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Watrous J.D.,University of California at San Diego | Alexandrov T.,University of Bremen | Dorrestein P.C.,University of California at San Diego | Dorrestein P.C.,San Diego Biotechnology
Journal of Mass Spectrometry | Year: 2011

Within the past decade, imaging mass spectrometry (IMS) has been increasingly recognized as an indispensable technique for studying biological systems. Its rapid evolution has resulted in an impressive array of instrument variations and sample applications, yet the tools and data are largely confined to specialists. It is therefore important that at this junction the IMS community begin to establish IMS as a permanent fixture in life science research thereby making the technology and/or the data approachable by non-mass spectrometrists, leading to further integration into biological and clinical research. In this perspective article, we provide insight into the evolution and current state of IMS and propose some of the directions that IMS could develop in order to stay on course to become one of the most promising new tools in life science research. © 2011 John Wiley & Sons, Ltd.

McDonald B.I.,University of Aarhus | McDonald B.I.,San Diego Biotechnology | Ponganis P.J.,San Diego Biotechnology
Journal of Experimental Biology | Year: 2014

Heart rate and peripheral blood flow distribution are the primary determinants of the rate and pattern of oxygen store utilisation and ultimately breath-hold duration in marine endotherms. Despite this, little is known about how otariids (sea lions and fur seals) regulate heart rate (fH) while diving. We investigated dive fH in five adult female California sea lions (Zalophus californianus) during foraging trips by instrumenting them with digital electrocardiogram (ECG) loggers and time depth recorders. In all dives, dive fH (number of beats/duration; 50±9 beats min-1) decreased compared with surface rates (113±5 beats min-1), with all dives exhibiting an instantaneous fH below resting (<54 beats min-1) at some point during the dive. Both dive fH and minimum instantaneous fH significantly decreased with increasing dive duration. Typical instantaneous fH profiles of deep dives (>100 m) consisted of: (1) an initial rapid decline in fH resulting in the lowest instantaneous fH of the dive at the end of descent, often below 10 beats min-1 in dives longer than 6 min in duration; (2) a slight increase in fH to 10-40 beats min-1 during the bottom portion of the dive; and (3) a gradual increase in fH during ascent with a rapid increase prior to surfacing. Thus, fH regulation in deep-diving sea lions is not simply a progressive bradycardia. Extreme bradycardia and the presumed associated reductions in pulmonary and peripheral blood flow during late descent of deep dives should (a) contribute to preservation of the lung oxygen store, (b) increase dependence of muscle on the myoglobin-bound oxygen store, (c) conserve the blood oxygen store and (d) help limit the absorption of nitrogen at depth. This fH profile during deep dives of sea lions may be characteristic of deep-diving marine endotherms that dive on inspiration as similar fH profiles have been recently documented in the emperor penguin, another deep diver that dives on inspiration. © 2014. Published by The Company of Biologists Ltd.

Su L.Y.,San Diego State University | Su L.Y.,San Diego Biotechnology | Willner D.L.,San Diego State University | Segall A.M.,San Diego State University
Antimicrobial Agents and Chemotherapy | Year: 2010

The hexapeptide WRWYCR was previously identified on the basis of its ability to inhibit bacteriophage lambda integrase-mediated recombination by trapping and preventing resolution of the Holliday junction intermediate. This peptide inhibits several unrelated DNA repair enzymes that bind to and process Holliday junctions and branched DNA substrates. WRWYCR and its D stereoisomer, wrwycr, are bactericidal against both Gram-positive and Gram-negative bacteria, causing the accumulation of DNA breaks, chromosome segregation defects, and the filamentation of cells. DNA repair is a novel target of antibiotics. In the present study, we examined the ability of the peptides to inhibit the growth of Salmonella in mammalian cells. J774A.1 macrophage-like cells and murine peritoneal macrophages were infected with Salmonella enterica serovar Typhimurium and grown in the presence or absence of peptide. We found that peptide wrwycr reduced the number of Salmonella cells recovered after 24 h growth in J774A.1 cells by 100 to 1,000 times, depending on the multiplicity of infection. The peptide also inhibited Salmonella growth in peritoneal macrophages, and although higher doses were required, these were not toxic to the host cells. The apparent lower level of potency of the peptide paralleled the lower level of replication of Salmonella and the lower level of permeation of the peptide in the peritoneal macrophages than in the J774.1 cells. Treatment with peptide wrwycr elicited the SOS response in a significant fraction of the intracellular bacteria, as would be expected if the mechanism of bacterial killing was the same in pure culture and in host cells. These results represent a proof of principle of the antimicrobial activities of compounds that target DNA repair. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Ethell D.W.,Western University of Health Sciences | Ethell D.W.,San Diego Biotechnology
Journal of Alzheimer's Disease | Year: 2014

Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa. Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas - among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis - all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL. © 2014 - IOS Press and the authors. All rights reserved.

