Progenitor cell therapy is hindered in patients with diabetes mellitus (DM) due to cellular senescence. Glycogen synthase kinase-3β (GSK3β) activity is increased in DM, potentially exacerbating ...impaired cell-based therapies. Thus, we aimed to determine if and how GSK3β inhibitors (GSKi) can improve therapeutic efficacy of endothelial progenitor cells (EPC) from patients with DM. Patients with DM had fewer EPCs and increased rates of apoptosis. DM EPCs also exhibited higher levels of GSK3β activity resulting in increased levels of phosphorylated β-catenin. Proteomic profiling of DM EPCs treated with GSKi identified 37 nonredundant, differentially regulated proteins. Cathepsin B (cathB) was subsequently confirmed to be differentially regulated and showed 40% less baseline activity in DM EPCs, an effect reversed by GSKi treatment. Finally, in vivo efficacy of cell-based therapy was assessed in a xenotransplant femoral wire injury mouse model. Administration of DM EPCs reduced the intima-to-media ratio, an effect that was further augmented when DM EPCs were pretreated with GSKi yet absent when cathB was antagonized. In DM, increased basal GSK3β activity contributes to accelerated EPC cellular senescence, an effect reversed by small molecule antagonism of GSK3β, which enhanced cell-based therapy after vascular injury.
We present the preliminary results from implementing a new software tool that enables inspection of time-tagged photon data for the astronomical sources contained within individual GALEX ultraviolet ...(UV) images of the sky. We have inspected the photon data contained within 1802 GALEX images to reveal rapid, short-term ( unk500 s) UV source variability in the form of stellar "flares." The mean associated change in near-UV (NUV) magnitude due to this flaring activity is 2.7 plus or minus 0.3 mag. A list of 49 new UV variable star candidates is presented, together with their associated Sloan Digital Sky Survey (SDSS) photometric magnitudes. From these data we can associate the main source of these UV flare events with magnetic activity on M dwarf stars. Photometric parallaxes have been determined for 32 of these sources, placing them at distances ranging from approximately 25 to 1000 pc. The average UV flare energy for these flare events is 2.5 x 10 super(30) ergs, which is of a similar energy to that of U-band, X-ray, and EUV flares observed on many local M dwarf stars. We have found that stars of classes M0 to M5 flare with energies spanning a far larger range and with an energy approximately 5 times greater than those of later (M6 to M8) spectral type.
In April and May of 2020, a large phytoplankton bloom composed primarily of the dinoflagellate Lingulodinium polyedra reached historic levels in geographic expanse, duration, and density along the ...coast of southern California, United States, and Baja California Norte, Mexico. Here, we report the water quality parameters of dissolved oxygen and pH over the course of the red tide, as measured by multiple sensors deployed in various locations along San Diego County, and document the extent of mass organism mortality using field surveys and community science observations. We found that dissolved oxygen and pH corresponded with bloom dynamics, with extreme hypoxic and hyperoxic conditions occurring at multiple locations along the coast, most notably within select estuaries where dissolved oxygen reached 0 mg L−1 and hypoxia occurred for up to 254 consecutive hours, as well as along the inner shelf of the open coast where dissolved oxygen dropped as low as 0.05 mg L−1. Similarly, pH ranged widely (6.90–8.79) across the bloom over both space and time, largely corresponding with dissolved oxygen level. Extreme changes in dissolved oxygen and pH, in addition to changes to other water parameters that affect organismal health, ultimately led to documented mortalities of thousands of demersal and benthic fishes and invertebrates (primarily within estuarine and inner-shelf environments), and long-term surveys within one lagoon showed protracted changes to benthic infaunal density and species composition. In addition to field observations, we also quantified water quality parameters and organism mortalities from four local aquarium facilities, with varying levels of filtration and artificial oxygenation, and documented the morphological changes in the gills of captive-held Pacific sardine in response to the red tide. We show that multiple factors contributed to organismal stress, with hypoxia likely being the most widespread, but not the only, cause of mortality.
CFTR possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase A (PKA) in the R-domain and an obligatory dependence on phosphorylation is a hallmark of CFTR Cl
...− channel function. Removal of as many as 11 of these sites reduces the conformational change in the R-domain and the degree of channel activation in response to PKA. However, until recently a completely PKA-unresponsive CFTR variant has not been reported, leaving open the possibility that the residual response may be mediated by associating ancillary phosphoproteins. We traced the residual PKA-catalyzed
32P-labelling of the variant with 11 sites mutagenized (11SA) to distinct CNBr phosphopeptides within the R-domain. Mutagenesis of 4 additional monobasic sites in these segments produced a 15SA variant in which Cl
− channel response to PKA was abolished. Therefore, it can be concluded that ancillary phosphoproteins do not contribute to CFTR activation by PKA. Notably, however, the 15SA protein did exhibit a low level of constitutive channel activity not dependent on PKA, which might have reflected a down-regulating effect of phosphorylation of one or two of the 15 sites as suggested by others. However, this did not prove to be the case.
