Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers

<p>Abstract</p> <p>Background</p> <p>This study was conducted to identify potential biomarkers that could be used to evaluate disease progression and monitor responses to enzyme replacement therapy (ERT) in patients with mucopolysaccharidosis (MPS) IVA.</p> <p>Methods</p> <p>Levels of 88 candidate biomarkers were compared in plasma samples from 50 healthy controls and 78 MPSIVA patients not receiving ERT to test for significant correlations to the presence of MPSIVA. MPSIVA samples were also tested for correlations between candidate biomarkers and age, endurance, or urinary keratin sulfate (KS) levels. Then, levels of the same 88 analytes were followed over 36 weeks in 20 MPSIVA patients receiving ERT to test for significant correlations related to ERT, age, or endurance.</p> <p>Results</p> <p>Nineteen candidate biomarkers were significantly different between MPSIVA and unaffected individuals. Of these, five also changed significantly in response to ERT: alpha-1-antitrypsin, eotaxin, lipoprotein(a), matrix metalloprotein (MMP)-2, and serum amyloid P. Three of these were significantly lower in MPSIVA individuals versus unaffected controls and were increased during ERT: alpha-1-antitrypsin, lipoprotein(a), and serum amyloid P.</p> <p>Conclusions</p> <p>Candidate biomarkers alpha-1-antitrypsin, lipoprotein(a), and serum amyloid P may be suitable markers, in addition to urinary KS, to follow the response to ERT in MPSIVA patients.</p

Hemocyanin conformational changes associated with SDS-induced phenol oxidase activation

The enzymatic activity of phenoloxidase is assayed routinely in the presence of SDS. Similar assay conditions elicit phenoloxidase activity in another type 3 copper protein, namely hemocyanin, which normally functions as an oxygen carrier. The nature of the conformational changes induced in type 3 copper proteins by the denaturant SDS is unknown. This comparative study demonstrates that arthropod hemocyanins can be converted from being an oxygen carrier to a form which exhibits phenoloxidase activity by incubation with SDS, with accompanying changes in secondary and tertiary structure. Structural characterisation, using various biophysical methods, suggests that the micellar form of SDS is required to induce optimal conformational transitions in the protein which may result in opening a channel to the di-copper centre allowing bulky phenolic substrates access to the catalytic site

Jellyfish, Forage Fish, and the World\u27s Major Fisheries

A majority of the world’s largest net-based fisheries target planktivorous forage fish that serve as a critical trophic link between the plankton and upper-level consumers such as large predatory fishes, seabirds, and marine mammals. Because the plankton production that drives forage fish also drives jellyfish production, these taxa often overlap in space, time, and diet in coastal ecosystems. This overlap likely leads to predatory and competitive interactions, as jellyfish are effective predators of fish early life stages and zooplankton. The trophic interplay between these groups is made more complex by the harvest of forage fish, which presumably releases jellyfish from competition and is hypothesized to lead to an increase in their production. To understand the role forage fish and jellyfish play as alternate energy transfer pathways in coastal ecosystems, we explore how functional group productivity is altered in three oceanographically distinct ecosystems when jellyfish are abundant and when fish harvest rates are reduced using ecosystem modeling. We propose that ecosystem-based fishery management approaches to forage fish stocks include the use of jellyfish as an independent, empirical “ecosystem health” indicator

Jellyfish, Forage Fish, and the World\u27s Major Fisheries

A majority of the world’s largest net-based fisheries target planktivorous forage fish that serve as a critical trophic link between the plankton and upper-level consumers such as large predatory fishes, seabirds, and marine mammals. Because the plankton production that drives forage fish also drives jellyfish production, these taxa often overlap in space, time, and diet in coastal ecosystems. This overlap likely leads to predatory and competitive interactions, as jellyfish are effective predators of fish early life stages and zooplankton. The trophic interplay between these groups is made more complex by the harvest of forage fish, which presumably releases jellyfish from competition and is hypothesized to lead to an increase in their production. To understand the role forage fish and jellyfish play as alternate energy transfer pathways in coastal ecosystems, we explore how functional group productivity is altered in three oceanographically distinct ecosystems when jellyfish are abundant and when fish harvest rates are reduced using ecosystem modeling. We propose that ecosystem-based fishery management approaches to forage fish stocks include the use of jellyfish as an independent, empirical “ecosystem health” indicator

