Traffic matrix estimation in IP networks

An Origin-Destination (OD) traffic matrix provides a major input to the design, planning and management of a telecommunications network. Since the Internet is being proposed as the principal delivery mechanism for telecommunications traffic at the present time, and this network is not owned or managed by a single entity, there are significant challenges for network planners and managers needing to determine equipment and topology configurations for the various sections of the Internet that are currently the responsibility of ISPs and traditional telcos. Planning of these sub-networks typically requires a traffic matrix of demands that is then used to infer the flows on the administrator's network. Unfortunately, computation of the traffic matrix from measurements of individual flows is extremely difficult due to the fact that the problem formulation generally leads to the need to solve an under-determined system of equations. Thus, there has been a major effort from among researchers to obtain the traffic matrix using various inference techniques. The major contribution of this thesis is the development of inference techniques for traffic matrix estimation problem according to three different approaches, viz: (1) deterministic, (2) statistical, and (3) dynamic approaches. Firstly, for the deterministic approach, the traffic matrix estimation problem is formulated as a nonlinear optimization problem based on the generalized Kruithof approach which uses the Kullback distance to measure the probabilistic distance between two traffic matrices. In addition, an algorithm using the Affine scaling method is developed to solve the constrained optimization problem. Secondly, for the statistical approach, a series of traffic matrices are obtained by applying a standard deterministic approach. The components of these matrices represent estimates of the volumes of flows being exchanged between all pairs of nodes at the respective measurement points and they form a stochastic counting process. Then, a Markovian Arrival Process of order two (MAP-2) is applied to model the counting processes formed from this series of estimated traffic matrices. Thirdly, for the dynamic approach, the dual problem of the multi-commodity flow problem is formulated to obtain a set of link weights. The new weight set enables flows to be rerouted along new paths, which create new constraints to overcome the under-determined nature of traffic matrix estimation. Since a weight change disturbs a network, the impact of weight changes on the network is investigated by using simulation based on the well-known ns2 simulator package. Finally, we introduce two network applications that make use of the deterministic and the statistical approaches to obtain a traffic matrix respectively and also describe a scenario for the use of the dynamic approach

The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.

Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

LEE: A photorealistic virtual environment for assessing driver-vehicle interactions in self-driving mode

Photorealistic virtual environments are crucial for developing and testing automated driving systems in a safe way during trials. As commercially available simulators are expensive and bulky, this paper presents a low-cost, extendable, and easy-to-use (LEE) virtual environment with the aim to highlight its utility for level 3 driving automation. In particular, an experiment is performed using the presented simulator to explore the influence of different variables regarding control transfer of the car after the system was driving autonomously in a highway scenario. The results show that the speed of the car at the time when the system needs to transfer the control to the human driver is critical

Stability assessment of roadbed affected by ground subsidence adjacent to urban railways

In recent years, leakages in aged pipelines for water and sewage in urban areas have frequently induced ground loss, resulting in cavities and ground subsidence, causing roadbed settlement greater than the allowable value. In this study, FLAC3D, which is a three-dimensional finite-difference numerical modeling software, is used to perform stability and risk level assessment for the roadbed adjacent to urban railways with respect to various groundwater levels and the geometric characteristics of cavities. Numerical results show that roadbed settlement increases as the diameter (D) of the cavity increases and the distance (d) between the roadbed and the cavity decreases. The regression analyses results show that, as D∕d is greater than 0.2 and less than 0.3, the roadbed is in the status of caution or warning. It requires a database of measurement sensors for real-time monitoring of the roadbed, structures and groundwater to prevent disasters in advance. As D∕d exceeds 0.35, the roadbed settlement substantially increases and the roadbed is in danger. Since this may result in highly probable traffic accidents, train operation should be stopped and the roadbed should be reinforced or repaired. The effects of groundwater level on roadbed settlement are examined and the analysis results indicate that roadbed settlement is highly influenced by groundwater levels to an extent greater than even the influence of the size of the cavity.</p

Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders

Background: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. Methods: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. Results: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p \u3c 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). Conclusions: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders

Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis.

Tuberculosis (TB) remains a global health pandemic and greater understanding of underlying pathogenesis is required to develop novel therapeutic and diagnostic approaches. Matrix metalloproteinases (MMPs) are emerging as key effectors of tissue destruction in TB but have not been comprehensively studied in plasma, nor have gender differences been investigated. We measured the plasma concentrations of MMPs in a carefully characterised, prospectively recruited clinical cohort of 380 individuals. The collagenases, MMP-1 and MMP-8, were elevated in plasma of patients with pulmonary TB relative to healthy controls, and MMP-7 (matrilysin) and MMP-9 (gelatinase B) were also increased. MMP-8 was TB-specific (p<0.001), not being elevated in symptomatic controls (symptoms suspicious of TB but active disease excluded). Plasma MMP-8 concentrations inversely correlated with body mass index. Plasma MMP-8 concentration was 1.51-fold higher in males than females with TB (p<0.05) and this difference was not due to greater disease severity in men. Gender-specific analysis of MMPs demonstrated consistent increase in MMP-1 and -8 in TB, but MMP-8 was a better discriminator for TB in men. Plasma collagenases are elevated in pulmonary TB and differ between men and women. Gender must be considered in investigation of TB immunopathology and development of novel diagnostic markers

Relation of Cumulative Low-Level Lead Exposure to Depressive and Phobic Anxiety Symptom Scores in Middle-Age and Elderly Women

Background: Different lines of evidence suggest that low-level lead exposure could be a modifiable risk factor for adverse psychological symptoms, but little work has explored this relation