Albumin concentrations are primarily determined by the body cell mass and the systemic inflammatory response in cancer patients with weight loss

The association between hypoalbuminemia and poor prognosis in patients with cancer is well recognized. However, the factors that contribute to the fall in albumin concentrations are not well understood. In the present study, we examined the relationship between circulating albumin concentrations, weight loss, the body cell mass (measured using total body potassium), and the presence of an inflammatory response (measured using C- reactive protein) in male patients (n=40) with advanced lung or gastrointestinal cancer. Albumin concentrations were significantly correlated with the percent ideal body weight (r=0.390, p lt 0.05), extent of reported weight loss (r=-0.492, p lt 0.01), percent predicted total body potassium (adjusted for age, height, and weight, r=0.686, p lt 0.001), and logo C-reactive protein concentrations (r=-0.545, p lt 0.001). On multiple regression analysis, the percent predicted total body potassium and log(10) C-reactive protein concentrations accounted for 63% of the variation in albumin concentrations (r(2) = 0.626, p lt 0.001). The interrelationship between albumin, body cell mass, and the inflammatory response is consistent with the concept that the presence of an ongoing inflammatory response contributes to the progressive loss of these vital protein components of the body and the subsequent death of patients with advanced cancer

An investigation of fingerstick blood collection for pointof- care HIV-1 viral load monitoring in South Africa

Background: Viral load (VL) quantification is an important tool in determining newly developed drug resistance or problems with adherence to antiretroviral therapy (ART) in HIV-positive patients. VL monitoring is becoming the standard of care in many resource-limited settings. Testing in resource-limited settings may require sampling by fingerstick because of general shortages of skilled phlebotomists and the expense of venepuncture supplies and problems with their distribution.Objective: To assess the feasibility and ease of collecting 150 μL capillary blood needed for the use of a novel collection device following a classic fingerstick puncture.Methods: Patients were recruited by the study nurse upon arrival for routine ART monitoring at the Themba Lethu Clinic in Johannesburg, South Africa. Each step of the fingerstick and blood collection protocol was observed, and their completion or omission was recorded.Results: One hundred and three patients consented to the study, of whom three were excluded owing to the presence of callouses. From a total of 100 patients who consented and were enrolled, 98% of collection attempts were successful and 86% of participants required only one fingerstick to successfully collect 150 μL capillary blood. Study nurse adherence to the fingerstick protocol revealed omissions in several steps that may lower the success rate of capillary blood collection and reduce the performance of a subsequent VL assay.Conclusion: The findings of this study support the feasibility of collecting 150 μL of capillary blood via fingerstick for point-of-care HIV-1 VL testing in a resource-limited setting

Synthesis-View: visualization and interpretation of SNP association results for multi-cohort, multi-phenotype data and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Initial genome-wide association study (GWAS) discoveries are being further explored through the use of large cohorts across multiple and diverse populations involving meta-analyses within large consortia and networks. Many of the additional studies characterize less than 100 single nucleotide polymorphisms (SNPs), often include multiple and correlated phenotypic measurements, and can include data from multiple-sites, multiple-studies, as well as multiple race/ethnicities. New approaches for visualizing resultant data are necessary in order to fully interpret results and obtain a broad view of the trends between DNA variation and phenotypes, as well as provide information on specific SNP and phenotype relationships.</p> <p>Results</p> <p>The Synthesis-View software tool was designed to visually synthesize the results of the aforementioned types of studies. Presented herein are multiple examples of the ways Synthesis-View can be used to report results from association studies of DNA variation and phenotypes, including the visual integration of p-values or other metrics of significance, allele frequencies, sample sizes, effect size, and direction of effect.</p> <p>Conclusions</p> <p>To truly allow a user to visually integrate multiple pieces of information typical of a genetic association study, innovative views are needed to integrate multiple pieces of information. As a result, we have created "Synthesis-View" software for the visualization of genotype-phenotype association data in multiple cohorts. Synthesis-View is freely available for non-commercial research institutions, for full details see <url>https://chgr.mc.vanderbilt.edu/synthesisview</url>.</p

On acceleration of Krylov-subspace-based Newton and Arnoldi iterations for incompressible CFD: replacing time steppers and generation of initial guess

We propose two techniques aimed at improving the convergence rate of steady state and eigenvalue solvers preconditioned by the inverse Stokes operator and realized via time-stepping. First, we suggest a generalization of the Stokes operator so that the resulting preconditioner operator depends on several parameters and whose action preserves zero divergence and boundary conditions. The parameters can be tuned for each problem to speed up the convergence of a Krylov-subspace-based linear algebra solver. This operator can be inverted by the Uzawa-like algorithm, and does not need a time-stepping. Second, we propose to generate an initial guess of steady flow, leading eigenvalue and eigenvector using orthogonal projection on a divergence-free basis satisfying all boundary conditions. The approach, including the two proposed techniques, is illustrated on the solution of the linear stability problem for laterally heated square and cubic cavities

