The MiniBooNE experiment at Fermilab reports results from an analysis of ν_{e} appearance data from 12.84×10^{20} protons on target in neutrino mode, an increase of approximately a factor of 2 over ...previously reported results. A ν_{e} charged-current quasielastic event excess of 381.2±85.2 events (4.5σ) is observed in the energy range 200<E_{ν}^{QE}<1250 MeV. Combining these data with the νover ¯_{e} appearance data from 11.27×10^{20} protons on target in antineutrino mode, a total ν_{e} plus νover ¯_{e} charged-current quasielastic event excess of 460.5±99.0 events (4.7σ) is observed. If interpreted in a two-neutrino oscillation model, ν_{μ}→ν_{e}, the best oscillation fit to the excess has a probability of 21.1%, while the background-only fit has a χ^{2} probability of 6×10^{-7} relative to the best fit. The MiniBooNE data are consistent in energy and magnitude with the excess of events reported by the Liquid Scintillator Neutrino Detector (LSND), and the significance of the combined LSND and MiniBooNE excesses is 6.0σ. A two-neutrino oscillation interpretation of the data would require at least four neutrino types and indicate physics beyond the three neutrino paradigm. Although the data are fit with a two-neutrino oscillation model, other models may provide better fits to the data.
Live donor kidney transplantation is the best treatment option for most patients with late‐stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. ...A consensus conference was held June 5–6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.
This article summarizes the proceedings of the June 2014 Consensus Conference on Best Practices in Live Kidney Donation, which include recommendations for educating transplant candidates and potential living donors, improving efficiencies in the living donor evaluation process, reducing disparities in living kidney donation, and steering future research and policy priorities to remove barriers to donation.
The MiniBooNE experiment at Fermilab reports a total excess of 638.0 ± 52.1 (stat .) ± 122.2 (syst.) electronlike events from a data sample corresponding to 18.75 × 10 20 protons-on-target in ...neutrino mode, which is a 46% increase in the data sample with respect to previously published results and 11.27 × 10 20 protons-on-target in antineutrino mode. The overall significance of the excess, 4.8σ, is limited by systematic uncertainties, assumed to be Gaussian, as the statistical significance of the excess is 12.2σ. The additional statistics allow several studies to address questions on the source of the excess. First, we provide two-dimensional plots in visible energy and the cosine of the angle of the outgoing lepton, which can provide valuable input to models for the event excess. Second, we test whether the excess may arise from photons that enter the detector from external events or photons exiting the detector from π 0 decays in two model independent ways. Beam timing information shows that almost all of the excess is in time with neutrinos that interact in the detector. The radius distribution shows that the excess is distributed throughout the volume, while tighter cuts on the fiducial volume increase the significance of the excess. The data likelihood ratio disfavors models that explain the event excess due to entering or exiting photons.
Classical hydrodynamics is a remarkably versatile description of the coarse-grained behaviour of many-particle systems once local equilibrium has been established1. The form of the hydrodynamical ...equations is determined primarily by the conserved quantities present in a system. Some quantum spin chains are known to possess, even in the simplest cases, a greatly expanded set of conservation laws, and recent work suggests that these laws strongly modify collective spin dynamics, even at high temperature2,3. Here, by probing the dynamical exponent of the one-dimensional Heisenberg antiferromagnet KCuF3 with neutron scattering, we find evidence that the spin dynamics are well described by the dynamical exponent z = 3/2, which is consistent with the recent theoretical conjecture that the dynamics of this quantum system are described by the Kardar–Parisi–Zhang universality class4,5. This observation shows that low-energy inelastic neutron scattering at moderate temperatures can reveal the details of emergent quantum fluid properties like those arising in non-Fermi liquids in higher dimensions.Quantum systems possessing conserved quantities are expected to show quantum fluid properties governed by hydrodynamic equations. This behaviour is now evidenced in a neutron scattering study on the one-dimensional Heisenberg antiferromagnet KCuF3.
