I Know Where You are and What You are Sharing: Exploiting P2P Communications to Invade Users' Privacy

In this paper, we show how to exploit real-time communication applications to determine the IP address of a targeted user. We focus our study on Skype, although other real-time communication applications may have similar privacy issues. We first design a scheme that calls an identified targeted user inconspicuously to find his IP address, which can be done even if he is behind a NAT. By calling the user periodically, we can then observe the mobility of the user. We show how to scale the scheme to observe the mobility patterns of tens of thousands of users. We also consider the linkability threat, in which the identified user is linked to his Internet usage. We illustrate this threat by combining Skype and BitTorrent to show that it is possible to determine the file-sharing usage of identified users. We devise a scheme based on the identification field of the IP datagrams to verify with high accuracy whether the identified user is participating in specific torrents. We conclude that any Internet user can leverage Skype, and potentially other real-time communication systems, to observe the mobility and file-sharing usage of tens of millions of identified users.Comment: This is the authors' version of the ACM/USENIX Internet Measurement Conference (IMC) 2011 pape

Study of Negative effects of Traffic Localization

Català: Les xarxes P2P s'han convertit en una important xarxa per usuaris i ISP. Els usuaris volen compartir i aprofitar aquestes noves xarxes. D'altra banda, els ISP no volen que els usuaris utilitzin de manera tan intensa les seves connexions a Internet. Això causa que els seus beneficis es redueixin. La localització de tràfic ha estat anunciat com una solució per als inconvenients del P2P. Redueix el tràfic intercanviat entre els usuaris fent clúster. Només uns pocs usuaris d'un cluster intercanviaren dades amb altres xarxes. Hi ha diversos estudis que mostren els beneficis d'aquesta mesura, però no hi ha massa estudis sobre els efectes negatius. En el nostre treball hem tractat de simular una xarxa BitTorrent. Un cop tinguem aquesta xarxa preparada simularem una xarxa que utilitzi tècniques de localització de trànsit. Fent diverses simulacions volem demostrar com la localització de trànsit afecta l'experiència dels usuaris.Castellano: Las redes P2P se han convertido en una importante red para usuarios e ISP. Los usuarios quieren compartir y aprovechar estas nuevas redes. Por otra parte, los ISP no les interesa que los usuarios utilicen de manera tan intensa sus conexiones. Esto es debido a que sus beneficios se ven reducidos. La localización de tráfico ha sido anunciada como una de las mejores soluciones para los inconvenientes del P2P. Reduce el tráfico intercambiado entre los usuarios lejanos o de diferentes redes haciendo clúster. Sólo unos pocos usuarios de un clúster van a intercambiar datos con otros usuarios de otras redes. Hay varios estudios que indican los beneficios de esta medida, pero no hay demasiados estudios acerca de los efectos negativos. En nuestro trabajo hemos tratado de simular una red BitTorrent. Una vez que tengamos esta red lista simularemos una red P2P con alguna técnica de localización de tráfico. Haciendo varias simulaciones queremos demostrar cómo la localización de tráfico afecta a la experiencia de los usuarios.English: P2P networks has become one important network for users and ISP. Users wants to share and take profit of this new networks. On the other hand, ISP don not want users' to use so intensively their internet connections because their profits are being reduced. Traffic Localization has been announced as a solution for P2P disadvantages. It reduces the traffic exchanged between users making cluster. Only a few users from one cluster are going to change data to other networks. There are several studies that indicates the benefits of this measure but there are not too much studies about negative effects. In our work we tried to simulate a BitTorrent network. Once we have this network ready we constructed it making clusters simulating some Traffic Localization technique. Making several simulations we want to prove how traffic localization affects users' experience

HoughLaneNet: Lane Detection with Deep Hough Transform and Dynamic Convolution

The task of lane detection has garnered considerable attention in the field of autonomous driving due to its complexity. Lanes can present difficulties for detection, as they can be narrow, fragmented, and often obscured by heavy traffic. However, it has been observed that the lanes have a geometrical structure that resembles a straight line, leading to improved lane detection results when utilizing this characteristic. To address this challenge, we propose a hierarchical Deep Hough Transform (DHT) approach that combines all lane features in an image into the Hough parameter space. Additionally, we refine the point selection method and incorporate a Dynamic Convolution Module to effectively differentiate between lanes in the original image. Our network architecture comprises a backbone network, either a ResNet or Pyramid Vision Transformer, a Feature Pyramid Network as the neck to extract multi-scale features, and a hierarchical DHT-based feature aggregation head to accurately segment each lane. By utilizing the lane features in the Hough parameter space, the network learns dynamic convolution kernel parameters corresponding to each lane, allowing the Dynamic Convolution Module to effectively differentiate between lane features. Subsequently, the lane features are fed into the feature decoder, which predicts the final position of the lane. Our proposed network structure demonstrates improved performance in detecting heavily occluded or worn lane images, as evidenced by our extensive experimental results, which show that our method outperforms or is on par with state-of-the-art techniques

