PfgPDI: Pocket feature-enabled graph neural network for protein-drug interaction prediction.

Biomolecular interaction recognition between ligands and proteins is an essential task, which largely enhances the safety and efficacy in drug discovery and development stage. Studying the interaction between proteins and ligands can improve the understanding of disease pathogenesis and lead to more effective drug targets. Additionally, it can aid in determining drug parameters, ensuring proper absorption, distribution, and metabolism within the body. Due to incomplete feature representation or the model's inadequate adaptation to protein-ligand complexes, the existing methodologies suffer from suboptimal predictive accuracy. To address these pitfalls, in this study, we designed a new deep learning method based on transformer and GCN. We first utilized the transformer network to grasp crucial information of the original protein sequences within the smile sequences and connected them to prevent falling into a local optimum. Furthermore, a series of dilation convolutions are performed to obtain the pocket features and smile features, subsequently subjected to graphical convolution to optimize the connections. The combined representations are fed into the proposed model for classification prediction. Experiments conducted on various protein-ligand binding prediction methods prove the effectiveness of our proposed method. It is expected that the PfgPDI can contribute to drug prediction and accelerate the development of new drugs, while also serving as a valuable partner for drug testing and Research and Development engineers.

Supplementation of SkQ1 Increases Mouse In Vitro Oocyte Maturation and Subsequent Embryonic Development by Reducing Oxidative Stress.

In vitro oocyte maturation (IVM) technology is important for assisted animal and human reproduction. However, the maturation rates and developmental potential of in vitro-matured oocytes are usually lower than those of in vivo-matured oocytes. Oxidative stress is a main factor that causes the lower maturation rates and quality of in vitro-matured oocytes. The purpose of this study was to investigate the effects of treatment with SkQ1, a mitochondria-targeted antioxidant, on mouse IVM and subsequent embryonic development. The results demonstrated that the supplementation of SkQ1 during IVM improves the maturation rates of mouse oocytes and the subsequent developmental competence of in vitro-fertilized embryos. The addition of SkQ1 to the IVM medium also decreased oxidative stress and apoptosis, and increased mitochondrial membrane potential in matured mouse oocytes. This study provides a new method through which to enhance the maturation rates and the quality of in vitro-matured mouse oocytes, thus promoting the application and development of assisted animal and human reproductive technology.

Predictive value of 8-year blood pressure measures in intracerebral hemorrhage risk over 5 years.

AIMS: The relationships between long-term blood pressure (BP) measures and intracerebral hemorrhage (ICH), as well as their predictive ability on ICH, were unclear. We aimed to investigate the independent associations of multiple BP measures with subsequent 5-year ICH risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. METHODS: We included 12,398 participants from the China Kadoorie Biobank (CKB) who completed three surveys every four to five years. The following long-term BP measures were calculated: mean, minimum, maximum, standard deviation, coefficient of variation, average real variability, and cumulative BP exposure (cumBP). Cox proportional hazard models were used to examine the associations between these measures and ICH. The potential incremental value of these measures in ICH risk prediction was assessed using Harrell's C statistics, continuous net reclassification improvement (cNRI), and relative integrated discrimination improvement (rIDI). RESULTS: The hazard ratios (95% confidence intervals) of incident ICH associated with per SD increase in cumSBP and cumDBP were 1.62 (1.25, 2.10) and 1.59 (1.23, 2.07), respectively. When cumBP was added to the conventional 5-year ICH risk prediction model, the C-statistic change was 0.009 (-0.001, 0.019), the cNRI was 0.267 (0.070, 0.464), and the rIDI was 18.2% (5.8%, 30.7%). Further subgroup analyses revealed a consistent increase in cNRI and rIDI in men, rural residents, and participants without diabetes. Other long-term BP measures showed no statistically significant associations with incident ICH and generally did not improve model performance. CONCLUSION: The nearly 10-year cumBP was positively associated with an increased 5-year risk of ICH and could significantly improve risk reclassification for the ICH risk prediction model that included single-point BP measurement.

This prospective cohort study of Chinese adults investigated the independent associations of multiple blood pressure (BP) measures with subsequent 5-year intracerebral hemorrhage (ICH) risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. The cumulative BP exposure (cumBP) was positively associated with subsequent 5-year risk of ICH, independent of the recent single-point SBP and DBP levels.The cumBP could improve the risk reclassification of the conventional 5-year ICH risk prediction model that included single-point BP measurement for all participants, as well as for men, rural residents, and participants without diabetes.

