The proapoptotic Bcl-2 protein Bax is predominantly found in the cytosol of nonapoptotic cells and is commonly thought to translocate to mitochondria following an apoptotic stimulus. The current ...model for Bax activation is that BH3 proteins bind to cytosolic Bax, initiating mitochondrial targeting and outer-membrane permeabilization. Here, we challenge this and show that Bax is constitutively targeted to mitochondria but in nonapoptotic cells is constantly translocated back to the cytosol. Using live-cell spinning-disk confocal imaging with a combination of FLIP, FRAP, and photoactivatable GFP-Bax, we demonstrate that disrupting adhesion-dependent survival signals slows the rate of Bax’s dissociation from mitochondria, leading to its accumulation on the outer mitochondrial membrane. The overall accumulation of mitochondrial Bax following loss of survival signaling sensitizes cells to proapoptotic BH3 proteins. Our findings show that Bax is normally in a dynamic equilibrium between cytosol and mitochondria, enabling fluctuations in survival signals to finely adjust apoptotic sensitivity.
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► Bax exists in equilibrium between the cytosol and mitochondria ► The retrotranslocation of Bax is independent of direct-activator BH3 proteins ► Changes in survival signaling modulate the dissociation rate of mitochondrial Bax ► Accumulation of Bax on mitochondria sensitizes cells to apoptosis
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of one in 3000-4000 individuals with no currently effective therapies. The NF1 gene ...encodes neurofibromin, which functions as a negative regulator of RAS. NF1 is a chronic multisystem disorder affecting many different tissues. Due to cell-specific complexities of RAS signaling, therapeutic approaches for NF1 will likely have to focus on a particular tissue and manifestation of the disease. Areas covered: We discuss the multisystem nature of NF1 and the signaling pathways affected due to neurofibromin deficiency. We explore the cell-/tissue-specific molecular and cellular consequences of aberrant RAS signaling in NF1 and speculate on their potential as therapeutic targets for the disease. We discuss recent genomic, transcriptomic, and proteomic studies combined with molecular, cellular, and biochemical analyses which have identified several targets for specific NF1 manifestations. We also consider the possibility of patient-specific gene therapy approaches for NF1. Expert opinion: The emergence of NF1 genotype-phenotype correlations, characterization of cell-specific signaling pathways affected in NF1, identification of novel biomarkers, and the development of sophisticated animal models accurately reflecting human pathology will continue to provide opportunities to develop therapeutic approaches to combat this multisystem disorder.
Herein we report the first copper vial catalysed CuAAC reaction. Under solvent-free mechanochemical conditions the reaction is complete in as little as 15 minutes and the triazole product isolated ...straight from the reaction vial with no further purification.
Flapping flight is the most energetically demanding form of sustained forwards locomotion that vertebrates perform. Flock dynamics therefore have significant implications for energy expenditure. ...Despite this, no studies have quantified the biomechanical consequences of flying in a cluster flock or pair relative to flying solo. Here, we compared the flight characteristics of homing pigeons (Columba livia) flying solo and in pairs released from a site 7 km from home, using high-precision 5 Hz global positioning system (GPS) and 200 Hz tri-axial accelerometer bio-loggers. As expected, paired individuals benefitted from improved homing route accuracy, which reduced flight distance by 7% and time by 9%. However, realising these navigational gains involved substantial changes in flight kinematics and energetics. Both individuals in a pair increased their wingbeat frequency by 18% by decreasing the duration of their upstroke. This sharp increase in wingbeat frequency caused just a 3% increase in airspeed but reduced the oscillatory displacement of the body by 22%, which we hypothesise relates to an increased requirement for visual stability and manoeuvrability when flying in a flock or pair. The combination of the increase in airspeed and a higher wingbeat frequency would result in a minimum 2.2% increase in the total aerodynamic power requirements if the wingbeats were fully optimised. Overall, the enhanced navigational performance will offset any additional energetic costs as long as the metabolic power requirements are not increased above 9%. Our results demonstrate that the increases in wingbeat frequency when flying together have previously been underestimated by an order of magnitude and force reinterpretation of their mechanistic origin. We show that, for pigeons flying in pairs, two heads are better than one but keeping a steady head necessitates energetically costly kinematics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Decentralised gambling applications are a new way for people to gamble online. Decentralised gambling applications are distinguished from traditional online casinos in that players use cryptocurrency ...as a stake. Also, rather than being stored on a single centralised server, decentralised gambling applications are stored on a cryptocurrency's blockchain. Previous work in the player behaviour tracking literature has examined the spending profiles of gamblers on traditional online casinos. However, similar work has not taken place in the decentralised gambling domain. The profile of gamblers on decentralised gambling applications are therefore unknown. This paper explores 2,232,741 transactions from 24,234 unique addresses to three such applications operating atop the Ethereum cryptocurrency network over 583 days. We present spending profiles across these applications, providing the first detailed summary of spending behaviours in this technologically advanced domain. We find that the typical player spends approximately $110 equivalent across a median of 6 bets in a single day, although heavily involved bettors spend approximately $100,000 equivalent over a median of 644 bets across 35 days. Our findings suggest that the average decentralised gambling application player spends less than in other online casinos overall, but that the most heavily involved players in this new domain spend substantially more. This study also demonstrates the use of these applications as a research platform, specifically for large scale longitudinal in-vivo data analysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The rates of Brønsted-acid-catalyzed reactions of ethyl tert -butyl ether, tert -butanol, levoglucosan, 1,2-propanediol, fructose, cellobiose, and xylitol were measured in solvent mixtures of water ...with three polar aprotic cosolvents: γ-valerolactone; 1,4-dioxane; and tetrahydrofuran. As the water content of the solvent environment decreases, reactants with more hydroxyl groups have higher catalytic turnover rates for both hydrolysis and dehydration reactions. We present classical molecular dynamics simulations to explain these solvent effects in terms of three simulation-derived observables: (1) the extent of water enrichment in the local solvent domain of the reactant; (2) the average hydrogen bonding lifetime between water molecules and the reactant; and (3) the fraction of the reactant accessible surface area occupied by hydroxyl groups, all as a function of solvent composition. We develop a model, constituted by linear combinations of these three observables, that predicts experimentally determined rate constants as a function of solvent composition for the entire set of acid-catalyzed reactions.
