Integrating network pharmacology and experimental validation reveals therapeutic effects of D-mannose on NAFLD through mTOR suppression.

Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition and metabolic disorder, has emerged as a significant health issue worldwide. D-mannose, a natural monosaccharide widely existing in plants and animals, has demonstrated metabolic regulatory properties. However, the effect and mechanism by which D-mannose may counteract NAFLD have not been studied. In this study, network pharmacology followed by molecular docking analysis was utilized to identify potential targets of mannose against NAFLD, and the leptin receptor-deficient, genetically obese db/db mice was employed as an animal model of NAFLD to validate the regulation of D-mannose on core targets. As a result, 67 targets of mannose are predicted associated with NAFLD, which are surprisingly centered on the mechanistic target of rapamycin (mTOR). Further analyses suggest that mTOR signaling is functionally enriched in potential targets of mannose treating NAFLD, and that mannose putatively binds to mTOR as a core mechanism. Expectedly, repeated oral gavage of supraphysiological D-mannose ameliorates liver steatosis of db/db mice, which is based on suppression of hepatic mTOR signaling. Moreover, daily D-mannose administration reduced hepatic expression of lipogenic regulatory genes in counteracting NAFLD. Together, these findings reveal D-mannose as an effective and potential NAFLD therapeutic through mTOR suppression, which holds translational promise.

Blockchain-Assisted Privacy-Preserving and Context-Aware Trust Management Framework for Secure Communications in VANETs.

Vehicular ad hoc networks (VANETs) are used for improving traffic efficiency and road safety. However, VANETs are vulnerable to various attacks from malicious vehicles. Malicious vehicles can disrupt the normal operation of VANET applications by broadcasting bogus event messages that may cause accidents, threatening people's lives. Therefore, the receiver node needs to evaluate the authenticity and trustworthiness of the sender vehicles and their messages before acting. Although several solutions for trust management in VANETs have been proposed to address these issues of malicious vehicles, existing trust management schemes have two main issues. Firstly, these schemes have no authentication components and assume the nodes are authenticated before communicating. Consequently, these schemes do not meet VANET security and privacy requirements. Secondly, existing trust management schemes are not designed to operate in various contexts of VANETs that occur frequently due to sudden variations in the network dynamics, making existing solutions impractical for VANETs. In this paper, we present a novel blockchain-assisted privacy-preserving and context-aware trust management framework that combines a blockchain-assisted privacy-preserving authentication scheme and a context-aware trust management scheme for securing communications in VANETs. The authentication scheme is proposed to enable anonymous and mutual authentication of vehicular nodes and their messages and meet VANET efficiency, security, and privacy requirements. The context-aware trust management scheme is proposed to evaluate the trustworthiness of the sender vehicles and their messages, and successfully detect malicious vehicles and their false/bogus messages and eliminate them from the network, thereby ensuring safe, secure, and efficient communications in VANETs. In contrast to existing trust schemes, the proposed framework can operate and adapt to various contexts/scenarios in VANETs while meeting all VANET security and privacy requirements. According to efficiency analysis and simulation results, the proposed framework outperforms the baseline schemes and demonstrates to be secure, effective, and robust for enhancing vehicular communication security.

A phase II study of bevacizumab in non-squamous, non-small-cell lung cancer patients with malignant pleural effusion.

Aim: To investigate the efficacy, safety and optimal dosage of bevacizumab in non-squamous, non-small-cell lung cancer (NSCLC) patients with malignant pleural effusion (MPE). Methods: 20 patients were enrolled and received intrapleural injection of bevacizumab (group A: 2.5 mg/kg d1, d8; group B: 5 mg/kg d1, d8; group C: 7.5 mg/kg d1, d8). Results: The objective response rate (ORR) of MPE was 50%. The median progression-free survival (PFS) of MPE was 7.0 months (95% CI 4.9-9.2). The ORR and PFS of MPE from group B were better than those of group A and group C. The most common adverse events (AEs) were hypertension (15%) and anemia (15%). Conclusion: Bevacizumab has certain efficacy in non-squamous NSCLC patients with MPE. Clinical Trial Registration: NCT02942043 (ClinicalTrials.gov).

