Search

Mobile live video streaming is expected to become mainstream in the fifth generation (5G) mobile networks. To boost the Quality of Experience (QoE) of streaming services, the integration of Scalable Video Coding (SVC) with Mobile Edge Computing (MEC) becomes a natural candidate due to its scalability and the reliable transmission supports for real-time interactions. However, it still takes efforts to integrate MEC into video streaming services to exploit its full potentials. We find that the efficiency of the MEC-enabled cellular system can be significantly improved when the requests of users can be redirected to proper MEC servers through optimal user associations. In light of this observation, we jointly address the caching placement, video quality decision and user association problem in the live video streaming service. Since the proposed nonlinear integer optimization problem is NP-hard, we firstly develop a two-step approach from a Lagrangian optimization under the dual pricing specification. Further, to have a computation-efficient solution and less performance loss, we provide a one-step Lagrangian dual pricing algorithm by the convex transformation of non-convex constraints. The simulations show that the service quality of live video streaming can be remarkably enhanced by the proposed algorithms in the MEC-enabled cellular system.

Tripartite motif (TRIM) proteins comprise a large family of RING-type ubiquitin E3 ligases that regulate important biological processes. In this study, full-length MnTRIM32 cDNA was obtained from oriental river prawn Macrobrachium nipponense, and eight MnTRIM32 isoforms generated by alternative splicing were identified. The open reading frames of the eight MnTRIM32 isoforms were predicted to be separately composed of 402, 346, 347, 346, 414, 358, 359, and 358 amino acid residues. Protein structural analysis revealed that all MnTRIM32 isoforms contained a RING domain and a coiled coil region. MnTRIM32 was ubiquitously expressed in all tissues tested, with the highest expression in the hepatopancreas. The mRNA levels of MnTRIM32 in the gills, stomach, and intestine of prawns were found to undergo time-dependent enhancement following white spot syndrome virus (WSSV) stimulation. Double-stranded RNA interference studies revealed that MnTRIM32 silencing significantly downregulated the expression levels of interferon (IFN) regulatory factor MnIRF, IFN-like factor MnVago4, and tumor necrosis factor MnTNF. Furthermore, knockdown of MnTRIM32 in WSSV-challenged prawns increased the expression of VP28 and the number of WSSV copies, suggesting that MnTRIM32 plays a positive role in limiting WSSV infection. These findings provided strong evidence for the important role of MnTRIM32 in the antiviral innate immunity of M. nipponense.

In Taiwan, there were only 799 confirmed COVID-19 cases in 2020. The unique backdrop amidst a pandemic and promotion of nonpharmaceutical interventions generated some distinct changes in the epidemiology of common respiratory pathogens. In this study, we aimed to investigate the dynamic changes in respiratory pathogens in children during 2020.We performed a retrospective cohort study at a tertiary hospital in southern Taiwan during 2020. Patients aged 0-18 years who visited the pediatric emergency department were enrolled. Children who presented with clinical symptoms (fever or respiratory illness) and received nasopharyngeal swabs for multiplex polymerase chain reaction (PCR) were included in our analysis. We also compared respiratory syncytial virus (RSV) trends from previous years by PCR and lateral flow immunochromatographic assays from 2017 to 2020.A total of 120 children were tested. The overall detection rate was 55%. With strengthened restrictions, the detection rate dropped from 70% to 30%. However, non-enveloped viruses (rhinovirus/enterovirus and adenovirus) were in constant circulation. Upon easing prevention measures, the detection rate remained above 60%, and an outbreak of an enveloped virus (RSV and parainfluenza virus) was noted. Compared with 2017-2019, the cyclical RSV epidemic was delayed, with a large surge in late 2020.We observed a constant circulation of non-enveloped viruses when strict nonpharmaceutical interventions were employed and a delayed surge of enveloped viruses during the easing of restrictions. Continuous surveillance and monitoring of the evolutionary dynamics of respiratory viruses is important, while easing restrictions requires balanced judgment.

