A Dual-Porosity-Stokes Model and Finite Element Method for Coupling Dual-Porosity Flow and Free Flow

In this paper, we propose and numerically solve a new model considering confined flow in dual-porosity media coupled with free flow in embedded macrofractures and conduits. Such situation arises, for example, for fluid flows in hydraulic fractured tight/shale oil/gas reservoirs. The flow in dual-porosity media, which consists of both matrix and microfractures, is described by a dual-porosity model. And the flow in the macrofractures and conduits is governed by the Stokes equation. Then the two models are coupled through four physically valid interface conditions on the interface between dual-porosity media and macrofractures/conduits, which play a key role in a physically faithful simulation with high accuracy. All the four interface conditions are constructed based on fundamental properties of the traditional dual-porosity model and the well-known Stokes-Darcy model. The weak formulation is derived for the proposed model, and the well-posedness of the model is analyzed. A finite element semidiscretization in space is presented based on the weak formulation, and four different schemes are then utilized for the full discretization. The convergence of the full discretization with the backward Euler scheme is analyzed. Four numerical experiments are presented to validate the proposed model and demonstrate the features of both the model and the numerical method, such as the optimal convergence rate of the numerical solution, the detail flow characteristics around macrofractures and conduits, and the applicability to the real world problems

SIRT1-mediated downregulation of p27(Kip1) is essential for overcoming contact inhibition of Kaposi's sarcoma-associated herpesvirus transformed cells

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), a malignancy commonly found in AIDS patients. Despite intensive studies in the last two decades, the mechanism of KSHV-induced cellular transformation and tumorigenesis remains unclear. In this study, we found that the expression of SIRT1, a metabolic sensor, was upregulated in a variety of KSHV-infected cells. In a model of KSHV-induced cellular transformation, SIRT1 knockdown with shRNAs or knockout by CRISPR/Cas9 gene editing dramatically suppressed cell proliferation and colony formation in soft agar of KSHV-transformed cells by inducing cell cycle arrest and contact inhibition. SIRT1 knockdown or knockout induced the expression of cyclin-dependent kinase inhibitor 1B (p27(Kip1)). Consequently, p27 knockdown rescued the inhibitory effect of SIRT1 knockdown or knockout on cell proliferation and colony formation. Furthermore, treatment of KSHV-transformed cells with a SIRT1 inhibitor, nicotinamide (NAM), had the same effect as SIRT1 knockdown and knockout. NAM significantly inhibited cell proliferation in culture and colony formation in soft agar, and induced cell cycle arrest. Significantly, NAM inhibited the progression of tumors and extended the survival of mice in a KSHV-induced tumor model. Collectively, these results demonstrate that SIRT1 suppression of p27 is required for KSHV-induced tumorigenesis and identify a potential therapeutic target for KS.

The Ubiquitin/Proteasome System Mediates Entry and Endosomal Trafficking of Kaposi's Sarcoma-Associated Herpesvirus in Endothelial Cells

Ubiquitination, a post-translational modification, mediates diverse cellular functions including endocytic transport of molecules. Kaposi's sarcoma-associated herpesvirus (KSHV), an enveloped herpesvirus, enters endothelial cells primarily through clathrin-mediated endocytosis. Whether ubiquitination and proteasome activity regulates KSHV entry and endocytosis remains unknown. We showed that inhibition of proteasome activity reduced KSHV entry into endothelial cells and intracellular trafficking to nuclei, thus preventing KSHV infection of the cells. Three-dimensional (3-D) analyses revealed accumulation of KSHV particles in a cytoplasmic compartment identified as EEA1+ endosomal vesicles upon proteasome inhibition. KSHV particles are colocalized with ubiquitin-binding proteins epsin and eps15. Furthermore, ubiquitination mediates internalization of both KSHV and one of its receptors integrin β1. KSHV particles are colocalized with activated forms of the E3 ligase c-Cbl. Knock-down of c-Cbl or inhibition of its phosphorylation reduced viral entry and intracellular trafficking, resulting in decreased KSHV infectivity. These results demonstrate that ubiquitination mediates internalization of both KSHV and one of its cognate receptors integrin β1, and identify c-Cbl as a potential E3 ligase that facilitates this process

