In this paper, we investigate the content deployment problem from precaching and device-to-device communication perspectives. In the precaching stage, contents are prefetched and stored in edge nodes ...to be quickly provided to end users. In the device-to-device communication process, intermediate nodes face a dilemma in deciding whether to cache contents coming from or going to neighboring nodes to accelerate the content delivery. We call the former proactive caching and the latter reactive caching. We then design ProRec, a unified caching framework, by jointly considering the two cases with the goal of maximizing the content hit ratio. ProRec first addresses the optimization problem using the method of Lagrangian multipliers and obtains a general solution to the optimal content copies. Second, a greedy solution, proven to achieve the optimum with a probability of at least
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, is used to cache and replace contents. Finally, an edge computing simulation platform that includes real and synthetic traces is built as a case study to verify the effectiveness of ProRec. The numerical results show that it simultaneously improves the cache hit ratio and content delivery delay.
Capacity is a fundamental metric for mobile edge computing scenarios, where the system state plays an important role. Previous studies have mostly been based on the premise that the system state is ...stable. In reality, the network is dynamic and the system state changes with time. In this paper, we study the capacity of a mobile edge system in which users continuously join or leave the coverage of base station. We first change the problem of maximum network capacity into a minimum transmission distance problem. We observe that both the probability of the files being requested and the distance of the files transmission are related to the degree of files, i.e., the number of users who are interested in a file and request it with a certain probability. Then, we evaluate the degree of files in a time-varying situation, and calculate the probability of the files being requested and the transmission distance according to the degree of files. Finally, we calculate the capacity of the network under time-varying conditions. In the experimental section, we analyze the degree of files, the optimal copies number, and the change in network capacity over time. In addition, we compare the capacity in our system with classic studies. The experimental results verify the superiority of the proposed method.
Myelin sheaths surrounding axons are critical for electrical signal transmission in the central nervous system (CNS). Diseases with myelin defects such as multiple sclerosis (MS) are devastating ...neurological conditions for which few effective treatments are available. Dysfunction of the dopaminergic system has been observed in multiple neurological disorders. Its role in myelin pathogenesis, however, is unclear.
This work used a combination of literature curation, bioinformatics, pharmacological and genetic manipulation, as well as confocal imaging techniques. Literature search was used to establish a complete set of genes which is associated with MS in humans. Bioinformatics analyses include pathway enrichment and crosstalk analyses with human genetic association studies as well as gene set enrichment and causal relationship analyses with transcriptome data. Pharmacological and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) genetic manipulation were applied to inhibit the dopaminergic signaling in zebrafish. Imaging techniques were used to visualize myelin formation in vivo.
Systematic analysis of human genetic association studies revealed that the dopaminergic synapse signaling pathway is enriched in candidate gene sets. Transcriptome analysis confirmed that expression of multiple dopaminergic gene sets was significantly altered in patients with MS. Pathway crosstalk analysis and gene set causal relationship analysis reveal that the dopaminergic synapse signaling pathway interacts with or is associated with other critical pathways involved in MS. We also found that disruption of the dopaminergic system leads to myelin deficiency in zebrafish.
Dopaminergic signaling may be involved in myelin pathogenesis. This study may offer a novel molecular mechanism of demyelination in the nervous system.
Pancreatic ductal adenocarcinoma (PDAC) is one of refractory malignancies without efficient therapeutics. Babao Dan (BBD) was partially effective to suppress tumor growth of PDAC in clinical ...practice. However, the molecular mechanisms were unclear.
We established PDAC mice models and treated them with BBD through intragastric administration. Treatment and control groups were then subjected to high-throughput RNA sequencing. We presented the transcriptional changes upon BBD treatment by using computational analysis comparing BBD treatment and control groups. Functional enrichment analysis was employed to investigate the biological processes or pathways that BBD modulates.
BBD treatment showed strong suppression on tumor growth of PDAC, even stronger than Gemcitabine. Through differential analysis comparing BBD treatment and control groups, we identified 638 up-regulated and 259 down-regulated genes in the BBD treatment group. BBD was found to activate tumor suppressor genes, such as MTUS1, PDGFB, SOD3, and UCHL1. Furthermore, we revealed that BBD treatment inhibited cancer-related pathways and elevated activities of metabolism-related processes. The BBD-modulated metabolic genes were further showed to be associated with patient survival in an independent cohort with pancreatic cancer.
BBD repressed the tumor growth of PDAC. BBD treatment modulated expression of cancer-related genes in PDAC. BBD suppressed cancer-related pathways and activated metabolic processes in PDAC. Our study suggests BBD treatment as potential effective therapeutics for patients with pancreatic cancer.
After spinal cord injury (SCI), the irreversible loss of neurons and the dense glial scar are two of the leading causes of axon regeneration failure. The adult mammalian spinal cord lacks the ability ...to spontaneously produce new neurons, making it a key challenge to provide new neurons for spinal cord regeneration. Additionally, the dual role of the glial scar (both inhibitory and protective) makes it difficult to manipulate it for therapeutic purposes. In this study, using a single transcription factor Sry‐related HMG‐box 2 (Sox2) delivered by adeno‐associated virus (AAV), we reprogrammed some of the astrocytes targeted by the viral vectors in the glial scar into neurons in a severe SCI model. We show that this astrocytic reprogramming alone can propel axon regeneration by not only replenishing the lost neurons, but also moderately reducing the density of the glial scar without interrupting its integrity. Beyond that, astrocytic reprogramming can significantly improve functional recovery when combined with running wheel rehabilitation, which provides use‐dependent plasticity. These findings may provide us with a new idea for how to manipulate the glial scar and a promising therapeutic strategy that combines biological intervention with a rehabilitation strategy.