LaFexNi1−xO3 perovskite oxides were prepared by the sol–gel method under various conditions, including different pH values (pH 0 and pH 7) and different calcination temperatures (500–800 °C) as well as different Fe/Ni ratios (1/9, 3/7, 5/5, 7/3, 9/1). The samples were examined by XRD, DRS, BET, and SEM to reveal their crystallinity, light-absorption ability, specific surface area, and surface features, respectively. The photocatalytic Fenton reaction was conducted using various LaFexNi1−xO3 perovskite oxides to decompose the methylene blue molecules. Accordingly, the synthesis condition of pH 0, calcination temperature at 700 °C, and Fe/Ni ratio = 7/3 could form LaFe0.7Ni0.3O3 perovskite oxides as highly efficient photocatalysts. Moreover, various conditions during the photocatalytic degradation were verified, such as pH value, catalyst dosage, and the additional amount of H2O2. LaFe0.7Ni0.3O3 perovskite oxides could operate efficiently under pH 3.5, catalyst dosage of 50 mg/150 mL, and H2O2 concentration of 133 ppm to decompose the MB dye in the 1st order kinetic rate constant of 0.0506 s−1.

Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

Mobile Edge Computing (MEC) is a promising technique in the 5G Era to improve the Quality of Experience (QoE) for online video streaming due to its ability to reduce the backhaul transmission by caching certain content. However, it still takes effort to address the user association and video quality selection problem under the limited resource of MEC to fully support the low-latency demand for live video streaming. We found the optimization problem to be a non-linear integer programming, which is impossible to obtain a globally optimal solution under polynomial time. In this paper, we formulate the problem and derive the closed-form solution in the form of Lagrangian multipliers; the searching of the optimal variables is formulated as a Multi-Arm Bandit (MAB) and we propose a Deep Deterministic Policy Gradient (DDPG) based algorithm exploiting the supply-demand interpretation of the Lagrange dual problem. Simulation results show that our proposed approach achieves significant QoE improvement, especially in the low wireless resource and high user number scenario compared to other baselines.

In general, manual methods are often used to inspect defects in the production of metal screws. As deep learning shines in the field of visual detection, this study employs the You Only Look At CoefficienTs (YOLACT) algorithm to detect the surface defects of the metal screw heads. The raw images with different defects are collected by an automated microscopic camera scanning system to build the training and validation datasets. The experimental results demonstrate that the trained YOLACT is sufficient to achieve a mean average accuracy of 92.8 % with low missing and false rates. The processing speed of the trained YOLACT reaches 30 frames per second. Compared with other segmentation methods, the proposed model provides excellent performance in both segmentation and detection accuracy. Our efficient deep learning-based system may support the advancement of non-contact defect assessment methods for quality control of the screw manufacture.

Salvia miltiorrhiza Burge (Danshen), a member of the Lamiaceae family, has been used in traditional Chinese medicine for many centuries as a valuable medicinal herb with antioxidative, anti-inflammatory, and antifibrotic potential. Several evidence-based reports have suggested that Salvia miltiorrhiza and its components prevent vascular diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy, and cardiac fibrosis. Tanshinone IIA (TanIIA), a lipophilic component of Salvia miltiorrhiza, has gained attention because of its possible preventive and curative activity against cardiovascular disorders. TanIIA, which possesses antioxidative, anti-inflammatory, and antifibrotic properties, could be a key component in the therapeutic potential of Salvia miltiorrhiza. Vascular diseases are often initiated by endothelial dysfunction, which is accompanied by vascular inflammation and fibrosis. In this review, we summarize how TanIIA suppresses tissue inflammation and fibrosis through signaling pathways such as PI3K/Akt/mTOR/eNOS, TGF-β1/Smad2/3, NF-κB, JNK/SAPK (stress-activated protein kinase)/MAPK, and ERK/Nrf2 pathways. In brief, this review illustrates the therapeutic value of TanIIA in the alleviation of oxidative stress, inflammation, and fibrosis, which are critical components of cardiovascular disorders.