A global agenda for advancing freshwater biodiversity research

Global freshwater biodiversity is declining dramatically, and meeting the challenges of this crisis requires bold goals and the mobilisation of substantial resources. While the reasons are varied, investments in both research and conservation of freshwater biodiversity lag far behind those in the terrestrial and marine realms. Inspired by a global consultation, we identify 15 pressing priority needs, grouped into five research areas, in an effort to support informed stewardship of freshwater biodiversity. The proposed agenda aims to advance freshwater biodiversity research globally as a critical step in improving coordinated actions towards its sustainable management and conservation.Peer reviewe

Improving the Management of COPD in Women

COPD is a highly debilitating disease that represents a substantial and growing health burden in women. There is increasing evidence for sex-related differences in COPD risk, progression, and outcomes. However, the disease receives scant attention as a women's health issue. Thus, a multifaceted approach is required to address COPD in women, including greater awareness, minimization of risk, and further elucidation of the sex-specific factors (biological and cultural) that affect risk, disease progression, and treatment success. This article reviews the current literature on the topic and provides suggestions for achieving better outcomes for the millions of women with COPD worldwide

Credit Constraint, Credit Adjustment, and Sustainable Growth of Farmers’ Income

Research on financial theory and practice has shown that the development of transition economies generally faces two major challenges. First, the less developed regions face more severe financial repression, which leads to imbalanced and unsustainable development of regional economies. Second, farmers face different credit constraints because of their productivity differences, which can further polarize the internal inequality of their income. Based on cross-sectional data of 2037 counties in 30 provinces of China in 2010, this paper employs quantile regression to investigate the relationships among credit constraints, credit adjustment, and the sustainable growth of farmers’ income. Our results confirm that rural residents generally face credit constraints, and there are significant stratified differences in the impact of farmer credit on farmers’ income. Farmers with higher income are more likely to obtain bank credit and continue to grow their income, while farmers with lower income are more likely to fall into the “vicious circle of poverty„ because of their lack of capital accumulation. Therefore, to promote more fair and sustainable growth of farmers’ income, it is important to increase the credit available to farmers. Furthermore, it is critical to promote healthy competition among county financial institutions and accelerate the establishment of inclusive financial systems. This can ultimately help ensure sustainable development of agriculture and rural economy

Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects

Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects

Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene

Background: The increasing emergence of clinical infections caused by methicillin-resistant Staphylococcus aureus (MRSA) challenges existing therapeutic options and highlights the need to develop novel treatment strategies. The ftsZ gene is essential to bacterial cell division. Methods: In this study, two antisense peptide nucleic acids (PNAs) conjugated to a cell-penetrating peptide were used to inhibit the growth of MRSA. PPNA1, identified with computational prediction and dot-blot hybridization, is complementary to nucleotides 309–323 of the ftsZ mRNA. PPNA2 was designed to target the region that includes the translation initiation site and the ribosomal-binding site (Shine–Dalgarno sequence) of the ftsZ gene. Scrambled PPNA was constructed with mismatches to three bases within the antisense PPNA1 sequence. Results: PPNA1 and PPNA2 caused concentration-dependent growth inhibition and had bactericidal effects. The minimal bactericidal concentrations of antisense PPNA1 and PPNA2 were 30 μmol/l and 40 μmol/l, respectively. The scrambled PPNA had no effect on bacterial growth, even at higher concentrations, confirming the sequence specificity of the probes. RT-PCR showed that the antisense PPNAs suppressed ftsZ mRNA expression in a dose-dependent manner. Conclusion: Our results demonstrate that the potent effects of PNAs on bacterial growth and cell viability were mediated by the down-regulation or even knock-out of ftsZ gene expression. This highlights the utility of ftsZ as a promising target for the development of new antisense antibacterial agents to treat MRSA infections