Junctophilin proteins maintain close contacts between the endoplasmic/sarcoplasmic reticulum (ER/SR) and the plasma membrane in many types of cells, as typified by junctophilin-2 (JPH2), which is ...necessary for the formation of the cardiac dyad. Here, we report that JPH2 is the most abundant junctophilin isotype in native smooth muscle cells (SMCs) isolated from cerebral arteries and that acute knockdown diminishes the area of sites of interaction between the SR and plasma membrane. Superresolution microscopy revealed nanometer-scale colocalization of JPH2 clusters with type 2 ryanodine receptor (RyR2) clusters near the cell surface. Knockdown of JPH2 had no effect on the frequency, amplitude, or kinetics of spontaneous Ca2+ sparks generated by transient release of Ca2+ from the SR through RyR2s, but it did nearly abolish Ca2+ spark-activated, large-conductance, Ca2+-activated K⁺ (BK) channel currents. We also found that JPH2 knockdown was associated with hypercontractility of intact cerebral arteries. We conclude that JPH2 maintains functional coupling between RyR2s and BK channels and is critically important for cerebral arterial function.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Under normal physiological conditions, tissue remodeling in response to injury leads to tissue regeneration without permanent damage. However, if homeostasis between synthesis and degradation of ...extracellular matrix (ECM) components is altered, fibrosis - or the excess accumulation of ECM - can disrupt tissue architecture and function. Several organs, including the heart, lung and kidney, exhibit age-associated fibrosis. Here we investigated whether fibrosis underlies aging in the ovary - an organ that ages chronologically before other organs. We used Picrosirius Red (PSR), a connective tissue stain specific for collagen I and III fibers, to evaluate ovarian fibrosis. Using bright-field, epifluorescence, confocal and polarized light microscopy, we validated the specific staining of highly ordered PSR-stained fibers in the ovary. We next examined ovarian PSR staining in two mouse strains (CD1 and CB6F1) across an aging continuum and found that PSR staining was minimal in ovaries from reproductively young adult animals, increased in distinct foci in animals of mid-to-advanced reproductive age, and was prominent throughout the stroma of the oldest animals. Consistent with fibrosis, there was a reproductive age-associated increase in ovarian hydroxyproline content. We also observed a unique population of multinucleated macrophage giant cells, which are associated with chronic inflammation, within the ovarian stroma exclusively in reproductively old mice. In fact, several genes central to inflammation had significantly higher levels of expression in ovaries from reproductively old mice relative to young mice. These results establish fibrosis as an early hallmark of the aging ovarian stroma, and this altered microenvironment may contribute to the age-associated decline in gamete quality.
Obesity, diabetes mellitus, and liver fibrosis Chiang, Dian J; Pritchard, Michele T; Nagy, Laura E
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
05/2011, Volume:
300, Issue:
5
Journal Article
Peer reviewed
Open access
Obesity is a global epidemic with more than 1 billion overweight adults and at least 300 million obese patients worldwide. Diabetes is characterized by a defect in insulin secretion or a decrease in ...sensitivity to insulin, which results in elevated fasting blood glucose. Both obesity and elevated fasting glucose are risk factors for nonalcoholic fatty liver disease, a disease spectrum that includes hepatic steatosis (nonalcoholic fatty liver), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from NASH to fibrosis through the development of a profibrotic mileau in the liver, including increased hepatocellular death, increased reactive oxygen species generation, and an altered adipokine/cytokine balance. This review will summarize recent advances in our understanding of the pathological interactions among excessive fat accumulation, insulin resistance, and hepatic fibrogenesis and discuss specific molecular pathways that may be of interest in the development of therapeutic interventions to prevent and/or reverse hepatic fibrosis.
Inflammaging is a state of chronic, low-grade inflammation associated with aging which contributes to age-related diseases. Recently, an age-associated increase in inflammation has been documented in ...the mammalian ovary, which is accompanied by a shift in the immune cell profile. In this Point of View article, we consider a unique population of macrophage-derived multinucleated giant cells, found in reproductively old mouse ovaries, as potential markers or functional drivers of inflammation in ovarian aging.
