Ensemble learning for integrative prediction of genetic values with genomic variants.

BACKGROUND: Whole genome variants offer sufficient information for genetic prediction of human disease risk, and prediction of animal and plant breeding values. Many sophisticated statistical methods have been developed for enhancing the predictive ability. However, each method has its own advantages and disadvantages, so far, no one method can beat others. RESULTS: We herein propose an Ensemble Learning method for Prediction of Genetic Values (ELPGV), which assembles predictions from several basic methods such as GBLUP, BayesA, BayesB and BayesCπ, to produce more accurate predictions. We validated ELPGV with a variety of well-known datasets and a serious of simulated datasets. All revealed that ELPGV was able to significantly enhance the predictive ability than any basic methods, for instance, the comparison p-value of ELPGV over basic methods were varied from 4.853E-118 to 9.640E-20 for WTCCC dataset. CONCLUSIONS: ELPGV is able to integrate the merit of each method together to produce significantly higher predictive ability than any basic methods and it is simple to implement, fast to run, without using genotype data. is promising for wide application in genetic predictions.

Meta-Analysis and Network Analysis Differentially Detect Various Pro-Inflammatory Mediators and Risk Factors for Type 2 Diabetes in the Elderly.

Type 2 diabetes (T2D) has a pathophysiological component that includes inflammation. Inflammation-sensitive marker measurement may be helpful in determining the risk of complications for both older T2D patients and the public. This study aimed to investigate the association between blood pro-inflammatory mediators and the characteristics of elderly patients with T2D using meta and network analyses. The Web of Science, Scopus, PubMed, and Cochrane Library databases were selected as study methodology. The Quality in Prognosis Studies (QUIPS) tool in the meta-analysis assessed the studies' methodological quality. The selected studies were statistically analyzed using the META-MAR tool based on the standardized mean difference (SMD). The selected studies included nine examinations involving 6399 old people [+>+55 years old, 65.9+±+4.09 (mean+±+SD)]. The meta-analysis showed that pro-inflammatory mediators (SMD 0.82) and patient-related variables [risk factors (SMD 0.71)] were significantly associated with T2D (p+<+0.05). Subgroup analysis revealed that tumor necrosis factor alpha (TNF-α; SMD 1.08), body mass index (SMD 0.64), high-density lipoprotein (HDL; SMD -0.61), body weight (SMD 0.50), and blood pressure (SMD 1.11) were factors significantly associated with T2D (p+<+0.05). Network analysis revealed that among patient characteristics, diastolic blood pressure and, among inflammatory mediators, leptin were the most closely associated factors with T2D in older adults. Moreover, network analysis showed that TNF-α and systolic blood pressure were most closely associated with leptin. Overall, alternate techniques, such as meta-analysis and network analysis, might identify different markers for T2D in older people. A therapeutic decision-making process needs to consider these differences in advance.

NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression.

Pulmonary fibrosis is a progressive lung disease often occurring secondary to environmental exposure. Asbestos exposure is an important environmental mediator of lung fibrosis and remains a significant cause of disease despite strict regulations to limit exposure. Lung macrophages play an integral role in the pathogenesis of fibrosis induced by asbestos (asbestosis), in part by generating reactive oxygen species (ROS) and promoting resistance to apoptosis. However, the mechanism by which macrophages acquire apoptosis resistance is not known. Here, we confirm that macrophages isolated from asbestosis subjects are resistant to apoptosis and show they are associated with enhanced mitochondrial content of NADPH oxidase 4 (NOX4), which generates mitochondrial ROS generation. Similar results were seen in chrysotile-exposed WT mice, while macrophages from Nox4-/- mice showed increased apoptosis. NOX4 regulated apoptosis resistance by activating Akt1-mediated Bcl-2-associated death phosphorylation. Demonstrating the importance of NOX4-mediated apoptosis resistance in fibrotic remodeling, mice harboring a conditional deletion of Nox4 in monocyte-derived macrophages exhibited increased apoptosis and were protected from pulmonary fibrosis. Moreover, resolution occurred when Nox4 was deleted in monocyte-derived macrophages in mice with established fibrosis. These observations suggest that NOX4 regulates apoptosis resistance in monocyte-derived macrophages and contributes to the pathogenesis of pulmonary fibrosis. Targeting NOX4-mediated apoptosis resistance in monocyte-derived macrophages may provide a novel therapeutic target to protect against the development and/or progression of pulmonary fibrosis.

