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BACKGROUND: Adverse pregnancy outcomes (APO) contribute to higher risk of maternal cerebrovascular disease, but longitudinal data that include APO and stroke timing are lacking. We hypothesized that APO are associated with younger age at first stroke, with a stronger relationship in those with >1 pregnancy with APO. METHODS: We analyzed longitudinal Finnish nationwide health registry data from the FinnGen Study. We included women who gave birth after 1969 when the hospital discharge registry was established. We defined APO as a pregnancy affected by gestational hypertension, preeclampsia, eclampsia, preterm birth, small for gestational age infant, or placental abruption. We defined stroke as first hospital admission for ischemic stroke or nontraumatic intracerebral or subarachnoid hemorrhage, excluding stroke during pregnancy or within 1 year postpartum. We used Kaplan-Meier survival curves and multivariable-adjusted Cox and generalized linear models to assess the relationship between APO and future stroke. RESULTS: We included 144 306 women with a total of 316 789 births in the analysis sample, of whom 17.9% had at least 1 pregnancy with an APO and 2.9% experienced an APO in ≥2 pregnancies. Women with APO had more comorbidities including obesity, hypertension, heart disease, and migraine. Median age at first stroke was 58.3 years in those with no APO, 54.8 years in those with 1 APO, and 51.6 years in those with recurrent APO. In models adjusted for sociodemographic characteristics and stroke risk factors, risk of stroke was greater in women with 1 APO (adjusted hazard ratio, 1.3 [95% CI, 1.2–1.4]) and recurrent APO (adjusted hazard ratio, 1.4 [95% CI, 1.2–1.7]) compared with those with no APO. Women with recurrent APO had more than twice the stroke risk before age 45 (adjusted odds ratio, 2.1 [95% CI, 1.5–3.1]) compared with those without APO. CONCLUSIONS: Women who experience APO have earlier onset of cerebrovascular disease, with the earliest onset in those with more than 1 affected pregnancy.

Background The acute inhibition of glymphatic after stroke has been shown to aggravate post-stroke inflammation and apoptosis; however, the related mechanisms remain ambiguous. This study aimed to assess the specific mechanism of inflammation and apoptosis after cerebral ischemia-reperfusion (I/R) injury by improving glymphatic dysfunction. Materials and Methods Ischemic stroke was induced using the mice middle cerebral artery occlusion (MCAO) model. The C57/BL6 mice were randomly divided into three groups as follows: sham operation, Ischemia-reperfusion (I/R) 48 hours, and N-(1,3,4-thiadiazol-2-yl) pyridine-3-carboxamide dihydrochloride (TGN-020) + I/R 48 hours treatment. Neurological examination, TTC, fluorescence tracer, western blot, and immunofluorescence staining were performed in all mice in sequence. The glymphatic function in the cortex surrounding cerebral infarction was determined using tracer, glial fibrillary acid protein (GFAP), aquaporin-4 (AQP4) co-staining, and beta-amyloid precursor protein (APP) staining, differential genes were detected using RNA-seq. Iba-1, IL-1β, TNF-α, cleaved caspase 3, and tunel staining were used to verify inflammation and apoptosis after TGN-020 treatment. Results Compared with I/R group, the degree of neurological deficit was alleviated in TGN-020 group. TGN-020 alleviated glymphatic dysfunction by improving astrocyte proliferation and reducing tracer accumulation in the peri-infarct area. RNA-seq showed that the differentially expressed genes were mainly involved in the activation of astrocytes and microglia, and involved in the ERK pathway. RNA-seq was verified by western blot and immunofluorescence. Conclusions The inflammation of astrocytes and microglia after cerebral ischemia-reperfusion (I/R) is closely related to the glymphatic system. The improvement of glymphatic function may play a neuroprotective role after cerebral I/R by inhibiting inflammation through ERK pathway.

Hela cells or A549 cells stably expressing histone H2B-RFP were incubated with 10 μM of different PIPs for 24 h. Cells were then subjected to live-imaging using confocal microscopy. Scale bar, 10 μm.