Orthotopic liver transplantation (OLT) is an established therapeutic option for pediatric end-stage liver disease (PELD). The postoperative respiratory conditions of OLT recipients may be associated with subsequent clinical outcomes including length of stay (LOS) in the pediatric intensive care unit (PICU). This study aimed to characterize the postoperative respiratory conditions, associated factors, and outcomes after pediatric OLT.Clinical data of children receiving OLT from July 2014 to July 2020 were retrospectively collected. Postoperative respiratory conditions were defined as time to extubation, significant pleural effusion, and initial postoperative PaO2/FiO2 ratio. Logistic and multiple regressions were applied to analyze the associations among clinical factors, postoperative respiratory conditions, and clinical outcomes.Twenty-two patients with median age of 1.4-year-old (range: 25 days to 12 years old) were analyzed. Mortality within 28 days was 4.5% and median LOS in the PICU was 18 days. Of 22 patients, 11 patients (50.0%) were extubated over 24 hours after surgery, and 8 patients (36.4%) required drainage for pleural effusions. Longer LOS in the PICU were noted in patients extubated over 24 hours (p = 0.008), complicated with significant pleural effusions (p = 0.02) after surgery, and having low initial postoperative PaO2/FiO2 (300 mmHg) (p = 0.001). Among clinical factors, massive intraoperative blood transfusion (40 mL/kg) was significantly associated with prolonged intubations, significant pleural effusions, low initial postoperative PaO2/FiO2, and prolonged LOS in the PICU (14 days). The initial postoperative PaO2/FiO2 significantly depended on age, disease severity (PELD score), and whether the patient received massive intraoperative blood transfusion.Pediatric patients of OLT with poor postoperative respiratory conditions including low initial PaO2/FiO2 ratio, extubation over 24 hours or significant pleural effusions have longer LOS in the PICU, and the requirement of massive intraoperative transfusion was a risk factor for both poor postoperative respiratory conditions and prolonged LOS in the PICU.

Supplementary Figure S1

Supplementary Information

Purpose:The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway.Experimental Design:The underlying intracellular mechanism that sustains the oncogenic network involved in neuroendocrine differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via IHC and other assays.Results:We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of LIF. Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers.Conclusions:Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46–LIF axis may therefore inhibit CRPC development and neuroendocrine differentiation after ADT.

Supplementary Figure S6

Supplementary Figure S5

Supplementary Figure S2

Supplementary Figure S3

Supplementary Figure S4

(A and B) TWIST1 (A) and miR-1 (B) expressions in patient samples at different clinical stages in the prostate cancer samples collected and analyzed at MSKCC. * vs. T2A. * p

(A) Endogenous levels of miR-1 in a panel of prostate cancer cell lines. * vs. RasB1. (B) Relative EGFR expression levels in various prostate cancer cell lines. * vs. LNCap. (C) Cellular migration and invasion of LNCap and 22Rv1 cells following EGF treatment for 6 hours and then fixation and staining with a 0.5% crystal violet fixative solution. (D) Representative histological images of bone metastases in mice from RasB1/miR-1 (miR-1/EV), and EGFR-rescued RasB1/miR-1 (miR-1/EGFR) cells. Bone metastases are indicated by arrows and red dotted lines.

(A and B) GSEA showed enrichment of two prostate cancer datasets, MSKCC (A) and TCGA (B), with EGFR signaling downregulation-responsive genes in cancers expressing high levels of miR-1. NES, normalized enrichment score; FDR, false discovery rate. (C and D) Mean expression of miR-1 for signatures separated on the basis of up- and downregulated EGFR signaling-responsive genes in the MSKCC (C) and TCGA (D) datasets.

(A) IF staining of RasB1 and PC3 cells with an antibody for EGFR following EGF and CI1033 treatment. Scale bars represent 50 µm. (B) IHC staining of FFPE cell blocks of RasB1 and PC3 cells with an antibody for p-EGFR (Y1068) following EGF and CI1033 treatment. (C) The intensity of total EGFR was normalized to the internal control, histone 3 or β-actin, from Western blots of nuclear and cytoplasmic cell extracts of RasB1 cells following EGF treatment. (D) The intensity of p-ERK1/2 was normalized to total ERK1/2 from Western blots of nuclear and cytoplasmic cell extracts of RasB1 cells following EGF treatment. (E) ChIP analyses of predicted ATRSs in the pri-miR-1-1 promoter region of 22Rv1 cells following EGF treatment. Enrichment of each protein at each site is given as a percentage of the total input and then normalized to each IgG. Data are presented as the mean {plus minus} SEM, n=3. * vs. -EGF. ** p

(A) Mean TWIST1 levels in human normal (n=28), primary (n=98), and metastatic (n=13) prostate samples collected and analyzed at MSKCC. * vs. normal tissue; # vs. primary cancer tissues. * p

Table S1. Positions of AT-rich minimal consensus sequences (ATRSs). Table S2. Primer sequences of the 3'UTR and promoter reporter constructs. Table S3. Primer sequences for the qRT-PCR. Table S4. Antibody information for Western blotting. Table S5. Antibody information and primer sequences of the ChIP assay.

