Clinical impact of double protease inhibitor boosting with Lopinavir/Ritonavir and Amprenavir as part of salvage antiretroviral therapy

Purpose: Double protease inhibitor (PI) boosting is being explored as a new strategy in salvage antiretroviral (ARV) therapy. However, if a negative drug interaction leads to decreased drug levels of either or both PIs, double PI boosting could lead to decreased virologic response. A negative drug interaction has been described between amprenavir (APV) and lopinavir/ritonavir (LPV/r). This observational cohort study assessed the virologic impact of the addition of APV to a salvage ARV regimen, which also contains LPV/r, compared to a regimen containing LPV/r alone. Method: Patients initiated on a salvage ARV regimen that included LPV/r obtained from the expanded access program in Toronto, Canada, were evaluated. APV (600-1,200 mg bid) was added at the discretion of the treating physician. Results: Using multivariate Cox proportional hazards models, we found that the addition of APV to a LPV/r-containing salvage regimen was not significantly associated with time to virologic suppression (< 50 copies/mL; adjusted hazard ratio [HR] = 0.75, p = .12) or with time to virologic rebound (adjusted HR = 1.46, p = .34). Those patients who received higher doses of APV had an increased chance of virologic suppression (p = .03). In a subset of 27 patients, the median LPV Ctrough was significantly lower in patients receiving APV (p = .04), and the median APV Ctrough was reduced compared to reported controls. Conclusion: Our data do not support an additional benefit in virologic reduction of double boosting with APV and LPV/r relative to LPV/r alone in salvage ARV therapy. Our study's limitations include its retrospective nature and the imbalance between the two groups potentially confounding the results. Although these factors were adjusted for in the multivariate analysis, a prospective randomized controlled trial is warranted to confirm our findings

Borel-Cantelli sequences

A sequence $\{x_{n}\}_1^\infty$ in $[0,1)$ is called Borel-Cantelli (BC) if for all non-increasing sequences of positive real numbers $\{a_n\}$ with $\underset{i=1}{\overset{\infty}{\sum}}a_i=\infty$ the set $$\underset{k=1}{\overset{\infty}{\cap}} \underset{n=k}{\overset{\infty}{\cup}} B(x_n, a_n))=\{x\in[0,1)\mid |x_n-x|<a_n \text{for} \infty \text{many}n\geq1\}$$ has full Lebesgue measure. (To put it informally, BC sequences are sequences for which a natural converse to the Borel-Cantelli Theorem holds). The notion of BC sequences is motivated by the Monotone Shrinking Target Property for dynamical systems, but our approach is from a geometric rather than dynamical perspective. A sufficient condition, a necessary condition and a necessary and sufficient condition for a sequence to be BC are established. A number of examples of BC and not BC sequences are presented. The property of a sequence to be BC is a delicate diophantine property. For example, the orbits of a pseudo-Anosoff IET (interval exchange transformation) are BC while the orbits of a "generic" IET are not. The notion of BC sequences is extended to more general spaces.Comment: 20 pages. Some proofs clarifie

A Fuzzy Social Network Analysis Method and a Case Study on Tianya

Social networking service (SNS) has become online service platforms that focus on facilitating the building of social networks among people who share interests, activities, backgrounds, or real-life connections and has had a rapid development in China in the past few years. This paper aims to develop a fuzzy social network service analysis method, which combines graph theory with related fuzzy approach, to analyze the social network structural features and the distribution characteristics of interpersonal nodes in SNS community. A case study on a very famous Chinese tourism BBS-Tianya-is conducted to illustrate and validate the proposed approach. The research findings are as follows: (1) The attraction degrees of various areas in the forum are significantly different; (2) interpersonal nodes in the forum are concentrated relatively; (3) the fuzzy out-degrees and the fuzzy in-degrees of interpersonal nodes in the forum conflict each other; and (4) the distribution of interpersonal nodes is influenced by geographical relations. These findings can directly support social network service management and particularly tourism online service developments. © Springer-Verlag Berlin Heidelberg 2014