(a) Hela cells or (b) A549 cells stably expressing histone H2B-RFP were incubated with 10 μM of PIP3. At different time points, cells were harvested, stained, and imaged. Scale bar, 50 μm. (c) Nuclear localization of PIP3 in A549 cells. Scale bar, 10 μm.

Live imaging of mitotic progression in PIP3 treated hTERT-RPE1 cells

(a and b) Plk1 mRNA levels (a) and Plk1 protein levels (b) in various cell lines. (c-e) Pearson correlation co-efficiency was calculated between Plk1 mRNA level, Plk1 protein expression level, and PIP3 sensitivity (represented by IC50 value).

(a and b) A549 cells were treated with different concentrations of PIP2 or PIP3. After 72 h of treatment, cells were incubated with 10 ng/ml TNF-α for additional 12 h, and then harvested for IL6 (a) and IL8 (b) qRT-PCR analysis.

(a) Comparison of the cellular uptake of PIP3 and Hoechst 33258. Hela cells were incubated with different concentrations of PIP3 or Hoechst 33258 for 24 hours. Fluorescent microscopy images were acquired and as shown. (b) PIP3 but not Hoechst 33258 shows Plk1 suppression ability. Hela cells were treated with different concentrations of PIP3 or Hoechst 33258 for 72 hours and then collected for western blotting analysis to examine the Plk1 expression. (c) Evaluation of PIP3 stability in vitro. Hela cells were treated with 10 μM PIP3 for 72 hours, then cells were collected and lysed. Released PIP3 was monitored by RP-HPLC analysis. PIP3 dissolved in water was served as control.

Live imaging of mitotic progression in PIP3 treated A549 cells

Live imaging of mitotic progression in control Hela cells.

Live imaging of mitotic progression in control A549 cells

Live imaging of mitotic progression in PIP3 treated Hela cells

(a) Representative images of mice from vehicle group and PIP3-treated group on the sacrifice day. Yellow arrows indicate tumor locations. (b) Images of isolated tumors from vehicle group or PIP3-treated group. (c) In vivo cellular localization of PIP3. Frozen sections of tumors from PIP3-treated group were imaged under microscopy to visualize the cellular uptake of PIP3 in vivo. The nuclei were stained by Topro3. Scale bar, 100 μm.

(a and b) The hTERT-RPE1 cells and HUVEC cells were synchronized, PIP3 treated, and analyzed as in Figure 4a and 4b. Plk1 inhibition efficiency examined by western blotting was shown in the top. (c and d) Percentages of mitotic cells at different phases were quantified in these treated cells (n.s, not significant; n=3). (e) Time-lapse microscopy of nontransformed cells with or without PIP3 treatment. hTERT-RPE1 cells and HUVEC cells stably expressing histone H2B-RFP were treated with 0.1% DMSO or 20 μM of PIP3 for 72 h and analyzed by time-lapse imaging. (f and g) The duration of total mitosis (f) and time spent in each sub-stage of mitosis (g) were further quantified (n.s, not significant; n{greater than or equal to}25).

Live imaging of mitotic progression in PIP3 treated HUVEC cells

Live imaging of mitotic progression in control HUVEC cells

Live imaging of mitotic progression in control hTERT-RPE1 cells

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide–Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle–regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. Mol Cancer Ther; 17(5); 988–1002. ©2018 AACR.

Hela cells were treated with or without 10 μM PIP3 for 72 hours and then labeled by Propidium iodide and Annexin V-FITC for detecting early and late apoptotic signal.

ObjectivesTo recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform.DesignBiobank-based recontacting pilot study.SettingThree Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021.ParticipantsAll eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s).Outcome measuresThe primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies.ResultsThe overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18–69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92.ConclusionIn summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.