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux.

The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use.

Associations of traditional cardiovascular risk factors with 15-year blood pressure change and trajectories in Chinese adults: a prospective cohort study.

OBJECTIVE: How traditional cardiovascular disease (CVD) risk factors are related to long-term blood pressure change (BPC) or trajectories remain unclear. We aimed to examine the independent associations of these factors with 15-year BPC and trajectories in Chinese adults. METHODS: We included 15 985 participants who had attended three surveys, including 2004-2008 baseline survey, and 2013-2014 and 2020-2021 resurveys, over 15 years in the China Kadoorie Biobank (CKB). We measured systolic and diastolic blood pressure (SBP and DBP), height, weight, and waist circumference (WC). We asked about the sociodemographic characteristics and lifestyle factors, including smoking, alcohol drinking, intake of fresh vegetables, fruits, and red meat, and physical activity, using a structured questionnaire. We calculated standard deviation (SD), cumulative blood pressure (cumBP), coefficient of variation (CV), and average real variability (ARV) as long-term BPC proxies. We identified blood pressure trajectories using the latent class growth model. RESULTS: Most baseline sociodemographic and lifestyle characteristics were associated with cumBP. After adjusting for other characteristics, the cumSBP (mmHg × year) increased by 116.9 [95% confidence interval (CI): 111.0, 122.7] for every 10 years of age. The differences of cumSBP in heavy drinkers of ≥60 g pure alcohol per day and former drinkers were 86.7 (60.7, 112.6) and 48.9 (23.1, 74.8) compared with less than weekly drinkers. The cumSBP in participants who ate red meat less than weekly was 29.4 (12.0, 46.8) higher than those who ate red meat daily. The corresponding differences of cumSBP were 127.8 (120.7, 134.9) and 70.2 (65.0, 75.3) for BMI per 5 kg/m2 and WC per 10 cm. Most of the findings of other BPC measures by baseline characteristics were similar to the cumBP, but the differences between groups were somewhat weaker. Alcohol drinking was associated with several high-risk trajectories of SBP and DBP. Both BMI and WC were independently associated with all high-risk blood pressure trajectories. CONCLUSIONS: Several traditional CVD risk factors were associated with unfavorable long-term BPC or blood pressure trajectories in Chinese adults.

PEDF inhibits VEGF-induced vascular leakage through binding to VEGFR2 in acute myocardial infarction.

Pigment epithelium-derived factor (PEDF) could bind to vascular endothelial growth factor receptor 2 (VEGFR2) and inhibit its activation induced by VEGF. But how PEDF affects VEGFR2 pathway is still poorly understood. In this study, we elucidated the precise mechanism underlying the interaction between PEDF and VEGFR2, and subsequently corroborated our findings using a rat AMI model. PEDF prevented endocytosis of VE-cadherin induced by hypoxia, thereby protecting the endothelium integrity. A three-dimensional model of the VEGFR2-PEDF complex was constructed by protein-protein docking method. The results showed that the VEGFR2-PEDF complex was stable during the simulation. Hydrogen bonds, binding energy and binding modes were analyzed during molecular dynamics simulations, which indicated that hydrogen bonds and hydrophobic interactions were important for the recognition of VEGFR2 with PEDF. In addition, the results from exudation of fibrinogen suggested that PEDF inhibits vascular leakage in acute myocardial infarction and confirmed the critical role of key amino acids in the regulation of endothelial cell permeability. This observation is also supported by echocardiography studies showing that the 34mer peptide sustained cardiac function during acute myocardial infarction. Besides, PEDF and 34mer could inhibit the aggregation of myofiber in the heart and promoted the formation of a dense cell layer in cardiomyocytes, which suggested that PEDF and 34mer peptide protect against AMI-induced cardiac dysfunction. These results suggest that PEDF inhibits the phosphorylation of downstream proteins, thereby preventing vascular leakage, which provides a new therapeutic direction for the treatment of acute myocardial infarction.Communicated by Ramaswamy H. Sarma.

Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. METHODS: For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. RESULTS: PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. CONCLUSIONS: Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/ß-catenin pathway.

Comparison of analgesic effects of percutaneous and transthoracic intercostal nerve block in video-assisted thoracic surgery: a propensity score-matched study.

