An exact approach to the problem of extracting an embedded network matrix

We study the problem of detecting a maximum embedded network submatrix in a {−1,0,+1}-matrix. Our aim is to solve the problem to optimality. We introduce a 0–1 integer linear programming formulation for this problem based on its representation over a signed graph. A polyhedral study is presented and a branch-and-cut algorithm is described for finding an optimal solution to the problem. Some computational experiments are carried out over a set of instances available in the literature as well as over a set of random instances.     

Cobra Venom Factor Boosts Arteriogenesis in Mice

Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU⁺) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68⁺/MRC-1⁺ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth.     

Bacterial Nucleotidyl Cyclases Activated by Calmodulin or Actin in Host Cells: Enzyme Specificities and Cytotoxicity Mechanisms Identified to Date

Many pathogens manipulate host cell cAMP signaling pathways to promote their survival and proliferation. Bacterial Exoenzyme Y (ExoY) toxins belong to a family of invasive, structurally-related bacterial nucleotidyl cyclases (NC). Inactive in bacteria, they use proteins that are uniquely and abundantly present in eukaryotic cells to become potent, unregulated NC enzymes in host cells. Other well-known members of the family include Bacillus anthracis Edema Factor (EF) and Bordetella pertussis CyaA. Once bound to their eukaryotic protein cofactor, they can catalyze supra-physiological levels of various cyclic nucleotide monophosphates in infected cells. Originally identified in Pseudomonas aeruginosa, ExoY-related NC toxins appear now to be more widely distributed among various γ- and β-proteobacteria. ExoY-like toxins represent atypical, poorly characterized members within the NC toxin family. While the NC catalytic domains of EF and CyaA toxins use both calmodulin as cofactor, their counterparts in ExoY-like members from pathogens of the genus Pseudomonas or Vibrio use actin as a potent cofactor, in either its monomeric or polymerized form. This is an original subversion of actin for cytoskeleton-targeting toxins. Here, we review recent advances on the different members of the NC toxin family to highlight their common and distinct functional characteristics at the molecular, cytotoxic and enzymatic levels, and important aspects that need further characterizations.     

Solvation,Cancer Cell Photoinactivation and the Interaction of Chlorin Photosensitizers with a Potential Passive Carrier Non-Ionic Surfactant Tween 80

Cancer and drug-resistant superinfections are common and serious problems afflicting millions worldwide. Photodynamic therapy (PDT) is a successful and clinically approved modality used for the management of many neoplastic and nonmalignant diseases. The combination of the light-activated molecules, so-called photosensitizers (PSs), with an appropriate carrier, is proved to enhance PDT efficacy both in vitro and in vivo. In this paper, we focus on the solvation of several potential chlorin PSs in the 1-octanol/phosphate saline buffer biphasic system, their interaction with non-ionic surfactant Tween 80 and photoinactivation of cancer cells. The chlorin conjugates containing d-galactose and l-arginine fragments are found to have a much stronger affinity towards a lipid-like environment compared to ionic chlorins and form molecular complexes with Tween 80 micelles in water with two modes of binding. The charged macrocyclic PSs are located in the periphery of surfactant micelles near hydrophilic head groups, whereas the d-galactose and l-arginine conjugates are deeper incorporated into the micelle structure occupying positions around the first carbon atoms of the hydrophobic surfactant residue. Our results indicate that both PSs have a pronounced affinity toward the lipid-like environment, leading to their preferential binding to low-density lipoproteins. This and the conjugation of chlorin e₆ with the tumor-targeting molecules are found to enhance their accumulation in cancer cells and PDT efficacy.     

Salvage Chemotherapy with Cisplatin,Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer

Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.     

Fluorescence Spectroscopy of Low-Level Endogenous β-Adrenergic Receptor Expression at the Plasma Membrane of Differentiating Human iPSC-Derived Cardiomyocytes

The potential of human-induced pluripotent stem cells (hiPSCs) to be differentiated into cardiomyocytes (CMs) mimicking adult CMs functional morphology, marker genes and signaling characteristics has been investigated since over a decade. The evolution of the membrane localization of CM-specific G protein-coupled receptors throughout differentiation has received, however, only limited attention to date. We employ here advanced fluorescent spectroscopy, namely linescan Fluorescence Correlation Spectroscopy (FCS), to observe how the plasma membrane abundance of the β₁- and β₂-adrenergic receptors (β_1/2-ARs), labelled using a bright and photostable fluorescent antagonist, evolves during the long-term monolayer culture of hiPSC-derived CMs. We compare it to the kinetics of observed mRNA levels in wildtype (WT) hiPSCs and in two CRISPR/Cas9 knock-in clones. We conduct these observations against the backdrop of our recent report of cell-to-cell expression variability, as well as of the subcellular localization heterogeneity of β-ARs in adult CMs.     

High‐efficiency p‐i‐n organic light‐emitting diodes with long lifetime

Abstract— High‐performance organic light‐emitting diodes (OLEDs) are promoting future applications of solid‐state lighting and flat‐panel displays. We demonstrate here that the performance demands for OLEDs are met by the PIN (p‐doped hole‐transport layer/intrinsically conductive emission layer/n‐doped electron‐transport layer) approach. This approach enables high current efficiency, low driving voltage, as well as long OLED lifetimes. Data on very‐high‐efficiency diodes (power efficiencies exceeding 70 lm/W) incorporating a double‐emission layer, comprised of two bipolar layers doped with tris(phenylpyridine)iridium [Ir(ppy)₃], into the PIN architecture are shown. Lifetimes of more than 220,000 hours at a brightness of 150 cd/m² are reported for a red PIN diode. The PIN approach further allows the integration of highly efficient top‐emitting diodes on a wide range of substrates. This is an important factor, especially for display applications where the compatibility of PIN OLEDs with various kinds of substrates is a key advantage. The PIN concept is very compatible with different backplanes, including passive‐matrix substrates as well as active‐matrix substrates on low‐temperature polysilicon (LTPS) or, in particular, amorphous silicon (a‐Si).     

Poly(N-glycidyl carbazole): A new crosslinkable conjugated polymer

A poly(N-glycidyl carbazole) was synthesized by electropolymerization of 3,6-dibromo-N-glycidyl carbazole. Characterization of both products by different chemical and electrochemical techniques is then discussed. The polymer that showed electronic conductive properties when doped was crosslinked by cis-cyclohexane 1,2 dicarboxylic anhydride. The crosslinking reaction was followed by Fourier-transform infrared spectroscopy (FT-IR). An optimization of the crosslinking conditions was first performed on the monomer and subsequently applied to the polymer. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 73: 1483–1492, 1999