The kidney epithelial barrier has multifaceted functions in body fluids, electrolyte homeostasis, and urine production. The renal epithelial barrier (REB) frequently faces and challenges osmotic dynamics, which gives rise to osmotic pressure (a physical force). Osmotic pressure overloading can crack epithelial integrity and damage the REB. The endurance of REB to osmotic pressure forces remains obscure. LMO7 (LIM domain only 7) is a protein associated with the cell–cell junctional complex and cortical F-actin. Its upregulation was observed in cells cultured under hypertonic conditions. LMO7 is predominantly distributed in renal tubule epithelial cells. Hypertonic stimulation leads to LMO7 and F-actin assembly in the cortical stress fibers of renal epithelial cells. Hypertonic-isotonic alternation, as a pressure force pushing the plasma membrane inward/outward, was set as osmotic disturbance and was applied to test FAK signaling and LMO7 functioning in maintaining junctional integrity. LMO7 depletion in cells resulted in junctional integrity loss in the epithelial sheet-cultured hypertonic medium or hypertonic-isotonic alternation. Conversely, FAK inhibition by PF-573228 led to failure in robust cortical F-actin assembly and LMO7 association with cortical F-actin in epithelial cells responding to hypertonic stress. Epithelial integrity against osmotic stress and LMO7 and FAK signaling are involved in assembling robust cortical F-actin and maintaining junctional integrity. LMO7 elaborately manages FAK activation in renal epithelial cells, which was demonstrated excessive FAK activation present in LMO7 depleted NRK-52E cells and epithelial integrity loss when cells with LMO7 depletion were exposed to a hypertonic environment. Our data suggests that LMO7 regulates FAK activation and is responsible for maintaining REB under osmotic disturbance.

Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.

Conventional treatment of prostate cancer (PCa) uses androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to AR-negative phenotype with neuroendocrine (NE) features on histology, which is associated with metabolic disturbances and poor prognosis. However, the association between the metabolic pathways that regulate mitochondrial function and promote NE differentiation (NED) in PCa remains unclear. Here, we show a regulatory mechanism in PCa pathogenesis whereby overexpression of pyruvate kinase L/R (PKLR) mediates mitochondrial disorder and oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED-related aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to mitochondrial dysfunction and NED in PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT-induced NED. Our findings link ADT resistance-driven metabolic reprogramming to NED of PCa through upregulation of PKLR/MYCN/ROMO1 signaling, and further explored the clinical significance of targeting the nuclear PKLR/MYCN complex and evaluated serum ROMO1 as a potential biomarker for aggressive NE-like PCa. Citation Format: Yen-Nien Liu, Wei-Yu Chen, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Zi-Qing Chen, Wan-Hsin Wang, Yu-Ching Wen. ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3062.

Androgen deprivation therapy (ADT)-induced neuroendocrine differentiation (NED) is a well-known lethal subtype of prostate cancer (PCa) with a median survival rate of less than one year. Despite the increasing research attention on this variant of PCa, the underlying mechanism orchestrating therapy-related neuroendocrine prostate cancer (NEPC) remains elusive. We found that ADT-induced hypoxia-associated ZBTB46/FOXA2/HIF1A signaling enhances the multiple C2 domain transmembrane protein 1 (MCTP1), which promotes NED and epithelial-to-mesenchymal transition (EMT) of PCa. Mechanistically, ZBTB46 physically interacts with the HIF1A/FOXA2 complex, in which ZBTB46 may be a co-activator of the hypoxia-related FOXA2 transcription factor. Interestingly, this ZBTB46/FOXA2/HIF1A complex accumulates after hypoxia and functions as a transcriptional activator of MCTP1. Hypoxia-upregulated MCTP1 subsequently leads to NED and the increase in EMT, whereas the opposite is true for the knockdown of MCTP1 in PCa cells. Consistent with previous results, MCTP1 is highly expressed in high-grade castration-resistance prostate cancer (CRPC) and small-cell PCa (SCPC) tissues and is associated with NE markers and ZBTB46/FOXA2/HIF1A abundance. In this study, we explored the direct interaction of ZBTB46 protein with hypoxia-related FOXA2/HIF1A complex in PCa cells under hypoxic conditions, which promote MCTP1-driven EMT and NED. Our finding suggests that MCTP1 could be used as a biomarker for diagnosing NEPC and as a therapeutic target in clinical applications. Citation Format: Vu Thuy Dung Phan, Yu-Ching Wen, Wei-Yu Chen, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Van Thi Ngoc Tram, Zi-Qing Chen, Wan-Hsin Wang, Yen-Nien Liu. ZBTB46/FOXA2/HIF1A transcription activator complex promotes MCTP1-regulated neuroendocrine differentiation and epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3736.