Using the Multi-Theory Model (MTM) of Health Behavior Change to Explain Yoga Practice.

BACKGROUND: Diverse groups, including college students, are being encouraged to practice yoga. Research suggests that college students fail to attain the mental and physical benefits of yoga practice. OBJETIVE: The purpose of this study was to utilize the fourth-generation, multi-theory model (MTM) of health behavior change to explain change regarding yoga practice of asanas, shava asana, pranayama, dhyana, yama and niyama among college students. METHOD: This cross-sectional study relied on a quota sample of students 18 years and older attending Jackson State University, a historically black college in Jackson, Mississippi, United States. MEASURES: A 36-item face and content valid instrument was used to collect data. Stepwise multiple regression was used to analyze the survey data for identifying the best possible predictors of yoga practice. A statistical significance level of 0.05 was set a priori. RESULTS: A total of 70 participants, mean age 28.62 years (SD, 6.11), predominately female (84%) and black (87%) completed the survey. The initiation model constructs- changes in the physical environment (ß = 3.99, P = .002) and behavioral confidence (ß = 0.331, P = .008)-were significant, explaining 40% of the variability in the dependent variable. Practice change was statistically significant (F1,65 =7.569; P = .0001; adjusted R2 = 0.460) for the maintenance model, explaining 46% of the variability. CONCLUSION: The MTM model of health behavior change is effective for explaining the intent to initiate and maintain yoga behavior among college students.

A Blockchain-Enabled Incentive Trust Management with Threshold Ring Signature Scheme for Traffic Event Validation in VANETs.

As a part of the intelligent transportation system, vehicular ad hoc networks (VANETs) provide timely information about road events and traffic to improve road safety and traffic efficiency. However, VANETs face many challenges, such as attacks from malicious vehicles, identity privacy leakage, and the absence of trust between vehicular nodes. In addition, vehicles nearby an event usually lack the motivation to participate in the traffic event validation whenever it occurs, which requires the cooperation of vehicles on the network. To solve these problems, a blockchain-enabled incentive trust model with a privacy-preserving threshold ring signature scheme for VANETs is proposed. Firstly, a threshold ring signature scheme is designed in order to allow participants in the non-trusted environment to anonymously witness the message's authenticity and reliability while guaranteeing the vehicle's privacy. Second, a blockchain-enabled incentive trust management model is presented to enable the roadside units (RSUs) to thwart various attacks and guarantee the trustworthiness of event messages transmitted in VANETs and also motivate the senders of the traffic information and their witnesses with incentives. Finally, to improve efficiency, a practical Byzantine fault-tolerant consensus mechanism is used. Our proposed system is demonstrated to be effective and secure for VANETs, according to both security analysis and performance evaluation.

Effect of tourniquet application on postoperative outcomes in sinus tarsi approach for intra-articular calcaneus fractures.

