Deconvolution analysis for classifying gastric adenocarcinoma patients based on differential scanning calorimetry serum thermograms

Recently, differential scanning calorimetry (DSC) has been acknowledged as a novel tool for diagnosing and monitoring several diseases. This highly sensitive technique has been traditionally used to study thermally induced protein folding/unfolding transitions. In previous research papers, DSC profiles from blood samples of patients were analyzed and they exhibited marked differences in the thermal denaturation profile. Thus, we investigated the use of this novel technology in blood serum samples from 25 healthy subjects and 30 patients with gastric adenocarcinoma (GAC) at different stages of tumor development with a new multiparametric approach. The analysis of the calorimetric profiles of blood serum from GAC patients allowed us to discriminate three stages of cancer development (I to III) from those of healthy individuals. After a multiparametric analysis, a classification of blood serum DSC parameters from patients with GAC is proposed. Certain parameters exhibited significant differences (P < 0.05) and allowed the discrimination of healthy subjects/patients from patients at different tumor stages. The results of this work validate DSC as a novel technique for GAC patient classification and staging, and offer new graphical tools and value ranges for the acquired parameters in order to discriminate healthy from diseased subjects with increased disease burden

Proper motions of the HH1 jet

We describe a new method for determining proper motions of extended objects, and a pipeline developed for the application of this method. We then apply this method to an analysis of four epochs of [S~II] HST images of the HH~1 jet (covering a period of $\sim 20$~yr). We determine the proper motions of the knots along the jet, and make a reconstruction of the past ejection velocity time-variability (assuming ballistic knot motions). This reconstruction shows an "acceleration" of the ejection velocities of the jet knots, with higher velocities at more recent times. This acceleration will result in an eventual merging of the knots in $\sim 450$~yr and at a distance of $\sim 80"$ from the outflow source, close to the present-day position of HH~1.Comment: 12 pages, 8 figure

Pranlukast Antagonizes CD49f and Reduces Sternness in Triple-Negative Breast Cancer Cells

Introduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clini-cally tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces con-formational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transacti-vation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients

High-Frequency (> 100 GHz) Electronic Devices

Contains reports on four research projects, the research facility and a list of publications.Defense Advanced Research Projects Agency Contract MDA972-90-C-0021National Aeronautics and Space Administration Grant NAG2-693National Science Foundation Grant ECS 91-0933

Measurement report: Atmospheric new particle formation at a peri-urban site in Lille, northern France

Formation of ultrafine particles (UFPs) in the urban atmosphere is expected to be less favored than in the rural atmosphere due to the high existing particle surface area acting as a sink for newly formed particles. Despite large condensation sink (CS) values, previous comparative studies between rural and urban sites reported higher frequency of new particle formation (NPF) events over urban sites in comparison to background sites as well as higher particle formation and growth rates attributed to the higher concentration of condensable species. The present study aims at a better understanding the environmental factors favoring, or disfavoring, atmospheric NPF over Lille, a large city in the north of France, and to analyze their impact on particle number concentration using a 4-year long-term dataset. The results highlight a strong seasonal variation of NPF occurrences with a maximum frequency observed during spring (27 events) and summer (53 events). It was found that high temperature (T&gt;295 K), low relative humidity (RH &lt;45 %), and high solar radiation are ideal to observe NPF events over Lille. Relatively high CS values (i.e., ∼2×10-2 s−1) are reported during event days suggesting that high CS does not inhibit the occurrence of NPF over the ATmospheric Observations in LiLLE (ATOLL) station. Moreover, the particle growth rate was positively correlated with temperatures most probably due to higher emission of precursors. Finally, the nucleation strength factor (NSF) was calculated to highlight the impact of those NPF events on particle number concentrations. NSF reached a maximum of four in summer, evidencing a huge contribution of NPF events to particle number concentration at this time of the year.</p

Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy.

The underlying genetic defect in most cases of dilated cardiomyopathy (DCM), a common inherited heart disease, remains unknown. Intriguingly, many patients carry single missense variants of uncertain pathogenicity targeting the giant protein titin, a fundamental sarcomere component. To explore the deleterious potential of these variants, we first solved the wild-type and mutant crystal structures of I21, the titin domain targeted by pathogenic variant p.C3575S. Although both structures are remarkably similar, the reduced hydrophobicity of deeply buried position 3575 strongly destabilizes the mutant domain, a scenario supported by molecular dynamics simulations and by biochemical assays that show no disulfide involving C3575. Prompted by these observations, we have found that thousands of similar hydrophobicity-reducing variants associate specifically with DCM. Hence, our results imply that titin domain destabilization causes DCM, a conceptual framework that not only informs pathogenicity assessment of gene variants but also points to therapeutic strategies counterbalancing protein destabilization.S