The capability of producing complex, high performance metal parts on demand has established laser powder bed fusion (LPBF) as a promising additive manufacturing technology, yet deeper understanding ...of the laser-material interaction is crucial to exploit the potential of the process. By simultaneous in-situ synchrotron x-ray and schlieren imaging, we probe directly the interconnected fluid dynamics of the vapour jet formed by the laser and the depression it produces in the melt pool. The combined imaging shows the formation of a stable plume over stable surface depressions, which becomes chaotic following transition to a full keyhole. We quantify process instability across several parameter sets by analysing keyhole and plume morphologies, and identify a previously unreported threshold of the energy input required for stable line scans. The effect of the powder layer and its impact on process stability is explored. These high-speed visualisations of the fluid mechanics governing LPBF enable us to identify unfavourable process dynamics associated with unwanted porosity, aiding the design of process windows at higher power and speed, and providing the potential for in-process monitoring of process stability.
These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, ...Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The AAAAI and ACAAI have jointly accepted responsibility for establishing “The diagnosis and management of acute and chronic urticaria: 2014 update.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. The JTFPP understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because a given test or agent's cost is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In extraordinary circumstances, when the cost/benefit ratio of an intervention is prohibitive, as supported by pharmacoeconomic data, commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion. The JTFPP is committed to ensuring that the practice parameters are based on the best scientific evidence that is free of commercial bias. To this end, the parameter development process includes multiple layers of rigorous review. These layers include the workgroup convened to draft the parameter, the task force reviewers, and peer review by members of each sponsoring society. Although the task force has the final responsibility for the content of the documents submitted for publication, each reviewer comment will be discussed, and reviewers will receive written responses to comments, when appropriate. To preserve the greatest transparency regarding potential conflicts of interest, all members of the JTFPP and the practice parameter workgroups will complete a standard potential conflict of interest disclosure form, which will be available for external review by the sponsoring organization and any other interested individual. In addition, before confirming the selection of a Work Group chairperson, the Joint Task Force will discuss and resolve all relevant potential conflicts of interest associated with this selection. Finally, all members of parameter workgroups will be provided a written statement regarding the importance of ensuring that the parameter development process is free of commercial bias. Practice parameters are available online at www.jcaai.org and www.allergyparameters.org.
Inertial confinement fusion implosions must achieve high in-flight shell velocity, sufficient energy coupling between the hot spot and imploding shell, and high areal density (ρR=∫ρdr) at stagnation. ...Asymmetries in ρR degrade the coupling of shell kinetic energy to the hot spot and reduce the confinement of that energy. We present the first evidence that nonuniformity in the ablator shell thickness (∼0.5% of the total thickness) in high-density carbon experiments is a significant cause for observed 3D ρR asymmetries at the National Ignition Facility. These shell-thickness nonuniformities have significantly impacted some recent experiments leading to ρR asymmetries on the order of ∼25% of the average ρR and hot spot velocities of ∼100 km/s. This work reveals the origin of a significant implosion performance degradation in ignition experiments and places stringent new requirements on capsule thickness metrology and symmetry.
Bitopic integral membrane proteins with a single transmembrane helix play diverse roles in catalysis, cell signaling, and morphogenesis. Complete monospanning protein structures are needed to show ...how interaction between the transmembrane helix and catalytic domain might influence association with the membrane and function. We report crystal structures of full-length Saccharomyces cerevisiae lanosterol 14αdemethylase, a membrane monospanning cytochrome P450 of the CYP51 family that catalyzes the first postcyclization step in ergosterol biosynthesis and is inhibited by triazole drugs. The structures reveal a well-ordered N-terminal amphipathic helix preceding a putative transmembrane helix that would constrain the catalytic domain orientation to lie partly in the lipid bilayer. The structures locate the substrate lanosterol, identify putative substrate and product channels, and reveal constrained interactions with triazole antifungal drugs that are important for drug design and understanding drug resistance.
