The C5 variant of the butyrylcholinesterase tetramer includes a noncovalently bound 60 kDa lamellipodin fragment

© 2017 by the authors. Licensee MDPI. Humans with the C5 genetic variant of butyrylcholinesterase (BChE) have 30–200% higher plasma BChE activity, low body weight, and shorter duration of action of the muscle relaxant succinylcholine. The C5 variant has an extra, slow-moving band of BChE activity on native polyacrylamide gel electrophoresis. This band is about 60 kDa larger than wild-type BChE. Umbilical cord BChE in 100% of newborn babies has a C5-like band. Our goal was to identify the unknown, 60 kDa protein in C5. Both wild-type and C5 BChE are under the genetic control of two independent loci, the BCHE gene on Chr 3q26.1 and the RAPH1 (lamellipodin) gene on Chr 2q33. Wild-type BChE tetramers are assembled around a 3 kDa polyproline peptide from lamellipodin. Western blot of boiled C5 and cord BChE showed a positive response with an antibody to the C-terminus of lamellipodin. The C-terminal exon of lamellipodin is about 60 kDa including an N-terminal polyproline. We propose that the unknown protein in C5 and cord BChE is encoded by the last exon of the RAPH1 gene. In 90% of the population, the 60 kDa fragment is shortened to 3 kDa during maturation to adulthood, leaving only 10% of adults with C5 BChE

Efficient coupler between silicon photonic and metal-insulator-silicon-metal plasmonic waveguides

We report the experimental realization of a compact, efficient coupler between silicon waveguides and vertical metal-insulator-silicon-metal (MISM) plasmonic waveguides. Devices were fabricated using complementary metal-oxide-silicon technology processes, with copper layers that support low-loss plasmonic modes in the MISM structures at a wavelength of 1550 nm. By implementing a short (0.5 μm) optimized metal-insulator-silicon-insulator structure inserted between the photonic and plasmonic waveguide sections, we demonstrate experimental coupling loss of 2.5 dB, despite the high optical confinement of the MISM mode and mismatch with the silicon waveguide mode

Domestic chicken diversity: Origin, distribution, and adaptation

Chicken is the most numerous among the domesticated livestock species. Across cultures, religions, and societies, chicken is widely accepted with little or no taboo compared to other domestic animals. Its adaptability to diverse environmental conditions and demonstrated potential for breeding improvement provide a unique genetic resource for addressing the challenges of food security in a world impacted by climatic change and human population growth. Recent studies, shedding new knowledge on the chicken genomes, have helped reconstruct its past evolutionary history. Here, we review the literature concerning the origin, dispersion, and adaptation of domestic chicken. We highlight the role of human and natural selection in shaping the diversity of the species and provide a few examples of knowledge gaps that may be the focus of future research

Molecular polymorphism of human enzymes as the basis of individual sensitivity to drugs. Supercomputer-assisted modeling as a tool for analysis of structural changes and enzymatic activity of proteins

© 2016, Springer Science+Business Media New York.The nature of individual sensitivity to drugs associated with molecular polymorphism of human enzymes is discussed. The influence of molecular polymorphism on the activity of key human esterases, in particular, cholinesterases and carboxylesterase, responsible for hydrolytic metabolism of ester-containing drugs, is analyzed. A method was developed, which involves supercomputer-assisted modeling as a tool for assessment of molecular mechanism of the impact of point mutations on the catalytic activity of enzymes. This work is a part of a study aimed at elaboration of the concept and methods of personalized medicine

Chlorpromazine reduces avoidance performance deficit in rats with dorsomedial thalamic lesions

Rats with bilateral lesions of the dorsomedial area of the thalamus were shown to have a significant performance deficit on the acquisition of a one-way active shock-avoidance task relative to sham-operated controls. Administration of chlorpromazine prior to testing was shown to reduce this deficit among the DMT-lesioned animals

Galectin-8 in IgA Nephritis: Decreased Binding of IgA by Galectin-8 Affinity Chromatography and Associated Increased Binding in Non-IgA Serum Glycoproteins

Background Immunoglobulin A nephritis (IgAN) is the most common primary glomerulonephritis worldwide. It is caused by accumulation of IgA1-containing immune complexes in the kidney resulting in renal failure, which is thought to be due to altered glycosylation of IgA with a decrease of 2-3-sialylated galactosides (NeuAc alpha 2-3Gal). less thanbrgreater than less thanbrgreater thanPurpose The purpose of this study was to analyze whether altered glycosylation of IgA would lead to an altered binding to galectin-8, an endogenous lectin with strong affinity for 2-3-sialylated galactosides. Galectins are a family of beta-galactoside-binding proteins; by binding various glycoproteins, they play important roles in the regulation of cellular functions in inflammation and immunity. Hence, an altered binding of IgA to galectin-8 could lead to pathologic immune functions, such as glomerulonephritis. less thanbrgreater than less thanbrgreater thanMethods Affinity chromatography of serum glycoproteins on the human sialogalactoside-binding lectin galectin-8N permitted quantitation of bound and unbound fractions, including IgA. less thanbrgreater than less thanbrgreater thanResults Analysis of similar to 100 IgA nephritis sera showed that the galectin-8N unbound fraction of IgA increased compared to similar to 100 controls, consistent with the known loss of galactosylation. A subgroup of similar to 15% of the IgAN patients had a ratio of galectin-8 bound/unbound IgA andlt;0.09, not found for any of the controls. Unexpectedly, the galectin-8N-binding fraction of serum glycoproteins other than IgA increased in the sera of IgAN patients but not in controls, suggesting a previously unrecognized change in this disease. less thanbrgreater than less thanbrgreater thanConclusion This is the first study that relates a galectin, an endogenous lectin family, to IgA nephritis and thus should stimulate new avenues of research into the pathophysiology of the disease.Funding Agencies|Swedish Research Council (Vetenskapsradet)|2008-3356|Swedish Foundation for Swedish Research|FFL4|Swedish Healthcare System (ALF)||Region Skane||</p