FUNCTION OF ANDROGEN RECEPTOR IN PROSTATE CANCER EPITHELIAL MESENCHYMAL TRANSITION AND MICROTUBULE TARGETING

Prostate cancer is the most frequently diagnosed non-skin cancer and the third leading cause of cancer mortality among men in the US. Androgens are functionally required for the normal growth of the prostate gland and play a critical role in prostate tumor development and progression. Epithelial-mesenchymal-transition (EMT) is an important process during normal development, and cancer cell metastasis. This study examined the ability of androgens to influence EMT of prostate cancer epithelial cells and evaluate the effect of taxol chemotherapy on androgen signaling in prostate cancer cells in prostate cancer. The EMT pattern was evaluated on the basis of expression of the epithelial markers as well as cytoskeleton reorganization in respond to DHT (1nM) and/or TGFβ (5ng/ml). Overexpressing and silencing approaches to regulate androgen receptor (AR) expression were conducted to determine the involvement of AR in EMT in the presence or absence of an AR antagonist. The AR transcriptional activity was determined on the basis of prostate specific antigen (PSA) mRNA expression and the androgen-response element (ARE) luciferase reporter assay. The interaction of AR and tubulin was investigated using immunoprecipitation, immunofluorescence as well as introduction of a truncated AR in human prostate cancer cells. Our results demonstrate that androgens induce the EMT pattern in prostate tumor epithelial cell with Snail activation and led to significant changes in prostate cancer cell migration and invasion potential. Expression levels of AR inversely correlated with androgen-mediated EMT in prostate tumor epithelial cells, pointing to a low AR content required for the EMT phenotype. Our study also reveals that treatment of prostate cancer cells with Paclitaxel or Nocodaxol inhibits androgen-dependent, as well as androgen-independent AR nuclear translocation and activation potentially via targeting the interaction of AR and microtubule cytoskeletal structures. Our findings on multiple aspects of AR function in prostate cancer development and progression may enhance the understanding of AR targeting therapy being a double-sided sword in the context of tumor microenvironment. These studies provide new insights into the mechanism of action of chemotherapy agents and the development of therapeutic resistance within tubulin/microtubule repertoire in prostate cancer cells

Native Functions of the Androgen Receptor are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy

Spinobulbar muscular atrophy (SBMA) is a progressive, late-onset disease characterized by degeneration of motor neurons in the brainstem and spinal cord. The disease is caused by expansion of a polyglutamine tract in the androgen receptor (AR) and is dependent on exposure to AR ligand. The expanded polyglutamine tract confers toxic function to the protein through unknown mechanisms, although the ligand-dependent nature of SBMA suggests that the mechanism of pathogenesis may be tied to ligand-dependent alterations in AR function. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated ligand-dependent modifications of AR in a Drosophila model of SBMA. We demonstrate in vivo that nuclear translocation of mutant AR is necessary but not sufficient for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. As proof of this principle, we perform epistasis experiments using the AR coregulator limpet, which we find modifies polyglutamine-expanded AR toxicity in an AF-2-dependent manner. In addition, we use expression profiling to examine the molecular phenotype of polyglutamine-expanded AR degeneration, revealing that expression of wild-type AR results in a molecular phenotype that is very similar to that caused by polyglutamine-expanded AR. These findings suggest that expanded-polyglutamine AR toxicity may be mediated by amplification of normal function, a mechanism that may be broadly applicable to other polyglutamine diseases

Structural, Biochemical, and Cell Biological Characterization of Rab7 Mutants That Cause Peripheral Neuropathy

Coordinated trafficking of intracellular vesicles is of critical importance for the maintenance of cellular health and homeostasis. Members of the Rab GTPase family serve as master regulators of vesicular trafficking, maturation, and fusion by reversibly associating with distinct target membranes and recruiting specific effector proteins. Rabs act as molecular switches by cycling between an active, GTP-bound form and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins such as guanine nucleotide exchange factors and GTPase activating proteins. Rab7 specifically regulates the trafficking and maturation of vesicle populations that are involved in protein degradation including late endosomes, lysosomes, and autophagic vacuoles. Missense mutations of Rab7 cause a dominantly-inherited axonal degeneration known as Charcot-Marie-Tooth type 2B (CMT2B) through an unknown mechanism. Patients with CMT2B present with length-dependent degeneration of peripheral sensory and motor neurons that leads to weakness and profound sensory loss. To gain insight into the pathogenesis of CMT2B, we undertook extensive characterization of two disease-causing Rab7 mutants, L129F and V162M. We present the 2.8 Å crystal structure of GTP-bound L129F mutant Rab7 which reveals normal conformations of the effector binding regions and catalytic site, but an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. We further demonstrate that disease-associated mutations in Rab7 do not lead to an intrinsic GTPase defect as previously suggested, but permit unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Using an unbiased proteomics approach, we characterize effector interactions in wild-type and mutant Rab7 and identify several novel Rab7 interactors. Consistent with augmented activity, mutant Rab7 shows significantly enhanced interaction with a subset of effector proteins. In addition, dynamic imaging demonstrates that mutant Rab7 is abnormally retained on target membranes. However, we show that increased activation of mutant Rab7 is counterbalanced by unregulated, GTP-hydrolysis-independent membrane cycling. Thus, we demonstrate that disease mutations uncouple Rab7 from the spatial and temporal control normally imposed by regulatory proteins and cause disease by misregulation of native Rab7 activity. Future experiments will address the impact of Rab7 misregulation on neuronal trafficking and trophic signaling