INTRODUCTION: Tourniquets are commonly used during foot and ankle surgery to provide a bloodless operative field and increase surgical comfort, despite the potential risks associated with it. This study compared postoperative outcomes of tourniquet-assisted and non-tourniquet-assisted operative fixation of calcaneal fractures via the sinus tarsi approach. MATERIALS AND METHODS: A retrospective study from March 2015 to December 2018 revealed 131 patients with closed calcaneal fractures who underwent minimally invasive surgery at our hospital. Visualization, operating time, blood loss, and postoperative pain were collected. Patients in the tourniquet group (n = 62) were compared with patients in the non-tourniquet group (n = 69). RESULTS: The visibility of the surgical field was fair/poor in 2 cases in the tourniquet group and fair/poor in 19 cases in the non-tourniquet group (P < 0.05). The mean operative time was 64.7 ± 3.5 min in the tourniquet group and 76.0 ± 6.1 min in the non-tourniquet group (P < 0.05). The estimated intraoperative and postoperative blood loss was 56.6 ± 33.3 and 100.0 ± 25.3 mL, respectively, in the tourniquet group and 205.0 ± 31.6 and 38.3 ± 19.8 mL, respectively, in the non-tourniquet group (P < 0.05). The VAS pain scores 24 h, 48 h, and 72 h postoperatively were 4.3 ± 1.8, 3.1 ± 1.2, and 2.0 ± 0.5 points, respectively, in the tourniquet group and 2.1 ± 1.1, 1.6 ± 1.0, and 1.0 ± 0.3 points, respectively, in the non-tourniquet group (P < 0.05). CONCLUSION: Tourniquet application during the sinus tarsi approach for calcaneal fractures can significantly improve surgical visualization and reduce intraoperative blood loss. However, adverse events associated with the use of tourniquets include increased postoperative pain and bleeding. Due to increased postoperative bleeding and pain, more attention should be given to the postoperative phase in patients treated with tourniquets.

Nanobar Array Assay Revealed Complementary Roles of BIN1 Splice Isoforms in Cardiac T-Tubule Morphogenesis.

Bridging integrator-1 (BIN1) is a family of banana-shaped molecules implicated in cell membrane tubulation. To understand the curvature sensitivity and functional roles of BIN1 splicing isoforms, we engineered vertical nanobars on a cell culture substrate to create high and low curvatures. When expressed individually, BIN1 isoforms with phosphoinositide-binding motifs (pBIN1) appeared preferentially at high-curvature nanobar ends, agreeing well with their membrane tubulation in cardiomyocytes. In contrast, the ubiquitous BIN1 isoform without phosphoinositide-binding motif (uBIN1) exhibited no affinity to membranes around nanobars but accumulated along Z-lines in cardiomyocytes. Importantly, in pBIN1-uBIN1 coexpression, pBIN1 recruited uBIN1 to high-curvature membranes at nanobar ends, and uBIN1 attached the otherwise messy pBIN1 tubules to Z-lines. The complementary cooperation of BIN1 isoforms (comboBIN1) represents a novel mechanism of T-tubule formation along Z-lines in cardiomyocytes. Dysregulation of BIN1 splicing, e.g., during myocardial infarction, underlied T-tubule disorganization, and correction of uBIN1/pBIN1 stoichiometry rescued T-tubule morphology in heart disease.

The IL-6 rs1800795 and rs1800796 polymorphisms are associated with coronary artery disease risk.

Studies examining the associations between the interleukin-6 (IL-6) rs1800795 and rs1800796 gene polymorphisms and risk of coronary artery disease (CAD) remain controversial. Our aim was to evaluate the accurately determine role of these two polymorphisms in CAD risk. PubMed, Embase, VIP, Wan fang and China National Knowledge Infrastructure databases were searched. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The trial sequential analysis (TSA) was conducted, and bioinformatics tools were employed. A total of thirty-seven articles were obtained. For the IL-6 rs1800795 polymorphism, 9411 CAD patients and 3161 controls were included, 4720 patients with CAD, and 5000 controls were included for the IL-6 rs1800796 polymorphism. In the pooled analysis, significant associations were only observed for the rs1800796 polymorphism (allelic: OR [95%CI] = 1.28 [1.13, 1.44], dominant: OR [95%CI] = 1.35 [1.17, 1.57], recessive: OR [95%CI] = 1.35 [1.18, 1.55], heterozygote: OR [95%CI] = 1.26 [1.15, 1.37], homozygote: OR [95%CI] = 1.62 [1.23, 2.13]). Significant associations were detected in the Asian and Mongoloid populations and 'more than 500' subgroup for the rs1800795 polymorphism. TSA confirmed the true-positive results for the rs1800796 polymorphism. The bioinformatics analysis showed that the two polymorphisms played important roles in the gene transcription. The IL-6 rs1800796 polymorphism is associated with an increased susceptibility to CAD and is a risk factor for CAD. The IL-6 rs1800795 polymorphism is associated with an increased risk of CAD in Asians, particularly in Chinese, and a decreased risk of CAD in an African population is remarkably observed.

Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial.

Objectives: This randomized, controlled clinical trial aims to compare the efficacy and safety of glucocorticoid combined with MMF and glucocorticoid monotherapy for patients with IgG4-related disease. Methods: Sixty-nine patients newly diagnosed with IgG4-related disease were randomly divided into two groups (35 patients in Group I and 34 patients in Group II). Patients in Group I received glucocorticoid monotherapy (0.6-0.8 mg/(kg·day) and tapered gradually); patients in Group II received glucocorticoid combined with MMF therapy (1-1.5 g/day). All the patients were followed up at 1, 3, 6 and 12 months. The primary endpoint was response rate in 12 months and the secondary endpoints were relapse, remission rate and adverse reactions. Results: Group I and Group II shared almost the same efficacy at the 1 month treatment, but during the follow-up, the complete response rate in Group II was much higher than that in Group I at different time points, and the cumulative relapse rate during 1 year of therapy was much higher in Group I than that in Group II (40.00 vs 20.59%). The remission rate was lower in Group I (51.42 vs 76.47%). Relapses were more likely to happen in lung, lacrimal gland, salivary gland, paranasal sinus and kidney. MMF could reduce relapse, especially organs recurrence. No serious adverse reactions occurred in the two groups. Conclusion: Combination treatment with glucocorticoid and MMF was more effective than the monotherapy, and the relapse of IgG4-related disease might be associated with the elevated levels of serum IgG4 and the low glucocorticoid maintenance dose. Trial registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02458196.

Determination of oxytetracycline hydrochloride in milk and egg white samples using Ru(bipy)3 2+ -Ce(SO4 )2 chemiluminescence.

A novel, rapid and sensitive chemiluminescence (CL) method for the determination of oxytetracycline hydrochloride (OTCH) is described in this paper. The presented method was based on the fact that OTCH could immensely enhance the CL of the reaction of cerium sulfate and tris(2,2-bipyridyl) ruthenium (II) in acidic medium. Under optimal experimental conditions, CL intensity was favorably linear for OTCH in the range 5.0 × 10-7 to 5.0 × 10-5  g/ml, with a detection limit of 1.5 × 10-7  g/ml (S/N = 3). The relative standard detection was 4.76% for 5.0 × 10-6  g/ml (n = 11). This method was successfully applied to the analysis of OTCH in milk and egg white samples. According to the results of the kinetic curves for OTCH in the Ru(bipy)3 2+ -Ce(SO4 )2 CL system, together with CL and ultraviolet (UV)-visible spectra, the possible mechanism of the CL reaction is discussed briefly.

Diverse subcellular localizations of the insect CMP-sialic acid synthetases.

