A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer

Pretreatment with phenoxybenzamine attenuates the radial artery's vasoconstrictor response to α-adrenergic stimuli

AbstractBackgroundAlthough the radial artery bypass conduit has excellent intermediate-term patency, it has a proclivity to vasospasm. We tested the hypothesis that brief pretreatment of a radial artery graft with the irreversible adrenergic antagonist phenoxybenzamine attenuates the vasoconstrictor response to the vasopressors phenylephrine and norepinephrine compared with the currently used papaverine/lidocaine.MethodsSegments of human radial artery grafts were obtained after a 30-minute intraoperative pretreatment with a solution containing 20 mL of heparinized blood, 0.4 mL of papaverine (30 mg/mL), and 1.6 mL of lidocaine (1%). The segments were transported to the laboratory and placed into a bath containing Krebs-Henseleit solution and 10, 100, or 1000 μmol/L phenoxybenzamine or vehicle. The segments were tested in organ chambers for contractile responses to increasing concentrations of phenylephrine and norepinephrine (0.5-15 μmol/L).ResultsContractile responses to 15 μmol/L phenylephrine in control radial artery segments averaged 44.2% ± 9.1% of the maximal contractile response to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated contraction to 15 μmol/L phenylephrine (32.1% ± 5.9%; P = .22), but 1000 μmol/L phenoxybenzamine completely abolished radial artery contraction (−7.2% ± 4.4%; P < .001). The effect of 10 and 100 μmol/L phenoxybenzamine on attenuating vasocontraction was intermediate between 1000 μmol/L phenoxybenzamine and papaverine/lidocaine. Responses to 15 μmol/L norepinephrine in control radial artery segments averaged 54.7% ± 7.5% of maximal contraction to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated the contraction response of radial artery segments (35.6% ± 5.1%; P = .04). In contrast, 1000 μmol/L phenoxybenzamine showed the greatest attenuation of norepinephrine-induced contraction (−10.5% ± 2.0%; P < .001).ConclusionsA brief pretreatment of the human radial artery bypass conduit with 1000 μmol/L phenoxybenzamine completely attenuates the vasoconstrictor responses to the widely used vasopressors norepinephrine and phenylephrine. Papaverine/lidocaine alone did not block vasoconstriction to these α-adrenergic agonists

Plant water potential improves prediction of empirical stomatal models

Climate change is expected to lead to increases in drought frequency and severity, with deleterious effects on many ecosystems. Stomatal responses to changing environmental conditions form the backbone of all ecosystem models, but are based on empirical relationships and are not well-tested during drought conditions. Here, we use a dataset of 34 woody plant species spanning global forest biomes to examine the effect of leaf water potential on stomatal conductance and test the predictive accuracy of three major stomatal models and a recently proposed model. We find that current leaf-level empirical models have consistent biases of over-prediction of stomatal conductance during dry conditions, particularly at low soil water potentials. Furthermore, the recently proposed stomatal conductance model yields increases in predictive capability compared to current models, and with particular improvement during drought conditions. Our results reveal that including stomatal sensitivity to declining water potential and consequent impairment of plant water transport will improve predictions during drought conditions and show that many biomes contain a diversity of plant stomatal strategies that range from risky to conservative stomatal regulation during water stress. Such improvements in stomatal simulation are greatly needed to help unravel and predict the response of ecosystems to future climate extremes.Funding for this research was provided by NSF DEB EF-1340270 and the Climate Mitigation Initiative at the Princeton Environmental Institute, Princeton University. SL acknowledges financial support from the China Scholarship Council (CSC). VRD acknowledges funding from Ramón y Cajal fellowship (RYC-2012-10970). BTW was supported by the Next Generation Ecosystem Experiments-Tropics, funded by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research. DJC acknowledges funding from the National Science Centre, Poland (NN309 713340). WRLA was supported in part by NSF DEB 1714972

Woody plants optimise stomatal behaviour relative to hydraulic risk

Stomatal response to environmental conditions forms the backbone of all ecosystem and carbon cycle models, but is largely based on empirical relationships. Evolutionary theories of stomatal behaviour are critical for guarding against prediction errors of empirical models under future climates. Longstanding theory holds that stomata maximise fitness by acting to maintain constant marginal water use efficiency over a given time horizon, but a recent evolutionary theory proposes that stomata instead maximise carbon gain minus carbon costs/risk of hydraulic damage. Using data from 34 species that span global forest biomes, we find that the recent carbon‐maximisation optimisation theory is widely supported, revealing that the evolution of stomatal regulation has not been primarily driven by attainment of constant marginal water use efficiency. Optimal control of stomata to manage hydraulic risk is likely to have significant consequences for ecosystem fluxes during drought, which is critical given projected intensification of the global hydrological cycle.W.R.L.A. acknowledges funding for this research from NSF 1714972 and from the USDA National Institute of Food and Agriculture, Agricultural and Food Research Initiative Competitive Programme, Ecosystem Services and Agro-Ecosystem Management, grant no. 2017-05521. We thank T. Brodribb and one anonymous reviewer for their insightful reviews, B. Medlyn and Y.S. Lin for sharing data and R. Norby for providing Vcmax data for several species. We appreciate the assistance from Marion Feifel in collecting data of leaf photosynthetic parameters of five European tree species. S.L. acknowledges financial support from the China Scholarship Council (CSC). VRD acknowledges funding from a Ram on y Cajal fellowship (RYC-2012-10970). B.T.W. was supported by the Next Generation Ecosystem Experiments-Tropics, funded by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research. DJC acknowledges funding from the National Science Centre, Poland (NN309 713340)