Neuroinflammation is critically involved in nerve injury-induced neuropathic pain, characterized by local and systemic increased levels of proinflammatory cytokines. Interleukin-24 (IL-24), a key ...member of the IL-10 family, has been extensively studied for its therapeutic potential in various diseases, including cancer, autoimmune disorders, and bacterial infections, but whether it is involved in the regulation of neuropathic pain caused by peripheral nerve injury (PNI) has not been well established. In this study, we reported that spared nerve injury (SNI) induced a significant upregulation of IL-24 in fibroblasts, neurons, and oligodendrocyte precursor cells (OPCs, also called NG2-glia) in the affected spinal dorsal horns (SDHs), as well as dorsal root ganglions (DRGs). We also found that tumor necrosis factor α (TNF-α) induced the transcriptional expression of IL-24 in cultured fibroblasts, neurons, and NG2-glia; in addition, astrocytes, microglia, and NG2-glia treated with TNF-α exhibited a prominent increase in interleukin-20 receptor 2 (IL-20R2) expression. Furthermore, we evaluated the ability of IL-24 and IL-20R2 to attenuate pain in preclinical models of neuropathic pain. Intrathecal (i.t.) injection of IL-24 neutralizing antibody or IL-20R2 neutralizing antibody could effectively alleviate mechanical allodynia and thermal hyperalgesia after PNI. Similarly, intrathecal injection of IL-24 siRNA or IL-20R2 siRNA also alleviated mechanical allodynia after SNI. The inhibition of IL-24 reduced SNI-induced proinflammatory cytokine (IL-1β and TNF-α) production and increased anti-inflammatory cytokine (IL-10) production. Meanwhile, the inhibition of IL-20R2 also decreased IL-1β mRNA expression after SNI. Collectively, our findings revealed that IL-24/IL-20R might contribute to neuropathic pain through inflammatory response. Therefore, targeting IL-24 could be a promising strategy for treating neuropathic pain induced by PNI.
Recent evidence has highlighted that long noncoding RNAs (lncRNA) are associated with many diseases, particularly cancer. However, current understanding of the lncRNA deleted in lymphocytic leukemia ...1 (DLEU1) in pancreatic ductal adenocarcinoma (PDAC) remains limited. Our studies indicated that the DLEU1 expression level was upregulated in PDAC tissue samples compared with adjacent normal tissue. Moreover, the aberrant overexpression of DLEU1 indicated poor prognosis of patients with PDAC. Loss‐of‐function experiments revealed that DLEU1 knockdown inhibited the proliferation, migration, and invasion of PDAC cells in vitro and decreased tumor growth in vivo. Bioinformatics analysis predicted that miR‐381 potentially targeted the DLEU1 3′‐untranslated region (UTR), suggesting an interaction between miR‐381 and DLEU1. Furthermore, miR‐381 also targeted the chemokine receptor‐4 (CXCR4) messenger RNA 3′‐UTR, which was validated by luciferase reporter assay. Taken together, our study demonstrated the oncogenic role of DLEU1 in clinical PDAC specimens and cellular experiments, showing the potential involvement of DLEU1/miR‐381/CXCR4 pathway. These results provide novel insight into PDAC tumorigenesis.
Long noncoding RNAs (lncRNA)‐DLEU1 was significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) tissues and cells and negatively associated with miR‐381 expression. Furthermore, DLEU1 knockdown inhibited PDAC cell growth, metastasis, and invasion by acting as a molecular sponge of miR‐381, illustrating the oncogenic role of DLEU1 in PDAC and its underlying mechanism.
•Dysfunction of dopaminergic signaling may lead to a series of developmental disorders.•DA regulates physiological functions by projecting to a wide range of brain regions.•DA influences the ...pathogenesis of several diseases related to brain development.
Dopamine (DA), a critical neurotransmitter of both the central and peripheral nerve system, plays important roles in a series of biological processes. Dysfunction of dopaminergic signalling may lead to a series of developmental disorders, including attention deficit/hyperactivity disorder, autism and schizophrenia. However, the exact roles of dopaminergic signalling in these diseases are far from fully understood. We analyse the roles of dopaminergic signalling in multiple physiological and pathological processes, focusing on brain development and related disorders. By summarizing current research in this area, we provide guidance for future studies. This review seeks to deepen our understanding of dopaminergic signalling in developmental disorders, which may offer clues for developing more effective therapeutic drugs.
System capacity is an important metric for evaluating the performance of edge-caching networks. In most previous studies, the caching content was assumed to remain unchanged in a base station. Hence, ...the requested probability for each content was treated as stable; In fact, both the number of content and users can change overtime, which impacts the system performance. This article firstly constructs a new user-content evolution model to infer such performance changes, and analyzes the number of links between users and content (i.e., degree). Then, the requested probability of the content and the optimal copy number are calculated by using the content degree. Next, the minimum average transmission distance of the content and system capacity under the cache scheme are given. Finally, a user-content time-varying system is simulated. The results show that the proposed model can characterize the evolution relationship between users and content and achieve better performance in terms of system capacity.
Content offloading in mobile edge computing is one of the effective ways to alleviate network congestion. This paper studies the content offloading problem in buffer-constraint edge scenarios. First, ...the content offloading problem is transformed into the maximum delivery rate and minimum transmission delay problem integrating the heterogeneous contact rate between users and small base stations. Second, a Lagrangian multiplier method is employed to compute the optimal numbers of offloading copy for each file, and then a greedy algorithm which can achieve the optimality with a probability 1 - 1/e is proposed, followed by a distributed algorithm with the same performance as the greedy one. Finally, the proposed schemes are compared with the classical algorithms, and the simulation results show that they enhance the content delivery rate and reduce the transmission delay in different popularity distributions and buffer sizes.
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