A spectral projection method for transmission eigenvalues

In this paper, we consider a nonlinear integral eigenvalue problem, which is a reformulation of the transmission eigenvalue problem arising in the inverse scattering theory. The boundary element method is employed for discretization, which leads to a generalized matrix eigenvalue problem. We propose a novel method based on the spectral projection. The method probes a given region on the complex plane using contour integrals and decides if the region contains eigenvalue(s) or not. It is particularly suitable to test if zero is an eigenvalue of the generalized eigenvalue problem, which in turn implies that the associated wavenumber is a transmission eigenvalue. Effectiveness and efficiency of the new method are demonstrated by numerical examples.Comment: The paper has been accepted for publication in SCIENCE CHINA Mathematic

Inhibition of Intestinal Thiamin Transport in Rat Model of Sepsis.

ObjectivesThiamin deficiency is highly prevalent in patients with sepsis, but the mechanism by which sepsis induces thiamin deficiency is unknown. This study aimed to determine the influence of various severity of sepsis on carrier-mediated intestinal thiamin uptake, level of expressions of thiamin transporters (thiamin transporter-1 and thiamin transporter-2), and mitochondrial thiamin pyrophosphate transporter.DesignRandomized controlled study.SettingResearch laboratory at a Veterans Affairs Medical Center.SubjectsTwenty-four Sprague-Dawley rats were randomized into controls, mild, moderate, and severe sepsis with equal number of animals in each group.InterventionsSepsis was induced by cecal ligation and puncture with the cecum ligated below the cecal valve at 25%, 50%, and 75% of cecal length, defined as severe, moderate, and mild sepsis, respectively. Control animals underwent laparotomy only.Measurements and main resultsAfter 2 days of induced sepsis, carrier-mediated intestinal thiamin uptake was measured using [H]thiamin. Expressions of thiamin transporter-1, thiamin transporter-2, and mitochondrial thiamin pyrophosphate transporter proteins and messenger RNA were measured. Proinflammatory cytokines (interleukin-1β and interleukin-6) and adenosine triphosphate were also measured. Sepsis inhibited [H]thiamin uptake, and the inhibition was a function of sepsis severity. Both cell membrane thiamin transporters and mitochondrial thiamin pyrophosphate transporter expression levels were suppressed; also levels of adenosine triphosphate in the intestine of animals with moderate and severe sepsis were significantly lower than that of sham-operated controls.ConclusionsFor the first time, we demonstrated that sepsis inhibited carrier-mediated intestinal thiamin uptake as a function of sepsis severity, suppressed thiamin transporters and mitochondrial thiamin pyrophosphate transporter, leading to adenosine triphosphate depletion

Mechanism of Anti-Virulence Compound 187R Inhibiting Pseudomonas Aeruginosa Type III Secretion System

Antibiotics have been widely used for treating bacterial infectious diseases. However, the rapidly emerging of antibiotic resistance has dramatically decreased the efficacy of antibiotics and poses a serious worldwide crisis. In addition, the cell components serving as antibiotics’ targets are conserved in many different bacterial species, as a result, antibiotic treatments disrupt the host microbiota and negatively influence the hosts health condition. Therefore, new alternative strategies for fighting infectious diseases without causing antibiotic resistance and disturbing the host microbiota are needed. Type 3 secretion system (T3SS) is a highly conserved virulence factor presents in many different Gram-negative pathogens. It is required for pathogens such as P. aeruginosa, surviving and initiating infection in their hosts. Therefore, targeting the T3SS is a promising alternative strategy for developing new antimicrobial therapies without disrupting the hosts’ microbial community. Here, we identified a potent T3SS inhibitor, designated 187R, which strongly inhibits the expression of P. aeruginosa T3SS. Our data suggests that 187R inhibits T3SS expression through reducing the T3SS master regulator ExsA at the post-translational level. The impact of this anti-virulence compound on the hosts’ microbial community was also tested using Arabidopsis thaliana phyllosphere as a model. We demonstrates that compared to the traditional antibiotics, our T3SS inhibitor 187R can preserve the microbial community better than antibiotics

Roles of B Cell-Intrinsic TLR Signals in Systemic Lupus Erythematosus

Toll-like receptors (TLRs) are a large family of pattern recognition receptors. TLR signals are involved in the pathogenesis of systemic lupus erythematosus. Mouse and human B cells constitutively express most TLRs. Many B cell subpopulations are highly responsive to certain TLR ligation, including B-1 B cells, transitional B cells, marginal zone B cells, germinal center B cell and memory B cells. The B cell-intrinsic TLR signals play critical roles during lupus process. In this review, roles of B cell-intrinsic TLR2, 4, 7, 8 and 9 signals are discussed during lupus pathogenesis in both mouse model and patients. Moreover, mechanisms underlying TLR ligation-triggered B cell activation and signaling pathways are highlighted.published_or_final_versio

Probing binding and cellular activity of pyrrolidinone and piperidinone small molecules targeting the urokinase receptor