Summary Co-trimoxazole is an inexpensive, broad-spectrum antimicrobial drug that is widely used in developing countries. Before antiretroviral therapy (ART) scale-up, co-trimoxazole prophylaxis ...reduced morbidity and mortality in adults and children with HIV by preventing bacterial infections, diarrhoea, malaria, and Pneumocystis jirovecii pneumonia, despite high levels of microbial resistance. Co-trimoxazole prophylaxis reduces early mortality by 58% (95% CI 39–71) in adults starting ART. Co-trimoxazole provides ongoing protection against malaria and non-malaria infections after immune reconstitution in ART-treated individuals in sub-Saharan Africa, leading to a change in WHO guidelines, which now recommend long-term co-trimoxazole prophylaxis for adults and children in settings with a high prevalence of malaria or severe bacterial infections. Co-trimoxazole prophylaxis is recommended for HIV-exposed infants from age 4–6 weeks; however, the risks and benefits of co-trimoxazole during infancy are unclear. Co-trimoxazole prophylaxis reduces anaemia and improves growth in children with HIV, possibly by reducing inflammation, either through direct immunomodulatory activity or through effects on the intestinal microbiota leading to reduced microbial translocation. Ongoing trials are now assessing the ability of adjunctive co-trimoxazole to reduce mortality in children after severe anaemia or severe acute malnutrition. In this Review, we discuss the mechanisms of action, benefits and risks, and clinical trials of co-trimoxazole in developing countries.
Lattice compression through hydrostatic pressure has emerged as an effective means of tuning the structural and optoelectronic properties of hybrid halide perovskites. In addition to external ...pressure, the local strain present in solution-processed thin films also causes significant heterogeneity in their photophysical properties. However, an atomistic understanding of structural changes of hybrid perovskites under pressure and their effects on the electronic landscape is required. Here, we use high level ab initio simulation techniques to explore the effect of lattice compression on the formamidinium (FA) lead iodide compound, FA1–x Cs x PbI3 (x = 0, 0.25). We show that, in response to applied pressure, the Pb–I bonds shorten, the PbI6 octahedra tilt anisotropically, and the rotational dynamics of the FA+ molecular cation are partially suppressed. Because of these structural distortions, the compressed perovskites exhibit band gaps that are narrower (red-shifted) and indirect with spin-split band edges. Furthermore, the shallow defect levels of intrinsic iodide defects transform to deep-level states with lattice compression. This work highlights the use of hydrostatic pressure as a powerful tool for systematically modifying the photovoltaic performance of halide perovskites.
The use of polar aprotic solvents in acid-catalyzed biomass conversion reactions can lead to improved reaction rates and selectivities. We show that further increases in catalyst performance in polar ...aprotic solvents can be achieved through the addition of inorganic salts, specifically chlorides. Reaction kinetics studies of the Brønsted acid-catalyzed dehydration of fructose to hydroxymethylfurfural (HMF) show that the use of catalytic concentrations of chloride salts leads to a 10-fold increase in reactivity. Furthermore, increased HMF yields can be achieved using polar aprotic solvents mixed with chlorides. Ab initio molecular dynamics simulations (AIMD) show that highly localized negative charge on Cl
allows the chloride anion to more readily approach and stabilize the oxocarbenium ion that forms and the deprotonation transition state. High concentrations of polar aprotic solvents form local hydrophilic environments near the reactive hydroxyl group which stabilize both the proton and chloride anions and promote the dehydration of fructose.
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