 1.213-6.647), children with educational problems (OR=0.333, 0.164-0.676), and residual fatigue symptoms (OR=4.539, 1.828-11.271) affected the number of headache attacks within the one month of treatment. CONCLUSIONS: Auricular acupressure combined with Tongtian Oral Liquid can relieve the acute pain of migraine without aura and reduce the number of pain episodes. The curative effect of this combination is better than that of western medicine alone.

Molecular mechanism of endophytic bacteria DX120E regulating polyamine metabolism and promoting plant growth in sugarcane.

Introduction: Sugarcane endophytic nitrogen-fixing bacterium Klebsiella variícola DX120E displayed broad impact on growth, but the exact biological mechanism, especially polyamines (PAs) role, is still meager. Methods: To reveal this relationship, the content of polyamine oxidase (PAO), PAs, reactive oxygen species (ROS)-scavenging antioxidative enzymes, phytohormones, 1-aminocyclopropane-1-carboxylic synthase (ACS), chlorophyll content, and biomass were determined in sugarcane incubated with the DX120E strain. In addition, expression levels of the genes associated with polyamine metabolism were measured by transcriptomic analysis. Results: Genomic analysis of Klebsiella variícola DX120E revealed that 39 genes were involved in polyamine metabolism, transport, and the strain secrete PAs in vitro. Following a 7-day inoculation period, DX120E stimulated an increase in the polyamine oxidase (PAO) enzyme in sugarcane leaves, however, the overall PAs content was reduced. At 15 days, the levels of PAs, ROS-scavenging antioxidative enzymes, and phytohormones showed an upward trend, especially spermidine (Spd), putrescine (Put), catalase (CAT), auxin (IAA), gibberellin (GA), and ACS showed a significant up-regulation. The GO and KEGG enrichment analysis found a total of 73 differentially expressed genes, involving in the cell wall (9), stimulus response (13), peroxidase activity (33), hormone (14) and polyamine metabolism (4). Discussion: This study demonstrated that endophytic nitrogen-fixing bacteria stimulated polyamine metabolism and phytohormones production in sugarcane plant tissues, resulting in enhanced growth. Dual RNA-seq analyses provided insight into the early-stage interaction between sugarcane seedlings and endophytic bacteria at the transcriptional level. It showed how diverse metabolic processes selectively use distinct molecules to complete the cell functions under present circumstances.

Insights into the role of the N6-methyladenosine reader IGF2BP3 in the progression of oral squamous cell carcinoma and its connection to cell-cycle control.

The genome of oral squamous cell carcinoma (OSCC) has been extensively characterized via bulk sequencing, revealing a multitude of genetic changes. The gene IGF2BP3, which encodes for the insulin-like growth factor 2 mRNA-binding protein 3, has been observed to be highly expressed in several types of cancer. This finding suggests that IGF2BP3 may play a significant role in the initiation and advancement of cancer. Nevertheless, the mechanisms by which IGF2BP3 contribute to OSCC are yet to be fully understood. In this study, we have observed that IGF2BP3 exhibits overexpression in OSCC. Based on our findings from bulk sequencing analysis, we have concluded that IGF2BP3 could potentially serve as a biomarker for predicting poor prognosis in OSCC. Moreover, it has been demonstrated that IGF2BP3 exhibits a significant association with the initiation and advancement of tumors both in vivo and in vitro. The evaluation of IGF2BP3 expression levels in relation to the cell cycle stage was conducted using single-cell RNA sequencing data. Tumor cells characterized by elevated IGF2BP3 expression demonstrated a higher percentage of cells in the G2/M transition phase. This study presents new findings indicating that the molecular target IGF2BP3 can serve as a prognostic indicator for tumors and has an impact on the development and progression of OSCC by influencing the regulation of the cell cycle.

High-Fidelity Sensitive Tracing Circulating Tumor Cell Telomerase Activity.

Dynamic tracing of intracellular telomerase activity plays a crucial role in cancer cell recognition and correspondingly in earlier cancer diagnosis and personalized precision therapy. However, due to the complexity of the required reaction system and insufficient loading of reaction components into cells, achieving a high-fidelity determination of telomerase activity is still a challenge. Herein, an Aptamer-Liposome mediated Telomerase activated poly-Molecular beacon Arborescent Nanoassembly(ALTMAN) approach was described for direct high-fidelity visualization of telomerase activity. Briefly, intracellular telomerase activates molecular beacons, causing their hairpin structures to unfold and produce fluorescent signals. Furthermore, multiple molecular beacons can self-assemble, forming arborescent nanostructures and leading to exponential amplification of fluorescent signals. Integrating the enzyme-free isothermal signal amplification successfully increased the sensitivity and reduced interference by leveraging the skillful design of the molecular beacon and the extension of the telomerase-activated TTAGGG repeat sequence. The proposed approach enabled ultrasensitive visualization of activated telomerase exclusively with a prominent detection limit of 2 cells·µL-1 and realized real-time imaging of telomerase activity in living cancer cells including blood samples from breast cancer patients and urine samples from bladder cancer patients. This approach opens an avenue for establishing a telomerase activity determination and in situ monitoring technique that can facilitate both telomerase fundamental biological studies and cancer diagnostics.

