Acute dynamic exercise mobilizes CD34+ hematopoietic stem cells (HSCs) to the bloodstream, potentially serving as an economical adjuvant to boost the collection of HSCs from stem cell transplant ...donors. The mechanisms responsible for HSC mobilization with exercise are unknown but are likely due to hemodynamic perturbations, endogenous granulocyte-colony stimulating factor (G-CSF), and/or β
-adrenergic receptor (β
-AR) signaling. We characterized the temporal response of HSC mobilization and plasma G-CSF following exercise, and determined the impact of in vivo β-AR blockade on the exercise-induced mobilization of HSCs. Healthy runners (n = 15) completed, in balanced order, two single bouts of steady state treadmill running exercise at moderate (lasting 90-min) or vigorous (lasting 30-min) intensity. A separate cohort of healthy cyclists (n = 12) completed three 30-min cycling ergometer trials at vigorous intensity after ingesting: (i) 10 mg bisoprolol (β
-AR antagonist); (ii) 80 mg nadolol (β
+ β
-AR antagonist); or (iii) placebo, in balanced order with a double-blind design. Blood samples collected before, during (runners only), immediately after, and at several points during exercise recovery were used to determine circulating G-CSF levels (runners only) and enumerate CD34+ HSCs by flow cytometry (runners and cyclists). Steady state vigorous but not moderate intensity exercise mobilized HSCs, increasing the total blood CD34+ count by ∼4.15 ± 1.62 Δcells/µl (+202 ± 92%) compared to resting conditions. Plasma G-CSF increased in response to moderate but not vigorous exercise. Relative to placebo, nadolol and bisoprolol lowered exercising heart rate and blood pressure to comparable levels. The number of CD34+ HSCs increased with exercise after the placebo and bisoprolol trials, but not the nadolol trial, suggesting β
-AR signaling mediated the mobilization of CD34+ cells Placebo: 2.10 ± 1.16 (207 ± 69.2%), Bisoprolol 1.66 ± 0.79 (+163 ± 29%), Nadolol: 0.68 ± 0.54 (+143 ± 36%) Δcells/µL. We conclude that the mobilization of CD34+ HSCs with exercise is not dependent on circulating G-CSF and is likely due to the combined actions of β
-AR signaling and hemodynamic shear stress.
In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and ...substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.
20-HETE is a potent vasoconstrictor that is implicated in the regulation of blood pressure, cerebral blood flow and neuronal death following ischemia. Numerous human genetic studies have shown that ...inactivating variants in the cytochrome P450 enzymes that produce 20-HETE are associated with hypertension, stroke and cerebrovascular disease. However, little is known about the expression and cellular distribution of the cytochrome P450A enzymes (CYP4A) that produce 20-HETE or the newly discovered 20-HETE receptor (GPR75) in the brain. The present study examined the cell types and regions in the rat forebrain that express CYP4A and GPR75. Brain tissue slices from Sprague Dawley (SD), Dahl Salt-Sensitive (SS) and CYP4A1 transgenic rat strains, as well as cultured human cerebral pericytes and cerebral vascular smooth muscle cells, were analyzed by fluorescent immunostaining. Tissue homogenates from these strains and cultured cells were examined by Western blot. In the cerebral vasculature, CYP4A and GPR75 were expressed in endothelial cells, vascular smooth muscle cells and the glial limiting membrane of pial arteries and penetrating arterioles but not in the endothelium of capillaries. CYP4A, but not GPR75, was expressed in astrocytes. CYP4A and GPR75 were both expressed in a subpopulation of pericytes on capillaries. The diameters of capillaries were significantly decreased at the sites of first and second-order pericytes that expressed CYP4A. Capillary diameters were unaffected at the sites of other pericytes that did not express CYP4A. These findings implicate 20-HETE as a paracrine mediator in various components of the neurovascular unit and are consistent with 20-HETE's emerging role in the regulation of cerebral blood flow, blood-brain barrier integrity, the pathogenesis of stroke and the vascular contributions to cognitive impairment and dementia. Moreover, this study highlights GPR75 as a potential therapeutic target for the treatment of these devastating conditions.