Non-surgical therapies have the advantage of lower postoperative pain and complication rates compared with surgical therapies. Rubber band ligation and coagulation are two kinds of non-surgical therapies. The aim of this study is to compare the clinical outcomes of rubber band ligation and coagulation. A systematic review was conducted to identify randomised clinical trials that compare rubber band ligation and coagulation treatments for haemorrhoids. PubMed and Web of Science were searched, from inception to April 30th,2022. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Fifty-nine studies were identified. Nine trials met the inclusion criteria. All trials were of moderate methodological quality. No significant difference was found between rubber band ligation and coagulation in terms of efficacy rate, postoperative prolapse rate, recurrence rate and postoperative urine retention rate after treatment. Patients undergoing rubber band ligation had higher postoperative pain rate and lower postoperative bleeding rate than patients undergoing coagulation. The subgroup analysis showed that there was no significant difference between rubber band ligation and infrared coagulation or non-infrared coagulation in terms of efficacy rate, postoperative bleeding and postoperative urine retention rate after treatment. Patients undergoing rubber band ligation had a higher postoperative pain rate than patients undergoing infrared coagulation or non-infrared coagulation. We believe that coagulation for haemorrhoids still has a good future. PROSPERO registration number CRD42022311281.

Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium, has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2. As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.

As a successful business model, “in-app purchase” has been adopted by massive applications (Apps) gradually. Users can purchase various virtual goods in different kinds of Apps, such as the license to download movies or songs. In-app purchase helps App operators gain huge income, and meanwhile provides users with flexibility in using Apps. Recently, iOS Apps have suffered the attack of fraudulent purchase. Attackers leverage the vulnerabilities in iOS payment system to purchase virtual goods at zero or low cost. More seriously, unscrupulous attackers solicit customers publicly and provide purchasing services, which has caused huge financial loss to business entities. It becomes of great importance to detect the fraudulent in-app purchases in iOS Apps, and then take measures such as confiscating goods to minimize profit loss. In this paper, we propose a system called Payment-Guard to achieve this objective, which designs various features to characterize a purchase from four perspectives including App account behavior, device behavior, IP behavior and union behavior of (App account, device, IP), then conducts detection based on the features. We perform comprehensive experiments based on data collected from “Honor of Kings” App, which is one of the most famous MOBA games in China and allows players to recharge App accounts for virtual currency. Experimental results demonstrated that Payment-Guard can detect 92.2% malicious in-app purchases and with only 2% false positive rate.

Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AFWe studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia.These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.

Vanadium oxides, as highly efficiently catalysts, are widely applied in various catalytic reactions, such as the dehydrogenation of light alkanes and epoxidation of alkenes. In this paper, a series of VO x /Al 2 O 3 catalysts were fabricated by the 1-pot method for catalytic propane dehydrogenation. The results indicated that the VO x /Al 2 O 3 catalysts with loading of 10 wt.% vanadium exhibited optimized catalytic performance. The as-prepared catalysts were characterized by N 2 adsorption-desorption, XRD, TEM, H 2 -TPR, and XPS to explore the texture properties, morphology, and electronic environment of vanadium. In addition, several vanadium catalysts were also prepared by the incipient wetness impregnation (IWI) method to compare their catalytic performance with the 1-pot synthesized catalysts. The catalysts synthesized by the 1-pot method exhibited higher selectivity of propylene and longer catalyst lifetime at high propane conversion when compared to the counterpart synthesized by the IWI method.

Aurora kinase A (Aurora A) plays a critical role in regulating cell mitotic progression and has been considered as a promising drug target for cancer therapy. To develop a novel molecule targeting Aurora A with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide (PIP) Hoechst conjugate, PIP-Ht, targeting to a cell-cycle regulated DNA sequence locating at the promoter of human Aurora A gene (AURKA). PIP-Ht potently suppressed AURKA promoter activities, mRNA expression and protein level, induced tumor cell cycle delay and inhibited tumor cell proliferation in vitro. Furthermore, subcutaneous injection of PIP-Ht into mice bearing human cancer xenografts induced significant tumor growth suppression and cell apoptosis. Collectively, PIP-Ht exhibits the potential as an effective therapeutic candidate for the tumor treatment.

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients’ sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients., Author summary DENV is the most common mosquito-transmitted viral pathogen in humans. In general, DENV-infected patients are asymptomatic or have flu-like symptoms with fever and rash. However, in severe cases of DENV infection, the diseases may progress to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), the leading causes of morbidity and mortality in school-age children in tropical and subtropical regions. DENV-induced vascular leakage is characterized by enhanced vascular permeability without morphological damage to the capillary endothelium. This study reveals a possible mechanism by which DENV NS1 and MMP-9 cooperatively induce vascular leakage. NS1 also recruits MMP-9 to degrade β-catenin, ZO-1, and ZO-2 that leads to intervene endothelial hyperpermeability in human endothelial cells and mouse vascular. Moreover, the authors further reveal that DENV activates NF-κB signaling pathway to induce MMP-9 expression in patients, mice, PBMC, and macrophages though NS1 protein. This study would provide new in signs into the pathogenesis of DENV infection, and suggest that MMP-9 may act as a drug target for the prevention and treatment of DENV-associated diseases.