The occurrence and biological importance of sialic acid (Sia) and its metabolic enzymes in insects have been studied using Drosophila melanogaster. The most prominent feature of D. melanogaster CMP-Sia synthetase (DmCSS) is its Golgi-localization, contrasted with nuclear localization of vertebrate CSSs. However, it remains unclear if the Golgi-localization is common to other insect CSSs and why it happens. To answer these questions, Aedes aegypti (mosquito) CSS (AaCSS) and Tribolium castaneum (beetle) CSS (TcCSS) were cloned and characterized for their activity and subcellular localization. Our new findings show: (1) AaCSS and TcCSS share a common overall structure with DmCSS in terms of evolutionarily conserved motifs and the absence of the C-terminal domain typical to vertebrate CSSs; (2) when expressed in mammalian and insect cells, AaCSS and TcCSS showed in vivo and in vitro CSS activities, similar to DmCSS. In contrast, when expressed in bacteria, they lacked CSS activity because the N-terminal hydrophobic region appeared to induce protein aggregation; (3) when expressed in Drosophila S2 cells, AaCSS and TcCSS were predominantly localized in the ER, but not in the Golgi. Surprisingly, DmCSS was mainly secreted into the culture medium, although partially detected in Golgi. Consistent with these results, the N-terminal hydrophobic regions of AaCSS and TcCSS functioned as a signal peptide to render them soluble in the ER, while the N-terminus of DmCSS functioned as a membrane-spanning region of type II transmembrane proteins whose cytosolic KLK sequence functioned as an ER export signal. Accordingly, the differential subcellular localization of insect CSSs are distinctively more diverse than previously recognized.

Clinical characteristics, survival analysis and influencing factors of distant metastasis in patients with acromelanomas: A retrospective study.

The prognosis of acromelanomas (AM) is worse. The objective of this study was to investigate the clinical features of distant metastasis of AM and the factors affecting the survival and prognosis of patients. In this study, a retrospective study was conducted to select 154 AM patients admitted to Nanjing Pukou People's Hospital from January 2018 to April 2021 for clinical research. The clinical characteristics of distant metastasis were statistically analyzed, and the survival curve was drawn with 5-year follow-up outcomes. The median survival time of the patients was calculated, and the clinicopathological features and peripheral blood laboratory indexes of the surviving and dead patients were analyzed. Logistic regression model was used to analyze the risk factors affecting the prognosis of AM patients. In this study, 154 patients with AM were treated, including 88 males and 76 females, aged from 27 to 79 years old, with an average age of (59.3 ±â€…11.7) years old. Among them, 90 cases had distant metastasis. The main metastatic sites were lung (47.78%) and lymph nodes (42.22%). Among them, single site metastasis accounted for 41.11% and multiple site metastasis 58.89%. 89 cases survived and 65 cases died. The survival time was 22 months to 60 months, and the median survival time was 48.0 months. The Breslow thickness, stage at diagnosis, distant metastasis, site of metastasis and ulceration were compared between the survival group and the death group (P < .05). serum lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR) and lymphocyte monocyte ratio (LMR) were compared between the survival group and the death group (P < .05). The results of Logistic regression model showed that LDH ≥ 281 U/L, NLR ≥ 2.96, LMR ≤ 3.57, newly diagnosed stage > stage II, distant metastasis, multiple site metastasis and tumor ulcer were independent risk factors for poor prognosis of AM patients (P < .05). Patients with AM had a higher proportion of distant metastasis, mainly lung and lymph node metastasis. Increased LDH, increased NLR, decreased LMR, higher initial stage, distant metastasis, multiple site metastasis, and combined tumor ulcer were closely related to the poor prognosis of patients after surgery.

In-situ sequential crystallization of fenofibrate and tristearin - Understanding the distribution of API in particles and stability of solid lipid microparticles from the perspective of crystallization.

In-situ API crystallization in carrier matrices has attracted extensive attention in recent years for its advantages over traditional preparation processes. However, due to the lack of systemic research on molecular self-assembly behaviors, the products obtained by in-situ crystallization suffer from the problems of polymorphic transformation and drug expulsion during storage, limiting its industrial application. This paper investigates the in-situ sequential crystallization behavior of tristearin (SSS) and fenofibrate (FEN), utilizing SSS as the carrier and FEN as the API. It was found that the behavior of mixed crystallization significantly differs from single-component crystallization, including direct formation of stable form of SSS and the rapid crystallization of FEN. During the crystallization process, the melting FEN promotes the movement of SSS molecules, while the sliding of SSS lamellae, in turn, provides a mechanical stimulus to enhance the nucleation of FEN. Based on the observed synergistic crystallization behavior, the distribution and stability of the API within FEN solid lipid microparticles (SLMs) during storage were evaluated, while also examining the stability variations in SLMs formulated at different cooling rates and drug loading concentrations. The findings indicate that the initial nucleated FEN results in a decrease in the surrounding molten FEN and the irregularity of the SSS lamellas, thereby preventing the remaining molten FEN from achieving complete crystallization within a brief period. Due to the compatibility between FEN and SSS, some SSS may blend with the molten FEN, potentially resulting in further crystallization during storage and consequently increasing the risk of drug expulsion.

