The calcium ion is quite possibly the single most pervasive signaling molecule used by living organisms for the purpose of communicating internal and external states. It differs from other messengers ...in that it is neither created nor destroyed, but just moved around inside and outside the cell via transporters, pumps and channels to alter its concentration in specific cellular locations. These changes in free Ca(2+) are then detected by a wide array of Ca(2+)-binding effector proteins whose affinities are appropriately tuned to respond to a particular type of Ca(2+) change. This deceptively simple paradigm dominates the function of many cell types, for example in driving contraction of muscle, action potential generation in nerves, fluid, hormone, and enzyme secretion in secretory cells, and certain immune responses. However, the Ca(2+) signal does not work in strict isolation, but rather is fine-tuned by many other signals, not the least of which is the other major second messenger, cyclic AMP (cAMP). Conversely, the cAMP pathway is subject to modification by the calcium signal and its various effectors at many different levels. These two fundamental second messengers, used throughout eukaryotes and even prokaryotes, are thus inextricably intertwined. The purpose of the present article is to provide an update on some of the recently described forms of reciprocal regulation between Ca(2+) and cAMP signaling circuits, with emphasis on interactions that take place in localized domains of the cell.
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1β and IL-18, and as ...such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca ²⁺ mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca ²⁺ mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca ²⁺ signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca ²⁺ release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca ²⁺-mediated mitochondrial damage.
We present estimates of sea-level change caused by the global surface mass balance of glaciers, based on the reconstruction and projection of the surface mass balance of all the individual glaciers ...of the world, excluding the ice sheets in Greenland and Antarctica. The model is validated using a leave-one-glacier-out cross-validation scheme against 3997 observed surface mass balances of 255 glaciers, and against 756 geodetically observed, temporally integrated volume and surface area changes of 341 glaciers. When forced with observed monthly precipitation and temperature data, the glaciers of the world are reconstructed to have lost mass corresponding to 114 ± 5 mm sea-level equivalent (SLE) between 1902 and 2009. Using projected temperature and precipitation anomalies from 15 coupled general circulation models from the Coupled Model Intercomparison Project phase 5 (CMIP5) ensemble, they are projected to lose an additional 148 ± 35 mm SLE (scenario RCP26), 166 ± 42 mm SLE (scenario RCP45), 175 ± 40 mm SLE (scenario RCP60), or 217 ± 47 mm SLE (scenario RCP85) during the 21st century. Based on the extended RCP scenarios, glaciers are projected to approach a new equilibrium towards the end of the 23rd century, after having lost either 248 ± 66 mm SLE (scenario RCP26), 313 ± 50 mm SLE (scenario RCP45), or 424 ± 46 mm SLE (scenario RCP85). Up until approximately 2100, ensemble uncertainty within each scenario is the biggest source of uncertainty for the future glacier mass loss; after that, the difference between the scenarios takes over as the biggest source of uncertainty. Ice mass loss rates are projected to peak 2040 ∼ 2050 (RCP26), 2050 ∼ 2060 (RCP45), 2070 ∼ 2090 (RCP60), or 2070 ∼ 2100 (RCP85).
Cyclic AMP (cAMP)-dependent phosphorylation has been reported to exert biological effects in both the mitochondrial matrix and outer mitochondrial membrane (OMM). However, the kinetics, targets, and ...effectors of the cAMP cascade in these organellar domains remain largely undefined. Here we used sensitive FRET-based sensors to monitor cAMP and protein kinase A (PKA) activity in different mitochondrial compartments in real time. We found that cytosolic cAMP did not enter the matrix, except during mitochondrial permeability transition. Bicarbonate treatment (expected to activate matrix-bound soluble adenylyl cyclase) increased intramitochondrial cAMP, but along with membrane-permeant cAMP analogues, failed to induce measureable matrix PKA activity. In contrast, the OMM proved to be a domain of exceptionally persistent cAMP-dependent PKA activity. Although cAMP signaling events measured on the OMM mirrored those of the cytosol, PKA phosphorylation at the OMM endured longer as a consequence of diminished control by local phosphatases. Our findings demonstrate that mitochondria host segregated cAMP cascades with distinct functional and kinetic signatures.