User attributes, such as gender and education, face severe incompleteness in social networks. In order to make this kind of valuable data usable for downstream tasks like user profiling and personalized recommendation, attribute inference aims to infer users' missing attribute labels based on observed data. Recently, variational autoencoder (VAE), an end-to-end deep generative model, has shown promising performance by handling the problem in a semi-supervised way. However, VAEs can easily suffer from over-fitting and over-smoothing when applied to attribute inference. To be specific, VAE implemented with multi-layer perceptron (MLP) can only reconstruct input data but fail in inferring missing parts. While using the trending graph neural networks (GNNs) as encoder has the problem that GNNs aggregate redundant information from neighborhood and generate indistinguishable user representations, which is known as over-smoothing. In this paper, we propose an attribute \textbf{Infer}ence model based on \textbf{A}dversarial \textbf{VAE} (Infer-AVAE) to cope with these issues. Specifically, to overcome over-smoothing, Infer-AVAE unifies MLP and GNNs in encoder to learn positive and negative latent representations respectively. Meanwhile, an adversarial network is trained to distinguish the two representations and GNNs are trained to aggregate less noise for more robust representations through adversarial training. Finally, to relieve over-fitting, mutual information constraint is introduced as a regularizer for decoder, so that it can make better use of auxiliary information in representations and generate outputs not limited by observations. We evaluate our model on 4 real-world social network datasets, experimental results demonstrate that our model averagely outperforms baselines by 7.0$\%$ in accuracy.

A Large-Eddy Simulation (LES) modeling framework, dedicated to ultra-lean spark-ignition engines, is proposed and validated in the present work. A direct injection research engine is retained as benchmark configuration. The LES model is initially validated using the cold gas-exchange conditions by comparing numerical results with PIV (Particle Imaging Velocimetry) experimental data. Then, the fired configuration is investigated, combining ECFM (Extended Coherent Flame Model) turbulent combustion model with Adaptive Mesh Refinement (AMR). The capability of the model to reproduce experimental pressure envelope and cycle-to-cycle variability is assessed. Within the major scope of the work, a particular focus on the Combustion Cyclic Variability (CCV) is made correlating them with the variability encountered in the in-cylinder aerodynamic variations. R3P4. Finally two post-processing tools, Empirical Mode Decomposition (EMD) and Γ3p function, are proposed and combined to analyse for the first time the aerodynamic tumble-based in-cylinder velocity field. Both tools make it possible to get deeply into the insight and visualization of the flow field and to understand the links between its cyclic variability and the combustion cyclic variability.

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide–Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle–regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. Mol Cancer Ther; 17(5); 988–1002. ©2018 AACR.

Aromatic nitriles are important structural motifs that frequently existed in pharmaceutical drugs. Due to the convenient synthesis of aldoximes from aldehydes, the dehydration of aldoximes to corresponding nitriles by aldoxime dehydratases (Oxds) is considered as a safe and robust enzymatic production route. Although the Oxd genes are widely distributed in microbial kingdom, so far less than ten Oxds were expressed and further characterized. In this study, we found 26 predicted putative Oxd genes from the GenBank database using a genome mining strategy. The Oxd gene from Pseudomonas putida F1 was cloned and functionally expressed in Escherichia coli BL21 (DE3). The amino acid sequence of OxdF1 shows high identities of 33∼85 % to other characterized Oxds, and contained a ferrous heme as the catalytic site. The optimum reaction pH and temperature of recombinant OxdF1 were 7.0 and 35 °C, respectively. OxdF1 was stable in pH 7.0 potassium phosphate buffer at 30 °C, and its half-life was approximately 3.8 h. OxdF1 can efficiently dehydrate aromatic and heterocyclic aldoximes to nitriles, such as 2-bromobenzaldoxime, 2-chloro-6-fluorobenzaldoxime, thiophene-2-carboxaldoxime, and pyridine-3-aldoxime. Therefore, the recombinant OxdF1 shows a potential application in the cyanide-free synthesis of aromatic nitriles.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.