Post-translational regulation of PGC-1α modulates fibrotic repair.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-É£ (PPARÉ£) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

Cadmium-mediated lung injury is exacerbated by the persistence of classically activated macrophages.

Heavy metals released into the environment have a significant effect on respiratory health. Lung macrophages are important in mounting an inflammatory response to injury, but they are also involved in repair of injury. Macrophages develop mixed phenotypes in complex pathological conditions and polarize to a predominant phenotype depending on the duration and stage of injury and/or repair. Little is known about the reprogramming required for lung macrophages to switch between these divergent functions; therefore, understanding the mechanism(s) by which macrophages promote metabolic reprogramming to regulate lung injury is essential. Here, we show that lung macrophages polarize to a pro-inflammatory, classically activated phenotype after cadmium-mediated lung injury. Because metabolic adaptation provides energy for the diverse macrophage functions, these classically activated macrophages show metabolic reprogramming to glycolysis. RNA-Seq revealed up-regulation of glycolytic enzymes and transcription factors regulating glycolytic flux in lung macrophages from cadmium-exposed mice. Moreover, cadmium exposure promoted increased macrophage glycolytic function with enhanced extracellular acidification rate, glycolytic metabolites, and lactate excretion. These observations suggest that cadmium mediates the persistence of classically activated lung macrophages to exacerbate lung injury.

Macrophage Rac2 Is Required to Reduce the Severity of Cigarette Smoke-induced Pneumonia.

RATIONALE: Cigarette smoking is prevalent in the United States and is the leading cause of preventable diseases. A prominent complication of smoking is an increase in lower respiratory tract infections (LRTIs). Although LRTIs are known to be increased in subjects that smoke, the mechanism(s) by which this occurs is poorly understood. OBJECTIVES: Determine how cigarette smoke (CS) reduces reactive oxygen species (ROS) production by the phagocytic NOX2 (NADPH oxidase 2), which is essential for innate immunity in lung macrophages. METHODS: NOX2-derived ROS and Rac2 (Ras-related C3 botulinum toxin substrate 2) activity were determined in BAL cells from wild-type and Rac2-/- mice exposed to CS or cadmium and in BAL cells from subjects that smoke. Host defense to respiratory pathogens was analyzed in mice infected with Streptococcus pneumoniae. MEASUREMENTS AND MAIN RESULTS: NOX2-derived ROS in BAL cells was reduced in mice exposed to CS via inhibition of the small GTPase Rac2. These mice had greater bacterial burden and increased mortality compared with air-exposed mice. BAL fluid from CS-exposed mice had increased levels of cadmium, which mediated the effect on Rac2. Similar observations were seen in human subjects that smoke. To support the importance of Rac2 in the macrophage immune response, overexpression of constitutively active Rac2 by lentiviral administration increased NOX2-derived ROS, decreased bacterial burden in lung tissue, and increased survival compared with CS-exposed control mice. CONCLUSIONS: These observations suggest that therapies to maintain Rac2 activity in lung macrophages restore host defense against respiratory pathogens and diminish the prevalence of LRTIs in subjects that smoke.

Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.

Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+ influx in alveolar macrophages from wild-type, but not MCU+/-, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU-mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+ suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis.-Gu, L., Larson-Casey, J. L., Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.

Differential binding of the HIV-1 envelope to phosphatidylserine receptors.

Prior work has shown that the HIV-1 envelope of the human immunodeficiency virus (HIV) interacts directly with T-cell immunoglobulin mucin (TIM) family proteins. Herein, we demonstrate that HIV-1 envelope glycoproteins from varying HIV-1 clades bind differentially to TIM proteins and functionally similar proteins acting as phosphatidylserine (PtdSer) receptors. Using enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) technology, we show that lysate containing HIV-1 envelope and recombinant HIV-1 envelope glycoproteins bind TIM-4 and advanced glycosylation end product-specific receptor (AGER). The complex binding of HIV-1 UG21 gp140 to TIM-4 or AGER suggests a biphasic interaction with these proteins.