U-sphere: strengthening scalable flat-name routing for decentralized networks

Supporting decentralized peer-to-peer communication between users is crucial for maintaining privacy and control over personal data. State-of-the-art protocols mostly rely on distributed hash tables (DHTs) in order to enable user-to-user communication. They are thus unable to provide transport address privacy and guaranteed low path stretch while ensuring sub-linear routing state together with tolerance of insider adversaries. In this paper we present U-Sphere, a novel location-independent routing protocol that is tolerant to Sybil adversaries and achieves low O (1) path stretch while maintaining View the MathML source per-node state. Departing from DHT designs, we use a landmark-based construction with node color groupings to aid flat name resolution while maintaining the stretch and state bounds. We completely remove the need for landmark-based location directories and build a name-record dissemination overlay that is able to better tolerate adversarial attacks under the assumption of social trust links established between nodes. We use large-scale emulation on both synthetic and actual network topologies to show that the protocol successfully achieves the scalability goals in addition to mitigating the impact of adversarial attacks

Mechanism Of Action And Regulation Of Membrane Serine Protease Prostasin In The Prostate And Prostate Cancer

The glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin (PRSS8) is expressed at the apical membrane surface of epithelial cells and acts as a suppressor of tumor invasion when re-expressed in highly invasive human prostate and breast cancer cell lines. To better understand the molecular mechanisms underlying the anti-invasion phenotype associated with prostasin re-expression in prostate cancer cells, we expressed wild-type human prostasin or a serine active-site mutant prostasin in the PC-3 human prostate carcinoma cells. Molecular changes were measured at the mRNA and the protein levels. The expression of several invasion-promoting molecules is regulated by prostasin re-expression, mediated by a protein-level down-regulation of the epidermal growth factor receptor (EGFR). As a result, the cellular response to EGF was reduced as shown by the down-regulation of EGF-stimulated Erk1/2 phosphorylation. The expression of Slug, urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and granulocyte-macrophage colony stimulating factor (GM-CSF) was also down-regulated by prostasin re-expression in the PC-3 cells. Co-expression of prostasin and its activating protease matriptase with EGFR in FT-293 cells induces an apparent proteolytic cleavage of the EGFR in the extracellular domain at two specific sites, generating two N-terminally truncated EGFR fragments, named EGFR135 and EGFR110. The EGFR110 is constitutively tyrosine-phosphorylated, and in its presence the phosphorylation of downstream signaling molecules including Erk1/2 and Akt is increased under serum-free conditions. Neither EGFR135 nor EGFR110 is responsive to EGF stimulation. Deletions of the EGFR extracellular domain (ECD) were generated to map the matriptase-prostasin cleavage sites. Two candidate sites were localized to regions AA1-273 and AA273-410. These data support a mechanism of action for the matriptase-prostasin epithelial extracellular serine protease activation cascade by proteolytically modulating the EGF-EGFR signaling. Prostasin gene expression is down-regulated in high-grade and hormone-refractory prostate cancers. We investigated the mechanisms by which androgens regulate prostasin expression in the prostate and prostate cancer. We treated the LNCaP human prostate cancer cells with dihydrotestosterone (DHT) and measured the mRNA expression of prostasin and potential transcription regulators of prostasin predicted by interrogation of the prostasin gene promoter sequence. Prostasin mRNA expression in the LNCaP cells was not responsive to DHT treatment. DHT marginally up-regulated mRNA expression of SREBP-1c, SREBP-2, and SNAIL, but not SREBP-1a, while dramatically increased SLUG mRNA expression, in a dose-dependent manner. Co-transfection of a prostasin promoter-reporter and SREBP cDNA in HEK-293 cells resulted in stimulation of the promoter activity at ~2 fold by SREBP-1c, and up to 6 fold by SREBP-2; while co-transfection with SNAIL or SLUG cDNA resulted in repression of the promoter activity to 43% or 59%, respectively. Co-transfection of the SLUG cDNA negated SREBP-2 s stimulation of the prostasin promoter in a dose-dependent manner. Transfection of an SREBP-2 cDNA in HEK-293 and DU-145 cells resulted in up-regulation of the endogenously expressed prostasin while transfection of a SLUG cDNA in the LNCaP cells repressed prostasin expression. Multiple SREBP-2 binding sites, known as sterol regulatory elements (SRE s), were identified at positions -897, -538, +8, +71, and +98 (named SRE-897, SRE-538, SRE+8, SRE+71, and SRE+98) in the human prostasin gene promoter. Mutagenesis of the five SRE s was carried out to evaluate their roles in SREBP-2 up-regulation of prostasin. SRE+98, a novel functional sterol regulatory element was found to be the major site for the stimulatory response of prostasin gene expression to SREBP-2. CONCLUSIONS: Prostasin regulates the expression of several invasion-promoting molecules in prostate cancer cells by down-modulating the EGF-EGFR signaling pathway. Active prostasin induces proteolytic cleavage in the EGFR ECD at two specific sites. One of the N-terminally truncated EGFR, the EGFR110 is auto-phosphorylated along with increased phosphorylation of downstream signaling molecules. The effect of the androgen DHT on prostasin expression in prostate cells is mediated via SREBP s, which stimulate the promoter, and Slug, which represses the promoter. Slug is up-regulated by DHT and EGF, providing a molecular mechanism by which epithelial cell-specific genes are silenced during prostate cancer development and progression

