Video streaming has become a major usage scenario for the Internet. The growing popularity of new applications, such as 4K and 360-degree videos, mandates that network resources must be carefully ...apportioned among different users in order to achieve the optimal Quality of Experience (QoE) and fairness objectives. This results in a challenging online optimization problem, as networks grow increasingly complex and the relevant QoE objectives are often nonlinear functions. Recently, data-driven approaches, deep Reinforcement Learning (RL) in particular, have been successfully applied to network optimization problems by modeling them as Markov decision processes. However, existing RL algorithms involving multiple agents fail to address nonlinear objective functions on different agents’ rewards. To this end, we leverage MAPG-finite, a policy gradient algorithm designed for multi-agent learning problems with nonlinear objectives. It allows us to optimize bandwidth distributions among multiple agents and to maximize QoE and fairness objectives on video streaming rewards. Implementing the proposed algorithm, we compare the MAPG-finite strategy with a number of baselines, including static, adaptive, and single-agent learning policies. The numerical results show that MAPG-finite significantly outperforms the baseline strategies with respect to different objective functions and in various settings, including both constant and adaptive bitrate videos. Specifically, our MAPG-finite algorithm maximizes QoE by 15.27% and maximizes fairness by 22.47% compared to the standard SARSA algorithm for a 2000 KB/s link.
In Parkinson's disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with inflammation. Nucleotide-binding ...oligomerization domain-containing protein (NOD)2, one of the first discovered NOD-like receptors, plays an important role in inflammation. However, the role of NOD2 has not been elucidated in PD.
NOD2 mRNA and protein expression in the SN and the striatum of C57BL/6 mice treated with 6-hydroxydopamine (6-OHDA) was measured. We next investigated the potential contribution of the NOD2-dependent pathway to 6-OHDA-induced DA degeneration using NOD2-deficient (NOD2
) mice. Assays examining DA degeneration and inflammation include HPLC, Western blot, immunohistochemistry, TUNEL staining, and cytometric bead array. To further explore a possible link between NADPH oxidase 2 (NOX2) and NOD2 signaling in PD, microglia were transfected with shRNA specific to NOX2 in vitro and apocynin were given to mice subjected to 6-OHDA and muramyl dipeptide (MDP) striatal injection.
The expression of NOD2 was upregulated in an experimental PD model induced by the neurotoxin 6-OHDA. NOD2 deficiency resulted in a protective effect against 6-OHDA-induced DA degeneration and neuronal death, which was associated with the attenuated inflammatory response. Moreover, silencing of NOX2 in microglia suppressed the expression of NOD2 and the inflammatory response induced by 6-OHDA and attenuated the toxicity of conditioned medium from 6-OHDA or MDP-stimulated microglia to neuronal cells. Furthermore, apocynin treatment inhibited NOD2 upregulation and DA degeneration in the SN of WT mice induced by 6-OHDA and MDP.
This study provides the direct evidence that NOD2 is related to 6-OHDA-induced DA degeneration through NOX2-mediated oxidative stress, indicating NOD2 is a novel innate immune signaling molecule participating in PD inflammatory response.
In this study, the influence of two distinct reactive aggregate dosages on the alkali–silica reaction (ASR) of concrete was investigated. The expansion ratio, axial compressive strength, splitting ...tensile strength, and relative dynamic elastic modulus (RDEM) of concrete were considered as the main parameters to study the failure criteria of concrete induced by ASR at 40°C. Microscopic experiments, such as scanning electron microscopy and X-ray computed microtomography, were applied to analyze the damage induced by ASR on the concrete prisms and the propagation of internal cracks of the reactive aggregates in nanospace. The results showed that the two ranges can be used as the failure criteria produced by the ASR of concrete containing 3 and 6% dosages of reactive aggregates at 40°C, respectively, when the RDEM of concrete was reduced to 70‒75% and 85‒90%. Additionally, the results of CT indicated that microcracks tended to extend from the initial defects of aggregate to the cement slurry. Meanwhile, ASR gel packed with the pores, which reduced the porosity. It was noteworthy that the adhesive force between the ASR gel and the cement matrix after filling pores could not make up for the loss of the mechanical properties of concrete.