Hughes C.C.,San Diego Biotechnology | Fenical W.,San Diego Biotechnology
Chemistry - A European Journal | Year: 2010

The ocean contains a host of macroscopic life in a great microbial soup. Unlike the terrestrial environment, an aqueous environment provides perpetual propinquity and blurs spatial distinctions. Marine organisms are under a persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metabolite'ribosomal and non-ribosomal peptides, alkaloids, polyketides, and terpenes'have been shown to exhibit antibacterial activity. The sophistication and diversity of these metabolites points to the ingenuity and flexibility of biosynthetic processes in Nature. Compared with their terrestrial counterparts, antibacterial marine natural products have received much less attention. Thus, a concerted effort to discover new antibacterials from marine sources has the potential to contribute significantly to the treatment of the ever increasing drug-resistant infectious diseases. Cures from the ocean: Marine organisms synthesize complex metabolites with antibacterial properties (see picture) to fend off co-occurring microbes. Representatives from each of five classes of natural products (ribosomal and non-ribosomal peptides, polyketides, alkaloids, and terpenes) isolated as new antibacterial metabolites from marine organisms are described (picture courtesy of X. Alvarez-Micó). © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

McDonald B.I.,San Diego Biotechnology | Ponganis P.J.,San Diego Biotechnology
Journal of Experimental Biology | Year: 2013

The management and depletion of O2 stores underlie the aerobic dive capacities of marine mammals. The California sea lion (Zalophus californianus) presumably optimizes O2 store management during all dives, but approaches its physiological limits during deep dives to greater than 300?m depth. Blood O2 comprises the largest component of total body O2 stores in adult sea lions. Therefore, we investigated venous blood O2 depletion during dives of California sea lions during maternal foraging trips to sea by: (1) recording venous partial pressure of O2 (PO2) profiles during dives, (2) characterizing the O2-hemoglobin (Hb) dissociation curve of sea lion Hb and (3) converting the PO2 profiles into percent Hb saturation (SO2) profiles using the dissociation curve. The O2-Hb dissociation curve was typical of other pinnipeds (P50=28±2mmHg at pH7.4). In 43% of dives, initial venous SO2 values were greater than 78% (estimated resting venous SO2), indicative of arterialization of venous blood. Blood O2 was far from depleted during routine shallow dives, with minimum venous SO2 values routinely greater than 50%. However, in deep dives greater than 4?min in duration, venous SO2 reached minimum values below 5% prior to the end of the dive, but then increased during the last 30-60?s of ascent. These deep dive profiles were consistent with transient venous blood O2 depletion followed by partial restoration of venous O2 through pulmonary gas exchange and peripheral blood flow during ascent. These differences in venous O2 profiles between shallow and deep dives of sea lions reflect distinct strategies of O2 store management and suggest that underlying cardiovascular responses will also differ. © 2013. Published by The Company of Biologists Ltd.

Sule S.V.,Rensselaer Polytechnic Institute | Dickinson C.D.,San Diego Biotechnology | Lu J.,Eli Lilly and Company | Chow C.-K.,Eli Lilly and Company | Tessier P.M.,Rensselaer Polytechnic Institute
Molecular Pharmaceutics | Year: 2013

A key challenge in developing therapeutic antibodies is their highly variable propensities to self-associate at high antibody concentrations (>50 mg/mL) required for subcutaneous delivery. Identification of monoclonal antibodies (mAbs) in the initial discovery process that not only have high binding affinity but also have high solubility and low viscosity would simplify the development of safe and effective antibody therapeutics. Unfortunately, the low purities, small quantities and large numbers of antibody candidates during the early discovery process are incompatible with current methods of measuring antibody self-association. We report a method (affinity-capture self-interaction nanoparticle spectroscopy, AC-SINS) capable of identifying mAbs with low self-association propensity that is robust even at low mAb concentrations (5-50 μg/mL) and in the presence of cell culture media. Gold nanoparticles are coated with polyclonal antibodies specific for human antibodies, and then human mAbs are captured from dilute antibody solutions. We find that the wavelength of maximum absorbance (plasmon wavelength) of antibody-gold conjugates - which red-shifts as the distance between particles is reduced due to attractive mAb self-interactions - is well correlated with light scattering measurements conducted at several orders of magnitude higher antibody concentrations. The generality of AC-SINS makes it well suited for use in diverse settings ranging from antibody discovery to formulation development. © 2013 American Chemical Society.

Kale A.J.,San Diego Biotechnology | McGlinchey R.P.,San Diego Biotechnology | Lechner A.,San Diego Biotechnology | Moore B.S.,San Diego Biotechnology | Moore B.S.,University of California at San Diego
ACS Chemical Biology | Year: 2011

Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy, but susceptibility to drug resistance limits their efficacy. The marine actinobacterium Salinispora tropica produces salinosporamide A (NPI-0052, marizomib), a potent proteasome inhibitor and promising clinical agent in the treatment of multiple myeloma. Actinobacteria also possess 20S proteasome machinery, raising the question of self-resistance. We identified a redundant proteasome β-subunit, SalI, encoded within the salinosporamide biosynthetic gene cluster and biochemically characterized the SalI proteasome complex. The SalI β-subunit has an altered substrate specificity profile, 30-fold resistance to salinosporamide A, and cross-resistance to the FDA-approved proteasome inhibitor bortezomib. An A49V mutation in SalI correlates to clinical bortezomib resistance from a human proteasome β5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes. © 2011 American Chemical Society.

McDonald B.I.,San Diego Biotechnology | Ponganis P.J.,San Diego Biotechnology
Biology Letters | Year: 2012

Lung collapse is considered the primarymechanism that limits nitrogen absorption and decreases the risk of decompression sickness in deep-diving marine mammals. Continuous arterial partial pressure of oxygen (PO2) profiles in a free-diving female California sea lion (Zalophus californianus) revealed that (i) depth of lung collapse was near 225 m as evidenced by abrupt changes in PO2 during descent and ascent, (ii) depth of lung collapse was positively related to maximum dive depth, suggesting that the sea lion increased inhaled air volume in deeper dives and (iii) lung collapse at depth preserved a pulmonary oxygen reservoir that supplemented blood oxygen during ascent so that mean end-of-dive arterial PO2 was 74±17 mmHg (greater than 85% haemoglobin saturation). Such information is critical to the understanding and the modelling of both nitrogen and oxygen transport in diving marine mammals. © 2012 The Royal Society.

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