We report 4 cases of neonatal sepsis caused by Streptococcus gallolyticus. The clinical course was quite similar to early-and late-onset group B streptococcus disease. None of the mothers had group B streptococcus (GBS) colonization on prenatal screening nor received intrapartum antibiotics. We proposed the sporadic distribution of S. gallolyticus sepsis among neonates was partly due to relatively low colonization rate in adults compared with GBS. Species determination of S. gallolyticus may not be available using conventional microbiological methods and may contribute to underestimation or misclassification. In our series, we highlighted the importance of S. gallolyticus as an important pathogen in neonatal sepsis deserving further surveillance.

This study engaged a group of Taiwanese English-as-a-Foreign-Language (EFL) adolescent learners as multimodal composers who used PPT slides to retell important elements of Roald Dahl’s classic nove...

This study invited a group of Taiwanese English-as-a-foreign- language (EFL) tertiary-level students to help Google Translate (GT) Community to refine its translation output. The participants engaged in 5 types of translation refinement tasks by responding to the input provided by GT Community (the first four tasks) or entering translation suggestions when encountering inappropriate translation generated by GT (the fifth task). The results indicated that the participants were able to generate highly accurate output for the first four tasks. With regard to the fifth task, many students entered proverbs, idioms, cultural expressions or slang for GT to translate and deemed GT’s inability to translate beyond literal meaning as something to be improved upon. There were also nearly 25% of over-correction due to students’ excessive scrutiny.All in all, students generally enjoyed the experience of helping GT to improve its translation quality. As students took the role of active contributors of knowledge, they developed competence and gained experience of participating in the digital world. Their participation also helped them to refine their language knowledge and developed their research abilities. The current study ends with a few possible directions for future research. Keywords: Google Translate (GT), Google Translate Community, translation refinement tasks, online participation

研究グループは、肝臓に移行した腸内細菌叢の成分であるリポタイコ酸が、肝がん微小環境を変化させてがんの増殖進展を促進するSASP(Senescence-associated secretory phenotype、細胞老化随伴分泌現象)因子を老化肝星細胞から放出させるメカニズムを明らかにしました。がんの組織はがん細胞そのものだけでなく、線維芽細胞や免疫細胞など、様々な種類の細胞種が集まって「がん微小環境」を構成しています。進行したがん組織の微小環境ではがん細胞周囲の細胞ががんの増殖を助長していると考えられています。本グループは、脂肪肝を素地とする肝がん微小環境では、肝星細胞と呼ばれる線維芽細胞が細胞老化を引き起こしており、「細胞老化随伴分泌現象(SASP)」という様々な分泌因子を放出する現象が生じ、その分泌因子(SASP因子)ががんの増殖を促進することを以前から見出していました。しかしこれまでにSASP因子の放出メカニズムについては明らかにされていませんでした。本研究では高脂肪食摂取による肥満誘導性肝がんのマウスモデルを用い、老化肝星細胞の細胞膜上にガスダーミンDというタンパク質が酵素切断されて生じたN末端側の部分(以降GSDMD－Nと略記)が集合して形成される小孔を介して、SASP因子に含まれるサイトカインIL-1βとIL-33が細胞の外部に放出されることを明らかにしました。また、高脂肪食摂取マウスでは、腸管バリアが脆弱化しており、肝臓にグラム陽性腸内細菌の細胞壁成分であるリポタイコ酸が蓄積していました。さらに、蓄積したリポタイコ酸は老化肝星細胞にトル様受容体２(TLR2)を介した刺激を入れ続け、酵素切断で生じたGSDMD－Nによる細胞膜上の小孔形成とそれに続くIL-33やIL-1βの放出を促進していることもわかりました。老化肝星細胞から放出されたIL-33は、その受容体ST2が陽性の制御性T細胞(Treg細胞)に作用し、がんの増殖を促進させることがわかりました。また、GSDMD－NはヒトのNASH(Non-alcoholic steatohepatitis)肝がんの腫瘍部にある肝星細胞でもその存在が認められました。これらの結果から、ガスダーミンDによる小孔形成を阻害する薬剤は肝がんの予防や治療につながる可能性があります。, Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, ...