Structure and Function of ABCG2-Rich Extracellular Vesicles Mediating Multidrug Resistance

Multidrug resistance (MDR) is a major impediment to curative cancer chemotherapy. The ATP-Binding Cassette transporters ABCG2, ABCB1 and ABCC2 form a unique defense network against multiple structurally and functionally distinct chemotherapeutics, thereby resulting in MDR. Thus, deciphering novel mechanisms of MDR and their overcoming is a major goal of cancer research. Recently we have shown that overexpression of ABCG2 in the membrane of novel extracellular vesicles (EVs) in breast cancer cells results in mitoxantrone resistance due to its dramatic sequestration in EVs. However, nothing is known about EVs structure, biogenesis and their ability to concentrate multiple antitumor agents. To this end, we here found that EVs are structural and functional homologues of bile canaliculi, are apically localized, sealed structures reinforced by an actin-based cytoskeleton and secluded from the extracellular milieu by the tight junction proteins occludin and ZO-1. Apart from ABCG2, ABCB1 and ABCC2 were also selectively targeted to the membrane of EVs. Moreover, Ezrin-Radixin-Moesin protein complex selectively localized to the border of the EVs membrane, suggesting a key role for the tethering of MDR pumps to the actin cytoskeleton. The ability of EVs to concentrate and sequester different antitumor drugs was also explored. Taking advantage of the endogenous fluorescence of anticancer drugs, we found that EVs-forming breast cancer cells display high level resistance to topotecan, imidazoacridinones and methotrexate via efficient intravesicular drug concentration hence sequestering them away from their cellular targets. Thus, we identified a new modality of anticancer drug compartmentalization and resistance in which multiple chemotherapeutics are actively pumped from the cytoplasm and highly concentrated within the lumen of EVs via a network of MDR transporters differentially targeted to the EVs membrane. We propose a composite model for the structure and function of MDR pump-rich EVs in cancer cells and their ability to confer multiple anticancer drug resistance

Predicting impacts of food competition, climate, and disturbance on a long-distance migratory herbivore

Climate change is driving worldwide shifts in the distribution of biodiversity, and fundamental changes to global avian migrations. Some arctic-nesting species may shorten their migration distance as warmer temperatures allow them to winter closer to their high-latitude breeding grounds. However, such decisions are not without risks, since this intensifies pressure on resources when they are used for greater periods of time. In this study, we used an individual-based model to predict how future changes in food abundance, winter ice coverage, and human disturbance could impact an Arctic/sub-Arctic breeding goose species, black brant (Branta bernicla nigricans, Lawrence 1846), and their primary food source, common eelgrass (Zostera marina L.), at the Izembek Lagoon complex in southwest Alaska. Brant use the site during fall and spring migrations, and increasingly, for the duration of winter. The model was validated by comparing predictions to empirical observations of proportion of geese surviving, proportion of geese emigrating, mean duration of stay, mean rate of mass gain/loss, percentage of time spent feeding, number of bird days, peak population numbers, and distribution across the complex. The model predicted that reductions >50% of the current decadal (2007–2015) mean of eelgrass biomass, which have been observed in some years, or increases in the number of brant, could lead to a reduction in the proportion of birds that successfully migrate to their breeding grounds from the site. The model also predicted that access to eelgrass in lagoons other than Izembek was critical for overwinter survival and spring migration of brant, if overall eelgrass biomass was 50% of the decadal mean biomass. Geese were typically predicted to be more vulnerable to environmental change during winter and spring, when eelgrass biomass is lower, and thermoregulatory costs for the geese are higher than in fall. We discuss the consequences of these predictions for goose population trends in the face of natural and human drivers of change

Drilling constraints on lithospheric accretion and evolution at Atlantis Massif, Mid-Atlantic Ridge 30°N

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): B07103, doi:10.1029/2010JB007931.Expeditions 304 and 305 of the Integrated Ocean Drilling Program cored and logged a 1.4 km section of the domal core of Atlantis Massif. Postdrilling research results summarized here constrain the structure and lithology of the Central Dome of this oceanic core complex. The dominantly gabbroic sequence recovered contrasts with predrilling predictions; application of the ground truth in subsequent geophysical processing has produced self-consistent models for the Central Dome. The presence of many thin interfingered petrologic units indicates that the intrusions forming the domal core were emplaced over a minimum of 100–220 kyr, and not as a single magma pulse. Isotopic and mineralogical alteration is intense in the upper 100 m but decreases in intensity with depth. Below 800 m, alteration is restricted to narrow zones surrounding faults, veins, igneous contacts, and to an interval of locally intense serpentinization in olivine-rich troctolite. Hydration of the lithosphere occurred over the complete range of temperature conditions from granulite to zeolite facies, but was predominantly in the amphibolite and greenschist range. Deformation of the sequence was remarkably localized, despite paleomagnetic indications that the dome has undergone at least 45° rotation, presumably during unroofing via detachment faulting. Both the deformation pattern and the lithology contrast with what is known from seafloor studies on the adjacent Southern Ridge of the massif. There, the detachment capping the domal core deformed a 100 m thick zone and serpentinized peridotite comprises ∼70% of recovered samples. We develop a working model of the evolution of Atlantis Massif over the past 2 Myr, outlining several stages that could explain the observed similarities and differences between the Central Dome and the Southern Ridge