Annexin A2 (ANXA2) interacts with nonstructural protein 1 and promotes the replication of highly pathogenic H5N1 avian influenza virus.

BACKGROUND: Non-structural protein 1 (NS1) is a multifunctional protein and a crucial regulatory factor in the replication and pathogenesis of avian influenza virus (AIV). Studies have shown that NS1 can interact with a variety of host proteins to modulate the viral life cycle. We previously generated a monoclonal antibody against NS1 protein; In the current research study, using this antibody, we immunoprecipitated host proteins that interact with NS1 to better understand the roles played by NS1 in communications between virus and host. RESULTS: Co-immunoprecipitation experiments identified annexin A2 (ANXA2) as a target molecule interacting with NS1. Results from confocal laser scanning microscopy indicated that NS1 co-localized with ANXA2 in the cell cytoplasm. Overexpression of ANXA2 significantly increased the titer of H5N1 subtype HPAIV, whereas siRNA-mediated knockdown of ANXA2 markedly inhibited the expression of viral proteins and reduced the progeny virus titer. CONCLUSIONS: Our results indicate that ANXA2 interacts with NS1 and ANXA2 expression increases HPAIV replication.

Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis.

M2 macrophages are implicated in the development of pulmonary fibrosis as they generate profibrotic signals. The polarization process, at least in part, is regulated by epigenetic modulation. Because Cu,Zn-superoxide dismutase-induced H2O2 can polarize macrophages to a profibrotic M2 phenotype, we hypothesized that modulation of the redox state of the cell is involved in the epigenetic modulation of the macrophage phenotype. In this study, we show that signal transducer and activator of transcription 6 (STAT6) regulates Jumonji domain containing (Jmjd) 3, a histone H3 lysine 27 demethylase, and mutation of a redox-sensitive cysteine in STAT6 attenuates jmjd3 expression. Moreover, Jmjd3 deficiency abrogates profibrotic M2 gene expression. Treatment with leflunomide, which reduces mitochondrial reactive oxygen species production and tyrosine phosphorylation, inhibits jmjd3 expression and M2 polarization, as well as development of a fibrotic phenotype. Taken together, these observations provide evidence that the redox regulation of Jmjd3 is a unique regulatory mechanism for Cu,Zn-superoxide dismutase-mediated profibrotic M2 polarization. Furthermore, leflunomide, which reduces reactive oxygen species production and tyrosine phosphorylation, may prove to be therapeutic in the treatment of asbestos-induced pulmonary fibrosis.

Rapid Detection of Subtype H10N8 Influenza Virus by One-Step Reverse Transcription-Loop-Mediated Isothermal Amplification Methods.

We developed hemagglutinin- and neuraminidase-specific one-step reverse transcription-loop-mediated isothermal amplification assays for detecting the H10N8 virus. The detection limit of the assays was 10 copies of H10N8 virus, and the assays did not amplify nonspecific RNA. The assays can detect H10N8 virus from chicken samples with high sensitivity and specificity, and they can serve as an effective tool for detecting and monitoring H10N8 virus in live poultry markets.

Identification of a novel linear epitope on the NS1 protein of avian influenza virus.

BACKGROUND: The NS1 protein of avian influenza virus (AIV) is an important virulent factor of AIV. It has been shown to counteract host type I interferon response, to mediate host cell apoptosis, and to regulate the process of protein synthesis. The identification of AIV epitopes on NS1 protein is important for understanding influenza virus pathogenesis. RESULTS: In this paper, we describe the generation, identification, and epitope mapping of a NS1 protein-specific monoclonal antibody (MAb) D9. First, to induce the production of MAbs, BALB/c mice were immunized with a purified recombinant NS1 expressed in E. coli. The spleen cells from the immunized mice were fused with myeloma cells SP2/0, and through screening via indirect ELISAs, a MAb, named D9, was identified. Western blot assay results showed that MAb D9 reacted strongly with the recombinant NS1. Confocal laser scanning microscopy showed that this MAb also reacts with NS1 expressed in 293T cells that had been transfected with eukaryotic recombinant plasmids. Results from screening a phage display random 7-mer peptide library with MAb D9 demonstrated that it recognizes phages displaying peptides with the consensus peptide WNLNTV--VS, which closely matches the (182)WNDNTVRVS(190) of AIV NS1. Further identification of the displayed epitope was performed with a set of truncated polypeptides expressed as glutathione S-transferase fusion proteins, and the motif (182)WNDNT(186) was defined as the minimal unit of the linear B cell epitope recognized by MAb D9 in western blot assays. Moreover, homology analysis showed that this epitope is a conserved motif among AIV. CONCLUSIONS: We identified a conserved linear epitope, WNDNT, on the AIV NS1 protein that is recognized by MAb D9. This MAb and its epitope may facilitate future studies on NS1 function and aid the development of new diagnostic methods for AIV detection.

