Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum

γ-Secretase affects many physiological processes through targeting >100 substrates; malfunctioning links γ-secretase to cancer and Alzheimer’s disease. The spatiotemporal regulation of its stoichiometric assembly remains unresolved. Fractionation, biochemical assays, and imaging support prior formation of stable dimers in the ER, which, after ER exit, assemble into full complexes. In vitro ER budding shows that none of the subunits is required for the exit of others. However, knockout of any subunit leads to the accumulation of incomplete subcomplexes in COPII vesicles. Mutating a DPE motif in presenilin 1 (PSEN1) abrogates ER exit of PSEN1 and PEN-2 but not nicastrin. We explain this by the preferential sorting of PSEN1 and nicastrin through Sec24A and Sec24C/D, respectively, arguing against full assembly before ER exit. Thus, dimeric subcomplexes aided by Sec24 paralog selectivity support a stepwise assembly of γ-secretase, controlling final levels in post-Golgi compartments.     

IL-21 promotes the pathologic immune response to pneumovirus infection

IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased Ig production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has antitumor activity. In this study, we investigated the role of IL-21 in host defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4(+) T cells. Following infection, Il21r(-/-) mice exhibited less lung infiltration by neutrophils than did wild-type (WT) mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8(+), CD4(+), and γδ T cell numbers were also lower in the lungs of PVM-infected Il21r(-/-) mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r(-/-) mice. Strikingly, Il21r(-/-) mice had enhanced survival following PVM infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections.     

Great Lakes coastal wetland habitat use by seven turtle species: influences of wetland type, vegetation, and abiotic conditions

Great Lakes coastal wetlands are important habitats for turtles but few studies have looked at factors driving community structure in these systems. We evaluated the effects of wetland type, vegetation, and abiotic conditions on turtle communities for 56 wetlands in Lakes Huron, Michigan, and Superior with data collected during the summers of 2000–2008. Overall, 1,366 turtles representing seven species were captured using fyke nets. For the majority of species, catches were highest in drowned river mouth wetlands In addition, turtles tended to be more abundant in water lilies, submersed aquatic vegetation, and cattails compared to bulrush. We also found positive correlations between catches of four of the species as well as total turtle catch and turtle species richness with a human disturbance gradient. These correlations suggest that turtles may be able to utilize coastal wetland areas that are inhospitable to fish because of hypoxic conditions. Our results show the importance Great Lakes coastal wetlands to turtles, and stress the need for managers to take into account turtle populations when preparing conservation and restoration strategies.     

Expression of Cytoplasmic Antigens Linked to Orthokeratosis During the Development of Parakeratosis in Newborn Mouse Tail Epidermis

Abstract. An unusual example of two different types of epidermal differentiation occurs side by side in adult mouse tail. The neonate shows only orthokeratotic differentiation, but develops parakeratotic scales in precise patterns over the first two weeks of life, retaining orthokeratotic differentiation at the necks of hair follicles. Certain human IgG antibodies from patients receiving bone marrow transplants bind only to cytoplasmic components of orthokeratotic epithelium. As markers of orthokeratotic differentiation in indirect immunofluorescent studies, these antibodies allowed the timing and location of the change in epidermal differentiation. A specific loss of 'orthokeratotic' antigens in the natural switch from orthokeratosis to parakeratosis was demonstrated. The sequence of the orthokeratotic antigens disappearance suggested that the switch to parakeratotic differentation occurred at a supra-basal level.     

Mycorrhizal detection of native and non-native truffles in a historic arboretum and the discovery of a new North American species, <Emphasis Type="Italic">Tuber arnoldianum</Emphasis> sp. nov.