BACKGROUND: This study aimed to compare the analgesic efficacy of transthoracic intercostal nerve block (TINB) and percutaneous intercostal nerve block (PINB) for video-assisted thoracic surgery (VATS) using a retrospective analysis. METHODS: A total of 336 patients who underwent VATS between January 2021 and June 2022 were reviewed retrospectively. Of the participants, 194 received TINB and were assigned to the T group, while 142 patients received PINB and were assigned to the P group. Both groups received 25 ml of ropivacaine via TINB or PINB at the end of the surgery. The study measured opioid consumption, pain scores, analgesic satisfaction, and safety. Propensity score matching (PSM) analysis was performed to minimize selection bias due to nonrandom assignment. RESULTS: After propensity score matching, 86 patients from each group were selected for analysis. The P group had significantly lower cumulative opioid consumption than the T group (p < 0.01). The Visual Analogue Scale (VAS) scores were lower for the P group than the T group at 6 and 12 h post-surgery (p < 0.01); however, there was no significant difference in the scores between the two groups at 3, 24, and 48 h (p > 0.05). The analgesic satisfaction in the P group was higher than in the T group (p < 0.05). The incidence of back pain, nausea or vomiting, pruritus, dizziness, and skin numbness between the two groups was statistically insignificant (p > 0.05). CONCLUSION: The study suggests that PINB provides superior analgesia for patients undergoing thoracic surgery compared to TINB without any extra adverse effects.

Site-specific glycoproteomic analysis of purified lactoferrin from human and animal milk.

Lactoferrin is a highly glycosylated protein, which have important biological functions in the growth and development of neonates. However, the glycoforms and glycosylation sites differed between species. The aim of the study was to identify the glycosylation profile (including glycosites, glycan structures, and glycoforms) of purified lactoferrin from human and animal (cow, goat, sheep) milk by using site-specific glycoproteomics technique. In total, a number of 89 N-glycans were identified in human and animal milk lactoferrin. We identified three N-glycosites with 23 different compositions of N-glycans in cow lactoferrin (CLF), four distinctive N-glycosites with 34 dissimilar N-glycan compositions in goat lactoferrin (GLF), five N-glycosites with 57 different N-glycan compositions in sheep lactoferrin (SLF), while five unique N-glycosites with 50 different N-glycan compositions were ascertained in human lactoferrin (HLF). HLF had the most complex glycan, while animal lactoferrin had the most high-mannose glycoforms. The results of this study further our understanding of lactoferrin differences between human and animal milk, which can provide a perspective on the analysis of differences in functional characteristics.

C-Type Natriuretic Peptide Pre-Treatment Improves Maturation Rate of Goat Oocytes by Maintaining Transzonal Projections, Spindle Morphology, and Mitochondrial Function.

C-type natriuretic peptide (CNP) is a peptide molecule naturally found in follicles and can be used to extend meiotic resumption and enhance the potential for oocytes to develop. However, the mechanism by which CNP improves goat oocyte quality remains unclear. In this study, cumulus-oocyte complexes (COCs) from goats were pre-treated with CNP prior to IVM, and the results showed that pre-treatment with CNP enhanced goat oocyte maturation. First, we discovered that CNP maintained communication between cumulus cells and oocytes by regulating the transzonal projections (TZPs). We then found that CNP treatment reduced abnormal spindle formation and increased the expression of genes associated with spindle assembly and the spindle assembly checkpoint. Moreover, further analysis showed that oocytes exhibited better antioxidant ability in the CNP treatment group, which mainly manifested in higher glutathione (GSH) and lower reactive oxygen species (ROS) concentrations. Enhanced mitochondrial activity was signified via the augmented expression of mitochondrial oxidative metabolism and fusion and fission-related genes, thus diminishing the apoptosis of the oocytes. Overall, these results provide novel insights into the potential mechanism by which CNP treatment before IVM can improve oocyte quality.

Circular RNA PIP5K1A Promotes Glucose and Lipid Metabolism Disorders and Inflammation in Type 2 Diabetes Mellitus.

