To assess tissue sensitivity to insulin during the follicular and luteal phases of the menstrual cycle, two-step euglycemic, hyperinsulinemic clamp studies in combination with tritiated glucose ...infusion and indirect calorimetry were performed in regularly menstruating women in randomized order. There was no difference in the basal follicular and luteal phase levels of glucose, insulin or glucose turnover. A low-dose (0.25 mU/kg/min) insulin infusion suppressed endogenous hepatic glucose production. There was no difference in tissue insulin sensitivity during a high-dose insulin infusion (1.0 mU/kg/min). Nonoxidative glucose disposal also was similar in the basal and insulin infusion periods. Under euglycemic, hyperinsulinemic conditions, there is no difference in tissue sensitivity to insulin, and intracellular pathways of glucose disposal are not altered by the stage of the menstrual cycle.
Recent studies have shown that stem cell therapy can promote tissue regeneration; however, monitoring stem cells in vivo remains problematic owing to limitations of conventional histological assays ...and imaging modalities.
Murine embryonic stem (ES) cells were stably transduced with a lentiviral vector carrying a novel triple-fusion (TF) reporter gene that consists of firefly luciferase, monomeric red fluorescence protein, and truncated thymidine kinase (fluc-mrfp-ttk). ES cell viability, proliferation, and differentiation ability were not adversely affected by either reporter genes or reporter probes compared with nontransduced control cells (P=NS). Afterward, 1x10(7) of ES cells carrying the TF reporter gene (ES-TF) were injected into the myocardium of adult nude rats (n=20). Control animals received nontransduced ES cells (n=6). At day 4, the bioluminescence and positron emission tomography signals in study animals were 3.7x10(7)+/-5.8x10(6) photons.s(-1).cm(-2) per steradian (sr) and 0.08+/-0.03% injected dose/g, respectively (P<0.05 versus control). Both signals increased progressively from week 1 to week 4, which indicated ES cell survival and proliferation in the host. Histological analysis demonstrated the formation of intracardiac and extracardiac teratomas. Finally, animals (n=4) that were treated with intraperitoneal injection of ganciclovir (50 mg/kg) did not develop teratomas when compared with control animals (n=4) treated with saline (1 mL/kg).
This is the first study to characterize ES cells that stably express fluorescence, bioluminescence, and positron emission tomography reporter genes and monitor the kinetics of ES cell survival, proliferation, and migration. This versatile imaging platform should have broad applications for basic research and clinical studies on stem cell therapy.
Summary
Background
Transition of hair shaft keratinocytes from actively respiring, nucleated cells to structural cells devoid of nucleus and cytoplasm is key to hair production. This form of cell ...‘death’, or cornification, requires cellular organelle removal to allow the cytoplasm to become packed with keratin filament bundles that further require cross‐linking to create a strong hair fibre. Although these processes are well described in epidermal keratinocytes, there is a lack of understanding of such mechanisms, specifically in the hair follicle.
Objectives
To gain insights into cornification mechanisms within the hair follicle and thus improve our understanding of normal hair physiology.
Methods
Scalp biopsies and hair‐pluck samples were obtained from healthy human donors and analysed microscopically after immunohistochemical staining.
Results
A focal point of respiratory activity was evident in keratogenous zone cells within the hair shaft, which also exhibited nuclear damage. Nuclear degradation occurred via both caspase‐dependent and caspase‐independent pathways. Conversely, mitophagy was driven by Bnip3L and restricted to the boundary of the keratogenous zone at Adamson's Fringe.
Conclusions
We propose a model of stepwise living–dead transition within the first 1 mm of hair formation, whereby fully functional, nucleated cells first consolidate required functions by degrading nuclear DNA, yet continue to respire and provide the source of reactive oxygen species required for keratin cross‐linking. Finally, as the cells become packed with keratin bundles, Bnip3L expression triggers mitophagy to rid the cells of the last remaining ‘living’ characteristic, thus completing the march from ‘living’ to ‘dead’ within the hair follicle.
What's already known about this topic?
Cornification of keratinocytes is key to creation of a healthy hair fibre.
