Uterine quiescence must be maintained until pregnancy reaches term. Premature activation of myometrial contractility leads to preterm labor and delivery.
To scrutinize the potential of androgens to ...relax the myometrium and the mechanism of their action.
A pregnancy-derived myometrial smooth muscle cell line (PHM1-41) and myometrial strips prepared from tissues obtained from pregnant women (lean, n = 9; obese, n = 6) undergoing elective cesarean section at term and from nonpregnant C57BL/6 mice (n=5) were each utilized.
The contraction of collagen-embedded PHM1-41s and the stretch-induced contraction of human and murine myometrial strips were assessed after incubation with Testosterone (T), dihydrotestosterone (DHT), and T conjugated to BSA. Intracellular calcium (Ca(2+)) and phosphorylated myosin light chain concentrations were quantified in PHM1-41s using a Fluo-4 Ca(2+) assay and in-cell Westerns, respectively.
University research institute.
DHT and T, but not T conjugated to BSA, impaired the contractile function of PHM1-41s and of human and murine myometrial strips. The response was rapid (observed within minutes), was sustainable for up to 48 hours, and was not abolished on knockdown of the androgen receptor. DHT (100 μm) reduced the amplitude of lean strip contraction to 2 ± 2% of the pretreatment value and T (100 μm) to 3.3 ± 1%. These values for obese strips were 15 ± 6.7% and 11 ± 6.7%, respectively. At the same doses, in murine strips, DHT reduced the amplitude to 4.8 ± 3% and T to 4.9 ± 3%. DHT (50 μm) pretreatment reduced the oxytocin-stimulated increase in Ca(2+) (P < .0001; n = 6) and phosphorylated myosin light chain (P < .05; n = 5) in PHM1-41s.
Lipid-soluble androgens could be developed as tocolytic agents for the treatment of preterm labor.
Context:
Uterine quiescence must be maintained until pregnancy reaches term. Premature activation of myometrial contractility leads to preterm labor and delivery.
Objective:
To scrutinize the ...potential of androgens to relax the myometrium and the mechanism of their action.
Samples:
A pregnancy-derived myometrial smooth muscle cell line (PHM1-41) and myometrial strips prepared from tissues obtained from pregnant women (lean, n = 9; obese, n = 6) undergoing elective cesarean section at term and from nonpregnant C57BL/6 mice (n=5) were each utilized.
Design:
The contraction of collagen-embedded PHM1–41s and the stretch-induced contraction of human and murine myometrial strips were assessed after incubation with Testosterone (T), dihydrotestosterone (DHT), and T conjugated to BSA. Intracellular calcium (Ca2+) and phosphorylated myosin light chain concentrations were quantified in PHM1–41s using a Fluo-4 Ca2+ assay and in-cell Westerns, respectively.
Setting:
University research institute.
Results:
DHT and T, but not T conjugated to BSA, impaired the contractile function of PHM1–41s and of human and murine myometrial strips. The response was rapid (observed within minutes), was sustainable for up to 48 hours, and was not abolished on knockdown of the androgen receptor. DHT (100 μm) reduced the amplitude of lean strip contraction to 2 ± 2% of the pretreatment value and T (100 μm) to 3.3 ± 1%. These values for obese strips were 15 ± 6.7% and 11± 6.7%, respectively. At the same doses, in murine strips, DHT reduced the amplitude to 4.8 ± 3% and T to 4.9 ± 3%. DHT (50 μm) pretreatment reduced the oxytocin-stimulated increase in Ca2+ (P < .0001; n = 6) and phosphorylated myosin light chain (P < .05; n = 5) in PHM1–41s.
Conclusion:
Lipid-soluble androgens could be developed as tocolytic agents for the treatment of preterm labor.
It is often supposed that occlusive dressings potentiate wound infection. However, even though heavy colonization by skin and wound flora is often seen under certain types of occlusion, clinical ...infection is not a frequent occurrence. Commensal wound flora consists of a variety of Gram-positive and Gram-negative organisms and fungi which do not appear to be detrimental to healing. Certain aspects of wound healing may in fact be promoted by bacterial colonization, although clinical infection can lead to wound breakdown and systemic infection. Wounds compromised by devitalized tissue, drains or sutures are more susceptible than clean wounds to clinical infection. Occlusive dressings may help prevent infection by presenting a barrier to potential pathogens, and hydrocolloid occlusive dressings have been shown to prevent dissemination of methicillin-resistant Staphylococcus aureus. The rate of clinical infection as deduced from published trials of dressings is lower under occlusion than when non-occlusive dressings are used, and this is likely to be a result of normal activity of the host defences under occlusive dressings.
Economic impact of paratuberculosis Hutchinson, L J
The Veterinary clinics of North America. Food animal practice,
07/1996, Letnik:
12, Številka:
2
Journal Article
Recenzirano
The economic impact of paratuberculosis has been estimated in dairy cattle for several areas of the United States and in some other dairy-intensive areas of the world. Losses are primarily due to ...decreased milk production and unrealized income related to premature culling. Milk production losses in the range of 15% have been reported in paratuberculosis-infected cows. Additional economic costs include diagnostic testing, control measures, and accelerated cull and replacement rates.