Disorders of glucose and lipid metabolism are an important cause of type 2 diabetes mellitus (T2DM). Identifying the molecular mechanism of metabolic disorders is key to the treatment of T2DM. The study was to investigate the effect of circRNA PIP5K1A (circPIP5K1A) on glucose and lipid metabolism and inflammation in T2DM rats. A T2DM rat model was established, and then the T2DM rats were injected with lentiviral vectors that interfere with circPIP5K1A, miR-552-3p, or ENO1 expression. Fasting blood glucose (FBG) and fasting insulin (FINS) levels of rats were detected by an automatic analyzer and insulin detection kit, and HOMA-IR was calculated. Lipid metabolism was assessed by measuring serum levels of TG, TC, LDL-C, leptin, and resistin. Serum levels of inflammatory factors (TNF-α and IL-6) were detected by ELISA. The pathological conditions of pancreatic tissue were observed by HE staining. circPIP5K1A, miR-552-3p and ENO1 levels were recorded. The experimental results showed that circPIP5K1A and ENO1 were up-regulated, and miR-552-3p was down-regulated in T2DM rats. Down-regulating circPIP5K1A or up-regulating miR-552-3p reduced blood glucose and lipid levels, inhibited inflammation, and improved pancreatic histopathological changes in T2DM rats. In addition, up-regulating ENO1 rescued the ameliorating effects of down-regulated circPIP5K1A on T2DM rats. In general, downregulating circPIP5K1A improves insulin resistance and lipid metabolism disorders and inhibits inflammation by targeting miR-552-3p to mediate ENO1 expression.

Variations in deep iliac circumflex artery perforator chimeric flap design for single-stage customized-reconstruction of composite bone and soft-tissue defect.

BACKGROUND: The deep iliac circumflex artery (DICA) perforator (DICAP) chimeric flap is a valuable treatment strategy for single-stage reconstruction of composite bone and soft-tissue defects in upper and lower extremities. However, its utilization rate remains low owing to anatomical variations that lead to challenges when identifying and dissecting perforators. METHODS: A comprehensive anatomical investigation was conducted on the DICA system by injecting lead oxide into 12 fresh cadavers following a standardized procedure. From January 2008 to December 2020, 30 patients with composite bone and soft-tissue defects received reconstruction surgery with DICAP chimeric flap. One of the four specified surgical techniques was used to create a modified DICAP chimeric flap for the patients based on the size, shape, and location of the defect. RESULTS: Two branching patterns of DICA, transverse and ascending branches, were observed, and the former gave off the osteomusculocutaneous perforators and terminal musculocutaneous perforators. Thirty DICAP chimeric flaps were elevated successfully. The size of the skin paddles measured from 9 × 4.5 cm to 22 × 9 cm, and the bone components ranged from 3 × 2.5 × 1.5 cm to 6 × 3.5 × 2 cm. All flaps survived successfully after the operation, and all patients achieved primary closure of the donor sites. No patient encountered the fracture of transferred iliac segments. The mean bone union time was 5.5 months (ranging from 4 to 8 months). CONCLUSION: The DICA system is a suitable source for harvesting the DICAP chimeric flap to reconstruct composite bone and soft-tissue defects. It provides a flexible design for individualized coverage of such defects with limited donor-site morbidity.

Efficient Communications in V2V Networks with Two-Way Lanes Based on Random Linear Network Coding.

Vehicle-to-vehicle (V2V) communication has gained significant attention in the field of intelligent transportation systems. In this paper, we focus on communication scenarios involving vehicles moving in the same and opposite directions. Specifically, we model a V2V network as a dynamic multi-source single-sink network with two-way lanes. To address rapid changes in network topology, we employ random linear network coding (RLNC), which eliminates the need for knowledge of the network topology. We begin by deriving the lower bound for the generation probability. Through simulations, we analyzed the probability distribution and cumulative probability distribution of latency under varying packet loss rates and batch sizes. Our results demonstrated that our RLNC scheme significantly reduced the communication latency, even under challenging channel conditions, when compared to the non-coding case.

Pimavanserin tartrate induces apoptosis and cytoprotective autophagy and synergizes with chemotherapy on triple negative breast cancer.