Milk production, fertility, longevity and health records, were extracted from databases of two milk recording organisations in the United Kingdom for the first three lactations of the ...Holstein–Friesian breed. These included data related to health events (mastitis and lameness), voluntarily recorded on a proportion of farms. The data were analysed to calculate disease incidence levels and to estimate genetic parameters for health traits and their relationships with production and other functional traits. The resulting dataset consisted of 124 793 lactations from 75 137 animals of 1586 sires, recorded in 2434 herds. Incidence of health events increased with parity. The overall incidence of mastitis (MAS) and lameness (LAM), defined as binary traits, were 17% and 16%, respectively. Heritability estimates for MAS and LAM were 0.04 and 0.02, respectively, obtained from repeatability linear sire models. Heritability estimates of mastitis and lameness as count traits were slightly higher, 0.05 and 0.03, respectively. Genetic correlations were obtained by bivariate analyses of all pair-wise combinations between milk 305-day yield (MY), protein 305-day yield (PY), fat 305-day yield (FY), lactation average logₑ transformed lactation average somatic cell count (SCS), calving interval (CI), days to first service (DFS), non-return at 56 days (NR56), number of inseminations (NINS), mastitis (MAS), number of mastitis episodes (NMAS), lameness (LAM), number of lameness episodes (NLAM) and lifespan score (LS). As expected, MAS was correlated most strongly with SCS (0.69), which supports the use of SCS as an indicator trait for mastitis. Genetic correlations between MAS and yield and fertility traits were of similar magnitude ranging from 0.27 to 0.33. Genetic correlations between MAS with LAM and LS were 0.38 and −0.59, respectively. Not all genetic correlations between LAM and other traits were significant because of fewer numbers of lameness records. LAM had significant genetic correlations with MY (0.38), PY (0.28), CI (0.35), NINS (0.38) and LS (−0.53). The heritability estimates of mastitis and lameness were low; therefore, genetic gain through direct selection alone would be slow, yet still positive and cumulative. Direct selection against mastitis and lameness as additional traits should reduce incidence of both diseases, and simultaneously improve fertility and longevity. However, both health traits had antagonistic relationships with production traits, thus genetic gain in production would be slower.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The majority of observed pixels on the Transiting Exoplanet Survey Satellite (TESS) are delivered in the form of full-frame images (FFIs). However, the FFIs contain systematic effects such ...as pointing jitter and scattered light from the Earth and Moon that must be removed (i.e., “detrended”) before downstream analysis. We present
unpopular
, an open-source Python package to obtain detrended TESS FFI light curves optimized for variable sources. The
unpopular
package implements a variant of the causal pixel model to remove systematics and allows for simultaneous fitting with a polynomial component to capture nontransit astrophysical variations, such as supernova signals or stellar variability, that tend to be removed in techniques optimized for exoplanet detection. We validate our method by detrending different sources (e.g., supernovae, tidal disruption events (TDEs), exoplanet-hosting stars, fast-rotating stars) and comparing our light curves to those obtained by other pipelines when appropriate. Our supernova and TDE light curves are visually similar to those obtained by others using the ISIS image subtraction package, indicating that
unpopular
can be used to extract multisector light curves by preserving astrophysical signals on timescales of a TESS sector (∼27 days). We note that our method contains tuning parameters that are currently set heuristically, and that the optimal set of tuning parameters will likely depend on the particular signal the user is interested in obtaining. The
unpopular
source code and tutorials are freely available online.
Abstract
Rapidly evolving transients, or objects that rise and fade in brightness on timescales two to three times shorter than those of typical Type Ia or Type II supernovae (SNe), have uncertain ...progenitor systems and powering mechanisms. Recent studies have noted similarities between rapidly evolving transients and Type Ibn SNe, which are powered by ejecta interacting with He-rich circumstellar material (CSM). In this work we present multiband photometric and spectroscopic observations from Las Cumbres Observatory and Swift of four fast-evolving Type Ibn SNe. We compare these observations with those of rapidly evolving transients identified in the literature. We discuss several common characteristics between these two samples, including their light curve and color evolution as well as their spectral features. To investigate a common powering mechanism we construct a grid of analytical model light curves with luminosity inputs from CSM interaction as well as
56
Ni radioactive decay. We find that models with ejecta masses of ≈1–3
M
⊙
, CSM masses of ≈0.2–1
M
⊙
, and CSM radii of ≈20–65 au can explain the diversity of peak luminosities, rise times, and decline rates observed in Type Ibn SNe and rapidly evolving transients. This suggests that a common progenitor system—the core collapse of a high-mass star within a dense CSM shell—can reproduce the light curves of even the most luminous and fast-evolving objects, such as AT 2018cow. This work is one of the first to reproduce the light curves of both SNe Ibn and other rapidly evolving transients with a single model.
