Optimal Provisioning and Pricing of Differentiated Services Using QoS Class Promotion

This paper introduces a new method for optimally provisioning and pricing di#erentiated services, that maximizes profit and maintains a small blocking probability. Resources are provisioned per Quality of Service (QoS) class over the long-term (service level agreement duration), then priced based on user demand over the short-term. Unique to this method is the ability to dynamically promote tra#c from one QoS class to a higher QoS class, based on estimated demand statistics. This additional flexibility encourages better short-term utilization of the classes, resulting in higher profits while maintaining a low blocking probability. Experimental results will demonstrate QoS class promotion can obtain higher profits, as compared to other provisioning and allocation methods

Firewall Architectures for High-Speed Networks: Final Report

Firewalls are a key component for securing networks that are vital to government agencies and private industry. They enforce a security policy by inspecting and filtering traffic arriving or departing from a secure network. While performing these critical security operations, firewalls must act transparent to legitimate users, with little or no effect on the perceived network performance (QoS). Packets must be inspected and compared against increasingly complex rule sets and tables, which is a time-consuming process. As a result, current firewall systems can introduce significant delays and are unable to maintain QoS guarantees. Furthermore, firewalls are susceptible to Denial of Service (DoS) attacks that merely overload/saturate the firewall with illegitimate traffic. Current firewall technology only offers a short-term solution that is not scalable; therefore, the \textbf{objective of this DOE project was to develop new firewall optimization techniques and architectures} that meet these important challenges. Firewall optimization concerns decreasing the number of comparisons required per packet, which reduces processing time and delay. This is done by reorganizing policy rules via special sorting techniques that maintain the original policy integrity. This research is important since it applies to current and future firewall systems. Another method for increasing firewall performance is with new firewall designs. The architectures under investigation consist of multiple firewalls that collectively enforce a security policy. Our innovative distributed systems quickly divide traffic across different levels based on perceived threat, allowing traffic to be processed in parallel (beyond current firewall sandwich technology). Traffic deemed safe is transmitted to the secure network, while remaining traffic is forwarded to lower levels for further examination. The result of this divide-and-conquer strategy is lower delays for legitimate traffic, higher throughput, and traffic differentiation (a key component for maintaining QoS). Furthermore, the distributed design is scalable to traffic loads and is less susceptible to DoS attacks. Simulation and analytical results show these new architectures out-perform any current firewall system, providing higher throughput, lower delays, and predictable traffic differentiation

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

The 34-gene classifier, ClearCode34, identifies prognostically distinct molecular subtypes of clear cell renal cell carcinoma (ccRCC) termed ccA and ccB. The primary objective of this study was to describe clinical characteristics and comorbidities of relevance in patients stratified by ClearCode34

Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-Mediated High-Density Lipoprotein (HDL)-Cholesteryl Ester Uptake

Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr-/-, PCPE2-/- mice, which had elevated HDL levels compared with LDLr-/- mice with similar LDL concentrations. We found that LDLr-/-, PCPE2-/- mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr-/- mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr-/-, PCPE2-/- mice was similar to that reported for LDLr-/-, apoA-I-/- mice, which lack any apoA-I/HDL. Furthermore, LDLr-/-, PCPE2-/- mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr-/- mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system

Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection

Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division

The electronic version of this article is the complete one and can be found online at: http://www.pathogeneticsjournal.com/content/3/1/1Background: Aristaless related homeobox (ARX) is a paired-type homeobox gene. ARX function is frequently affected by naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX cause a range of intellectual disability and epilepsy phenotypes with or without additional features including hand dystonia, lissencephaly, autism or dysarthria. Severe malformation phenotypes, such as X-linked lissencephaly with ambiguous genitalia (XLAG), are frequently observed in individuals with protein truncating or missense mutations clustered in the highly conserved paired-type homeodomain. Results: We have identified two novel point mutations in the R379 residue of the ARX homeodomain; c.1135C>A, p.R379S in a patient with infantile spasms and intellectual disability and c.1136G>T, p.R379L in a patient with XLAG. We investigated these and other missense mutations (R332P, R332H, R332C, T333N: associated with XLAG and Proud syndrome) predicted to affect the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain. The NLS regions are required for correct nuclear import facilitated by Importin 13 (IPO13). We demonstrate that missense mutations in either the N- or C-terminal NLS regions of the homeodomain cause significant disruption to nuclear localisation of the ARX protein in vitro. Surprisingly, none of these mutations abolished the binding of ARX to IPO13. This was confirmed by co-immunoprecipitation and immmuno fluorescence studies. Instead, tagged and endogenous IPO13 remained bound to the mutant ARX proteins, even in the RanGTP rich nuclear environment. We also identify the microtubule protein TUBA1A as a novel interacting protein for ARX and show cells expressing mutant ARX protein accumulate in mitosis, indicating normal cell division may be disrupted. Conclusions: We show that the most likely, common pathogenic mechanism of the missense mutations in NLS regions of the ARX homeodomain is inadequate accumulation and distribution of the ARX transcription factor within the nucleus due to sequestration of ARX with IPO13.Cheryl Shoubridge, May Huey Tan, Tod Fullston, Desiree Cloosterman, David Coman, George McGillivray, Grazia M Mancini, Tjitske Kleefstra and Jozef Géc

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P = 0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P = 0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P = 0.08) and del(5q) (P = 0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progressionfree survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P = 0.05). These findings comprise the largest MDS R72P SNP analysis