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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.

(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).

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.

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.

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.

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.

// 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.

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.

The biological antagonism between the signaling proteins Numb and Notch has been implicated in the regulation of many developmental processes, especially in asymmetric cell division. Mechanistic studies show that Numb inactivates Notch via endocytosis and proteasomal degradation that directly reduce Notch protein levels at the cell surface. However, some aspects of how Numb antagonizes Notch remain unclear. Here, we report a novel mechanism in which Numb acts as a Notch antagonist by controlling the intracellular destination and stability of the Notch ligand Delta-like 4 (Dll4) through a postendocytic-sorting process. We observed that Numb/Numblike knockdown increases the stability and cell-surface accumulation of Dll4. Further study indicated that Numb acts as a sorting switch to control the postendocytic trafficking of Dll4. Of note, the Numb/Numblike knockdown decreased Dll4 delivery to the lysosome, while increasing the recycling of Dll4 to the plasma membrane. Moreover, we demonstrate that this enrichment of Dll4 at the cell surface within Numb/Numblike knockdown cells could activate Notch signaling in neighboring cells. We also provide evidence that Numb negatively controls the Dll4 plasma membrane recycling through a well-documented recycling regulator protein AP1. In conclusion, our study has uncovered a molecular mechanism whereby Numb regulates the endocytic trafficking of the Notch ligand Dll4. Our findings provide a new perspective on how Numb counteracts Notch signaling and sheds additional critical insights into the antagonistic relationship between Numb and Notch signaling.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Analytical models for electric potential, threshold voltage, and subthreshold swing of the junctionless surrounding-gate field-effect transistors are presented. Poisson equation is solved and the electric potential is obtained. With the potential model, explicit expressions for threshold voltage and subthreshold swing are obtained. The analytical results are compared with those from simulations and excellent agreements are observed. The analytical models are useful not only for fast circuit simulations, but also for device design and optimization.

Analytical models for the electric potential, threshold voltage and drain current of long-channel junctionless (JL) double-gate (DG) field-effect transistors (FET) are presented. A regional method is used to solve the Poisson equation under different gate biases, and the electric potential is obtained. With the potential model, an analytical expression for the threshold voltage is achieved. An expression for the drain current is derived from the potential model. The analytical results are compared with simulations, and excellent agreements are observed. The models accurately describe the characteristics of JLDG FETs, and they are very helpful for the design and optimization of devices.

Summary The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations. PaperClip, Graphical Abstract Highlights ► Whole-genome sequences of the Tasmanian devil and two distant cancer subclones ► The Tasmanian devil cancer lineage originated recently in a female devil ► The devil cancer genome is relatively stable despite ongoing evolution ► Clonal divergence and geographic spread elucidated through patterns of mutation, Whole-genome sequences of the Tasmanian devil and two devil cancer subclones suggest that the cancer first arose from a female devil and that the clone has subsequently genetically diverged during its spread across Tasmania.

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP,POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.−57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.−57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.−57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains

Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 “pathway phenotypes” that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold (P

Sphingosine-1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor (GPCR), controls vascular stability by stabilizing vascular endothelial (VE)-cadherin junctional localization and inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) signaling. However, the molecular mechanisms that link S1PR1 signaling to intracellular effectors remain unknown. In this study, we demonstrate that the heterotrimeric G protein subfamily member Gαs, encoded by GNAS, acts as a relay mediator of S1PR1 signaling to control vascular integrity by stabilizing VE-cadherin at endothelial junctions. The endothelial cell-specific deletion of Gαs in mice causes early embryonic lethality with massive hemorrhage and a disorganized vasculature. The immunostaining results revealed that Gαs deletion remarkably reduces the junctional localization of VE-cadherin, whereas the mural cell coverage of the vessels is not impaired. In addition, we found that Gαs depletion blocks the S1PR1-activation induced VE-cadherin stabilization at junctions, supporting that Gαs acts downstream of S1PR1 signaling. Thus, our results demonstrate that Gαs is an essential mediator to relay S1PR1 signaling and maintain vascular integrity.

[This corrects the article DOI: 10.1371/journal.pgen.1004798.].

Statistical factor analysis methods have previously been used to remove noise components from high dimensional data prior to genetic association mapping, and in a guided fashion to summarise biologically relevant sources of variation. Here we show how the derived factors summarising pathway expression can be used to analyse the relationships between expression, heritability and ageing. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarise patterns of gene expression, both to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" which summarised patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold (P

Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to identify quantitative trait loci (QTLs) that influence the binding of a transcription factor in humans, we measured binding of the multifunctional transcription and chromatin factor CTCF in 51 HapMap cell lines. We identified thousands of QTLs in which genotype differences were associated with differences in CTCF binding strength, hundreds of them confirmed by directly observable allele-specific binding bias. The majority of QTLs were either within 1 kb of the CTCF binding motif, or in linkage disequilibrium with a variant within 1 kb of the motif. On the X chromosome we observed three classes of binding sites: a minority class bound only to the active copy of the X chromosome, the majority class bound to both the active and inactive X, and a small set of female-specific CTCF sites associated with two non-coding RNA genes. In sum, our data reveal extensive genetic effects on CTCF binding, both direct and indirect, and identify a diversity of patterns of CTCF binding on the X chromosome., Author Summary We have systematically measured the effect of normal genetic variation present in a human population on the binding of a specific chromatin protein (CTCF) to DNA by measuring its binding in 51 human cell lines. We observed a large number of changes in protein binding that we can confidently attribute to genetic effects. The corresponding genetic changes are often clustered around the binding motif for CTCF, but only a minority are actually within the motif. Unexpectedly, we also find that at most binding sites on the X chromosome, CTCF binding occurs equally on both the X chromosomes in females at the same level as on the single X chromosome in males. This finding suggests that in general, CTCF binding is not subject to global dosage compensation, the process which equalizes gene expression levels from the two female X chromosomes and the single male X.