Regional differences in dendritic architecture can influence connectivity and dendritic signal integration, with possible consequences for neuronal computation. In the cerebellum, analyses of ...Purkinje cells (PCs), which are functionally critical as they provide the sole output of the cerebellar cortex, have suggested that the cerebellar cortex is not uniform in structure as traditionally assumed. However, the limitations of traditional staining methods and microscopy capabilities have presented difficulties in investigating possible local variations in PC morphology. To address this question, we used male mice expressing green fluorescent protein selectively in PCs. Using Neurolucida 360 with confocal image stacks, we reconstructed dendritic arbors of PCs residing in lobule V (anterior) and lobule IX (posterior) of the vermis. We then analyzed morphologies of individual arbors and the structure of the assembled “jungle,” comparing these features across anatomical locations and age groups. Strikingly, we found that in lobule IX, half of the reconstructed PCs had two primary dendrites emanating from their soma, whereas fewer than a quarter showed this characteristic in lobule V. Furthermore, PCs in lobule V showed more efficient spatial occupancy compared to lobule IX, as well as greater packing density and increased arbor overlap in the adult. When analyzing complete ensembles of PC arbors, we also observed “hot spots” of increased dendritic density in lobule V, whereas lobule IX showed a more homogeneous spread of dendrites. These differences suggest that input patterns and/or physiology of PCs could likewise differ along the vermis, with possible implications for cerebellar function.
We describe two distinct dendritic morphologies in the Purkinje cell population. One type (Type 1) conforms to the classical model of a Purkinje cell arbor, with a single primary dendrite and homogeneous density of branches throughout the thickness of the molecular layer. The second type (Type 2) has two primary dendrites and little branching in the lower part of their arbors. Type 1 arbors are predominantly found in vermis lobule V, contributing to an efficient spatial occupancy ensemble with regions of dense dendritic overlap. Conversely, Type 2 arbors are primarily observed in vermis lobule IX and give rise to a dendritic ensemble with a more homogeneous distribution of dendrites and less overlap.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Premature mortality and culling causes great wastage in the dairy industry, as a large number of heifers born never become productive or are culled before their full lactation potential is reached. ...The objectives of this study were to characterize survival and estimate genetic parameters for alternative longevity traits that considered (1) the survival of replacement heifers and (2) functional longevity of milking cows in the UK Holstein Friesian population, using combined information from the British Cattle Movement Service and milk recording organizations. Mortality of heifers was highest in the first month of life and was proportionately highest in calves born during winter months. Heifer mortality tended to decrease with age until about 16mo onward; it then gradually increased, expected to be associated with culls due to reproductive failure or problems during pregnancy and calving. In milking cows, days of productive life (DPL) was analyzed as an alternative to the current trait lifespan score. Cows that died in 2009 on average lived for 6.8yr with an average production of 4.3yr. Heritability estimates were low for both heifer and cow survival and were ~0.01 and ~0.06, respectively. The positive genetic correlation between heifer survival with lifespan score (0.31) indicates that bulls that sire daughters with longer productive lives are also likely to have calves that survive and become replacement heifers. However, the magnitude of the genetic correlation suggests that survival in the rearing period and the milking herd are different traits. Genetic correlations were favorable between DPL with somatic cell count and fertility traits indicating that animals with a longer productive life tend to have lower somatic cell count, a shorter calving interval, fewer days to first service, and require fewer inseminations. However, an antagonistic relationship existed between DPL with milk and fat yield traits.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We present a sample of Type Icn supernovae (SNe Icn), a newly discovered class of transients characterized by their interaction with H- and He-poor circumstellar material (CSM). This sample ...is the largest collection of SNe Icn to date and includes observations of two published objects (SN 2019hgp and SN 2021csp) and two objects not yet published in the literature (SN 2019jc and SN 2021ckj). The SNe Icn display a range of peak luminosities, rise times, and decline rates, as well as diverse late-time spectral features. To investigate their explosion and progenitor properties, we fit their bolometric light curves to a semianalytical model consisting of luminosity inputs from circumstellar interaction and radioactive decay of
56
Ni. We infer low ejecta masses (≲2
M
⊙
) and
56
Ni masses (≲0.04
M
⊙
) from the light curves, suggesting that normal stripped-envelope supernova (SESN) explosions within a dense CSM cannot be the underlying mechanism powering SNe Icn. Additionally, we find that an estimate of the star formation rate density at the location of SN 2019jc lies at the lower end of a distribution of SESNe, in conflict with a massive star progenitor of this object. Based on its estimated ejecta mass,
56
Ni mass, and explosion site properties, we suggest a low-mass, ultra-stripped star as the progenitor of SN 2019jc. For other SNe Icn, we suggest that a Wolf–Rayet star progenitor may better explain their observed properties. This study demonstrates that multiple progenitor channels may produce SNe Icn and other interaction-powered transients.
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