Cancer poses a serious threat to human health, and the search for safe and effective drugs for its treatment has aroused interest and become a long-term goal. Traditional Chinese herbal medicine ...(TCM), an ancient science with unique anti-cancer advantages, has achieved outstanding results in long-term clinical practice. Accumulating evidence shows that saponins are key bioactive components in TCM and have great research and development applications for their significant role in the treatment of cancer. Saponins are a class of glycosides comprising nonpolar triterpenes or sterols attached to hydrophilic oligosaccharide groups that exert antitumor effects by targeting the NF-κB, PI3Ks-Akt-mTOR, MAPK, Wnt-β-catenin, JAK-STAT3, APMK, p53, and EGFR signaling pathways. Presently, few advances have been made in physiological and pathological studies on the effect of saponins on signal transduction pathways involved in cancer treatment. This paper reviews the phytochemistry and extraction methods of saponins of TCM and their effects on signal transduction pathways in cancer. It aims to provide theoretical support for in-depth studies on the anticancer effects of saponins.
Background:
The COVID-19 pandemic has currently developed into a worldwide threat to humankind. Importantly, patients with severe COVID-19 are believed to have a higher mortality risk than those with ...mild conditions. However, despite the urgent need to develop novel therapeutic strategies, the biological features and pathogenic mechanisms of severe COVID-19 are poorly understood.
Methods:
Here, peripheral blood mononuclear cells (PBMCs) from four patients with severe COVID-19, four patients with mild COVID-19, and four healthy controls were examined by RNA sequencing (RNA-Seq). We conducted gene expression analysis and Venn diagrams to detect specific differentially expressed genes (DEGs) in patients with severe disease compared with those with mild conditions. Gene Ontology (GO) enrichment analysis was performed to identify the significant biological processes, and protein–protein interaction networks were constructed to extract hub genes. These hub genes were then subjected to regulatory signatures and protein–chemical interaction analysis for certain regulatory checkpoints and identification of potent chemical agents. Finally, to demonstrate the cell type-specific expression of these genes, we performed single-cell RNA-Seq analyses using an online platform.
Results:
A total of 144 DEGs were specifically expressed in severe COVID-19, and GO enrichment analysis revealed a significant association of these specific DEGs with autophagy. Hub genes such as
MVB12A
,
CHMP6
,
STAM
, and
VPS37B
were then found to be most significantly involved in the biological processes of autophagy at the transcriptome level. In addition, six transcription factors, including SRF, YY1, CREB1, PPARG, NFIC, and GATA2, as well as miRNAs, namely, hsa-mir-1-3p, and potent chemical agents such as copper sulfate and cobalt chloride, may cooperate in regulating the autophagy hub genes. Furthermore, classical monocytes may play a central role in severe COVID-19.
Conclusion:
We suggest that autophagy plays a crucial role in severe COVID-19. This study might facilitate a more profound knowledge of the biological characteristics and progression of COVID-19 and the development of novel therapeutic approaches to achieve a breakthrough in the current COVID-19 pandemic.
Accurate and reliable prediction of groundwater depth is a critical component in water resources management. In this paper, a new method based on coupling wavelet decomposition method (WA), ...autoregressive moving average (ARMA) model, and BP neural network (BP) model for groundwater depth forecasting applications was proposed. The relative performance of the proposed coupled model (WA-ARMA-BP) was compared to the regular autoregressive integrated moving average (ARIMA) and BP models for annual average groundwater depth forecasting using leave-one-out cross-validation (LOO-CV). The variables used to develop and validate the models were average groundwater depth data recorded from 1981 to 2010 in Jinghui Canal Irrigation District in the northwest of China. It was found that the WA-ARMA-BP model provided more accurate annual average groundwater depth forecasts compared to the ARIMA and BP models. The results of the study indicate the potential of the WA-ARMA-BP model in forecasting nonstationary time series such as groundwater depth.