National audience; Le choix du solveur CFD influence les résultats des simulations réalisées mais peut également impacter les résultats d’un processus d’optimisation. Cette étude compare le comportement des solveurs Code_Saturne et ANSYS Fluent dans le cadre d’une optimisation de la forme d’une ailette trapézoïdale. Les résultats mettent en évidence un écart maximum de 5% entre les évaluations des deux solveurs. Toutefois, les individus optimaux différent. Cela semble principalement causé par une réponse différente des solveurs dans une région de l’espace des paramètres. Celle-ci modifie la courbure de la surface de réponse et déplace ainsi le bassin d’attraction des formes optimales.

Vehicular Ad Hoc Network (VANET) is a multi-hop autonomous system that consists of vehicular nodes. VANETs aim to perform an efficient wireless communication in vehicular environments, and vehicular communication scenario is one of the typical high reliability and low delay scenarios in 5G networks. However, the special situations in VANETs like frequent link failure, unstable network topology and random change of vehicle mobility pose a number of challenges in routing protocol design. In this paper, we propose a delay sensitive routing protocol for VANETs to address these serious problems by using ant colony optimization (ACO) and we aim to find a path with a low average end-to-end delay from source to destination. We transform the next hop selection into a probability problem according to ACO concept. There are two mechanisms applied in routing discovery process which utilize pheromone information of transmission delay and heuristic information of vehicles. Two Mathematical models are proposed in pheromone deposit and evaporation prodecure to estimates transmission delay. Performance analysis and simulation results show that the proposed scheme has better performance.

// Jianchao Zhang 1 , Ximing Shao 1 , Haiyan Sun 1 , Ke Liu 1 , Zhihao Ding 1 , Juntao Chen 1 , Lijing Fang 1 , Wu Su 1 , Yang Hong 4 , Huashun Li 2, 3 , Hongchang Li 1 1 Shenzhen Key Laboratory for Molecular Biology of Neural Development, Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China 2 SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine and Advanced Institute of Translational Medicine, Shanghai 200123, China 3 ATCG Corporation, BioBay, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China 4 Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA Correspondence to: Hongchang Li, email: hc.li@siat.ac.cn Huashun Li, email: huashunli@tongji.edu.cn Keywords: NUMB, EMT, TNBC, Notch, metastasis Received: March 26, 2016 Accepted: July 19, 2016 Published: August 05, 2016 ABSTRACT Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC.

Numb is an endocytic protein that plays crucial roles in diverse cellular processes such as asymmetric cell division, cell migration and differentiation. However, the molecular mechanism by which Numb regulates endocytic trafficking is poorly understood. Here, we demonstrate that Numb is a docking regulator for homotypic fusion of early endosomes (EEs). Numb depletion causes clustered but unfused EEs, which can be rescued by overexpressing cytosolic Numb 65 and Numb 71 but not plasma membrane-attached Numb 66 or Numb 72. Time-lapse analysis reveals that paired vesicles tend to tether but not fuse with each other in the absence of Numb. We further show that Numb binds to another docking regulator, Mon1b, and is required for the recruitment of cytosolic Mon1b to the EE membrane. Consistent with this, deletion of Mon1b causes similar defects in EE fusion. Our study thus identifies a novel mechanism by which Numb regulates endocytic sorting by mediating EE fusion.

Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed selfish spermatogonial selection, explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia, Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (FGFR2, FGFR3, RET, PTPN11, HRAS and KRAS). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from 5 men (median age: 83 years). Following ultra-deep sequencing (~16,000x), development of a low-frequency variant prioritization strategy and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1 and SOS1), all of which encode components of RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the ageing male germline is a repository for such deleterious mutations.