The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here, we evaluate the binding and biological activity of a new class of pyrrolidinone and piperidinone compounds, along with derivatives of previously-identified pyrazole and propylamine compounds. Competition assays revealed that the compounds displace a fluorescently labeled peptide (AE147-FAM) with inhibition constant (Ki ) values ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics (MD) simulations and free energy calculations suggested the pyrazole-based and piperidinone-based compounds adopt different binding modes, despite their similar two-dimensional structures. In cells, pyrazole-based compounds showed significant inhibition of breast adenocarcinoma (MDA-MB-231) and pancreatic ductal adenocarcinoma (PDAC) cell proliferation, but piperidinone-containing compounds exhibited no cytotoxicity even at concentrations of 100 μM. One pyrazole-based compound impaired MDA-MB-231 invasion, adhesion, and migration in a concentration-dependent manner, while the piperidinone inhibited only invasion. The pyrazole derivative inhibited matrix metalloprotease-9 (gelatinase) activity in a concentration-dependent manner, while the piperidinone showed no effect suggesting different mechanisms for inhibition of cell invasion. Signaling studies further highlighted these differences, showing that pyrazole compounds completely inhibited ERK phosphorylation and impaired HIF1α and NF-κB signaling, while pyrrolidinones and piperidinones had no effect. Annexin V staining suggested that the effect of the pyrazole-based compound on proliferation was due to cell killing through an apoptotic mechanism. The compounds identified represent valuable leads in the design of further derivatives with higher affinities and potential probes to unravel the protein-protein interactions of uPAR

A Phantom Study on Target Localization Accuracy Using Cone-Beam Computed Tomography

The purpose of this study is to evaluate the 3-dimensional target localization accuracy of cone-beam computed tomography (CBCT) using an on-board imager (OBI). An anthropomorphic pelvis phantom was used to simulate a range of offsets in the three translational directions and rotations around each of the three axes. After a translational or rotational offset was applied, a CBCT scan of the phantom was followed by image registration to detect the offsets in six degrees. The detected offsets were compared to the offset actually applied to give the detection error of the phantom position. Afterwards, the phantom was positioned by automatically moving the couch based on the detected offsets. A second CBCT scan followed by image registration was performed to give the residual error of the phantom positioning. On the average the detection errors and their standard deviations along the lateral, longitudinal and vertical axis are 0.3 ± 0.1, 0.3 ± 0.1 and 0.4 ± 0.1 mm respectively with respect to translational shifts ranging from 0 to 10 mm. The corresponding residual errors after positioning are 0.3 ± 0.1, 0.5 ± 0.1 and 0.3 ± 0.1 mm. For simulated rotational shifts ranging from 0 to 5 degrees, the average detection error and their standard deviation around lateral, longitudinal, and vertical axes are 0.1 ± 0.0, 0.2 ± 0.0, and 0.2 ± 0.0 degrees respectively. The residual errors after positioning are 0.4 ± 0.1, 0.6 ± 0.1, and 0.3 ± 0.1 mm along the lateral, longitudinal and vertical directions. These results indicate that target localization based on CBCT is capable of achieving sub-millimeter accuracy

Exploring a structural protein-drug interactome for new therapeutics in lung cancer

The pharmacology of drugs is often defined by more than one protein target. This property can be exploited to use approved drugs to uncover new targets and signaling pathways in cancer. Towards enabling a rational approach to uncover new targets, we expand a structural protein-ligand interactome () by scoring the interaction among 1000 FDA-approved drugs docked to 2500 pockets on protein structures of the human genome. This afforded a drug-target network whose properties compared favorably with previous networks constructed using experimental data. Among drugs with the highest degree and betweenness two are cancer drugs and one is currently used for treatment of lung cancer. Comparison of predicted cancer and non-cancer targets reveals that the most cancer-specific compounds were also the most selective compounds. Analysis of compound flexibility, hydrophobicity, and size showed that the most selective compounds were low molecular weight fragment-like heterocycles. We use a previously-developed screening approach using the cancer drug erlotinib as a template to screen other approved drugs that mimic its properties. Among the top 12 ranking candidates, four are cancer drugs, two of them kinase inhibitors (like erlotinib). Cellular studies using non-small cell lung cancer (NSCLC) cells revealed that several drugs inhibited lung cancer cell proliferation. We mined patient records at the Regenstrief Medical Record System to explore the possible association of exposure to three of these drugs with occurrence of lung cancer. Preliminary in vivo studies using the non-small cell lung cancer (NCLSC) xenograft model showed that losartan- and astemizole-treated mice had tumors that weighed 50 (p < 0.01) and 15 (p < 0.01) percent less than the treated controls. These results set the stage for further exploration of these drugs and to uncover new drugs for lung cancer therapy

Quantum Algorithms and Lower Bounds for Finite-Sum Optimization

Finite-sum optimization has wide applications in machine learning, covering important problems such as support vector machines, regression, etc. In this paper, we initiate the study of solving finite-sum optimization problems by quantum computing. Specifically, let $f_1,\ldots,f_n\colon\mathbb{R}^d\to\mathbb{R}$ be $\ell$-smooth convex functions and $\psi\colon\mathbb{R}^d\to\mathbb{R}$ be a $\mu$-strongly convex proximal function. The goal is to find an $\epsilon$-optimal point for $F(\mathbf{x})=\frac{1}{n}\sum_{i=1}^n f_i(\mathbf{x})+\psi(\mathbf{x})$. We give a quantum algorithm with complexity $\tilde{O}\big(n+\sqrt{d}+\sqrt{\ell/\mu}\big(n^{1/3}d^{1/3}+n^{-2/3}d^{5/6}\big)\big)$, improving the classical tight bound $\tilde{\Theta}\big(n+\sqrt{n\ell/\mu}\big)$. We also prove a quantum lower bound $\tilde{\Omega}(n+n^{3/4}(\ell/\mu)^{1/4})$ when $d$ is large enough. Both our quantum upper and lower bounds can extend to the cases where $\psi$ is not necessarily strongly convex, or each $f_i$ is Lipschitz but not necessarily smooth. In addition, when $F$ is nonconvex, our quantum algorithm can find an $\epsilon$-critial point using $\tilde{O}(n+\ell(d^{1/3}n^{1/3}+\sqrt{d})/\epsilon^2)$ queries.Comment: 27 pages. To appear in the Forty-first International Conference on Machine Learning International Conference on Machine Learning (ICML 2024