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1.
Xuanxiao Xie Jennifer Shrimpton Gina M. Doody Philip G. Conaghan Frederique Ponchel 《Aging cell》2021,20(4)
BackgroundAge‐related immune deficiencies are thought to be responsible for increased susceptibility to infection in older adults, with alterations in lymphocyte populations becoming more prevalent over time. The loss of humoral immunity in ageing was attributed to the diminished numbers of B cells and the reduced ability to generate immunoglobulin.AimsTo compare the intrinsic B‐cell capacity for differentiation into mature plasma cells (PCs), between young and old donors, using in vitro assays, providing either effective T‐cell help or activation via TLR engagement.MethodsB cells were isolated from healthy individuals, in younger (30–38 years) and older (60–64 years) donors. An in vitro model system of B‐cell differentiation was used, analysing 5 differentiation markers by flow cytometry, under T‐dependent (TD: CD40/BCR stimulation) or T‐independent (TI: TLR7/BCR activation) conditions. Antibody secretion was measured by ELISA and gene expression using qPCR.ResultsTI and TD differentiation resulted in effective proliferation of B cells followed by their differentiation into PC. B‐cell‐executed TI differentiation was faster, all differentiation marker and genes being expressed earlier than under TD differentiation (day 6), although generating less viable cells and lower antibody levels (day 13). Age‐related differences in B‐cell capacity for differentiation were minimal in TD differentiation. In contrast, in TI differentiation age significantly affected proliferation, viability, differentiation, antibody secretion and gene expression, older donors being more efficient.ConclusionAltogether, B‐cell differentiation into PC appeared similar between age groups when provided with T‐cell help, in contrast to TI differentiation, where multiple age‐related changes suggest better capacities in older donors. These new findings may help explain the emergence of autoantibodies in ageing. 相似文献
2.
The alpha-like globin gene cluster in rabbits contains embryonic zeta-
globin genes, an adult alpha-globin gene, and theta-globin genes of
undetermined function. The basic arrangement of genes, deduced from
analysis of cloned DNA fragments, is 5'-zeta 0-zeta 1-alpha 1-theta 1- zeta
2-zeta 3-theta 2-3'. However, the pattern of restriction fragments
containing zeta- and theta-globin genes varies among individual rabbits.
Analysis of BamHI fragments of genomic DNA from 24 New Zealand white
rabbits revealed eight different patterns of fragments containing
zeta-globin genes. The large BamHI fragments containing genes zeta 0 and
zeta 1 are polymorphic in length, whereas a 1.9-kb fragment containing the
zeta 2 gene and the 3.5-kb fragment containing the zeta 3 gene do not vary
in size. In contrast to this constancy in the size of the restriction
fragments, the copy number of the zeta 2 and zeta 3 genes does vary among
different rabbits. No length polymorphism was detected in the BamHI
fragments containing the theta-globin genes, but again the copy number
varies for restriction fragments containing the theta 2 gene. The alpha 1-
and theta 1-globin genes are located in a nonpolymorphic 7.2-kb BamHI
fragment. The combined data from hybridization with both zeta and theta
probes shows that the BamHI cleavage pattern does not vary within the
region 5'-alpha 1-theta 1- zeta 2-zeta 3-theta 2-3', but the pattern
genomic blot-hybridization patterns for the progeny of parental rabbits
with different zeta-globin gene patterns shows that the polymorphic
patterns are inherited in a Mendelian fashion. Two different haplotypes
have been mapped based on the genomic blot-hybridization data. The
variation in the alpha-like globin gene cluster in the rabbit population
results both from differences in the copy number of the duplication block
containing the zeta-zeta-theta gene set and from the presence or absence of
polymorphic BamHI sites.
相似文献
3.
Trimethyloxonium modification of single batrachotoxin-activated sodium channels in planar bilayers. Changes in unit conductance and in block by saxitoxin and calcium 总被引:13,自引:9,他引:4
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Single batrachotoxin-activated sodium channels from rat brain were modified by trimethyloxonium (TMO) after incorporation in planar lipid bilayers. TMO modification eliminated saxitoxin (STX) sensitivity, reduced the single channel conductance by 37%, and reduced calcium block of inward sodium currents. These effects always occurred concomitantly, in an all-or-none fashion. Calcium and STX protected sodium channels from TMO modification with potencies similar to their affinities for block. Calcium inhibited STX binding to rat brain membrane vesicles and relieved toxin block of channels in bilayers, apparently by competing with STX for the toxin binding site. These results suggest that toxins, permeant cations, and blocking cations can interact with a common site on the sodium channel near the extracellular surface. It is likely that permeant cations transiently bind to this superficial site, as the first of several steps in passing inward through the channel. 相似文献
4.