The Relationship Between Modic Changes and Endplate Sclerosis in Patients with Lumbar Degenerative Disease: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: To explore the relationship between modic changes (MCs) and endplate sclerosis in patients with lumbar degenerative disease. METHODS: This network meta-analysis was performed on the basis of Preffered Reporting Items for Systematic Reviews and Meta-Analysis 2020 statement. This study was registered at the International Prospective Register of Systematic Reviews (CRD42024497370). We performed a systematic search of the PubMed, Web of Science, Embase, China national knowledge infrastructure, China Science and Technology Journal Database, and Wanfang databases from inception to December 22, 2023. STATA13.0 and RevMan 5.3 were applied to perform the meta-analysis. RESULTS: Seven studies with a total of 1510 endplates were divided into 6 groups according to the type of MCs. The endplate sclerosis rate in the single-type group was significantly lower than that in the mixed-type group. The endplate sclerosis rate in the type I MC (MC1) was significantly lower than that in the type II MC (MC2). The endplate sclerosis rate in the MC2 was significantly lower than that in the type III MC (MC3). The endplate sclerosis rate in the MC1/2 was significantly lower than that in the MC2/3. No significant difference was detected between MC1/2 and MC1/3 or between MC2/3 and MC1/3. For decreasing the endplate sclerosis rate, the order of the different types of MCs was MC1>MC2>MC1/2>MC2/3≈MC1/3>MC3. CONCLUSIONS: Endplate sclerosis occurs in all kinds of MCs. With increasing grade of MCs, the incidence of endplate sclerosis gradually increased. The endplate sclerosis rate in mixed-type MCs was significantly greater than that in MC2 and significantly lower than that in MC3. The endplate sclerosis rate in the mixed-type, including MC3 (MC1/3 and MC2/3), was significantly greater than that in the MC1/2.

TRPV Channels in Osteoarthritis: A Comprehensive Review.

Osteoarthritis (OA) is a debilitating joint disorder that affects millions of people worldwide. Despite its prevalence, our understanding of the underlying mechanisms remains incomplete. In recent years, transient receptor potential vanilloid (TRPV) channels have emerged as key players in OA pathogenesis. This review provides an in-depth exploration of the role of the TRPV pathway in OA, encompassing its involvement in pain perception, inflammation, and mechanotransduction. Furthermore, we discuss the latest research findings, potential therapeutic strategies, and future directions in the field, shedding light on the multifaceted nature of TRPV channels in OA.

Prognostic value of geriatric nutritional risk index in patients with amyotrophic lateral sclerosis.

BACKGROUND: The geriatric nutritional risk index (GNRI) is a prognostic indicator for several diseases, meanwhile, nutrition and inflammation play important roles in the disease progression of amyotrophic lateral sclerosis (ALS). However, the association between the GNRI and ALS remains unknown. METHODS: 443 patients diagnosed with ALS were divided into two groups based on the GNRI levels. Associations between GNRI and survival time were analyzed using Kaplan-Meier curves and compared by the log-rank test. Univariate and multivariate analyses were used to assess their prognostic values for survival time. Spearman correlation analysis was used to evaluate the correlation coefficients between GNRI and other clinical variables. RESULTS: No significant differences were found in diagnostic delay between the two groups. The onset age and disease progression rate (DPR) were significantly lower in high GNRI group while forced vital capacity (FVC), revised version of the ALS functional rating scale (ALSFRS-R), serum albumin and body mass index (BMI) were significantly lower in low GNRI group. Lower GNRI levels were linked with shorter ALS patients' survival time by Kaplan-Meier curves. The univariate and multivariate analysis identified the onset age, gender, onset site, diagnostic delay, DRP and GNRI as predictors of survival time in patients with ALS. CONCLUSION: Nutritional status was closely corelated with ALS progression. The GNRI may be used as a potential prognostic indictor for ALS patients.

Endothelial Slc35a1 Deficiency Causes Loss of LSEC Identity and Exacerbates Neonatal Lipid Deposition in the Liver in Mice.

