828 research outputs found
Serum 25-hydroxyvitamin D and cognitive decline in the very old: The Newcastle 85+ study
No full textBackground and purpose:
Studies investigating the association between 25-hydroxyvitamin D [25(OH)D] and cognition in the very old (85+) are lacking.
Methods:
Cross-sectional (baseline) and prospective data (up to 3 years follow-up) from 775 participants in the Newcastle 85+ Study were analysed for global (measured by the Standardized Mini-Mental State Examination) and attention-specific (measured by the attention battery of the Cognitive Drug Research test) cognitive performance in relation to season-specific 25(OH)D quartiles.
Results:
Those in the lowest and highest season-specific 25(OH)D quartiles had an increased risk of impaired prevalent (1.66, 95% confidence interval 1.06–2.60, P = 0.03; 1.62, 95% confidence interval 1.02–2.59, P = 0.04, respectively) but not incident global cognitive functioning or decline in functioning compared with those in the middle quartiles adjusted for sociodemographic, health and lifestyle confounders. Random effects models showed that participants belonging to the lowest and highest 25(OH)D quartiles, compared with those in the middle quartiles, had overall slower (log-transformed) attention reaction times for Choice Reaction Time (lowest, b = 0.023, P = 0.01; highest, b = 0.021, P = 0.02), Digit Vigilance Task (lowest, b = 0.009, P = 0.05; highest,b = 0.01, P = 0.02) and Power of Attention (lowest, b = 0.017, P = 0.02;highest, b = 0.022, P = 0.002) and greater Reaction Time Variability (lowest,b = 0.021, P = 0.02; highest, b = 0.02, P = 0.03). The increased risk of worse global cognition and attention amongst those in the highest quartile was not observed in non-users of vitamin D supplements/medication.
Conclusion:
Low and high season-specific 25(OH)D quartiles were associated with prevalent cognitive impairment and poorer overall performance in attention-specific tasks over 3 years in the very old, but not with global cognitive decline or incident impairment
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JAGGER localization and function are dependent on GPI anchor addition
No full textKey message: GPI anchor addition is important for JAGGER localization and in vivo function. Loss of correct GPI anchor addition in JAGGER, negatively affects its localization and function. Abstract: In flowering plants, successful double fertilization requires the correct delivery of two sperm cells to the female gametophyte inside the ovule. The delivery of a single pair of sperm cells is achieved by the entrance of a single pollen tube into one female gametophyte. To prevent polyspermy, Arabidopsis ovules avoid the attraction of multiple pollen tubes to one ovule–polytubey block. In Arabidopsis jagger mutants, a significant number of ovules attract more than one pollen tube to an ovule due to an impairment in synergid degeneration. JAGGER encodes a putative arabinogalactan protein which is predicted to be anchored to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Here, we show that JAGGER fused to citrine yellow fluorescent protein (JAGGER-cYFP) is functional and localizes mostly to the periphery of ovule integuments and transmitting tract cells. We further investigated the importance of GPI-anchor addition domains for JAGGER localization and function. Different JAGGER proteins with deletions in predicted ω-site regions and GPI attachment signal domain, expected to compromise the addition of the GPI anchor, led to disruption of JAGGER localization in the cell periphery. All JAGGER proteins with disrupted localization were also not able to rescue the polytubey phenotype, pointing to the importance of GPI-anchor addition to in vivo function of the JAGGER protein. © 2024, The Author(s).Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Gender differences in healthy life years within the EU: an exploration of the "health-survival" paradox.
No full textvan Oyen H, Nuselder W, Jagger C, Kolip P, Cambois E, Robine JM. Gender differences in healthy life years within the EU: an exploration of the "health-survival" paradox. International Journal of Public Health. 2013;58(1):143-155
The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.