Diffraction management and soliton dynamics in frequency-chirped ℙT symmetric lattices.

We address two closely related problems: diffraction management and soliton dynamics in parity-time ( ℙT) symmetric lattices with a quadratic frequency modulation. The normal, anomalous, or zero diffraction is possible for narrow beams with a broad band of spatial frequencies. The frequency band of nondiffraction beams can be enlarged by increasing the chirp rate of lattices. Counter-intuitively, the gain-loss component plays the same role as the real part of lattice on the suppression of diffraction, which leads to an effective reduction of critical lattice depth for nondiffraction beams. Additionally, we reveal the existence of a novel type of "bright" solitons in defocusing Kerr media modulated by chirped ℙT lattices. We also demonstrate that lattice chirp can be utilized to suppress the instability of solitons. Our results expand the concept of ℙT symmetry in both linear and nonlinear regimes, and may find interesting optical applications.

A recombinant adenovirus-based vector elicits a specific humoral immune response against the V3 loop of HIV-1 gp120 in mice through the "Antigen Capsid-Incorporation" strategy.

BACKGROUND: Due to potential advantages, human adenoviral vectors have been evaluated pre-clinically as recombinant vaccine vectors against several cancers and infectious diseases, including human immunodeficiency virus (HIV) infection. The V3 loop of HIV-1 glycoprotein 120 (gp120) contains important neutralizing epitopes and plays key roles in HIV entry and infectivity. METHODS: In order to investigate the humoral immune response development against portions of the V3 loop, we sought to generate four versions of adenovirus (Ad)-based V3 vectors by incorporating four different antigen inserts into the hypervariable region 1 (HVR1) of human adenovirus type 5 (hAd5) hexon. The strategy whereby antigens are incorporated within the adenovirus capsid is known as the "Antigen Capsid-Incorporation" strategy. RESULTS: Of the four recombinant vectors, Ad-HVR1-lgs-His6-V3 and Ad-HVR1-long-V3 had the capability to present heterologous antigens on capsid surface, while maintaining low viral particle to infectious particle (VP/IP) ratios. The VP/IP ratios indicated both high viability and stability of these two vectors, as well as the possibility that V3 epitopes on these two vectors could be presented to immune system. Furthermore, both Ad-HVR1-lgs-His6-V3 and Ad-HVR1-long-V3 could, to some extent escape the neutralization by anti-adenovirus polyclonal antibody (PAb), but rather not the immunity by anti-gp120 (902) monoclonal antibody (MAb). The neutralization assay together with the whole virus enzyme-linked immunosorbent assay (ELISA) suggested that these two vectors could present V3 epitopes similar to the natural V3 presence in native HIV virions. However, subsequent mice immunizations clearly showed that only Ad-HVR1-lgs-His6-V3 elicited strong humoral immune response against V3. Isotype ELISAs identified IgG2a and IgG2b as the dominant IgG isotypes, while IgG1 comprised the minority. CONCLUSIONS: Our findings demonstrated that human adenovirus (hAd) vectors which present HIV antigen via the "Antigen Capsid-Incorporation" strategy could successfully elicit antigen-specific humoral immune responses, which could potentially open an avenue for the development of Ad-based HIV V3 vaccines.

Pyrene-based sulfonated organic porous materials for rapid adsorption of cationic dyes in water.