We present the analysis of a very high-magnification (A ∼ 900) microlensing event KMT-2019-BLG-1953. A single-lens single-source (1L1S) model appears to approximately delineate the observed light ...curve, but the residuals from the model exhibit small but obvious deviations in the peak region. A binary-lens (2L1S) model with a mass ratio of q ∼ 2 × 10−3 improves the fits by Δχ2 = 181.8, indicating that the lens possesses a planetary companion. From additional modeling by introducing an extra planetary lens component (3L1S model) and an extra source companion (2L2S model), it is found that the residuals from the 2L1S model further diminish, but claiming these interpretations is difficult due to the weak signals with Δχ2 = 16.0 and 13.5 for the 3L1S and 2L2L models, respectively. From a Bayesian analysis, we estimate that the host of the planets has a mass of and that the planetary system is located at a distance of toward the Galactic center. The mass of the securely detected planet is . The signal of the potential second planet could have been confirmed if the peak of the light curve had been more densely observed by follow-up observations, and thus the event illustrates the need for intensive follow-up observations for very high-magnification events even in the current generation of high-cadence surveys.
Abstract We present the analysis of the microlensing event OGLE-2014-BLG-0221, a planetary candidate event discovered in 2014. The photometric light curve is best described by a binary-lens ...single-source model. Our light-curve modeling finds two degenerate models, with event timescales of t E ∼ 70 days and ∼110 days. These timescales are relatively long, indicating that the discovered system would possess a substantial mass. The two models are similar in their planetary parameters with a Jupiter mass ratio of q ∼ 10 −3 and a separation of s ∼ 1.1. Bayesian inference is used to estimate the physical parameters of the lens, revealing that the shorter timescale model predicts 65% and 25% probabilities of a late-type star and white dwarf host, respectively, while the longer timescale model favors a black hole host with a probability ranging from 60% to 95%, under the assumption that stars and stellar remnants have equal probabilities of hosting companions with planetary mass ratios. If the lens is a remnant, this would be the second planet found by microlensing around a stellar remnant. The current separation between the source and lens stars is 41–139 mas depending on the models. This indicates the event is now ready for high-angular-resolution follow-up observations to rule out either of the models. If precise astrometric measurements are conducted in multiple bands, the centroid shift due to the color difference between the source and lens would be detected in the luminous lens scenario.
This paper reexamines the influence of public opinion on presidential success on House and Senate roll calls from 1957 to 1980. We find that the President does not win more votes nor does he receive ...higher levels of support when he is popular than when he is unpopular. Similarly, presidential influence on roll call votes is not affected by the change in the President's popularity over the previous six months. And contrary to the major finding of Edwards' research (1976, 1977), we find no support for the proposition that partisan groups in Congress are more responsive to the President's popularity among their party identifiers in the public than to his overall popularity. Moreover, this pattern of weak relationships is not substantially different in the House or Senate, for domestic or foreign policy issues, for Key Votes or non-Key Votes, or for different Presidents.
We report a planet in a binary that was discovered from the analysis of the microlensing event OGLE-2018-BLG-1700. We identify the triple nature of the lens from the fact that the anomaly pattern can ...be decomposed into two parts produced by two binary-lens events, in which one binary pair has a mass ratio of ∼0.01 between the lens components and the other pair has a mass ratio of ∼0.3. We find two sets of degenerate solutions, in which one solution has a projected separation between the primary and its stellar companion less than the angular Einstein radius (close solution), while the other solution has a separation greater than (wide solution). From the Bayesian analysis with the constraints of the event timescale and angular Einstein radius, we find that the planet has a mass of and the stellar binary components have masses of and , respectively, and the distance to the lens is . The planet is a circumstellar planet according to the wide solution, while it is a circumbinary planet according to the close solution.