Transforming growth factor-beta (TGF-beta) signals by contacting two distantly related transmembrane serine/threonine kinases called receptors I (T beta R-I) and II (T beta R-II). TGF-beta binds to T beta R-II, which is a constitutively active kinase and this complex recruits T beta R-I, causing its phosphorylation and signal propagation to downstream substrates. The biochemical properties of this interaction were analyzed with reconstituted receptor systems. T beta R-I and T beta R-II baculovirally expressed at high levels in insect cells have the ligand binding properties of receptors expressed in mammalian cells, and form a complex in which T beta R-I phosphorylation is dependent on the kinase activity of T beta R-II. Furthermore, T beta R-I and T beta R-II can form a complex in vitro, and their cytoplasmic domains can specifically interact in a yeast two-hybrid system. In vitro complex formation with catalytically active T beta R-II is necessary and sufficient for T beta R-I phosphorylation, which within this complex does not require the catalytic activity of T beta R-I, thus mimicking T beta R-I phosphorylation in intact cells. In addition, T beta R-I phosphorylated in vitro remains associated with T beta R-II. These results suggest that T beta R-I and T beta R-II have affinity for each other, however, the ligand is required for stable complex formation under physiological conditions. Once formed, this complex is sufficient for T beta R-I phosphorylation by T beta R-II. 相似文献
5.
Niclas U. Lundsgaard Coen Hird Kathleen A. Doody Craig E. Franklin Rebecca L. Cramp 《Global Change Biology》2023,29(14):3857-3868
Ecological carryover effects, or delayed effects of the environment on an organism's phenotype, are central predictors of individual fitness and a key issue in conservation biology. Climate change imposes increasingly variable environmental conditions that may be challenging to early life-history stages in animals with complex life histories, leading to detrimental physiological and fitness effects in later life. Yet, the latent nature of carryover effects, combined with the long temporal scales over which they can manifest, means that this phenomenon remains understudied and is often overlooked in short-term studies limited to single life-history stages. Herein, we review evidence for the physiological carryover effects induced by elevated ultraviolet radiation (UVR; 280–400 nm) as a potential contributor to recent amphibian population declines. UVR exposure causes a suite of molecular, cellular and physiological consequences known to underpin carryover effects in other taxa, but there is a lack of research linking embryonic and larval UVR exposures to fitness consequences post-metamorphosis in amphibians. We propose that the key impacts of UVR on disease-related amphibian declines are facilitated through carryover effects that bridge embryonic and larval UVR exposure with potential increased disease susceptibility post-metamorphosis. We conclude by identifying a practical direction for the study of ecological carryover effects in amphibians that could guide future ecological research in the broader field of conservation physiology. Only by addressing carryover effects can many of the mechanistic links between environmental change and population declines be elucidated. 相似文献
6.
Regulation of expression of the 3β-hydroxysteroid dehydrogenases of human placenta and fetal adrenal
J.I. Mason K. Ushijima K.M. Doody K. Nagai D. Naville J.R. Head L. Milewich W.E. Rainey M.M. Ralph 《The Journal of steroid biochemistry and molecular biology》1993,47(1-6):151-159
The appropriate expression of 3β-hydroxysteroid dehydrogenase/Δ5→4-isomerase (3β-HSD) is vital for mammalian reproduction, fetal growth and life maintenance. Several isoforms of 3β-HSD, the products of separate genes, have been identified in various species including man. Current investigations are targeted toward defining the processes that regulate the levels of specific isoforms in various steroidogenic tissues of man. High levels of expression of 3β-HSD were observed in placental tissues. It has been generally considered that the multinucleated syncytiotrophoblastic cells are the principal sites of 3β-HSD expression and, moreover, that 3β-HSD expression is intimately associated with cyclic AMP-promoted formation of syncytia. Herein we report the presence of 3β-HSD immunoreactive and mRNA species in uninucleate cytotrophoblasts in the chorion laeve, similar to that in syncytia but not cytotrophoblast placenta. In vitro, 3β-HSD levels in chorion laeve cytotrophoblasts were not increased with time nor after treatment with adenylate cyclase activators, whereas villous cytotrophoblasts spontaneously demonstrated progressive, increased 3β-HSD expression. Moreover, 3β-HSD synthesis appeared to precede morphologic syncytial formation. Thus high steroidogenic enzyme expression in placenta is not necessarily closely linked to formation of syncytia. Both Western immunoblot and enzymic activity analyses also indicated that the 3β-HSD expressed in these cytotrophoblastic populations was the 3β-HSD type I gene product (Mr, 45K) and not 3β-HSD type II (Mr, 44K) expressed in fetal testis. In cultures of fetal zone and definitive zone cell of human fetal adrenal, 3β-HSD expression was not detected until ACTH was added. ACTH, likely acting in a cyclic AMP-dependent process, induced 3β-HSD type II activity and mRNA expression. The higher level of 3β-HSD mRNA in definitive zone compared with fetal zone cells was associated with parallel increases in cortisol secretion relative to dehydroepiandrosterone sulfate formation. 相似文献
7.