U-sphere: strengthening scalable flat-name routing for decentralized networks

Supporting decentralized peer-to-peer communication between users is crucial for maintaining privacy and control over personal data. State-of-the-art protocols mostly rely on distributed hash tables (DHTs) in order to enable user-to-user communication. They are thus unable to provide transport address privacy and guaranteed low path stretch while ensuring sub-linear routing state together with tolerance of insider adversaries. In this paper we present U-Sphere, a novel location-independent routing protocol that is tolerant to Sybil adversaries and achieves low O (1) path stretch while maintaining View the MathML source per-node state. Departing from DHT designs, we use a landmark-based construction with node color groupings to aid flat name resolution while maintaining the stretch and state bounds. We completely remove the need for landmark-based location directories and build a name-record dissemination overlay that is able to better tolerate adversarial attacks under the assumption of social trust links established between nodes. We use large-scale emulation on both synthetic and actual network topologies to show that the protocol successfully achieves the scalability goals in addition to mitigating the impact of adversarial attacks

Trafficking and Activity Dependent Function of Vesicular Transporters

Vesicular neurotransmitter transporters (VNTs) are a small family of proteins responsible for packaging neurotransmitter into secretory vesicles. Their presence and function are required for regulated secretion from neuronal and neuroendocrine cells. During both the biogenesis and the activity-dependent recycling of secretory vesicles, VNTs undergo trafficking that can determine the quality, quantity, and location of packaged neurotransmitter. Thus understanding the signals and mechanisms of VNT trafficking is essential to understanding the regulation of neurotransmission. Here, the synaptic vesicle specific trafficking of Vesicular Acetylcholine Transporter (VAChT) is investigated. A dileucine containing targeting motif, with dual properties for internalization and synaptic vesicle targeting, is identified in the C-terminus of VAChT. Chimeras between this motif and an unrelated plasma membrane protein localize to synaptic-vesicle-like vesicles in a neuroendocrine cell line. The specificity and generalization of this motif is assessed. Next, sorting nexin 5 (SNX5), implicated in the regulation of membrane traffic, is identified as a novel regulator of VAChT targeting to synaptic vesicles. Disruption of SNX5 function leads to a decrease in VAChT-directed synaptic vesicle targeting and a concomitant increase in targeting to large dense core vesicles. This shift between secretory granules suggests an important mechanism of VNT regulation with the potential to shape properties of neurotransmission. In order to understand the physiologic importance of VNT regulation, vesicular transport and its influence on activity-dependent release must be assessed in living neurons. However, this has not been possible. Therefore, a live cell assay was established to measure vesicular transport and its contributions to release in brain slice. Using a pH sensitive, fluorescent serotonin analog visualized by two-photon microscopy, activity dependent somatic release and vesicular monoamine transporter (VMAT) activity were measured in the dorsal raphe nucleus. Interestingly, while a portion of monoamine packaged at rest was held in reserve, monoamine packaged during stimulation was released efficiently. The work presented in this thesis provides a greater understanding of VNT trafficking and activity-dependent function. Furthermore, it provides the foundation for the comprehensive study of the active role of VNTs in shaping the properties of neurotransmission