No full textCiliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions
Calcium signalling mediated by the α9 acetylcholine receptor in a cochlear cell line from the Immortomouse
No full text1. We have investigated the characteristics of the alpha 9 acetylcholine receptor (alpha 9AChR) expressed in hair cell precursors in an immortalized cell line UB/OC-2 developed from the organ of Corti of the transgenic H-2Kb-tsA58 mouse (the Immortomouse) using both calcium imaging and whole-cell recording. 2. Ratiometric measurements of fura-2 fluorescence revealed an increase of intracellular calcium concentration in cells when challenged with 10 mu M ACh. The calcium increase was seen in 66 % of the cells grown at 39 degrees C in differentiated conditions. A smaller fraction (34 %) of cells grown at 33 degrees C in proliferative conditions responded. 3. Caffeine (10 mM) elevated cell calcium. In the absence of caffeine, the majority of imaged cells responded only once to ACh. A small proportion (<2 % of the total) responded with an increase in intracellular calcium to multiple ACh presentations. Pretreatment with caffeine inhibited all calcium responses to ACh. 4. In whole-cell tight-seal recordings 10 mu M ACh activated an inward, non-selective cation current. The reversal potential of the ACh-activated inward current was dependent on the extracellular calcium concentration with an estimated P(Ca)/P(Na) of 80 for the alpha 9 receptor at physiological calcium levels. 5. The data indicate that ACh activates a calcium-permeable channel alpha 9AChR in UB/OC-2 cells and that the channel has a significantly higher calcium permeability than other AChRs. The results indicate that the alpha 9AChR may be able to elevate intracellular calcium levels in hair cells both directly and via store release
DEVELOPMENT PATHWAYS AND LAND MANAGEMENT IN UGANDA: CAUSES AND IMPLICATIONS
No full textThis paper investigates the patterns and determinants of change in livelihood strategies ("development pathways"), land management practices, resource and human welfare conditions in Uganda since 1990, based upon a community-level survey conducted in 107 villages. The pattern of agricultural development since 1990 involved increasing specialization and commercialization of economic activities, consistent with local comparative advantages and market liberalization. Six dominant development pathways emerged, all but one of which involved increasing specialization in already dominant activities: expansion of cereal production, expansion of banana and coffee production, non-farm development, expansion of horticultural production, expansion of cotton, and stable coffee production. Of these, expansion of banana and coffee production was most strongly associated with adoption of resource-conserving practices and improvements in resource conditions and welfare. Other strategies are needed for areas not suited for this pathway. Other factors also influenced land management and resource and welfare outcomes. Road development was associated with improvements in many welfare and some natural resource conditions, except forest and wetland availability. Irrigation was found to reduce pressure to expand cultivated area at the expense of forest and wetlands, and is associated with improvement in some welfare and resource indicators. Government and non-governmental organization programs were found to contribute to improvements in several resource and welfare indicators, though there were some mixed results. Such programs may cause declines in one area by focusing on improvements in another area. Thus, trade-offs appear to be inherent in many efforts to improve agriculture or protect resources. Population growth had an insignificant impact on most indicators of change, though there is some evidence of population-induced agricultural intensification. The findings support neither the pessimism of some neo-Malthusian observers or the optimism of some neo-Boserupian observers regarding the impacts of population growth.International Development, Land Economics/Use,
The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway.
No full textAlström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS
Mode of action (MoA) analysis of slow-acting feeding inhibitors and pharmacogenetic profiling of a model chordotonal organ
No full textNo abstract available at author's request
Purinergic signalling in the auditory nerve: Functional expression of P2X and P2Y receptors in cochlear glial cells
No full textSensory and non-sensory cells of the inner ear express numerous P2X and P2Y receptor subtypes, suggesting purines play various roles in hearing. Spiral ganglion neurons (SGNs), the primary afferents in the auditory nerve, rely on satellite glial cells (SGCs) and Schwann cells (SCs) for their long-term survival. This project examined the role of P2X7 receptors (P2X7Rs) as mediators of neuro-glial interactions in the auditory nerve, and their potential as therapeutic targets. In transgenic reporter mice where EGFP expression is driven by the P2X7R promoter, cytoplasmic EGFP localised to SGCs and SCs, but was absent from SGNs and auditory nerve CNS glia. In spiral ganglion primary cultures from these mice, EGFP was detected only in Sox10-positive glia. Functional EGFP-tagged P2X7Rs in BAC transgenic mice localised to the membranes of SGCs and SCs, but not those of SGNs. Comparable patterns of expression were observed using a P2X7R-specific nanobody on mouse cochlea, and a commercial antibody on rat cochlea. These data identify an expression of P2X7Rs that is specific to peripheral glia within the auditory nerve. The properties of glial P2X7Rs were studied in rat spiral ganglion primary cultures. The P2X7R agonist BzATP activated instantaneous increases of intracellular calcium concentration, an effect dependent on extracellular calcium. BzATP application activated glial uptake of the large fluorescent molecule YO-PRO-1 within minutes, an effect slowed by selective P2X7R antagonists. Prolonged (6-hour) incubation in BzATP or ATP activated apoptotic cell death in glia, though cells were resistant to shorter (1-hour) exposures. Together, the data demonstrate functional P2X7R expression specifically in peripheral glia within the auditory nerve. Their functional properties suggest P2X7R activation may activate the uptake or release of large molecules in the neuro-glial space. This mechanism may be neuroprotective, to preserve auditory nerve function during conditions of stress
Fab fragment of an antibody selective for wild-type alpha-1-antitrypsin in complex with its antigen
No full textPDB ID: 6I3Z Protein crystal structur
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