Since immature CFTR has been claimed to be active in the endoplasmic reticulum (ER), we also examined whether it can be phosphorylated in cells and what influence if any this might have on its susceptibility to degradation. Teleologically, activation by phosphorylation of CFTR Cl
− channels in the ER might be undesirable to the cell. Using various phosphorylation site mutants and kinase and phosphatase inhibitors in pulse-chase experiments, we have found that although nascent CFTR can be phosphorylated at the ER, this is without effect on its ability to mature and avoid proteolysis. Furthermore, we found that microsomes from cells expressing CFTR processing mutants such as ΔF508 do not generate Cl
− active channels when fused with planar bilayers unless maturation is promoted, e.g. by growth of cells at reduced temperature or other means. We conclude that the ER-retained mutant nascent chains which are incapable of maturation may be phosphorylated but do not form active channels. Stimulation by PKA of the insertion of CFTR containing vesicles into the plasma membrane as part of the mechanism of stimulation of chloride secretion has been reported, as has an influence of CFTR on the balance between endocytosis and exocytosis but these findings have not been universally confirmed.
Coherent diffractive imaging of single particles using the single-shot “diffract and destroy” approach with an x-ray free electron laser (FEL) was recently demonstrated. A high-resolution low-noise ...coherent diffraction pattern, representative of the object before it turns into a plasma and explodes, results from the interaction of the FEL with the particle. Iterative phase retrieval algorithms are used to reconstruct two-dimensional projection images of the object from the recorded intensities alone. Here we describe the first single-shot diffraction data set that mimics the data proposed for obtaining 3D structure from identical particles. Ellipsoidal iron oxide nanoparticles (250nm×50nm ) were aerosolized and injected through an aerodynamic lens stack into a soft x-ray FEL. Particle orientation was not controlled with this injection method. We observed that, at the instant the x-ray pulse interacts with the particle, a snapshot of the particle’s orientation is encoded in the diffraction pattern. The results give credence to one of the technical concepts of imaging individual nanometer and subnanometer-sized objects such as single molecules or larger clusters of molecules using hard x-ray FELs and will be used to help develop robust algorithms for determining particle orientations and 3D structure.
Background
Fatigue is a major symptom of multiple sclerosis (MS) in patients, and it has been shown to improve with physical exercise. Although fingolimod might lessen fatigue, it is unclear how ...patients treated with fingolimod react to physical activity regarding fatigue.
Objective
This study evaluated the effect of an exercise intervention on fatigue in relapsing–remitting MS patients receiving fingolimod.
Methods
People with MS (PwMS) were randomized to either a structured internet-based exercise program (e-training) or no e-training intervention. The primary endpoint was the change in the Modified Fatigue Impact Scale (mFIS) after six months.
Results
The primary analysis showed no statistically significant difference between groups in the mFIS change. Subgroup analyses revealed a beneficial effect of physical exercise for PwMS with low aerobic capacity and with low aerobic capacity plus more severe fatigue. The incidence of adverse events was similar in both groups. No cardiovascular events were reported. The majority of PwMS were relapse free.
Conclusion
Physical exercise benefits on fatigue may depend on the physical capacity of the patient and requires individualized training. Consistent with previous studies, these results suggest that physical exercise generally does not impose a risk and that this holds true also for patients receiving fingolimod.
Trial registration: ClinicalTrials.gov, NCT01490840.
Previous research has shown the harmful effects of stereotypical messages on viewers, including increased negative attitudes toward outgroup members. In contrast, positive or counter-stereotypical ...portrayals can lead to less prejudiced attitudes toward outgroup members; however, these kinds of portrayals are not always easy to come by. As a result, alternative methods for combating the effects of stereotypical messages are necessary. The current study examined the ability of self-transcendent emotions, specifically awe, to reduce the negative effects of stereotypical portrayals of African American men. Contrary to expectations, results showed that participants who watched an awe-inducing video before a stereotypical video reported more negative explicit attitudes toward African Americans compared to those in control conditions.
This study describes the results of a four-year research effort to develop inpatient and outpatient questionnaires that have sufficient validity and reliability to be used to measure patient ...perceptions of quality. As part of this effort, over 50,000 inpatients, emergency room patients, and ambulatory surgery patients from over 300 hospitals representing every US census region were surveyed. Separate questionnaires, called Quality of Care Monitors, were developed for inpatients and outpatients. The inpatient questionnaire consisted of 8 scales: Physician Care, Nursing Care, Medical Outcome, Courtesy, Food Service, Comfort and Cleanliness, Admissions/Billing, and Religious Care. The outpatient questionnaire had 7 scales: Physician Care, Nursing Care, Medical Outcome, Facility Characteristics, Waiting Time, Testing Services and Registration Process. The study found strong evidence of construct validity, predictive validity, and internal consistency for both questionnaires. Each questionnaire is capable of measuring separate dimensions of patient experience. A data bank developed from these questionnaires is currently accessed regularly by participating hospitals to assess quality improvement and to make benchmark comparisons with similar hospitals.
The Sudbury Neutrino Observatory (SNO) has confirmed the standard solar model and neutrino oscillations through the observation of neutrinos from the solar core. In this paper we present a search for ...neutrinos associated with sources other than the solar core, such as gamma-ray bursters and solar flares. We present a new method for looking for temporal coincidences between neutrino events and astrophysical bursts of widely varying intensity. No correlations were found between neutrinos detected in SNO and such astrophysical sources.
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