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

Properties of continuous Fourier extension of the discrete cosine transform and its multidimensional generalization

A versatile method is described for the practical computation of the discrete Fourier transforms (DFT) of a continuous function $g(t)$ given by its values $g_{j}$ at the points of a uniform grid $F_{N}$ generated by conjugacy classes of elements of finite adjoint order $N$ in the fundamental region $F$ of compact semisimple Lie groups. The present implementation of the method is for the groups SU(2), when $F$ is reduced to a one-dimensional segment, and for $SU(2)\times ... \times SU(2)$ in multidimensional cases. This simplest case turns out to result in a transform known as discrete cosine transform (DCT), which is often considered to be simply a specific type of the standard DFT. Here we show that the DCT is very different from the standard DFT when the properties of the continuous extensions of these two discrete transforms from the discrete grid points $t_j; j=0,1, ... N$ to all points $t \in F$ are considered. (A) Unlike the continuous extension of the DFT, the continuous extension of (the inverse) DCT, called CEDCT, closely approximates $g(t)$ between the grid points $t_j$. (B) For increasing $N$, the derivative of CEDCT converges to the derivative of $g(t)$. And (C), for CEDCT the principle of locality is valid. Finally, we use the continuous extension of 2-dimensional DCT to illustrate its potential for interpolation, as well as for the data compression of 2D images.Comment: submitted to JMP on April 3, 2003; still waiting for the referee's Repor

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 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

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

Model for eukaryotic tail-anchored protein binding based on the structure of Get3

The Get3 ATPase directs the delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER). TA-proteins are characterized by having a single transmembrane helix (TM) at their extreme C terminus and include many essential proteins, such as SNAREs, apoptosis factors, and protein translocation components. These proteins cannot follow the SRP-dependent co-translational pathway that typifies most integral membrane proteins; instead, post-translationally, these proteins are recognized and bound by Get3 then delivered to the ER in the ATP dependent Get pathway. To elucidate a molecular mechanism for TA protein binding by Get3 we have determined three crystal structures in apo and ADP forms from Saccharomyces cerevisae (ScGet3-apo) and Aspergillus fumigatus (AfGet3-apo and AfGet3-ADP). Using structural information, we generated mutants to confirm important interfaces and essential residues. These results point to a model of how Get3 couples ATP hydrolysis to the binding and release of TA-proteins

Modelling Unsteady Processes with the Direct Simulation Monte Carlo Technique

Over the past 40 years, the Direct Simulation Monte Carlo (DSMC) technique has been developed into a flexible and effective solver for flow problems in the rarefied to near continuum regime. However, even with modern parallelised code, the efficient computation of unsteady near-continuum flows, which are important in processes such as Pulsed Pressure Chemical Vapour Deposition (PP-CVD), remains a challenge. We have developed an unsteady parallel DSMC code (PDSC) utilising advanced features such as transient adaptive sub-cells to ensure nearest neighbour collisions and a temporal-variable time step to reduce computation time. This technique is combined with a unique post-processor called the DMSC Rapid Ensemble Averaging Method (DREAM) which reduces the statistical scatter in the data sets produced by PDSC. The combined method results in a significant memory and computational reduction over ensemble averaging DSMC, while maintaining low statistical scatter in the results. The unsteady code has been validated by simulation of shock-tube flow and unsteady Couette flow, and a number of test cases have been demonstrated including shock impingement on wedges. The technique is currently being used to model the development of an underexpanded jet in a PP-CVD reactor

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

Scalar-Torsion Mode in a Cosmological Model of the Poincar\'{e} Gauge Theory of Gravity

We investigate the equation of state (EoS) of the scalar-torsion mode in Poincar\'{e} gauge theory of gravity. We concentrate on two cases with the constant curvature solution and positive kinetic energy, respectively. In the former, we find that the torsion EoS has different values in the various stages of the universe. In particular, it behaves like the radiation (matter) EoS of $w_r=1/3$ ($w_m=0$) in the radiation (matter) dominant epoch, while in the late time the torsion density is supportive for the accelerating universe. In the latter, our numerical analysis shows that in general the EoS has an asymptotic behavior in the high redshift regime, while it could cross the phantom divide line in the low redshift regime.Comment: 12 pages, 2 figures, title changed, revised version accepted for publication in JCA

Branching ratios and CP-violating asymmetries of Bs→h1h2B_s \to h_1 h_2 decays in the general two-Higgs doublet models

Based on the low-energy effective Hamiltonian with the generalized factorization, we calculate the new physics contributions to branching ratios and CP-violating asymmetries of the charmless hadronic decays $B_s \to h_1 h_2$ in the standard model and the general two-Higgs doublet models (models I, II, and III). Within the considered paramter space, we find the following. (a) In models I and II, the new physics corrections are always small in size and will be masked by other larger known theoretical uncertainties. (b) In model III, the new physics corrections to the branching ratios of those QCD penguin-dominated decays \ov B_s \to K^0\etapp, K^+ K^{-*}, etc., are large in size and insensitive to the variations of \mhp and \nceff. For tree- or electroweak penguin-dominated decay modes, however, the new physics corrections are very small in size. (c) For \ov B_s \to K^+ K^{-*} and other seven decay modes, the branching ratios are at the level of $(1-3)\times 10^{-5}$ and will be measurable at the future hadron colliders with large $b$ production. (d) Among the studied thirty nine $B_s$ meson decay modes, seven of them can have a CP-violating asymmetry ${\cal A}_{CP}$ larger than 20% in magnitude. The new physics corrections are small or moderate in magnitude. (e) Because of its large and \nceff stable branching ratio and CP violating asymmetry, the decay \ov B_s \to K^+ K^{-*} seems to be the "best" channel to find CP violation of $B_s$ system through studies of two-body charmless decays of $B_s$ meson.Comment: 39 pages, Revtex, 9 eps figures, final version accepted for publication in Phys.Rev.