During a study comparing the ectomycorrhizal root communities in a native forest with those at the Arnold Arboretum in Massachusetts (USA), the European species Tuber borchii was detected on the roots of a native red oak in the arboretum over two successive years. Since T. borchii is an economically important edible truffle native to Europe, we conducted a search of other roots in the arboretum to determine the extent of colonization. We also wanted to determine whether other non-native Tuber species had been inadvertently introduced into this 140-year-old Arboretum because many trees were imported into the site with intact soil and roots prior to the 1921 USDA ban on these horticultural practices in the USA. While T. borchii was not found on other trees, seven other native and exotic Tuber species were detected. Among the North American Tuber species detected from ectomycorrhizae, we also collected ascomata of a previously unknown species described here as Tuber arnoldianum. This new species was found colonizing both native and non-native tree roots. Other ectomycorrhizal taxa that were detected included basidiomycetes in the genera Amanita, Russula, Tomentella, and ascomycetes belonging to Pachyphlodes, Helvella, Genea, and Trichophaea. We clarify the phylogenetic relationships of each of the Tuber species detected in this study, and we discuss their distribution on both native and non-native host trees.     

Chromatic photoacclimation, photosynthetic electron transport and oxygen evolution in the Chlorophyll d-containing oxyphotobacterium Acaryochloris marina

Changes in photosynthetic pigment ratios showed that the Chlorophyll d-dominated oxyphotobacterium Acaryochloris marina was able to photoacclimate to different light regimes. Chl d per cell were higher in cultures grown under low irradiance and red or green light compared to those found when grown under high white light, but phycocyanin/Chl d and carotenoid/Chl d indices under the corresponding conditions were lower. Chl a, considered an accessory pigment in this organism, decreased respective to Chl d in low irradiance and low intensity non-white light sources. Blue diode PAM (Pulse Amplitude Modulation) fluorometry was able to be used to measure photosynthesis in Acaryochloris. Light response curves for Acaryochloris were created using both PAM and O₂ electrode. A linear relationship was found between electron transport rate (ETR), measured using a PAM fluorometer, and oxygen evolution (net and gross photosynthesis). Gross photosynthesis and ETR were directly proportional to one another. The optimum light for white light (quartz halogen) was about 206 ± 51 μmol m^− 2 s^− 1 (PAR) (Photosynthetically Active Radiation), whereas for red light (red diodes) the optimum light was lower (109 ± 27 μmol m^− 2 s^− 1 (PAR)). The maximum mean gross photosynthetic rate of Acaryochloris was 73 ± 7 μmol mg Chl d^− 1 h^− 1. The gross photosynthesis/respiration ratio (P_g/R) of Acaryochloris under optimum conditions was about 4.02 ± 1.69. The implications of our findings will be discussed in relation to how photosynthesis is regulated in Acaryochloris.     

Characteristics of lake sturgeon Acipenser fulvescens Rafinesque, 1817 in a tributary of Lake Michigan,USA: Status of the Muskegon River population

The overall goal of this study was to characterize the age, growth, condition, and total catch of lake sturgeon Acipenser fulvescens in a remnant population associated with a Lake Michigan, USA tributary. Lake sturgeon were captured (2008–2013) using large‐mesh (25.4 and 30.5 cm) and small‐mesh (6.4 and 7.6 cm) gill netting in Muskegon Lake (which connects the Muskegon River to Lake Michigan), and adults were captured with boat electrofishing in the Muskegon River. A total of 268 unique lake sturgeon (24.8–191.0 cm total length; <0.1–59.5 kg weight) were captured. Of these, 180 fish were aged using pectoral fin rays, representing 27 age cohorts and a mean age of 7.6 years. The weight–length relationship for lake sturgeon was log₁₀ (W) = 3.446·log₁₀ (L) ? 6.163 and the von Bertalanffy growth model was L = 180.719 [1?e^{?0.093(t + 0.902)}], where W was wet weight (kg), L was total length (cm), and t was age (years). Mean growth rate of juveniles (ages 3–6) recaptured in successive years was 8.6 cm/year and 558 g/year. Annual catch of adults during the spawning migration suggested that the number of spawners each year was low (i.e., probably <50 individuals in most years). Natural reproduction appeared to be occurring given the catch of juvenile lake sturgeon in Muskegon Lake. However, recovery of this remnant population is uncertain given the population age structure and low rate of adult recruitment during the study.     

Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties

Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.