Left-sided portal hypertension secondary to pancreatic cancer: clinical features, surgical treatment and outcome of 48 cases.

BACKGROUND/AIMS: Features of LSPH secondary to pancreatic cancer is ambiguous, and controversy remains in the treatment. METHODS: 48 cases from our department were retrospectively analyzed to evaluate the clinical features, as well as the feasibility and effect of surgical treatment. RESULTS: 16 patients had gastrointestinal hemorrhage history. Laboratory findings showed normocytic and normochromic anemia, thrombocytopenia, lymphocyte reduction, and elevated liver enzyme. Tumor markers were normal in 12 patients. Ultrasonography showed splenic venous obstruction in 40 patients and splenomegaly in 35. Esophagogastric varices could be detected by endoscopy in 40 patients and by CT in 37. Radical resection was performed in 43 patients and splenectomy or additional devascularization in 29. 15 patients had gastrointestinal bleeding during follow-up, and the median survival time was 11.0 months. CONCLUSION: Associated LSPH brought special features to pancreatic cancer. Radical resection, as well as splenectomy or additional devascularization for varices above Grade II, was worth performing.

Dissociable effects of transcranial direct current stimulation (tDCS) on early and later stages of visual motion perceptual learning.

Transcranial direct current stimulation (tDCS) has the potential to benefit visual perceptual learning (VPL). However, previous studies investigated the effect of tDCS on VPL within early sessions, and the influence of tDCS on learning effects at later stages (plateau level) is unclear. Here, participants completed 9 days of training on coherent motion direction identification to reach a plateau (stage 1) and then continued training for 3 days (stage 2). The coherent thresholds were measured before training, after stage 1 and after stage 2. In the first group, anodal tDCS was applied when participants trained over a period of 12 days (stage 1 + stage 2). In the second group, participants completed a 9-day training period without any stimulation to reach a plateau (stage 1); after that, participants completed a 3-day training period while anodal tDCS was administered (stage 2). The third group was treated the same as the second group except that anodal tDCS was replaced by sham tDCS. The results showed that anodal tDCS did not improve posttest performance after the plateau was reached. The comparison of learning curves between the first and third groups showed that anodal tDCS decreased the threshold at the early stage, but it did not improve the plateau level. For the second and third groups, anodal tDCS did not further enhance the plateau level after a continued 3-day training period. These results suggest that anodal tDCS boosts VLP during the early period of training sessions, but it fails to facilitate later learning effects. This study contributed to a deep understanding of the dissociable tDCS effects at distinct temporal stages, which may be due to the dynamic change in brain regions during the time course of VPL.

A bifunctional zoledronate sustained-release system in scaffold: Tumor therapy and bone repair.

