The role of Pex11-beta in peroxisome biogenesis, intracellular relationship to reactive oxygen species levels and redox-sensitive cell signaling

Peroxisomes are organelles whose roles in fatty acid metabolism and reactive oxygen species (ROS) elimination have contributed much attention in understanding their origin and biogenesis. Many studies have shown that de novo peroxisome biogenesis is an important regulatory process, while yeast studies suggest that total peroxisome numbers are in part regulated by proteins such as Pex11, which can facilitate the division of existing peroxisomes. Although de novo biogenesis and divisions are likely important mechanisms to peroxisome functioning, the regulation of peroxisome numbers during embryonic development is poorly understood. Peroxisome number and function are particularly crucial in oviparous animals such as frogs where large embryonic yolk and fatty acid stores must be quickly metabolized, and ROS eliminated. The central role of peroxisomes with respect to ROS is in the generation and scavenging of hydrogen peroxide. Recent studies have revealed their involvement in metabolism of oxygen free radicals that have important functions in cell signaling. Using Xenopus laevis as a developmental model, this study demonstrates that overexpression and inhibition of Pex11β directly increases and decreases peroxisome number in vitro, and induces an early- or delayed-onset to peroxisome biogenesis in vivo, respectively. Knockdown of Pex11β, decreasing peroxisome numbers, induced a bent/double-axis phenotype compared to that of control uninjected embryos. This phenotype has previously been linked to increases in the redox sensitive-noncanonical Wnt/Planar Cell Polarity (PCP) cell signaling. As a result, this study investigated if changes in peroxisome number could affect intracellular ROS levels, thereby activating redox-sensitive cell signaling pathways such as canonical and noncanonical Wnt signaling. Following inhibition of Pex11β, there were significant increases in ROS levels in X. laevis A6 cells. I show for the very first time that changes in cellular ROS levels, as a result of decreases in peroxisome numbers, perturb noncanonical Wnt cell signaling

Destabilization of α-helical structure in solution improves bactericidal activity of antimicrobial peptides: Opposing effects on bacterial and viral targets

We have previously examined the mechanism of antimicrobial peptides on the outer membrane of vaccinia virus. Here we show that the formulation of peptides LL37 and magainin-2B amide in polysorbate 20 (Tween-20™) results in greater reductions in virus titre than formulation without detergent, and the effect is replicated by substitution of polysorbate 20 with high ionic strength buffer. In contrast, formulation with polysorbate 20 or high ionic strength buffer has the opposite effect on bactericidal activity of both peptides, resulting in lesser reductions in titre for both gram-positive and gram-negative bacteria. Circular dichroism spectroscopy shows that the differential action of polysorbate 20 and salt on the virucidal and bactericidal activities correlates with the α-helical content of peptide secondary structure in solution, suggesting that the virucidal and bactericidal activities are mediated through distinct mechanisms. The correlation of a defined structural feature with differential activity against a host-derived viral membrane and the membranes of both gram-positive and gram-negative bacteria suggests that overall helical content in solution under physiological conditions is an important feature for consideration in the design and development of candidate peptide-based antimicrobial compounds

Bcl-xL-mediated remodeling of rod and cone synaptic mitochondria after postnatal lead exposure: electron microscopy, tomography and oxygen consumption.