Intelligent transportation system attracts a great deal of research attention because it helps enhance traffic safety, improve driving experiences, and transportation efficiency. Vehicular Ad Hoc Network (VANET) supports wireless connections among vehicles and offers information exchange, thus significantly facilitating intelligent transportation systems. Since the vehicles move fast and often change lanes unpredictably, the network topology evolves rapidly in a random fashion, which imposes diverse challenges in routing protocol design over VANET. When it comes to the 5G era, the fulfilment of ultra low end-to-end delay and ultra high reliability becomes more crucial than ever. In this paper, we propose a novel routing protocol that incorporates mobility status and MAC layer channel contention information. The proposed routing protocol determines next hop by applying mobility information and MAC contention information which differs from existing greedy perimeter stateless routing (GPSR) protocol. First, we use mobility information to estimate link expiration time and distance. Second, a mathematical model of backoff times is proposed based on the MAC layer backoff mechanism. Therefore, the MAC delay of each forwarding node can be evaluated on this basis. Finally, we combine these three aspects to evaluate the forwarding probability of each node. Simulation results of the proposed routing protocol show its performance superiority over the existing approach.

Device-to-Device (D2D) Communication enables User Equipment (UE) to establish direct link between each other to transmit data, which can improve both the efficiency of spectrum and throughput, has become a key technology in the Fifth Generation (5G) system. However, there still exist many challenges to ensure the D2D communication and the 5G standard hasn’t been released. In order to promote the development of D2D technology and provide a simulation tool for the research of 5G D2D communication, in this work, we present the design of system-level simulation platform for 5G D2D communication according to the guidelines of METIS Project. We introduce several key technologies in the simulation platform, including resource allocation, interference computation, power control, etc. Finally, we give the simulation results and summarize that our 5G D2D communication system-level simulation platform is able to offer rich interface for testing and evaluation of related technologies.

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This note presents a lower bound for the Strong Price of Anarchy (SPoA) of coordination mechanisms for unrelated parallel machine scheduling games with social cost of minimizing the makespan. The SPoA of any set of non-preemptive strongly local policies satisfying the IIA property is at least m , the number of machines. Combining with the upper bound of the worst-case ratio of Shortest First algorithm for unrelated parallel machine scheduling problem with objective of minimizing the makespan (Ibarra and Kim, 1977), the SPoA of S P T policy, as well as the worst-case ratio of Shortest First algorithm, is exactly m .

In this paper, we study the problem of minimizing the maximum total completion time per machine on m parallel and identical machines. We prove that the problem is strongly NP-hard if m is a part of the input. When m is a given number, a pseudo-polynomial time dynamic programming is proposed. We also show that the worst-case ratio of SPT is at most 2.608 and at least 2.5366 when m is sufficiently large. We further present another algorithm which has a worst-case ratio of 2.

A novel algorithm is proposed for the direction-of-arrival (DOA) estimation of coherently distributed (CD) sources. Based on the symmetric property of the uniform linear array (ULA) geometry, the DOA can be estimated by a one-dimensional peak search without estimating the distribution parameters, where N independent CD sources can be distinguished with a ULA of 2N + 1 elements. Compared with the existing algorithms, our proposed algorithm achieves higher element utilization rate with lower computational complexity. Numerical simulation results demonstrate our proposed algorithm provides an improved performance over the generalized eigenvalue decomposition (GEVD) algorithm.

Autophagy is a lysosome-dependent catabolic process involving in the degradation and recycling of unnecessary or damaged proteins and organelles. Emerging evidence indicates that autophagy dysfunction is closely related to various human diseases including cancer, aging, myopathies and neurodegenerative disorders. Here, using genetic knockdown, we uncover the role of Numb, an endocytic adaptor protein, in regulating the late steps of autophagy. We found that Numb depletion led to the accumulation of autophagic vacuole, as verified by RFP-LC3 staining combined with transmission electron microscopy. Further investigation indicated that Numb depletion impaired autophagic degradation through inhibiting the activities of lysosomal enzymes (Cathepsin D, β-glucuronidase and β-glucosidase). Moreover, Numb depletion induced elevation of lysosomal pH values and decrease of glycosylated lysosome-associated membrane proteins. We further observed that Rab7 activity was inhibited in Numb-depleted cells. Together, our findings revealed a novel function of Numb and its likely mechanism in regulation of autophagy events.