Background Prostate cancer (PCa) patients with bone metastases frequently exhibit abnormal calcium homeostasis. However, the molecular mechanisms underlying bone metastasis mediated by activated calcium transport signaling remain unclear. Our results showed that androgen deprivation therapy (ADT) of PCa upregulates a calcium sensor transmembrane protein, the multiple C2 domains transmembrane protein 1 (MCTP1), which is upregulated by hypoxia-induced ZBTB46/FOXA2/HIF1A signaling and is associated with SNAI1-driven neuroendocrine (NE) differentiation (NED) and epithelial-to-mesenchymal transition (EMT) in PCa. Methods Hypoxia induced interactions between ZBTB46, HIF1A, and FOXA2 were confirmed by immunoprecipitation (IP)-Western Blot (WB). Correlation between MCTP1 and ZBTB46/FOXA2/HIF1A complexes was analyzed by immunohistochemical (IHC) staining in consecutive tissue sections of PCa tissue microarray (TMA) comprising primary PCa and small cell PCa (SCPC) samples. The regulatory network between MCTP1 and the hypoxia-induced ZBTB46/FOXA2/HIF1A axis was investigated by chromatin IP (ChIP)-Seq analysis, ChIP assay, and promoter reporter assays. The effect of MCTP1 on SNAI1 expression driving NED and EMT in PCa was identified in PCa cell lines using mimic hypoxia, ADT, or long-term androgen receptor (AR) antagonist culture systems. Activation of the MCTP1-mediated calcium-related pathway induces SNAI1-driven NED and aggressive progression of PCa under hypoxic conditions was examined by Fluo-8 AM staining combined with flow cytometry, migration, invasion, and xenograft model validation. Results MCTP1 is highly expressed in advanced PCa tissues and is associated with ZBTB46/FOXA2/HIF1A abundance. Upregulation of MCTP1 enhances SNAI1-mediated cell migration and EMT responses and is associated with hypoxia-driven NED in PCa after ADT. Mechanistically, hypoxia enhances the MCTP1-mediated calcium/AKT pathway to stabilize SNAI1 in PCa to promote EMT and NED by increasing the SNAI1-driven expression of EMT and NE markers. MCTP1 knockdown abrogated hypoxia-enhanced EMT and NED by reducing calcium/AKT pathway-driven SNAI1 expression. Conclusions Our study shows the molecular mechanism by which hypoxia-associated ZBTB46/FOXA2/HIF1A transcription factor interaction upregulates the calcium sensor transmembrane protein MCTP1 in ADT-resistant PCa, and explores how MCTP1 promotes NED and EMT in PCa by upregulating SNAI1-driven EMT and NE markers.

LaFe

Live video streaming has become one of the key applications in mobile wireless networks. To offload the bandwidth requirement in both backhaul and radio access networks, the integration of Mobile Edge Computing (MEC) and multicasting have become a natural candidate. However, less attention has been paid to the user Quality of Experience-driven (QoE-driven) approach to optimize the radio resource management of multicasting in mobile wireless networks. In this work, we study the optimal radio resource management, including modulation and coding scheme (MCS) selection, radio resource blocks allocation, and Forward Error Correction (FEC), for multicasting in LTE networks with the assistance of MEC. We formulate it as a convex optimization problem and propose a weighted sub-gradient (WSG) method to find the near-optimal solution. In addition, we also propose a heuristic algorithm based on the concept of Maximizing marginal Gain and Minimizing marginal Loss (MGML). Our simulation results show that both approaches are able to achieve near-optimal solutions and outperform previous work, including MSML [11] and OLM [14] . Our simulation results also show that WSG yields the best QoE fairness index while MGML yields the best system utility in most scenarios.