Carbon and climate system coupling on timescales from the Precambrian to the Anthropocene

Author Posting. © Annual Reviews, 2007. This is the author's version of the work. It is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Environment and Resources 32 (2007): 31-66, doi:10.1146/annurev.energy.32.041706.124700.The global carbon and climate systems are closely intertwined, with biogeochemical processes responding to and driving climate variations. Over a range of geological and historical time-scales, warmer climate conditions are associated with higher atmospheric levels of CO2, an important climate-modulating greenhouse gas. The atmospheric CO2-temperature relationship reflects two dynamics, the planet’s climate sensitivity to a perturbation in atmospheric CO2 and the stability of non-atmospheric carbon reservoirs to evolving climate. Both exhibit non-linear behavior, and coupled carbon-climate interactions have the potential to introduce both stabilizing and destabilizing feedback loops into the Earth System. Here we bring together evidence from a wide range of geological, observational, experimental and modeling studies on the dominant interactions between the carbon cycle and climate. The review is organized by time-scale, spanning interannual to centennial climate variability, Holocene millennial variations and Pleistocene glacial-interglacial cycles, and million year and longer variations over the Precambrian and Phanerozoic. Our focus is on characterizing and, where possible quantifying, the emergent behavior internal to the coupled carbon-climate system as well as the responses of the system to external forcing from tectonics, orbital dynamics, catastrophic events, and anthropogenic fossil fuel emissions. While there are many unresolved uncertainties and complexity in the carbon cycle, one emergent property is clear across time scales: while CO2 can increase in the atmosphere quickly, returning to lower levels through natural processes is much slower, so the consequences of the human perturbation will far outlive the emissions that caused them.S. Doney acknowledges support from the NSF Geosciences Carbon and Water program (NSF ATM-0628582) and the WHOI W. Van Alan Clark Sr. Chair. D. Schimel acknowledges support from the NSF Biocomplexity in the Environment program (NSF EAR-0321918)

The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents

Morpholino Gene Knockdown in Adult Fundulus heteroclitus: Role of SGK1 in Seawater Acclimation

The Atlantic killifish (Fundulus heteroclitus) is an environmental sentinel organism used extensively for studies on environmental toxicants and salt (NaCl) homeostasis. Previous research in our laboratory has shown that rapid acclimation of killifish to seawater is mediated by trafficking of CFTR chloride channels from intracellular vesicles to the plasma membrane in the opercular membrane within the first hour in seawater, which enhances chloride secretion into seawater, thereby contributing to salt homeostasis. Acute transition to seawater is also marked by an increase in both mRNA and protein levels of serum glucocorticoid kinase 1 (SGK1) within 15 minutes of transfer. Although the rise in SGK1 in gill and its functional analog, the opercular membrane, after seawater transfer precedes the increase in membrane CFTR, a direct role of SGK1 in elevating membrane CFTR has not been established in vivo. To test the hypothesis that SGK1 mediates the increase in plasma membrane CFTR we designed two functionally different vivo-morpholinos to knock down SGK1 in gill, and developed and validated a vivo-morpholino knock down technique for adult killifish. Injection (intraperitoneal, IP) of the splice blocking SGK1 vivo-morpholino reduced SGK1 mRNA in the gill after transition from fresh to seawater by 66%. The IP injection of the translational blocking and splice blocking vivo-morpholinos reduced gill SGK1 protein abundance in fish transferred from fresh to seawater by 64% and 53%, respectively. Moreover, knock down of SGK1 completely eliminated the seawater induced rise in plasma membrane CFTR, demonstrating that the increase in SGK1 protein is required for the trafficking of CFTR from intracellular vesicles in mitochondrion rich cells to the plasma membrane in the gill during acclimation to seawater. This is the first report of the use of vivo-morpholinos in adult killifish and demonstrates that vivo-morpholinos are a valuable genetic tool for this environmentally relevant model organism

Nanomechanical Detection of Itinerant Electron Spin Flip

Spin is an intrinsically quantum property, characterized by angular momentum. A change in the spin state is equivalent to a change in the angular momentum or mechanical torque. This spin-induced torque has been invoked as the intrinsic mechanism in experiments ranging from the measurements of angular momentum of photons g-factor of metals and magnetic resonance to the magnetization reversal in magnetic multi-layers A spin-polarized current introduced into a nonmagnetic nanowire produces a torque associated with the itinerant electron spin flip. Here, we report direct measurement of this mechanical torque and itinerant electron spin polarization in an integrated nanoscale torsion oscillator, which could yield new information on the itinerancy of the d-band electrons. The unprecedented torque sensitivity of 10^{-22} N m/ \sqrt{Hz} may enable applications for spintronics, precision measurements of CP-violating forces, untwisting of DNA and torque generating molecules.Comment: 14 pages, 4 figures. visit http://nano.bu.edu/ for related paper