Chronic regular use of β₂-adrenoceptor (β₂-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of β₂-AR ...inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonist-induced signaling and reducing signaling by empty receptors, β-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the β-AR inverse agonists, we compared the asthma phenotype in β₂-AR-null and wild-type mice. Antigen challenge of β₂-AR-null mice produced results similar to what was observed with chronic β₂-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of β₂-AR inverse agonists are caused by inhibition of β₂-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a β-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced β₂-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, β₂-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.
As obesity rates increase worldwide, healthcare providers require methods to instill the lifestyle behaviours necessary for sustainable weight loss. Designing effective weight‐loss interventions ...requires an understanding of how these behaviours are elicited, how they relate to each other and whether they are supported by common neurocognitive mechanisms. This may provide valuable insights to optimize existing interventions and develop novel approaches to weight control. Researchers have begun to investigate the neurocognitive underpinnings of eating behaviour and the impact of physical activity on cognition and the brain. This review attempts to bring these somewhat disparate, yet interrelated lines of literature together in order to examine a hypothesis that eating behaviour and physical activity share a common neurocognitive link. The link pertains to executive functions, which rely on brain circuits located in the prefrontal cortex. These advanced cognitive processes are of limited capacity and undergo relentless strain in the current obesogenic environment. The increased demand on these neurocognitive resources as well as their overuse and/or impairment may facilitate impulses to over‐eat, contributing to weight gain and obesity. This impulsive eating drive may be counteracted by physical activity due to its enhancement of neurocognitive resources for executive functions and goal‐oriented behaviour. By enhancing the resources that facilitate ‘top‐down’ inhibitory control, increased physical activity may help compensate and suppress the hedonic drive to over‐eat. Understanding how physical activity and eating behaviours interact on a neurocognitive level may help to maintain a healthy lifestyle in an obesogenic environment.
The Central Georgia Bear Population (CGP) is the least abundant and most isolated of Georgia’s 3 American black bear (Ursus americanus) populations. Beginning in 2011, changes to regulations ...governing harvest of the CGP resulted in an increase in female bear harvest, creating concern that future harvest could be an important influence on population viability. Hence, our objective was to assess viability of the CGP under various levels of female mortality. During 2012–2016, we used barbed-wire hair snares to collect bear hair samples from within the range of the CGP in Georgia, USA. We used microsatellite genotyping to identify individual bears and created robust-design, spatial detection histories for all female bears detected. We fit open population spatial capture-recapture (SCR) models to the detection histories in a Bayesian framework. We used the Widely Applicable Information Criterion (WAIC) to rank models that varied with respect to sources of variation in detection probability, survival, and per capita recruitment, and used the model with the lowest WAIC to forecast dynamics of the CGP 50 years into the future under various levels of female mortality. We assessed the 50-year extinction probability under a continuation of mortality levels documented during 2012–2016, and under incremental increases in female mortality above this baseline. The top model included density-dependent per capita recruitment, annual variation in detection probability, and a trap-level behavioral response. Abundance increased from 106 (95% CI=86–132) females in 2012 to 136 (95% CI=113–161) females in 2013 and remained relatively stable thereafter. Annual female survival was 0.75 (95% CI=0.69–0.82) and did not vary among years. The per capita recruitment rate decreased over time as density increased, and was 0.49 (95% CI=0.33–0.66) during the first time interval and 0.29 (95% CI=0.20–0.38) during the final time interval. Annual growth rate (λt
) was 1.28 (95% CI=1.07–1.52) between 2012 and 2013 but decreased throughout the study, ending at 1.04 (95% CI=0.93–1.17). Forecasts indicated continuation of the female mortality levels experienced from 2012–2016 were sustainable over 50 years, with the estimated extinction risk being <0.001%. Increasing annual harvest by 5 females introduced a negligible increase in the 50-year probability of extinction, but harvesting an additional 10 females/year caused extinction risk to rise to 1.15%. We recommend that harvest regulations are structured such that mortality rates remain at current levels or do not increase by more than an annual average of 5 females above levels observed during our study. Furthermore, we recommend that managers continue to monitor the population so that harvest regulations and population models can be refined over time.
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