BACKGROUND & AIMS: The functional maturation of the liver largely occurs after birth. In the early stages of life, the liver of a newborn encounters enormous high-fat metabolic stress caused by the consumption of breast milk. It is unclear how the maturing liver adapts to high lipid metabolism. Liver sinusoidal endothelial cells (LSECs) play a fundamental role in establishing liver vasculature and are decorated with many glycoproteins on their surface. The Slc35a1 gene encodes a cytidine-5'-monophosphate (CMP)-sialic acid transporter responsible for transporting CMP-sialic acids between the cytoplasm and the Golgi apparatus for protein sialylation. This study aimed to determine whether endothelial sialylation plays a role in hepatic vasculogenesis and functional maturation. METHODS: Endothelial-specific Slc35a1 knockout mice were generated. Liver tissues were collected for histologic analysis, lipidomic profiling, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. RESULTS: Endothelial Slc35a1-deficient mice exhibited excessive neonatal hepatic lipid deposition, severe liver damage, and high mortality. Endothelial deletion of Slc35a1 led to sinusoidal capillarization and disrupted hepatic zonation. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) in LSECs was desialylated and VEGFR2 signaling was enhanced in Slc35a1-deficient mice. Inhibition of VEGFR2 signaling by SU5416 alleviated lipid deposition and restored hepatic vasculature in Slc35a1-deficient mice. CONCLUSIONS: Our findings suggest that sialylation of LSECs is critical for maintaining hepatic vascular development and lipid homeostasis. Targeting VEGFR2 signaling may be a new strategy to prevent liver disorders associated with abnormal vasculature and lipid deposition.

The long coiled-coil protein NECC2 regulates oxLDL-induced endothelial oxidative damage and exacerbates atherosclerosis development in apolipoprotein E -/- mice.

Oxidized low density lipoprotein (oxLDL)-induced endothelial oxidative damage promotes the development of atherosclerosis. Caveolae play an essential role in maintaining the survival and function of vascular endothelial cell (VEC). It is reported that the long coiled-coil protein NECC2 is localized in caveolae and is associated with neural cell differentiation and adipocyte formation, but its role in VECs needs to be clarified. Our results showed NECC2 expression increased in the endothelium of plaque-loaded aortas and oxLDL-treated HUVECs. Down-regulation of NECC2 by NECC2 siRNA or compound YF-307 significantly inhibited oxLDL-induced VEC apoptosis and the adhesion factors expression. Remarkably, inhibition of NECC2 expression in the endothelium of apoE-/- mice by adeno-associated virus (AAV)-carrying NECC2 shRNA or compound YF-307 alleviated endothelium injury and restricted atherosclerosis development. The immunoprecipitation results confirmed that NECC2 interacted with Tyk2 and caveolin-1(Cav-1) in VECs, and NECC2 further promoted the phosphorylation of Cav-1 at Tyr14 b y activating Tyk2 phosphorylation. On the other hand, inhibiting NECC2 levels suppressed oxLDL-induced phosphorylation of Cav-1, uptake of oxLDL by VECs, accumulation of intracellular reactive oxygen species and activation of NF-κB. Our findings suggest that NECC2 may contribute to oxLDL-induced VEC injury and atherosclerosis via modulating Cav-1 phosphorylation through Tyk2. This work provides a new concept and drug target for treating atherosclerosis.

Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery.

We present a user-friendly molecular generative pipeline called Pocket Crafter, specifically designed to facilitate hit finding activity in the drug discovery process. This workflow utilized a three-dimensional (3D) generative modeling method Pocket2Mol, for the de novo design of molecules in spatial perspective for the targeted protein structures, followed by filters for chemical-physical properties and drug-likeness, structure-activity relationship analysis, and clustering to generate top virtual hit scaffolds. In our WDR5 case study, we acquired a focused set of 2029 compounds after a targeted searching within Novartis archived library based on the virtual scaffolds. Subsequently, we experimentally profiled these compounds, resulting in a novel chemical scaffold series that demonstrated activity in biochemical and biophysical assays. Pocket Crafter successfully prototyped an effective end-to-end 3D generative chemistry-based workflow for the exploration of new chemical scaffolds, which represents a promising approach in early drug discovery for hit identification.

Simulation of the resistance switching performance and synaptic behavior of TiO2-based RRAM devices with CoFe2O4 insertion layers.

The electrothermal coupling model of Pt/CoFe2O4/TiO2/TiN devices was established to study their resistive switching characteristics and basic biological synaptic properties in our research. The processes of set and reset are simulated, and the distribution of the temperature, the electric field and the concentration of oxygen vacancies in the dielectric layer are obtained. The switching performance of the TiO2-based device is significantly improved after the CoFe2O4 layer is inserted, with the switching voltage, working current and power consumption being reduced, while the switching ratio is increased. By changing the thermal conductivity of the top electrode, the rupture position of the conductive filament can be controlled. The I-V characteristics of the Pt/CoFe2O4/TiO2/TiN device during the reset and set processes are fitted linearly in logarithmic coordinates, and the ohmic conduction mechanism or the space-limited charge conduction mechanism is mainly satisfied in the high and low resistance states. Finally, the application of dual-layer devices on biological synapses is studied, and the basic biological characteristics of enhancement, inhibition and paired pulse promotion are simulated successfully. In addition, the redox reaction induced by oxygen vacancy migration also promotes the formation and rupture of the conductive filament. Results of the study show this ferrite material as an insertion layer in a resistive random-access memory structure that offers potential for future information storage and bioneuromorphic computation devices.