Destruction of cellular organelles within keratinocytes creates space in the cytoplasm for keratin filaments.
Production of reactive oxygen species (ROS) has been reported in the hair follicle but is often associated with adverse effects on hair health.
What does this study add?
Destruction of the nucleus and mitochondria occur in an ordered, sequential fashion, via apoptotic and nonapoptotic mechanisms.
Differential mechanisms are employed in different hair follicle cell‐line layers to rid keratinocytes of organelles.
Targeted production of ROS in the keratinization zone correlating with the presence of active mitochondria is related to keratin cross‐linking and thus may be required for healthy hair.
What is the translational message?
Controlled cell death within the deepest 1 mm of the follicle is key to healthy hair.
After enucleation, the preprogrammed matrix cells and the forming hair shaft are susceptible to damage without the means to mount a transcriptional defence.
These results provide new insights for normal hair physiology, thus providing pathways and targets for therapy in perturbed hair states such as ageing, greyness and alopecia.
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Abstract
Using data from the IceCube Neutrino Observatory, we searched for high-energy neutrino emission from the gravitational-wave events detected by the advanced LIGO and Virgo detectors during ...their third observing run. We did a low-latency follow-up on the public candidate events released during the detectors’ third observing run and an archival search on the 80 confident events reported in the GWTC-2.1 and GWTC-3 catalogs. An extended search was also conducted for neutrino emission on longer timescales from neutron star containing mergers. Follow-up searches on the candidate optical counterpart of GW190521 were also conducted. We used two methods; an unbinned maximum likelihood analysis and a Bayesian analysis using astrophysical priors, both of which were previously used to search for high-energy neutrino emission from gravitational-wave events. No significant neutrino emission was observed by any analysis, and upper limits were placed on the time-integrated neutrino flux as well as the total isotropic equivalent energy emitted in high-energy neutrinos.
We present the large-scale correlation function measured from a spectroscopic sample of 46,748 luminous red galaxies from the Sloan Digital Sky Survey. The survey region covers 0.72 h super(-3) Gpc ...super(3) over 3816 deg super(2) and 0.16 < z < 0.47, making it the best sample yet for the study of large-scale structure. We find a well-detected peak in the correlation function at 100 h super(-1) Mpc separation that is an excellent match to the predicted shape and location of the imprint of the recombination-epoch acoustic oscillations on the low-redshift clustering of matter. This detection demonstrates the linear growth of structure by gravitational instability between z 1000 and the present and confirms a firm prediction of the standard cosmological theory. The acoustic peak provides a standard ruler by which we can measure the ratio of the distances to z = 0.35 and z = 1089 to 4% fractional accuracy and the absolute distance to z = 0.35 to 5% accuracy. From the overall shape of the correlation function, we measure the matter density sub(m)h super(2) to 8% and find agreement with the value from cosmic microwave background (CMB) anisotropies. Independent of the constraints provided by the CMB acoustic scale, we find sub(m) = 0.273 c 0.025 + 0.123 (1 + W sub(0)) + 0.137 sub(K). Including the CMB acoustic scale, we find that the spatial curvature is sub(K) = -0.010 c 0.009 if the dark energy is a cosmological constant. More generally, our results provide a measurement of cosmological distance, and hence an argument for dark energy, based on a geometric method with the same simple physics as the microwave background anisotropies. The standard cosmological model convincingly passes these new and robust tests of its fundamental properties.
Objective
To investigate the relationship between Krebs von den Lungen 6 (KL‐6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)–related interstitial lung disease (ILD).
...Methods
Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide CYC versus mycophenolate mofetil MMF) were included. Baseline and 12‐month plasma samples were analyzed by enzyme‐linked immunosorbent assay to assess CCL18 and KL‐6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL‐6 levels and the course of the FVC and DLco over 1 year according to treatment arm.
Results
Baseline KL‐6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL‐6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL‐6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only).
Conclusion
In a rigorously conducted clinical trial for SSc‐related ILD, KL‐6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL‐6 and CCL18 levels were more likely to experience disease progression despite treatment. KL‐6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.
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