It is of great challenges to repair bone defect and prevent tumor recurrence in bone tumors postoperative treatment. Bone scaffolds loaded with zoledronate (ZOL) are expected to solve these issues due to its osteogenesis and anti-tumor ability. Furthermore, ZOL needs to be sustained release to meet the requirement of long-term therapy. In this study, ZOL was loaded into amination functionalized mesoporous silicon (SBA15NH2), and then incorporated into poly (L-lactic acid) to prepare PLLA/SBA15NH2-ZOL scaffold via selective laser sintering technology. On one hand, ZOL of local release not only can inhibit growth and proliferation of bone tumor cells but also inhibit osteoclast differentiation through competitive binding of receptor activator of nuclear factor (NF)-kB (RANK) in osteoclast precursors. On the other hand, amination function could change the surface charge of mesoporous silica to positive charge to enhance the absorption of ZOL, mesoporous structure and abundant amino groups of SBA15NH2 play a barrier role and form hydrogen bond with phosphate groups of ZOL, respectively, thereby achieving its sustained release. The results showed that the loading amount of ZOL was 236.53 mg/g, and the scaffold could sustainedly release ZOL for more than 6 weeks. The scaffold inhibited proliferation of osteosarcoma cells through inducing apoptosis and cell cycle arrest. TRAP staining and F-actin ring formation experiment showed the scaffold inhibited differentiation and mature of osteoclast. Pit formation assay indicated that bone resorption activity was inhibited strongly.

Extracellular matrix modulates the spatial hepatic features in hepatocyte-like cells derived from human embryonic stem cells.

BACKGROUND: Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) can provide a valuable in vitro model for disease modelling and drug development. However, generating HLCs with characteristics comparable to hepatocytes in vivo is challenging. Extracellular matrix (ECM) plays an important role in supporting liver development and hepatocyte functions, but their impact on hepatocyte differentiation and maturation during hPSC differentiation remains unclear. Here, we investigate the effects of two ECM components-Matrigel and type I collagen on hepatic differentiation of human embryonic stem cells (hESCs). METHODS: hESC-derived HLCs were generated through multistage differentiation in two-dimensional (2D) and three-dimensional (3D) cultures, incorporating either type I collagen or Matrigel during hepatic specification and maturation. The resulting HLCs was characterized for their gene expression and functionality using various molecular and cellular techniques. RESULTS: Our results showed that HLCs cultured with collagen exhibited a significant increase in albumin and alpha-1 anti-trypsin expression with reduced AFP compared to HLCs cultured with Matrigel. They also secreted more urea than Matrigel cultures. However, these HLCs exhibited lower CYP3A4 activity and glycogen storage than those cultured with Matrigel. These functional differences in HLCs between collagen and Matrigel cultures closely resembled the hepatocytes of periportal and pericentral zones, respectively. CONCLUSION: Our study demonstrates that Matrigel and collagen have differential effects on the differentiation and functionality of HLCs, which resemble, to an extent, hepatic zonation in the liver lobules. Our finding has an important impact on the generation of hPSC-HLCs for biomedical and medical applications.

SATB2, coordinated with CUX1, regulates IL-1ß-induced senescence-like phenotype in endothelial cells by fine-tuning the atherosclerosis-associated p16INK4a expression.

Genome-wide association studies (GWAS) have validated a strong association of atherosclerosis with the CDKN2A/B locus, a locus harboring three tumor suppressor genes: p14ARF , p15INK4b , and p16INK4a . Post-GWAS functional analysis reveals that CUX is a transcriptional activator of p16INK4a via its specific binding to a functional SNP (fSNP) rs1537371 on the atherosclerosis-associated CDKN2A/B locus, regulating endothelial senescence. In this work, we characterize SATB2, another transcription factor that specifically binds to rs1537371. We demonstrate that even though both CUX1 and SATB2 are the homeodomain transcription factors, unlike CUX1, SATB2 is a transcriptional suppressor of p16INK4a and overexpression of SATB2 competes with CUX1 for its binding to rs1537371, which inhibits p16INK4a and p16INK4a -dependent cellular senescence in human endothelial cells (ECs). Surprisingly, we discovered that SATB2 expression is transcriptionally repressed by CUX1. Therefore, upregulation of CUX1 inhibits SATB2 expression, which enhances the binding of CUX1 to rs1537371 and subsequently fine-tunes p16INK4a expression. Remarkably, we also demonstrate that IL-1ß, a senescence-associated secretory phenotype (SASP) gene itself and a biomarker for atherosclerosis, induces cellular senescence also by upregulating CUX1 and/or downregulating SATB2 in human ECs. A model is proposed to reconcile our findings showing how both primary and secondary senescence are activated via the atherosclerosis-associated p16INK4a expression.