Porous organic polymers (POP) have gained attention because of their high specific surface area, porosity and their simplicity in synthesis, but for the most part, they are hydrophobic because of their organic backbone, making it difficult to expand their applications. Here, we have obtained poly(pyrene) porous organic polymers (PyPOP) through the polymerization of pyrene monomers catalysed by aluminium trichloride, which is a simple and inexpensive synthesis method. The sulfonated poly(pyrene) porous organic polymers (PyPOP-SO3H) obtained showed rapid adsorption of cationic dyes, especially malachite green (MG adsorption 1607 mg/g) and methylene blue (MB adsorption 1220 mg/g) in pH = 7 aqueous solution, room temperature. The results show that the Freundlich model is more in line with the adsorption process than the Langmuir model, whether for methylene blue or malachite green. In addition, the PSO kinetic model fits better than PFO kinetic model, whether it is for the adsorption of methylene blue or malachite green. The excellent adsorption performance of PyPOP-SO3H for cationic dyes may be due to the introduction of sulfonic acid groups, which not only increases the specific surface area but also allows better dispersion in water, increasing contact points and adsorption efficiency. This research expands the scope of exploration and application of POP.

Tumor risks of finerenone in patients with type 2 diabetes mellitus complicated with chronic kidney disease: a meta-analysis and systematic review of randomized controlled trials.

Introduction: This study aimed to assess the tumor risk of finerenone in individuals with type 2 diabetes mellitus (T2DM) aggravated by chronic kidney disease (CKD). Methods: A thorough search in the OVID Medline, OVID EMBASE, and Cochrane Library databases from their creation through 2 November 2022 yielded randomized controlled trials (RCTs) reporting on the tumor risks of finerenone in patients with T2DM complicated with CKD. A pair of reviewers selected the relevant studies based on selection criteria, collected data, and assessed the methodological quality of eligible RCTs. The Peto odds ratio (OR) with a 95% confidence interval (CI) was calculated, and subgroup analysis of tumor nature, tumor origin system, tumor origin organ, and follow-up time was performed. Furthermore, Egger's test was implemented to determine publication bias. Results: Four RCTs with 14,875 participants who had a low-to-moderate risk of bias were included. Compared with placebo treatment, finerenone did not increase the risk of overall neoplasms (Peto OR = 0.97; 95% CI, 0.83-1.14), malignant neoplasms (Peto OR = 1.03; 95% CI, 0.86-1.23), benign neoplasms (Peto OR = 0.94; 95% CI, 0.50-1.80), or in situ neoplasms (Peto OR = 0.14; 95% CI, 0.01-2.17). Subgroup analysis of the tumor origin system showed that finerenone was associated with an increased risk of malignant neoplasms of urinary tract compared with placebo treatment (Peto OR = 1.69; 95% CI, 1.07-2.67). The results were found to be robust in sensitivity analysis, and there was no indication of publication bias. Discussion: Finerenone is not associated with an increased risk of overall tumors, but it may be linked to an increased risk of malignant neoplasms in urinary tract. Additional well-planned cohort studies in larger research populations are needed to corroborate these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022374101, Identifier CRD42022374101.

Integrative Transcriptomics and Proteomics Analysis Reveals Immune Response Process in Bovine Viral Diarrhea Virus-1-Infected Peripheral Blood Mononuclear Cells.

Bovine viral diarrhea virus (BVDV) causes bovine viral diarrhea-mucosal disease, inflicting substantial economic losses upon the global cattle industry. Peripheral blood mononuclear cells (PBMCs) are the central hub for immune responses during host-virus infection and have been recognized as crucial targets for BVDV infection. In order to elucidate the dynamics of host-BVDV-1 interaction, this study harnessed RNA-seq and iTRAQ methods to acquire an extensive dataset of transcriptomics and proteomics data from samples of BVDV-1-infected PBMCs at the 12-h post-infection mark. When compared to mock-infected PBMCs, we identified 344 differentially expressed genes (DEGs: a total of 234 genes with downregulated expression and 110 genes with upregulated expression) and 446 differentially expressed proteins (DEPs: a total of 224 proteins with downregulated expression and 222 proteins with upregulated expression). Selected DEGs and DEPs were validated through quantitative reverse transcriptase-polymerase chain reaction and parallel reaction monitoring. Gene ontology annotation and KEGG enrichment analysis underscored the significant enrichment of DEGs and DEPs in various immunity-related signaling pathways, including antigen processing and presentation, complement and coagulation cascades, cytokine-cytokine receptor interaction, and the NOD-like receptor signaling pathway, among others. Further analysis unveiled that those DEGs and DEPs with downregulated expression were predominantly associated with pathways such as complement and coagulation cascades, the interleukin-17 signaling pathway, cytokine-cytokine receptor interaction, the PI3K-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the NOD-like receptor signaling pathway. Conversely, upregulated DEGs and DEPs were chiefly linked to metabolic pathways, oxidative phosphorylation, complement and coagulation cascades, and the RIG-I-like receptor signaling pathway. These altered genes and proteins shed light on the intense host-virus conflict within the immune realm. Our transcriptomics and proteomics data constitute a significant foundation for delving further into the interaction mechanism between BVDV and its host.