Orosz SE Morris PJ Doody MC Niemeyer GP Cortelyou Lee J Eaton NL Lothrop CD 《Theriogenology》1992,37(5):993-1004
Folliculogenesis in response to exogenous stimulation by human urinary follicle stimulating hormone (huFSH) and human menopausal gonadotropin (hMG) was evaluated in the domestic queen (Felis catus). The role of LH and/or FSH in folliculogenesis was examined by measuring concentrations of estradiol 17beta (E(2)) and progesterone (P) in the serum. Additionally, changes in the number and size of follicles from before the administration of exogenous hormones to surgical oocyte collection were monitored. Findings indicated that in queens receiving huFSH or hMG followed by human chorionic gonadotropin (hCG) to induce ovulation, the numbers of follicles from 1 to 3 mm increase with statistical significance (P<0.005) from before the initiation of treatment to surgical collection of oocytes. Although E(2) concentrations in cats receiving hMG increased above baseline by the third exogenous hormone injection, mean E(2) concentrations did not increase in the groups that received both huFSH and hCG, or hCG only, until after the administration of hCG. This suggests that the exogenous administration of LH contained in both hMG and hCG was necessary for E(2) to rise to levels associated with estrus. 相似文献
8.
Navin Kumar Verma Kieran Crosbie-Staunton Amro Satti Shane Gallagher Katie B Ryan Timothy Doody Colm McAtamney Ronan MacLoughlin Paul Galvin Conor S Burke Yuri Volkov Yurii K Gun’ko 《Journal of nanobiotechnology》2013,11(1):1-12
Background
Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe3O4 magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated.Results
Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting.Conclusion
We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route. 相似文献9.
Abstract Opportunistic sightings and strandings of Caperea marginata (n=196) from the vicinity of Australia and New Zealand (1884 to early 2007) were used to relate geographic and temporal patterns to oceanographic and broad-scale climatic variability. Records were not uniformly distributed along the coast and more (69%) were from Australia than New Zealand. Seven coastal whale ‘hotspots’ were identified which accounted for 61% of records with locality data. Half of the hotspot records were from southeast (37) and northwest (20) Tasmania—others each had 9–15 events. Upwelling and/or high zooplankton abundance has been documented near all whale hotspots. Records of C. marginata occurred in all months, with 75% in spring and summer. Inter-annual variability showed broad agreement between increased whale records (usually in spring/summer) and strongly positive ‘Niño 3.4’ during 1980–1995 but not thereafter. Coastal upwelling and productivity increase during climatic phenomena such as El Niño and are likely to be quickly beneficial to plankton-feeding whales such as C. marginata. 相似文献
10.
Black box and attics: Habitat selection and resource use by large threatened pythons in landscapes with contrasting human modification
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Woodland and forest degradation, driven predominately by agricultural and pastoral production, is a crisis facing many species globally, in particular hollow‐dependent fauna. Large predatory species play important roles in both ecosystems and conservation strategies, but few studies have examined habitat selection of such species in intensively human‐modified landscapes. We quantified habitat selection and resource use by a large, top‐order and threatened snake (carpet python, Morelia spilota), between adjacent areas of high and low anthropogenic modification in inland Australia, a region that has undergone considerable alteration since European settlement. At the low‐impact site, snakes preferred tree hollows and a structurally complex understorey, whereas at the high‐impact site, snakes preferred homestead attics. Based on the decline of the species in this region, however, high‐impact landscapes may only support snakes when they are adjacent to low‐impact habitats. Invasive species comprised a large part of snake diets in both landscape types. Carpet pythons, with large home ranges and habitat requirements that overlap with many smaller threatened mammalian and avian fauna, are generally well liked and easily identifiable by rural landholders. Accordingly, they may play a key role in conservation strategies aimed at the protection of woodland and hollow‐dependent fauna in heavily modified landscapes of Australia's inland regions. However, invasive species, which tend to contribute to declines in native species inhabiting arid and semi‐arid Australia, are beneficial and important to pythons. Our study therefore highlights the diversity of effects that two major threats to biodiversity – habitat loss and invasive species – can have on different species within the same ecosystem. 相似文献