Over the past several decades, RNA modifications have rapidly emerged as an indispensable topic in epitranscriptomics. N6-methyladenosine (m6A), namely, methylation at the sixth position of an ...adenine base in an RNA molecule, is the most prevalent RNA modification in both coding and noncoding RNAs. m6A has emerged as a crucial posttranscriptional regulator involved in both physiological and pathological processes. Based on accumulating evidence, m6A participates in the pathogenesis of immune-related diseases by regulating both innate and adaptive immune cells through various mechanisms. Autoimmune diseases are caused by a self-destructive immune response in the setting of genetic and environmental factors, and recent studies have discovered that m6A may play an essential role in the development of autoimmune diseases. In this review, we focus on the important role of m6A modification in biological functions and highlight its contributions to immune cells and the development of autoimmune diseases, thereby providing promising epitranscriptomic targets for preventing and treating autoimmune disorders.
•PAK1 was overexpressed in PBMCs and skin lesions from patients with CTCL.•Knockdown of PAK1 inhibited cell proliferation and promoted spontaneous apoptosis.•The PAK1 inhibitor decreased the ...proliferation of CTCL cells.•PAK1 suppression directly upregulated PUMA and p21 expression in human CTCL cells.
Cutaneous T cell lymphoma (CTCL) comprises a heterogeneous group of skin-homing T cell tumors. The small guanosine triphosphate effector p21-activated kinase 1 (PAK1) plays an important role in many fundamental cellular functions, including cell motility, proliferation, and apoptosis. The expression of PAK1 is up-regulated in several types of human cancers. However, little is known about the role of PAK1 in the pathogenesis of CTCL.
The aim of this study was to evaluate the expression pattern and underlying mechanism of PAK1 in CTCL.
Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect PAK1 mRNA expression in the peripheral blood mononuclear cells (PBMCs) of patients with CTCL. The expression of PAK1 protein in CTCL tumor tissues was determined by immunohistochemistry. CTCL cell lines were treated with a small molecule inhibitor of PAK1, p21-activated kinase inhibitor III (IPA3), at concentrations of 2, 3.5 and 5 μM for 24 h. Hut 78 and HH CTCL cells were transfected with lentiviral-based PAK1 gene knockdown vectors. We determined the effects of PAK1 knockdown on cell proliferation and apoptosis in CTCL cells by MTS assay and flow cytometry. Animal experiments were performed to investigate the effects of PAK1 knockdown on the growth of tumors in vivo. Transcriptomic sequencing was performed to detect the direct downstream targets of PAK1 silencing. Reverse transcription polymerase chain reaction and western blot analysis were applied to verify the results of the transcriptomic analysis.
We detected PAK1 overexpression in PBMCs and skin lesions from patients with CTCL compared with benign inflammatory dermatoses (BID). Knockdown of PAK1 inhibited cell proliferation and promoted spontaneous apoptosis. In addition, the inhibitory effect of IPA3 was validated in the CTCL cell lines. Additionally, mice injected with PAK1-silenced cells presented with a decreased rate of tumor growth compared with the control groups. Moreover, the mRNA and protein expression of PUMA (BBC3) and p21 (CDKN1A) were increased in PAK1-silenced Hut 78 and HH cells.
Our data indicated that PAK1 is upregulated in CTCL. PAK1 silencing induced apoptosis and inhibited cell growth by stimulating the expression of PUMA and p21. Thus, PAK1 may be a potential tumor marker and therapeutic target of CTCL.
While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an ...immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.
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•Cocktail of filovirus GPs elicited ebolavirus bNAb•The ebolavirus internal fusion loop is a conserved site of vulnerability•Proteolytically remodeled GP recognizes bNAb germline precursors with high affinity•Combination of two bNAbs confers full protection against all pathogenic ebolaviruses
Characterization of an immunization-induced broadly neutralizing antibody in macaques against ebolaviruses highlights the fusion loop region of the viral glycoprotein as a promising vaccine target.
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