[Modeling and simulation activities to design sampling scheme for population pharmacokinetic study on amlodipine].

Reasonable sampling scheme is the important basis for establishing reliable population pharmacokinetic model. It is an effective method for estimation of population pharmacokinetic parameters with sparse data to perform population pharmacokinetic analysis using the nonlinear mixed-effects models. We designed the sampling scheme for amlodipine based on D-optimal sampling strategy and Bayesian estimation method. First, optimized sample scenarios were designed using WinPOPT software according to the aim, dosage regimen and visit schedule of the clinical study protocol, and the amlodipine population model reported by Rohatagi et al. Second, we created a NONMEM-formatted dataset (n = 400) for each sample scenario via Monte Carlo simulation. Third, the estimation of amlodipine pharmacokinetic parameters (clearance (CL/F), volume (V/F) and Ka) was based on the simulation results. All modeling and simulation exercises were conducted with NONMEM version 7.2. Finally, the accuracy and precision of the estimated parameters were evaluated using the mean prediction error (MPE) and the mean absolute error (MAPE), respectively. Among the 6 schemes, schemes 6 and 3 have good accuracy and precision. MPE is 0.1% for scheme 6 and -0.6% for scheme 3, respectively. MAPE is 0.7% for both schemes. There is no significant difference in MPE and MAPE of volume among them. Therefore, we select scheme 3 as the final sample scenario because it has good accuracy and precision and less sample points. This research aims to provide scientific and effective sampling scheme for population pharmacokinetic (PK) study of amlodipine in patients with renal impairment and hypertension, provide a scientific method for an optimum design in clinical population PK/PD (pharmacodynamics) research.

A nomogram for predicting the risk of mortality in patients with acute pancreatitis and Gram-negative bacilli infection.

Objective: Gram-negative bacilli (GNB) are common pathogens of infection in severe acute pancreatitis (SAP), and their occurrence increases the mortality of SAP. Early identification of SAP severity and prognosis is of great significance to SAP treatment. This study explored risk factors for mortality in patients with SAP and GNB infection and established a model for early prediction of the risk of death in GNB-infected SAP patients. Methods: Patients diagnosed with SAP from January 1, 2016, to March 31, 2022, were included, and their baseline clinical characteristics were collected. Univariate logistic regression analysis was performed to screen for death related variables, and concurrently, a Boruta analysis was performed to identify potentially important clinical features associated with mortality. The intersection of the two results was taken for further multivariate logistic regression analysis. A logistic regression model was constructed according to the independent risk factor of death and then visualized with a nomogram. The performance of the model was further validated in the training and validation cohort. Results: A total of 151 patients with SAP developed GNB infections. Univariate logistic regression analysis identified 11 variables associated with mortality. The Boruta analysis identified 11 clinical features, and 4 out of 9 clinical variables: platelet counts (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.99-1.00; p = 0.007), hemoglobin (OR 0.96, 95% CI 0.92-1; p = 0.037), septic shock (OR 6.33, 95% CI 1.12-43.47; p = 0.044), and carbapenem resistance (OR 7.99, 95% CI 1.66-52.37; p = 0.016), shared by both analyses were further selected as independent risk factors by multivariate logistic regression analysis. A nomogram was used to visualize the model. The model demonstrated good performance in both training and validation cohorts with recognition sensitivity and specificity of 96% and 80% in the training cohort and 92.8% and 75% in the validation cohort, respectively. Conclusion: The nomogram can accurately predict the mortality risk of patients with SAP and GNB infection. The clinical application of this model allows early identification of the severity and prognosis for patients with SAP and GNB infection and identification of patients requiring urgent management thus allowing rationalization of treatment options and improvements in clinical outcomes.