Matrix Metalloproteinases: Pro- and Anti-Angiogenic Activities

Matrix metalloproteinases (MMP) are a family of structurally related proteinases most widely recognized for their ability to degrade extracellular matrix, although recent investigations have demonstrated other biologic functions for these enzymes. MMP are typically not constitutively expressed, but are regulated by: (1) cytokines, growth factors, and cell–cell and cell–matrix interactions that control gene expression; (2) activation of their proenzyme form; and (3) the presence of MMP inhibitors [tissue inhibitors of metalloproteinases, (TIMP)]. MMP have important roles in normal processes including development, wound healing, mammary gland, and uterine involution, but are also involved in angiogenesis, tumor growth, and metastasis. Angiogenesis, characteristically defined as the establishment of new vessels from pre-existing vasculature, is required for biologic processes such as wound healing and pathologic processes such as arthritis, tumor growth, and metastasis. Blocking of MMP activity has been studied for potential therapeutic efficacy in controlling such pathologic processes. Synthetic MMP inhibitors, most notably the hydroxymates, have been engineered for this purpose and are presently in clinical trial. These inhibitors may have broad versus specific MMP inhibitory activity. As increased nonmatrix degrading capabilities of MMP are recognized, however, i.e., cytokine activation, processing of proteins to molecules of distinct biologic function, it becomes less clear whether the nonselective inhibition of MMP activity for all pathologic processes involving MMP is appropriate. This review focuses upon the contribution of MMP to the process of tumor invasion and angiogenesis, and discusses the design and use of MMP inhibitors as therapeutic agents in these processes

Quality of Life with Late-Onset Pompe Disease: Qualitative Interviews and General Public Utility Estimation in the United Kingdom

Background: Late-onset Pompe disease (LOPD) is a rare, progressive neuromuscular condition typically characterized by weakness of skeletal muscles, including those involved in respiration and diaphragmatic dysfunction. Individuals with LOPD typically eventually require mobility and/or ventilatory support. / Objectives: This study aimed to develop health state vignettes and estimate health state utility values for LOPD in the United Kingdom. / Methods: Vignettes were developed for 7 health states of LOPD with states defined in terms of mobility and/or ventilatory support. Vignettes were drafted based on patient-reported outcome data from the Phase 3 PROPEL trial (NCT03729362) and supplemented by a literature review. Qualitative interviews with individuals living with LOPD and clinical experts were conducted to explore the health-related quality-of-life (HRQoL) impact of LOPD and to review the draft vignettes. Vignettes were finalized following a second round of interviews with individuals living with LOPD and used in health state valuation exercises with people of the UK population. Participants rated the health states using the EQ-5D-5L, visual analog scale, and time trade-off interviews. / Results: Twelve individuals living with LOPD and 2 clinical experts were interviewed. Following the interviews, 4 new statements were added regarding dependence on others, bladder control problems, balance issues/fear of falling, and frustration. One hundred interviews with a representative UK population sample were completed. Mean time trade-off utilities ranged from 0.754 (SD = 0.31) (no support) to 0.132 (SD = 0.50) (invasive ventilatory and mobility support-dependent). Similarly, EQ- 5D-5L utilities ranged from 0.608 (SD = 0.12) to -0.078 (SD = 0.22). / Discussion: The utilities obtained in the study are consistent with utilities reported in the literature (0.670-0.853 for nonsupport state). The vignette content was based on robust quantitative and qualitative evidence and captured the main HRQoL impacts of LOPD. The general public rated the health states consistently lower with increasing disease progression. There was greater uncertainty around utility estimates for the severe states, suggesting that participants found it harder to rate them. / Conclusion: This study provides utility estimates for LOPD that can be used in economic modeling of treatments for LOPD. Our findings highlight the high disease burden of LOPD and reinforce the societal value of slowing disease progression

Low frequency noise statistics for the breakdown characterization of ultra-thin gate oxides

We have investigated the statistics of low frequency noise in the tunneling current of ultrathin oxides (2.5nm-4nm) in metal oxide semiconductor capacitors as a function of the applied voltage stress. The statistical analysis includes (i) non-Gaussianity (nG), which is a measure of the degree of temporal correlation in the noise, and (ii) ratio of integrated noise power to the DC leakage current (R). The occurrence of high peaks in nG indicates the appearance of new percolation paths, and the subsequent conduction through these paths is indicated by R. Our results show that the nG and R characteristics are generic for the oxides of different thickness and growth quality and have the potential, in conjunction with leakage itself, of being used as a prognosticator of oxide reliability.Comment: 4 page

Dynamic Wireless Information and Power Transfer Scheme for Nano-Empowered Vehicular Networks