Questioning the rise of gelatinous zooplankton in the World's oceans

During the past several decades, high numbers of gelatinous zooplankton species have been reported in many estuarine and coastal ecosystems. Coupled with media-driven public perception, a paradigm has evolved in which the global ocean ecosystems are thought to be heading toward being dominated by “nuisance” jellyfish. We question this current paradigm by presenting a broad overview of gelatinous zooplankton in a historicalcontext to develop the hypothesis that population changes reflect the human-mediated alteration of global ocean ecosystems. To this end, we synthesize information related to the evolutionary context of contemporary gelatinous zooplankton blooms, the human frame of reference forchanges in gelatinous zooplankton populations, and whether sufficient data are available to have established the paradigm. We conclude that the current paradigm in which it is believed that there has been a global increase in gelatinous zooplankton is unsubstantiated, and we develop a strategy for addressing the critical questions about long-term, human-related changes in the sea as they relate to gelatinous zooplankton blooms

Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus

We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of α7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the α7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca2+-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the α7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP

Space Shuttle Orbiter Structures and Mechanisms

The Space Shuttle Orbiter has performed exceptionally well over its 30 years of flight experience. Among the many factors behind this success were robust, yet carefully monitored, structural and mechanical systems. From highlighting key aspects of the design to illustrating lessons learned from the operation of this complex system, this paper will attempt to educate the reader on why some subsystems operated flawlessly and why specific vulnerabilities were exposed in others. Specific areas to be covered will be the following: high level configuration overview, primary and secondary structure, mechanical systems ranging from landing gear to the docking system, and windows

Detection of the Epstein-Barr virus in blood and bone marrow mononuclear cells of patients with aggressive B-cell non Hodgkin's lymphoma is not associated with prognosis

The Epstein-Barr virus (EBV) is associated with a large spectrum of lymphoproliferative diseases. Traditional methods of EBV detection include the immunohistochemical identification of viral proteins and DNA probes to the viral genome in tumoral tissue. The present study explored the detection of the EBV genome, using the BALF5 gene, in the bone marrow or blood mononuclear cells of patients with diffuse large B-cell lymphomas (DLBCL) and related its presence to the clinical variables and risk factors. The results show that EBV detection in 21.5% of patients is not associated with age, gender, staging, B symptoms, international prog¬nostic index scores or any analytical parameters, including lactate dehydrogenase (LDH) or β-2 microglobulin (B2M). The majority of patients were treated with R-CHOP like (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone or an equivalent combination) and some with CHOP-like chemotherapy. Response rates [complete response (CR) + partial response (PR)] were not significantly different between EBV-negative and -positive cases, with 93.2 and 88.9%, respectively. The survival rate was also similar in the two groups, with 5-year overall survival (OS) rates of 64.3 and 76.7%, respectively. However, when analyzing the treatment groups separately there was a trend in EBV-positive patients for a worse prognosis in patients treated with CHOP-like regimens that was not identified in patients treated with R-CHOP-like regimens. We conclude that EBV detection in the bone marrow and blood mononuclear cells of DLBC patients has the same frequency of EBV detection on tumoral lymphoma tissue but is not associated with the risk factors, response rate and survival in patients treated mainly with immunochemotherapy plus rituximab. These results also suggest that the addition of rituximab to chemotherapy improves the prognosis associated with EBV detection in DLBCL

A clathrin coat assembly role for the muniscin protein central linker revealed by TALEN-mediated gene editing

Clathrin-mediated endocytosis is an evolutionarily ancient membrane transport system regulating cellular receptivity and responsiveness. Plasmalemma clathrin-coated structures range from unitary domed assemblies to expansive planar constructions with internal or flanking invaginated buds. Precisely how these morphologically-distinct coats are formed, and whether all are functionally equivalent for selective cargo internalization is still disputed. We have disrupted the genes encoding a set of early arriving clathrin-coat constituents, FCHO1 and FCHO2, in HeLa cells. Endocytic coats do not disappear in this genetic background; rather clustered planar lattices predominate and endocytosis slows, but does not cease. The central linker of FCHO proteins acts as an allosteric regulator of the prime endocytic adaptor, AP-2. By loading AP-2 onto the plasma membrane, FCHO proteins provide a parallel pathway for AP-2 activation and clathrin-coat fabrication. Further, the steady-state morphology of clathrin-coated structures appears to be a manifestation of the availability of the muniscin linker during lattice polymerization. DOI: http://dx.doi.org/10.7554/eLife.04137.00