PurposePostnatal lead exposure produces rod-selective and Bax-mediated apoptosis, decreased scotopic electroretinograms (ERGs), and scotopic and mesopic vision deficits in humans and/or experimental animals. Rod, but not cone, inner segment mitochondria were considered the primary site of action. However, photoreceptor synaptic mitochondria were not examined. Thus, our experiments investigated the structural and functional effects of environmentally relevant postnatal lead exposure on rod spherule and cone pedicle mitochondria and whether Bcl-xL overexpression provided neuroprotection.MethodsC57BL/6N mice pups were exposed to lead only during lactation via dams drinking water containing lead acetate. The blood [Pb] at weaning was 20.6±4.7 µg/dl, which decreased to the control value by 2 months. To assess synaptic mitochondrial structural differences and vulnerability to lead exposure, wild-type and transgenic mice overexpressing Bcl-xL in photoreceptors were used. Electron microscopy, three-dimensional electron tomography, and retinal and photoreceptor synaptic terminal oxygen consumption (QO(2)) studies were conducted in adult control, Bcl-xL, lead, and Bcl-xL/lead mice.ResultsThe spherule and pedicle mitochondria in lead-treated mice were swollen, and the cristae structure was markedly changed. In the lead-treated mice, the mitochondrial cristae surface area and volume (abundance: measure correlated with ATP (ATP) synthesis) were decreased in the spherules and increased in the pedicles. Pedicles also had an increased number of crista segments per volume. In the lead-treated mice, the number of segments/crista and fraction of cristae with multiple segments (branching) similarly increased in spherule and pedicle mitochondria. Lead-induced remodeling of spherule mitochondria produced smaller cristae with more branching, whereas pedicle mitochondria had larger cristae with more branching and increased crista junction (CJ) diameter. Lead decreased dark- and light-adapted photoreceptor and dark-adapted photoreceptor synaptic terminal QO(2). Bcl-xL partially blocked many of the lead-induced alterations relative to controls. However, spherules still had partially decreased abundance, whereas pedicles still had increased branching, increased crista segments per volume, and increased crista junction diameter. Moreover, photoreceptor and synaptic QO(2) were only partially recovered.ConclusionsThese findings reveal cellular and compartmental specific differences in the structure and vulnerability of rod and cone inner segment and synaptic mitochondria to postnatal lead exposure. Spherule and pedicle mitochondria in lead-exposed mice displayed complex and distinguishing patterns of cristae and matrix damage and remodeling consistent with studies showing that synaptic mitochondria are more sensitive to Ca(2+) overload, oxidative stress, and ATP loss than non-synaptic mitochondria. The lead-induced decreases in QO(2) likely resulted from the decreased spherule cristae abundance and smaller cristae, perhaps due to Bax-mediated effects as they occurred in apoptotic rod inner segments. The increase in pedicle cristae abundance and CJ diameter could have resulted from increased Drp1-mediated fission, as small mitochondrial fragments were observed. The mechanisms of Bcl-xL-mediated remodeling might occur via interaction with formation of CJ protein 1 (Fcj1), whereas the partial protection of synaptic QO(2) might result from the enhanced efficiency of energy metabolism via Bcl-xL's direct interaction with the F1F0 ATP synthase and/or regulation of cellular redox status. These lead-induced alterations in photoreceptor synaptic terminal mitochondria likely underlie the persistent scotopic and mesopic deficits in lead-exposed children, workers, and experimental animals. Our findings stress the clinical and scientific importance of examining synaptic dysfunction following injury or disease during development, and developing therapeutic treatments that prevent synaptic degeneration in retinal and neurodegenerative disorders even when apoptosis is blocked

Globalization: An Analytical Framework

The paradigm example of globalization is the global integration of financial markets. Globalization has significant implications for New Zealand--a small island nation far from the centers of world capital--that flow from the particular characteristics of New Zealand\u27s economy. In order to sustain current levels of economic growth, the New Zealand government has adopted a liberal policy to attractf oreign capital. In the future, a major taskf or New Zealand is to align further the internal logic of the deregulatory process as expressed in domestic legislation with an international environment in which domestic economies are more globally integrated. This article argues that the concept of globalization provides a new analytical framework for accomplishing that task. The article commences by identifying different meanings of globalization and key drivers in the globalization of the financial markets. Because globalization is an ambiguous concept, the second half of the paper attempts to sharpen understanding of the concept by considering concrete instances in which globalization has affected New Zealand. Examples provided are: the crash of 1987; the improvement of New Zealand\u27s international investment position through a noticeable increase in foreign investment; capital shortage; capital flight; political debate in New Zealand; New Zealand\u27s tax treatment of foreign investors; and exemptions for foreign issuers. Here, it is argued that as far as domestic policymakers are concerned, globalization demands, first, a clear set ofpriorities in the particular area (a microscopic view), and, second, a global view of the subject matter (a macroscopic view).The article concludes by suggesting n analyticalf rameworkf or domestic policymakers and legislators addressing globalizationissues. Complex systems can be viewed as the subject of macroscopic knowledge; hence, globalization can be characterized as macroscopic knowledge since it is complex, conceptual, and fuzzy. By contrast, domestic legislation can be characterized as microscopic knowledge; i.e.,focused on one domain in which there is little or no contradiction.On this view, globalization can be used as a tool to examine the context of any given domestic legislation, thereby enriching our understanding of specific legislation by introducing dynamic and predictive criteria. The concept of globalization radiates the possibility of a new analytical framework for policymakers. Coupled with the macroscopic/microscopic viewpoint, it enables us to avoid the pitfall of domestic introspection by introducing criteria of internal and external coherence. Internal coherence asks whether a proposed domestic policy is congruent with policy in related areas. For example, is there regulatory symmetry between domestic legislation in taxation, securities, and foreign investment areas? External coherence asks the globalization question: How should domestic legislation reflect change in the international context