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding

Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein−ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure−activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure−activity relationships of β2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions

Ephemeris and hazard assessment for near-Earth asteroid (101955) Bennu based on OSIRIS-REx data

Small bodies such as the near-Earth asteroid Bennu drift in their orbit due to thermal radiation forces (the Yarkovsky effect). Ground-based observations have indicated a nonzero probability of Bennu impacting Earth, depending on how its orbit evolves. Thus, among the goals of the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) mission to Bennu were to precisely measure the Yarkovsky effect and refine the impact hazard assessment for this body. Here we address these objectives. Using OSIRIS-REx spacecraft tracking data, we derive meter-level constraints on the distance between Earth and Bennu from January 2019 to October 2020. While these data greatly improve the knowledge of the trajectory of Bennu, they also require an unprecedented fidelity for the modeling of an asteroid’s trajectory. In particular, special care is needed to take into account the contribution of 343 small-body perturbers and the uncertainty in their masses. Radiation effects such as the Poynting–Robertson drag, so far only considered for interplanetary dust dynamics, now become a consideration for modeling the trajectory of a 500-m asteroid such as Bennu. By employing a thermophysical model based on OSIRIS-REx’s characterization of Bennu, we estimate a semimajor axis drift of−284.6 ± 0.2m/yr (signal-to-noise ratio∼1400) at epoch 2011 January 1 caused by the Yarkovsky effect. The largest source of modeling error is solar wind drag, which may lower the magnitude of the semimajor axis drift from the Yarkovsky effect by up to 0.16 m/yr. The Yarkovsky-related semimajor axis drift varies by roughly±1m/yr as the orbit of Bennu evolves due to planetary perturbations from 1900 to 2135. The Yarkovsky thermophysical model proves to be extremely accurate by predicting a bulk density estimate within 0.1% of that estimated through gravity science analysis. Compared to the information available before the OSIRIS-REx mission, the knowledge of the circumstances of the scattering Earth encounter that will occur in 2135 improves by a factor of 20, thus allowing us to rule out many previously possible impact trajectories. However, there remain some impact trajectories compatible with the data. Prior to the spacecraft encounter, the overall impact probability through 2200 was 3.7 × 10−4 (1 in 2700). As a result of our analysis, the cumulative impact probability through 2300 becomes 5.7 × 10−4 (1 in 1750) and the most significant individual impact solution is for September 2182, with an impact probability of 3.7 × 10−4 (1 in 2700). Both Bennu and (29075) 1950 DA have a Palermo scale value of −1.42 and share the distinction as the currently most hazardous object in the asteroid catalog

Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System

Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons

Fructooligosacharides Reduce Pseudomonas aeruginosa PAO1 Pathogenicity through Distinct Mechanisms

Pseudomonas aeruginosa is ubiquitously present in the environment and acts as an opportunistic pathogen on humans, animals and plants. We report here the effects of the prebiotic polysaccharide inulin and its hydrolysed form FOS on this bacterium. FOS was found to inhibit bacterial growth of strain PAO1, while inulin did not affect growth rate or yield in a significant manner. Inulin stimulated biofilm formation, whereas a dramatic reduction of the biofilm formation was observed in the presence of FOS. Similar opposing effects were observed for bacterial motility, where FOS inhibited the swarming and twitching behaviour whereas inulin caused its stimulation. In co-cultures with eukaryotic cells (macrophages) FOS and, to a lesser extent, inulin reduced the secretion of the inflammatory cytokines IL-6, IL-10 and TNF- a . Western blot experiments indicated that the effects mediated by FOS in macrophages are associated with a decreased activation of the NF- k B pathway. Since FOS and inulin stimulate pathway activation in the absence of bacteria, the FOS mediated effect is likely to be of indirect nature, such as via a reduction of bacterial virulence. Further, this modulatory effect is observed also with the highly virulent ptxS mutated strain. Co-culture experiments of P. aeruginosa with IEC18 eukaryotic cells showed that FOS reduces the concentration of the major virulence factor, exotoxin A, suggesting that this is a possible mechanism for the reduction of pathogenicity. The potential of these compounds as components of antibacterial and anti-inflammatory cocktails is discussed.The authors acknowledge financial support from FEDER funds and Fondo Social Europeo through grants from the Spanish Ministry of Economy and Competitiveness (grants SAF2011-22922, SAF2011-22812) the Andalusian regional government Junta de Andalucía (grant CVI-7335) and the Centre of Networked Biomedical Research on Hepatic and Digestive Diseases (CIBERehd) which is funded by the Carlos III Health Institute and the Ramón Areces Foundation, Spain