Triple negative breast cancer (TNBC) poses a significant clinical challenge due to its lack of targeted therapy options and the frequent development of chemotherapy resistance. Metastasis remains a primary cause of mortality in late-stage TNBC patients, underscoring the urgent need for alternative treatments. Repurposing existing drugs offers a promising strategy for the discovery of novel therapies. In this study, we investigated the potential of pimavanserin tartrate (PVT) as a treatment for TNBC. While previous studies have highlighted PVT's anticancer effects in various cancer types, its activity in TNBC remains unclear. Our investigation aimed to elucidate the anticancer effects and underlying mechanisms of PVT in TNBC. We evaluated the impact of PVT and combination treatments involving PVT on TNBC cell viability, apoptosis, autophagy, and associated signaling pathways. Our findings revealed that PVT may induce mitochondria-dependent intrinsic apoptosis and caused cytoprotective autophagy via the PI3K/Akt/mTOR pathway in TNBC cells in vitro. Notably, our study demonstrated strong synergistic anti-TNBC effects when combining PVT with doxorubicin. We also found PVT showed some efficacies to inhibit TNBC tumor growth in vivo. These results provided valuable insights into the potential of PVT as an anti-TNBC therapeutic and a possible option for enhancing the sensitivity of TNBC cells to conventional chemotherapy drugs. Further studies are needed to determine the activity and mechanism of PVT in inhibiting TNBC.

Adjunctive dexamethasone palmitate use for intercostal nerve block after video-assisted thoracoscopic surgery: A prospective, randomized control trial.

Objectives: The efficacy of dexamethasone palmitate in extending durations of local anesthetic blocks is uncertain. In a randomized, double-blind study of patients undergoing video-assisted thoracoscopic surgery, we tested whether intravenous or perineural dexamethasone palmitate caused prolonged analgesia after intercostal nerve block. Methods: A total of 90 patients subjected to video-assisted thoracoscopic surgery between May and December 2022 were randomly assigned to one of three intercostal nerve blocks study arms (n = 30 each), requiring the addition of 0.5% ropivacaine (23 ml) as follows: controls (C group), 2 ml saline; IV-DXP group, 2 ml saline + 2 ml (8 mg) intravenous dexamethasone palmitate; and PN-DXP group, 2 ml (8 mg) perineural dexamethasone palmitate. Time to first postoperative remedial analgesia served as primary outcome measure. Secondary endpoints included postoperative opioid consumption, pain scores by Visual Analog Scale, analgesia satisfaction, and related adverse effects. Results: Compared with controls or the IV-DXP group, time to first postoperative remedial analgesia was longer and postoperative opioid consumption for rescue analgesia was lower in the PN-DXP group (p < 0.01). Similarly, the Visual Analog Scale scores in patients at 8, 12, 18, and 24 h postoperatively were lower in the PN-DXP group than in controls and the IV-DXP group (p < 0.01). Patient satisfaction was statistically lower in the PN-DXP group, compared with either the control or IV-DXP group (p < 0.05). Clinically, the three groups did not differ significantly in occurrences of adverse effects during the 48-h postoperative monitoring period (p > 0.05). Conclusions: Perineural dexamethasone palmitate is a promising adjunct to ropivacaine intercostal nerve block by prolonging analgesia with almost no related adverse effects.

High-efficiency SERS platform based on 3D porous PPDA@Au NPs as a substrate for the detection of pesticides on vegetables.

Nowadays, the presence of highly toxic and persistent residues of pesticides in water and food around the world is becoming a serious problem, and so their rapid and sensitive detection is critical to human health. In this work, a 3D composite nanoparticle of porous PDA (polydopamine) microspheres and Au NPs (PPDA@Au NPs) was proposed as a SERS substrate to detect pesticides. Porous PDA as a substrate was first synthesized with F127 (Pluronic F127), dopamine hydrochloride, and 1,3,5-TMB (1,3,5-trimethylbenzene) under weakly alkaline conditions by a one-step method. Then, HAuCl4 was in situ reduced in the pores of PPDA spheres and grew sequentially for effecting the reducibility of PPDA. As a result, uniform 3D PPDA@Au NPs with "hot spots" were successfully synthesized as SERS substrates, which could effectively avoid the agglomeration of gold nanoparticles to greatly improve the sensitivity and uniformity of the SERS platform. At the same time, methyl parathion, 4-chlorophenol, and 2,4-D as representatives of pesticides were detected with the proposed PPDA@Au NP-based SERS platform, with detection limits lower than 7.26, 7.52, and 11 ng mL-1, separately. The current work presents a simple preparation method to prepare sensitive and uniform SERS platform PPDA@Au NPs, which have potential for applications in actual pesticide and drug testing.

Construction of subtype classifiers and validation of a prognostic risk model based on hypoxia-associated lncRNAs for lung adenocarcinoma.

