Activation of store-operated calcium entry in airway smooth muscle cells: insight from a mathematical model

Intracellular dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper-responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated entry (SOCE) in these dynamics by constructing a mathematical model of ASMC signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient depletion of the sarcoplasmic reticulum (SR), while receptor-operated entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced oscillations in the absence of other influx. SOCE up-regulation may thus contribute to AHR by increasing the oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of . This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC

Differentiation-Induced Remodelling of Store-Operated Calcium Entry Is Independent of Neuronal or Glial Phenotype but Modulated by Cellular Context

Neurogenesis is a complex process leading to the generation of neuronal networks and glial cell types from stem cells or intermediate progenitors. Mapping subcellular and molecular changes accompanying the switch from proliferation to differentiation is vital for developing therapeutic targets for neurological diseases. Neuronal (N-type) and glial (S-type) phenotypes within the SH-SY5Y neuroblastoma cell line have distinct differentiation responses to 9-cis-retinoic acid (9cRA). In both cell phenotypes, these were accompanied at the single cell level by an uncoupling of Ca2+ store release from store-operated Ca2+ entry (SOCE), mediated by changes in the expression of calcium release-activated calcium pore proteins. This remodelling of calcium signalling was moderated by the predominant cell phenotype within the population. N- and S-type cells differed markedly in their phenotypic stability after withdrawal of the differentiation inducer, with the phenotypic stability of S-type cells, both morphologically and with respect to SOCE properties, in marked contrast to the lability of the N-type phenotype. Furthermore, the SOCE response of I-type cells, a presumed precursor to both N- and S-type cells, varied markedly in different cell environments. These results demonstrate the unique biology of neuronal and glial derivatives of common precursors and suggest that direct or indirect interactions between cell types are vital components of neurogenesis that need to be considered in experimental models.</p

Supporting self-management for patients with Interstitial Lung Diseases: Utility and acceptability of digital devices.

This is the final version. Available from Public Library of Science via the DOI in this record. Data Availability Statement: The fully de-identified research data supporting this publication are openly available as S1 Data and at 10.6084/m9. figshare.24569851.INTRODUCTION: Patients diagnosed with Interstitial Lung Diseases (ILD) use devices to self-monitor their health and well-being. Little is known about the range of devices, selection, frequency and terms of use and overall utility. We sought to quantify patients' usage and experiences with home digital devices, and further evaluate their perceived utility and barriers to adaptation. METHODS: A team of expert clinicians and patient partners interested in self-management approaches designed a 48-question cross-sectional electronic survey; specifically targeted at individuals diagnosed with ILD. The survey was critically appraised by the interdisciplinary self-management group at Royal Devon University Hospitals NHS Foundation Trust during a 6-month validation process. The survey was open for participation between September 2021 and December 2022, and responses were collected anonymously. Data were analysed descriptively for quantitative aspects and through thematic analysis for qualitative input. RESULTS: 104 patients accessed the survey and 89/104 (86%) reported a diagnosis of lung fibrosis, including 46/89 (52%) idiopathic pulmonary fibrosis (IPF) with 57/89 (64%) of participants diagnosed >3 years and 59/89 (66%) female. 52/65(80%) were in the UK; 33/65 (51%) reported severe breathlessness medical research council MRC grade 3-4 and 32/65 (49%) disclosed co-morbid arthritis or joint problems. Of these, 18/83 (22%) used a hand- held spirometer, with only 6/17 (35%) advised on how to interpret the readings. Pulse oximetry devices were the most frequently used device by 35/71 (49%) and 20/64 (31%) measured their saturations more than once daily. 29/63 (46%) of respondents reported home-monitoring brought reassurance; of these, for 25/63 (40%) a feeling of control. 10/57 (18%) felt it had a negative effect, citing fluctuating readings as causing stress and 'paranoia'. The most likely help-seeking triggers were worsening breathlessness 53/65 (82%) and low oxygen saturation 43/65 (66%). Nurse specialists were the most frequent source of help 24/63 (38%). Conclusion: Patients can learn appropriate technical skills, yet perceptions of home-monitoring are variable; targeted assessment and tailored support is likely to be beneficial.Health Education Englan

Tidal and groundwater fluxes to a shallow, microtidal estuary : constraining inputs through field observations and hydrodynamic modeling

This paper is not subject to U.S. copyright. The definitive version was published in Estuaries and Coasts 35 (2012): 1285-1298, doi:10.1007/s12237-012-9515-x.Increased nutrient loading to estuaries has led to eutrophication, degraded water quality, and ecological transformations. Quantifying nutrient loads in systems with significant groundwater input can be difficult due to the challenge of measuring groundwater fluxes. We quantified tidal and freshwater fluxes over an 8-week period at the entrance of West Falmouth Harbor, Massachusetts, a eutrophic, groundwater-fed estuary. Fluxes were estimated from velocity and salinity measurements and a total exchange flow (TEF) methodology. Intermittent cross-sectional measurements of velocity and salinity were used to convert point measurements to cross-sectionally averaged values over the entire deployment (index relationships). The estimated mean freshwater flux (0.19 m3/s) for the 8-week period was mainly due to groundwater input (0.21 m3/s) with contributions from precipitation to the estuary surface (0.026 m3/s) and removal by evaporation (0.048 m3/s). Spring–neap variations in freshwater export that appeared in shorter-term averages were mostly artifacts of the index relationships. Hydrodynamic modeling with steady groundwater input demonstrated that while the TEF methodology resolves the freshwater flux signal, calibration of the index– salinity relationships during spring tide conditions only was responsible for most of the spring–neap signal. The mean freshwater flux over the entire period estimated from the combination of the index-velocity, index–salinity, and TEF calculations were consistent with the model, suggesting that this methodology is a reliable way of estimating freshwater fluxes in the estuary over timescales greater than the spring– neap cycle. Combining this type of field campaign with hydrodynamic modeling provides guidance for estimating both magnitude of groundwater input and estuarine storage of freshwater and sets the stage for robust estimation of the nutrient load in groundwater.Funding was provided by the USGS Coastal and Marine Geology Program and by National Science Foundation Award #0420575 from the Biocomplexity/Coupled Biogeochemical Cycles Program