Creatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP ...concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands.
We performed a systematic review and searched the electronic databases Pubmed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. Furthermore, we searched the internet and explored references from textbooks and reviews.
After applying the inclusion criteria, we retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake and increased fatigue tolerance. In heart tissue this shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. In brain tissue adaptations in energy metabolism resulted in enhanced ATP stability and survival during hypoxia.
Chronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spatially explicit integrated population models Chandler, Richard B.; Clark, Joseph D.; Cooch, Evan
Methods in ecology and evolution,
December 2014, Letnik:
5, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Summary
Studies of demographic processes are typically restricted to small geographic areas and short time periods due to the costs of marking and monitoring individuals. However, environmental ...changes are occurring at much broader spatial and temporal scales, and thus, inferences about the mechanisms governing population dynamics need to be scaled accordingly. Recently developed integrated population models (IPMs) represent an approach for doing so, by jointly analysing survey data and capture–recapture data.
Although promising, several shortcomings of conventional IPMs exist, including difficulties accounting for spatial variation in demographic, movement and detection parameters; limited ability to make spatially explicit predictions of abundance or vital rates; and a requirement that the survey data and the capture–recapture data are independent. We demonstrate how each of these limitations can be resolved by adopting a spatial population dynamics model upon which both the survey data and the capture–recapture data are conditioned.
We applied the model to 6 years of hair data collected on the threatened Louisiana black bear Ursus americanus luteolus. For years in which the hair samples were genotyped, the resulting data are information‐rich (but expensive) spatial capture–recapture (SCR) data. For the remaining years, the data are binary detection data, of the type often analysed using occupancy models. We compared estimates of demographic parameters and annual abundance using various combinations of the SCR and detection data, and found that combining the SCR data and the detection data resulted in more precise estimates of abundance relative to estimates that did not use the detection data. A simulation study provided additional evidence of increased precision, as well as evidence that the estimators of annual abundance are approximately unbiased.
The ability to combine survey data and capture–recapture data using a spatially explicit model opens many possibilities for designing cost effective studies and scaling up inferences about the demographic processes influencing spatial and temporal population dynamics.
Independent technological glitches forced two separate trading halts on different U.S. exchanges during the week of July 6, 2015. During each halt, all other exchanges remained open. We exploit ...exogenous variation provided by this unprecedented coincidence, in conjunction with a proprietary data set, to identify the causal impact of Designated Market Maker (DMM) participation on liquidity. When the voluntary liquidity providers on one exchange were removed, liquidity remained unchanged; when DMMs were removed, liquidity decreased market-wide. We find evidence consistent with the idea that these DMMs, despite facing only mild formal obligations, significantly improve liquidity in the modern electronic marketplace.
CRISPR-Cas-mediated genome editing relies on guide RNAs that direct site-specific DNA cleavage facilitated by the Cas endonuclease. Here we report that chemical alterations to synthesized single ...guide RNAs (sgRNAs) enhance genome editing efficiency in human primary T cells and CD34(+) hematopoietic stem and progenitor cells. Co-delivering chemically modified sgRNAs with Cas9 mRNA or protein is an efficient RNA- or ribonucleoprotein (RNP)-based delivery method for the CRISPR-Cas system, without the toxicity associated with DNA delivery. This approach is a simple and effective way to streamline the development of genome editing with the potential to accelerate a wide array of biotechnological and therapeutic applications of the CRISPR-Cas technology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced ...melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. Methods Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov , number NCT00623766. Findings We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8–31), as did one patient in cohort B (5%, 0·1–24). When the brain alone was assessed, 12 patients in cohort A (24%, 13–38) and two in cohort B (10%, 1–30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16–42) in cohort A and in one individual (5%, 0·1–24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients 12%) and fatigue (six 12%); in cohort B, they were dehydration (two individuals 10%), hyperglycaemia (two 10%), and increased concentrations of serum aspartate aminotransferase (two 10%). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients 12%) and rash (one 2%) in cohort A, and rash (one individual 5%) and increased concentrations of serum aspartate aminotransferase (two 10%) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. Interpretation Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. Funding Bristol-Myers Squibb.
In a previous study, we investigated whether reanalysis moist static energy (MSE) transport trends over the 1980 through 2018 period are consistent (a) with each other and (b) with the finding that ...these transport trends are downgradient, as found in climate models. Regarding point (a), our conclusion was that MSE transport trends were dependent on the reanalysis data set. However, Cox et al. (2023) correctly point out that the reanalysis dependence is reduced dramatically if a barotropic mass flux correction is applied at a monthly mean timescale prior to computing the MSE transport trends. In our reply below, we revisit point (b) after applying this correction. We find that even after the correction, reanalysis MSE transport trends are not downgradient nor poleward in the Northern Hemisphere extratropics. However, reanalysis does show a compensation between dry static and latent energy transport trends, which has been shown in climate models historically.
Plain Language Summary
Energy is transported poleward by the atmospheric circulation. As the climate warms, the amount of energy transported poleward is projected to increase. In a previous study, we investigated whether this holds in reanalysis data sets (data sets that obtain global coverage by combining measurements with numerical models). However, as pointed out by Cox et al. (2023), we did not account for the fact that reanalysis products do not respect mass conservation. Correcting for this, MSE transport trends do not exhibit a reanalysis dependence to the degree we previously found. Nevertheless, reanalysis MSE transports are not associated with changes in the surface MSE gradient, as models suggest, nor are these fluxes poleward in the Northern Hemisphere extratropics. An aspect that becomes more consistent between models and reanalysis after correcting the mass budget is an anticorrelation between dry static and latent energy transports trends.
Key Points
After mass correction, reanalysis moist static energy (MSE) transport trends are not downgradient
After mass correction, reanalysis dry static and latent energy transport trends oppose each other over most latitudes
The MSE transport trend is not in a poleward direction north of 30°N
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