Abstract
We present measurements of the Baryon Acoustic Oscillation (BAO) scale in redshift-space using the clustering of quasars. We consider a sample of 147 000 quasars from the extended Baryon ...Oscillation Spectroscopic Survey (eBOSS) distributed over 2044 square degrees with redshifts 0.8 < z < 2.2 and measure their spherically averaged clustering in both configuration and Fourier space. Our observational data set and the 1400 simulated realizations of the data set
allow us to detect a preference for BAO that is greater than 2.8σ. We determine the spherically averaged BAO distance to z = 1.52 to 3.8 per cent precision: DV(z = 1.52) = 3843 ± 147(rd/rd, fid)Mpc. This is the first time the location of the BAO feature has been measured between redshifts 1 and 2. Our result is fully consistent with the prediction obtained by extrapolating the Planck flat ΛCDM best-fitting cosmology. All of our results are consistent with basic large-scale structure (LSS) theory, confirming quasars to be a reliable tracer of LSS, and provide a starting point for numerous cosmological tests to be performed with eBOSS quasar samples. We combine our result with previous, independent, BAO distance measurements to construct an updated BAO distance-ladder. Using these BAO data alone and marginalizing over the length of the standard ruler, we find ΩΛ > 0 at 6.6σ significance when testing a ΛCDM model with free curvature.
Targetable NOTCH1 rearrangements in reninoma Treger, Taryn D; Lawrence, John E G; Anderson, Nathaniel D ...
Nature communications,
09/2023, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the ...central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.
Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed ...self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first
designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.
Electrothermal instability plays an important role in applications of current-driven metal, creating striations (which seed the magneto-Rayleigh-Taylor instability) and filaments (which provide a ...more rapid path to plasma formation). However, the initial formation of both structures is not well understood. Simulations show for the first time how a commonly occurring isolated defect transforms into the larger striation and filament, through a feedback loop connecting current and electrical conductivity. Simulations have been experimentally validated using defect-driven self-emission patterns.
The Miocene epoch, spanning 23.03–5.33 Ma, was a dynamic climate of sustained, polar amplified warmth. Miocene atmospheric CO2 concentrations are typically reconstructed between 300 and 600 ppm and ...were potentially higher during the Miocene Climatic Optimum (16.75–14.5 Ma). With surface temperature reconstructions pointing to substantial midlatitude and polar warmth, it is unclear what processes maintained the much weaker‐than‐modern equator‐to‐pole temperature difference. Here, we synthesize several Miocene climate modeling efforts together with available terrestrial and ocean surface temperature reconstructions. We evaluate the range of model‐data agreement, highlight robust mechanisms operating across Miocene modeling efforts and regions where differences across experiments result in a large spread in warming responses. Prescribed CO2 is the primary factor controlling global warming across the ensemble. On average, elements other than CO2, such as Miocene paleogeography and ice sheets, raise global mean temperature by ∼2°C, with the spread in warming under a given CO2 concentration (due to a combination of the spread in imposed boundary conditions and climate feedback strengths) equivalent to ∼1.2 times a CO2 doubling. This study uses an ensemble of opportunity: models, boundary conditions, and reference data sets represent the state‐of‐art for the Miocene, but are inhomogeneous and not ideal for a formal intermodel comparison effort. Acknowledging this caveat, this study is nevertheless the first Miocene multi‐model, multi‐proxy comparison attempted so far. This study serves to take stock of the current progress toward simulating Miocene warmth while isolating remaining challenges that may be well served by community‐led efforts to coordinate modeling and data activities within a common analytical framework.
Plain Language Summary
As human activity continues to increase atmospheric carbon dioxide concentrations, scientists turn to warm intervals in Earth's history to develop insight into the behavior of the climate system under elevated carbon dioxide and temperature. One such interval is the Miocene epoch which has become increasingly relevant as reconstructions of Miocene atmospheric CO2 concentrations point to values ranging between current concentrations of ∼400 ppm and those projected for the end of this century under Shared Socioeconomic Pathways 3 and 4. In this study, we evaluate the surface warming patterns simulated by a range of different climate models configured with Miocene paleogeography and CO2 concentrations spanning 200–850 ppm. We also synthesize available Miocene surface temperature reconstructions. The primary factor controlling the amount of global warming seen across the Miocene simulations analyzed is the CO2 concentration that was prescribed within a given simulation. On average, Miocene elements other than CO2, such as Miocene paleogeography and ice sheets, raise global mean temperature by ∼2°C. While some Miocene simulations with high CO2 forcing overlap with the reconstructed global mean surface temperature estimates for their target Miocene interval, they still generally fail to capture the reconstructed pattern of warming.
Key Points
A synthesis of Miocene modeling efforts, and surface temperature reconstructions, is presented within a single analysis framework
Miocene global mean surface temperature estimates span ∼5.3°C–11.5°C higher than preindustrial, only ∼2°C is explained by non–CO2 boundary conditions in climate models
Some simulations overlap with reconstructed global mean surface temperature estimates but fail to capture the weak temperature gradient
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