In this paper, we investigate the wireless power transfer and energy-efficiency (EE) optimization problem for nano-centric vehicular networks operating over the terahertz band. The inbody nano-sensors harvest energy from a power station via radio-frequency signal and then use the harvested energy to transmit data to the sink node. By considering the properties of terahertz band (i.e., sensitivity to distance and frequency over the communication path), we adopt the Brownian motion model to develop a time-variant terahertz channel model and to describe the mobility of the nano-sensors. Thus, based on the channel model and energy resources, we further develop a long-term EE optimization problem. The EE optimization is further converted into a series of energy-efficient resource allocation problems over the time slots via equivalent transformation method. The resource allocation problem for each timeslot, which is formulated as a mixed integer nonlinear programming (MINLP), is solved based on the particle swarm optimization (PSO) method. In addition, a dynamic PSO-based EE optimization (DPEEO) algorithm is developed to obtain the sub-optimal solution for the EE optimization problem. By exploiting the special structure of the reformulated problem, an improved DPEEO algorithm, is presented which can handle the problem’s constraints quite well, decreases the research space, and greatly reduces the length of the convergence time. Simulation results validate the theoretical analysis of our system

Molecular epidemiology of NDM-1-producing Enterobacteriaceae and Acinetobacter baumannii isolates from Pakistan

The molecular epidemiology of 66 NDM-producing isolates from 2 Pakistani hospitals was investigated, with their genetic relatedness determined using repetitive sequence-based PCR (Rep-PCR). PCR-based replicon typing and screening for antibiotic resistance genes encoding carbapenemases, other β-lactamases, and 16S methylases were also performed. Rep-PCR suggested a clonal spread of Enterobacter cloacae and Escherichia coli. A number of plasmid replicon types were identified, with the incompatibility A/C group (IncA/C) being the most common (78%). 16S methylase-encoding genes were coharbored in 81% of NDM-producing Enterobacteriaceae. Copyrigh

Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development

Objective: The aim of this study was to explore symptoms and symptom development during the earliest phases of rheumatoid arthritis (RA) in patients with seropositive arthralgia and patients newly diagnosed with RA

Genome-Wide characterization of ascorbate peroxidase gene family in peanut (Arachis hypogea L.) revealed their crucial role in growth and multiple stress tolerance

Ascorbate peroxidase (APX), an important antioxidant enzyme, plays a significant role in ROS scavenging by catalyzing the decrease of hydrogen peroxide under various environmental stresses. Nevertheless, information about the APX gene family and their evolutionary and functional attributes in peanut (Arachis hypogea L.) was not reported. Therefore, a comprehensive genome-wide study was performed to discover the APX genes in cultivated peanut genome. This study identified 166 AhAPX genes in the peanut genome, classified into 11 main groups. The gene duplication analysis showed that AhAPX genes had experienced segmental duplications and purifying selection pressure. Gene structure and motif investigation indicated that most of the AhAPX genes exhibited a comparatively well-preserved exon-intron pattern and motif configuration contained by the identical group. We discovered five phytohormones-, six abiotic stress-, and five growth and development-related cis-elements in the promoter regions of AhAPX. Fourteen putative ah-miRNAs from 12 families were identified, targeting 33 AhAPX genes. Furthermore, we identified 3,257 transcription factors from 38 families (including AP2, ARF, B3, bHLH, bZIP, ERF, MYB, NAC, WRKY, etc.) in 162 AhAPX genes. Gene ontology and KEGG enrichment analysis confirm the role of AhAPX genes in oxidoreductase activity, catalytic activity, cell junction, cellular response to stimulus and detoxification, biosynthesis of metabolites, and phenylpropanoid metabolism. Based on transcriptome datasets, some genes such as AhAPX4/7/17/77/82/86/130/133 and AhAPX160 showed significantly higher expression in diverse tissues/organs, i.e., flower, leaf, stem, roots, peg, testa, and cotyledon. Likewise, only a few genes, including AhAPX4/17/19/55/59/82/101/102/137 and AhAPX140, were significantly upregulated under abiotic (drought and cold), and phytohormones (ethylene, abscisic acid, paclobutrazol, brassinolide, and salicylic acid) treatments. qRT-PCR-based expression profiling presented the parallel expression trends as generated from transcriptome datasets. Our discoveries gave new visions into the evolution of APX genes and provided a base for further functional examinations of the AhAPX genes in peanut breeding programs

Nonlocal response in thin-film waveguides: Loss versus nonlocality and breaking of complementarity

We investigate the effects of nonlocal response on the surface-plasmon polariton guiding properties of the metal-insulator (MI), metal-insulator-metal (MIM), and insulator-metal-insulator (IMI) waveguides. The nonlocal effects are described by a linearized hydrodynamic model, which includes the Thomas-Fermi internal kinetic energy of the free electrons in the metal. We derive the nonlocal dispersion relations of the three waveguide structures taking into account also retardation and interband effects, and examine the delicate interplay between nonlocal response and absorption losses in the metal. We also show that nonlocality breaks the complementarity of the MIM and IMI waveguides found in the non-retarded limit.Comment: 9 pages, 5 figure