Experimental Study of Energy Evolution at a Discontinuity in Rock under Cyclic Loading and Unloading.

Energy is often dissipated and released in the process of rock deformation and failure. To study the energy evolution of rock discontinuities under cyclic loading and unloading, cement mortar was used as rock material and a CSS-1950 rock biaxial rheological testing machine was used to conduct graded cyclic loading and unloading tests on Barton's standard profile line discontinuities with different joint roughness coefficients (JRCs). According to the deformation characteristics of the rock discontinuity sample, the change of internal energy is calculated and analyzed. The experimental results show that under the same cyclic stress, the samples harden with the increase in the number of cycles. With the increase of cyclic stress, the dissipated energy density of each stage gradually exceeds the elastic energy density and occupies a dominant position and increases rapidly as failure becomes imminent. In the process of increasing the shear stress step-by-step, the elastic energy ratio shows a downward trend, but the dissipated energy is contrary to it. The energy dissipation ratio can be used to characterize the internal damage of the sample under load. In the initial stage of fractional loading, the sample is in the extrusion compaction stage, and the energy dissipation ratio remains quasi-constant; then the fracture develops steadily, the damage inside the sample intensifies, and the energy dissipation ratio increases linearly (albeit at a low rate). When the energy storage limit is reached, the growth rate of energy dissipation ratio increases and changes when the stress level reaches a certain threshold. The increase of the roughness of rock discontinuity samples will improve their energy storage capacity to a certain extent.

Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling.

The mitochondrial calcium uniporter (MCU) regulates metabolic reprogramming in lung macrophages and the progression of pulmonary fibrosis. Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism(s) by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid ß-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity. Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution when Bcl-2 was deleted or was inhibited with ABT-199 after fibrosis was established. These observations implicate an interplay between macrophage fatty acid ß-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.

Short-term and long-term prognostic value of circulating soluble suppression of tumorigenicity-2 concentration in acute coronary syndrome: a meta-analysis.

Background: Higher circulating soluble suppression of tumorigenicity-2 (sST2) concentration is suggested as a marker of prognosis in many cardiovascular diseases. However, the short-term and long-term prognostic value of sST2 concentration in acute coronary syndrome (ACS) remains to be summarized.Methods: A meta-analysis of follow-up studies was performed. Studies were identified via systematic search of databases including PubMed, Cochrane's Library, and Embase. A fixed- or random-effect model was applied according to the heterogeneity. We reported the prognostic value of sST2 concentration for all-cause mortality, heart failure (HF) events, and major adverse cardiovascular events (MACEs) within 1 month after hospitalization and during subsequent follow-up.Results: Twelve studies with 11690 ACS patients were included. Higher baseline sST2 concentration as continuous variables predicte the increased risk of all-cause mortality (risk ratio [RR]: 3.16, P=0.002), HF events (RR: 1.48, P<0.001), and MACEs (RR: 1.47, P<0.001) within 1 month after hospitalization, which is consistent with the results with sST2 concentration as categorized variables (RR = 2.14, 2.89, and 2.89 respectively, P all <0.001). Moreover, higher baseline sST2 concentration as continuous variables predict the increased risk of all-cause mortality (RR: 2.20, P<0.001), HF events (RR: 1.39, P<0.001), and MACEs (RR: 1.53, P=0.02) during subsequent follow-up. Meta-analysis with sST2 concentration as categorized variables retrieved similar results (RR = 2.65, 2.59, and 1.81 respectively, P all <0.001).Conclusions: Higher circulating sST2 concentration at baseline predicts poor clinical outcome in ACS patients.