A computational method for genotype calling in family-based sequencing data

Background: As sequencing technologies can help researchers detect common and rare variants across the human genome in many individuals, it is known that jointly calling genotypes across multiple individuals based on linkage disequilibrium (LD) can facilitate the analysis of low to modest coverage sequence data. However, genotype-calling methods for family-based sequence data, particularly for complex families beyond parent-offspring trios, are still lacking. Results: In this study, first, we proposed an algorithm that considers both linkage disequilibrium (LD) patterns and familial transmission in nuclear and multi-generational families while retaining the computational efficiency. Second, we extended our method to incorporate external reference panels to analyze family-based sequence data with a small sample size. In simulation studies, we show that modeling multiple offspring can dramatically increase genotype calling accuracy and reduce phasing and Mendelian errors, especially at low to modest coverage. In addition, we show that using external panels can greatly facilitate genotype calling of sequencing data with a small number of individuals. We applied our method to a whole genome sequencing study of 1339 individuals at ~10X coverage from the Minnesota Center for Twin and Family Research. Conclusions: The aggregated results show that our methods significantly outperform existing ones that ignore family constraints or LD information. We anticipate that our method will be useful for many ongoing family-based sequencing projects. We have implemented our methods efficiently in a C++ program FamLDCaller, which is available from http://www.pitt.edu/~wec47/famldcaller.html

The Top Window for dark matter

We investigate a scenario that the top quark is the only window to the dark matter particle. We use the effective Lagrangian approach to write down the interaction between the top quark and the dark matter particle. Requiring the dark matter satisfying the relic density we obtain the size of the effective interaction. We show that the scenario can be made consistent with the direct and indirect detection experiments by adjusting the size of the effective coupling. Finally, we calculate the production cross section for $t\bar t + \chi \bar \chi$ at the Large Hadron Collider (LHC), which will give rise to an interesting signature of a top-pair plus large missing energy.Comment: 17 pages including 8 figures; added references and a footnot

SplitPocket: identification of protein functional surfaces and characterization of their spatial patterns

SplitPocket (http://pocket.uchicago.edu/) is a web server to identify functional surfaces of protein from structure coordinates. Using the Alpha Shape Theory, we previously developed an analytical approach to identify protein functional surfaces by the geometric concept of a split pocket, which is a pocket split by a binding ligand. Our geometric approach extracts site-specific spatial information from coordinates of structures. To reduce the search space, probe radii are designed according to the physicochemical textures of molecules. The method uses the weighted Delaunay triangulation and the discrete flow algorithm to obtain geometric measurements and spatial patterns for each predicted pocket. It can also measure the hydrophobicity on a surface patch. Furthermore, we quantify the evolutionary conservation of surface patches by an index derived from the entropy scores in HSSP (homology-derived secondary structure of proteins). We have used the method to examine ∼1.16 million potential pockets and identified the split pockets in >26 000 structures in the Protein Data Bank. This integrated web server of functional surfaces provides a source of spatial patterns to serve as templates for predicting the functional surfaces of unbound structures involved in binding activities. These spatial patterns should also be useful for protein functional inference, structural evolution and drug design

Internet-based Framework to Support Integration of Customer in the Design of Customizable Products

A necessary element to design and produce customer-centric products is the integration of customers in the design process. Challenges faced during customer integration into the design process include generating models of the customized product, performing analysis of these to determine feasibility, and optimizing to increase the performance. These tasks have to be performed relatively quickly, if not in real time, to provide feedback to the customer. The focus of this article is to present a framework that utilizes CAD, finite element analysis (FEA), and optimization to integrate the customer into the design process via the Internet for delivering user customized products. The design analysis, evaluation, and optimization need to be automated and enhanced to enable operation over the Internet. A product family CAD/FEA template has been developed to perform analysis, along with a general formulation to optimize the customized product. The CAD/FEA template generalizes the geometry building and analysis of each configuration developed using a product platform approach. The proposed setup is demonstrated through the use of a bicycle frame family. In this study, the focus is on the application of optimization and FEA to facilitate the design of customer-centric products.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

α-Actinin and Filamin Cooperatively Enhance the Stiffness of Actin Filament Networks

BACKGROUND: The close subcellular proximity of different actin filament crosslinking proteins suggests that these proteins may cooperate to organize F-actin structures to drive complex cellular functions during cell adhesion, motility and division. Here we hypothesize that alpha-actinin and filamin, two major F-actin crosslinking proteins that are both present in the lamella of adherent cells, display synergistic mechanical functions. METHODOLOGY/PRINCIPAL FINDINGS: Using quantitative rheology, we find that combining alpha-actinin and filamin is much more effective at producing elastic, solid-like actin filament networks than alpha-actinin and filamin separately. Moreover, F-actin networks assembled in the presence of alpha-actinin and filamin strain-harden more readily than networks in the presence of either alpha-actinin or filamin. SIGNIFICANCE: These results suggest that cells combine auxiliary proteins with similar ability to crosslink filaments to generate stiff cytoskeletal structures, which are required for the production of internal propulsive forces for cell migration, and that these proteins do not have redundant mechanical functions