Globalization: An Analytical Framework

The paradigm example of globalization is the global integration of financial markets. Globalization has significant implications for New Zealand--a small island nation far from the centers of world capital--that flow from the particular characteristics of New Zealand\u27s economy. In order to sustain current levels of economic growth, the New Zealand government has adopted a liberal policy to attractf oreign capital. In the future, a major taskf or New Zealand is to align further the internal logic of the deregulatory process as expressed in domestic legislation with an international environment in which domestic economies are more globally integrated. This article argues that the concept of globalization provides a new analytical framework for accomplishing that task. The article commences by identifying different meanings of globalization and key drivers in the globalization of the financial markets. Because globalization is an ambiguous concept, the second half of the paper attempts to sharpen understanding of the concept by considering concrete instances in which globalization has affected New Zealand. Examples provided are: the crash of 1987; the improvement of New Zealand\u27s international investment position through a noticeable increase in foreign investment; capital shortage; capital flight; political debate in New Zealand; New Zealand\u27s tax treatment of foreign investors; and exemptions for foreign issuers. Here, it is argued that as far as domestic policymakers are concerned, globalization demands, first, a clear set ofpriorities in the particular area (a microscopic view), and, second, a global view of the subject matter (a macroscopic view).The article concludes by suggesting n analyticalf rameworkf or domestic policymakers and legislators addressing globalizationissues. Complex systems can be viewed as the subject of macroscopic knowledge; hence, globalization can be characterized as macroscopic knowledge since it is complex, conceptual, and fuzzy. By contrast, domestic legislation can be characterized as microscopic knowledge; i.e.,focused on one domain in which there is little or no contradiction.On this view, globalization can be used as a tool to examine the context of any given domestic legislation, thereby enriching our understanding of specific legislation by introducing dynamic and predictive criteria. The concept of globalization radiates the possibility of a new analytical framework for policymakers. Coupled with the macroscopic/microscopic viewpoint, it enables us to avoid the pitfall of domestic introspection by introducing criteria of internal and external coherence. Internal coherence asks whether a proposed domestic policy is congruent with policy in related areas. For example, is there regulatory symmetry between domestic legislation in taxation, securities, and foreign investment areas? External coherence asks the globalization question: How should domestic legislation reflect change in the international context

Enhancing Nonprofit Governance through Better Information Flow to Directors

To counteract the ability of a nonprofit’s chief executive officer to control information reaching the board of directors, we recommend that a nonprofit board consider requiring leaders of the organization’s various functions to provide operational reports directly to the board on at least an annual basis. Additionally, we recommend that a board discuss these reports directly with management members, preferably without the participation of the CEO. Implementing such a protocol should strengthen the board’s ability to make decisions based on information from sources in addition to that of the CEO, improve the directors’ ability to independently evaluate members of the management team, and increase the directors’ understanding of the nonprofit’s activities and performance

Corporate Governance Research on New Zealand Listed Companies

"The purpose of this article is to review and add to approximately fifty years of research on New Zealand listed companies from various disciplines. The main findings are not controversial, as corporate governance standards are high by international standards. To be sure, there has been a rolling set of corporate failures in the finance company sector since the global financial crisis--principally involving nonlisted finance companies issuing debt securities to the public--but these failures have been comprehensively addressed by recent legislative reforms. In this regard, the article will be of interest to corporate governance researchers seeking a topical review of corporate governance in a small, common law jurisdiction. A key commercial context, however, is supplied by the regional free trade agreement between New Zealand and Australia, the recent free trade agreement between Australia and the United States, and the (largely moot) free-trade agreement between New Zealand and the United States....As stated, this article comprehensively reviews and adds to extant research on corporate governance of New Zealand listed companies. It is crossdisciplinary in nature and considers legal, managerial, and accounting perspectives, as well as literature on corporate governance....We conclude that while corporate governance of listed companies was good, the same cannot be said for nonlisted issuers of debt securities. Here, poor corporate governance and supervisory failures were causal in the failure of nonlisted finance companies.