Background: Studies have shown that long non-coding RNAs (lncRNAs) are found to be hypoxia-regulated lncRNAs in cancer. Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, and despite early surgical removal, has a poor prognosis and a high recurrence rate. Thus, we aimed to identify subtype classifiers and construct a prognostic risk model using hypoxia-associated long noncoding RNAs (hypolncRNAs) for LUAD. Methods: Clinical data of LUAD samples with prognosis information obtained from the Gene Expression Omnibus (GEO), acted as validation dataset, and The Cancer Genome Atlas (TCGA) databases, served as training dataset, were used to screen hypolncRNAs in each dataset by univariate Cox regression analysis; the intersection set was used for subsequent analyses. Unsupervised clustering analysis was performed based on the expression of hypolncRNAs using the 'ConsensuClusterPlus' package. The tumor microenvironment (TME) was compared between LUAD subgroups by analyzing the expression of immune cell infiltration, immune components, stromal components, immune checkpoints, and chemokine secretion. To identify robust prognostically associated hypolncRNAs and construct a risk score model, multivariate Cox regression analysis was performed. Results: A total of 14 hypolncRNAs were identified. Based on the expression of these hypolncRNAs, patients with LUAD were classified into three hypolncRNA-regulated subtypes. The three subtypes differed significantly in immune cell infiltration, stromal score, specific immune checkpoints, and secretion of chemokines and their receptors. The Tumor Immune Dysfunction and Exclusion (TIDE) scores and myeloid-derived suppressor cell (MDSC) scores were also found to differ significantly among the three hypolncRNA-regulated subtypes. Four of the 14 hypolncRNAs were used to construct a signature to distinguish the overall survival (OS) in TCGA dataset (P<0.0001) and GEO dataset (P=0.0032) and sensitivity to targeted drugs in patients at different risks of LUAD. Conclusions: We characterized three regulatory subtypes of hypolncRNAs with different TMEs. We developed a signature based on hypolncRNAs, contributing to the development of personalized therapy and representing a new potential therapeutic target for LUAD.

Near-field multi-slice ptychography: quantitative phase imaging of optically thick samples with visible light and X-rays.

Ptychography is a form of lens-free coherent diffractive imaging now used extensively in electron and synchrotron-based X-ray microscopy. In its near-field implementation, it offers a route to quantitative phase imaging at an accuracy and resolution competitive with holography, with the added advantages of extended field of view and blind deconvolution of the illumination beam profile from the sample image. In this paper we show how near-field ptychography can be combined with a multi-slice model, adding to this list of advantages the unique ability to recover high-resolution phase images of larger samples, whose thickness places them beyond the depth of field of alternative methods.

Dual Pigment Epithelium-derived Factor and Hepatocyte Growth Factor Overexpression: A New Therapy for Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease characterized by advanced pulmonary vasculature remodeling that is thought to be curable only through lung transplantation. The application of angiogenic hepatocyte growth factor (HGF) is reported to be protective in PH through its anti-vascular remodeling effect, but excessive HGF-mediated immature neovascularization is not conducive to the restoration of pulmonary perfusion because of apparent vascular leakage. As a canonical antiangiogenic molecule, pigment epithelium-derived factor (PEDF) inhibits angiogenesis and reduces vascular permeability in a variety of diseases. However, the effect of PEDF on HGF-based PH treatment remains to be determined. In this study, monocrotaline-induced PH rats and endothelial cells isolated from rat and human PH lung tissues were used. We assessed PH progression, right cardiac function, and pulmonary perfusion in HGF- and/or PEDF-treated rats with PH. Additionally, the receptor and mechanism responsible for the role of PEDF in HGF-based PH therapy were investigated. In this study, we found that HGF and PEDF jointly prevent PH development and improve right cardiac function in rats with PH. Moreover, PEDF delivery increases the pulmonary perfusion in PH lungs and inhibits immature angiogenesis and vascular endothelial (VE)-cadherin junction disintegration induced by HGF without affecting the therapeutic inhibition of pulmonary vascular remodeling by HGF. Mechanistically, PEDF targets VE growth factor receptor 2 and suppresses its phosphorylation at Y951 and Y1175 but not Y1214. Finally, VE growth factor receptor 2/VE protein tyrosine phosphatase/VE-cadherin complex formation and Akt and Erk1/2 inactivation were observed in rat and human PH lung endothelial cells. Collectively, our data indicate that PEDF additively enhances the efficacy of HGF against PH, which may provide new insights into treatment strategies for clinical PH.