On average, older people remember less and walk more slowly than do younger persons. Some researchers argue that this is due in part to a common biologic process underlying age-related declines in ...both physical and cognitive functioning. Only recently have longitudinal data become available for analyzing this claim. We conducted a systematic review of English-language research published between 2000 and 2011 to evaluate the relations between rates of change in physical and cognitive functioning in older cohorts. Physical functioning was assessed using objective measures: walking speed, grip strength, chair rise time, flamingo stand time, and summary measures of physical functioning. Cognition was measured using mental state examinations, fluid cognition, and diagnosis of impairment. Results depended on measurement type: Change in grip strength was more strongly correlated with mental state, while change in walking speed was more strongly correlated with change in fluid cognition. Examining physical and cognitive functioning can help clinicians and researchers to better identify individuals and groups that are aging differently and at different rates. In future research, investigators should consider the importance of identifying different patterns and rates of decline, examine relations between more diverse types of measures, and analyze the order in which age-related declines occur.
The anti–interleukin-1 antibody canakinumab was effective at controlling and preventing recurrence of flares in autoimmune inflammatory diseases: familial Mediterranean fever, mevalonate kinase ...deficiency, and the TNF receptor–associated periodic syndrome.
Abstract
Objectives
Grip strength and cognitive function reflect upper body muscle strength and mental capacities. Cross-sectional research has suggested that in old age these two processes are ...moderately to highly associated, and that an underlying common cause drives this association. Our aim was to synthesize and evaluate longitudinal research addressing whether changes in grip strength are associated with changes in cognitive function in healthy older adults.
Methods
We systematically reviewed English-language research investigating the longitudinal association between repeated measures of grip strength and of cognitive function in community-dwelling older adults to evaluate the extent to which the two indices decline concurrently. We used four search engines: Embase, PsychINFO, PubMed, and Web of Science.
Results
Of 459 unique citations, 6 met our full criteria: 4 studies reported a longitudinal association between rates of change in grip strength and cognitive function in older adults, 2 of which reported the magnitudes of these associations as ranging from low to moderate; 2 studies reported significant cross-sectional but not longitudinal associations among rates of change. All studies concluded that cognitive function and grip strength declined, on average, with increasing age, although with little to no evidence for longitudinal associations among rates of change.
Conclusions
Future research is urged to expand the study of physical and cognitive associations in old age using a within-person and multi-study integrative approach to evaluate the reliability of longitudinal results with greater emphasis on the magnitude of this association.
Systematic review registration number
CRD42016038544.
Abstract
In the presence of a tune spread induced by chromaticity or amplitude detuning, decoherence will lead to the damping of the beam centroid motion after a single transverse excitation. This in ...turn has implications for the analysis of turn-by-turn based optics measurements, as it affects the precision of the spectral analysis. In the past, it has been shown how the effect of decoherence on spectral lines in a single plane can be accounted for. In this paper, this work will be extended to include the effect from both transverse planes.
The primary cilium permits compartmentalization of specific signaling pathways, including elements of the Hedgehog (Hh) pathway. Hh transcriptional activity is thought to be negatively regulated by ...constitutively high ciliary cAMP maintained by the Gα(s)-coupled GPCR, GPR161. However, cilia also sequester many other Gα(s)-coupled GPCRs with unknown potential to regulate Hh. Here we used biosensors optimized for ciliary cAMP and strategies to isolate signals in the cilium from the cell body and neighboring cells. We found that ciliary cAMP was not elevated relative to cellular cAMP, inconsistent with constitutive cAMP production. Gα(s)-coupled GPCRs (e.g., the 5-HT₆ serotonin and D1R dopamine receptor) had reduced ability to generate cAMP upon trafficking to the ciliary membrane. However, activation of the Hh pathway restored or amplified GPCR function to permit cAMP elevation selectively in the cilium. Hh therefore enables its own local GPCR-dependent cAMP regulatory circuit. Considering that GPCRs comprise much of the druggable genome, these data suggest alternative strategies to modify Hh signaling.
Replication of research findings across independent longitudinal studies is essential for a cumulative and innovative developmental science. Meta-analysis of longitudinal studies is often limited by ...the amount of published information on particular research questions, the complexity of longitudinal designs and the sophistication of analyses, and practical limits on full reporting of results. In many cases, cross-study differences in sample composition and measurements impede or lessen the utility of pooled data analysis. A collaborative, coordinated analysis approach can provide a broad foundation for cumulating scientific knowledge by facilitating efficient analysis of multiple studies in ways that maximize comparability of results and permit evaluation of study differences. The goal of such an approach is to maximize opportunities for replication and extension of findings across longitudinal studies through open access to analysis scripts and output for published results, permitting modification, evaluation, and extension of alternative statistical models and application to additional data sets. Drawing on the cognitive aging literature as an example, the authors articulate some of the challenges of meta-analytic and pooled-data approaches and introduce a coordinated analysis approach as an important avenue for maximizing the comparability, replication, and extension of results from longitudinal studies.
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