Key points
Uterine artery vasodilatation is a key mechanism for increasing utero‐placental blood flow and fetal nutrient supply.
Since the pioneering work of Joseph Barcroft, the natural laboratory ...of high altitude has been used to study the mechanisms regulating uterine artery blood supply and fetal growth.
Genes near the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK) have been implicated in genetic protection from high altitude‐associated fetal growth restriction.
We show that AMPK is present in utero‐placental tissues and has vasodilator effects in murine uterine arteries, and that exposure to chronic hypoxia sufficient to decrease fetal growth increases the vasodilator actions of AMPK in opposing phenylephrine‐induced vasoconstriction.
These results point to AMPK as being a key link between maternal vascular responses to pregnancy and fetal growth. Manipulation of AMPK may be a novel mechanism for developing new therapies in pregnancies complicated by chronic hypoxia.
Genes near adenosine monophosphate‐activated protein kinase‐α1 (PRKAA1) have been implicated in the greater uterine artery (UtA) blood flow and relative protection from fetal growth restriction seen in altitude‐adapted Andean populations. Adenosine monophosphate‐activated protein kinase (AMPK) activation vasodilates multiple vessels but whether AMPK is present in UtA or placental tissue and influences UtA vasoreactivity during normal or hypoxic pregnancy remains unknown. We studied isolated UtA and placenta from near‐term C57BL/6J mice housed in normoxia (n = 8) or hypoxia (10% oxygen, n = 7–9) from day 14 to day 19, and placentas from non‐labouring sea level (n = 3) or 3100 m (n = 3) women. Hypoxia increased AMPK immunostaining in near‐term murine UtA and placental tissue. RT‐PCR products for AMPK‐α1 and ‐α2 isoforms and liver kinase B1 (LKB1; the upstream kinase activating AMPK) were present in murine and human placenta, and hypoxia increased LKB1 and AMPK‐α1 and ‐α2 expression in the high‐ compared with low‐altitude human placentas. Pharmacological AMPK activation by A769662 caused phenylephrine pre‐constricted UtA from normoxic or hypoxic pregnant mice to dilate and this dilatation was partially reversed by the NOS inhibitor l‐NAME. Hypoxic pregnancy sufficient to restrict fetal growth markedly augmented the UtA vasodilator effect of AMPK activation in opposition to PE constriction as the result of both NO‐dependent and NO‐independent mechanisms. We conclude that AMPK is activated during hypoxic pregnancy and that AMPK activation vasodilates the UtA, especially in hypoxic pregnancy. AMPK activation may be playing an adaptive role by limiting cellular energy depletion and helping to maintain utero‐placental blood flow in hypoxic pregnancy.
Key points
Uterine artery vasodilatation is a key mechanism for increasing utero‐placental blood flow and fetal nutrient supply.
Since the pioneering work of Joseph Barcroft, the natural laboratory of high altitude has been used to study the mechanisms regulating uterine artery blood supply and fetal growth.
Genes near the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK) have been implicated in genetic protection from high altitude‐associated fetal growth restriction.
We show that AMPK is present in utero‐placental tissues and has vasodilator effects in murine uterine arteries, and that exposure to chronic hypoxia sufficient to decrease fetal growth increases the vasodilator actions of AMPK in opposing phenylephrine‐induced vasoconstriction.
These results point to AMPK as being a key link between maternal vascular responses to pregnancy and fetal growth. Manipulation of AMPK may be a novel mechanism for developing new therapies in pregnancies complicated by chronic hypoxia.
Microvascular haemodynamic alterations are associated with coronary artery disease (CAD). The conjunctival microcirculation can easily be assessed non-invasively. However, the microcirculation of the ...conjunctiva has not been previously explored in clinical algorithms aimed at identifying patients with CAD. This case-control study involved 66 patients with post-myocardial infarction and 66 gender-matched healthy controls. Haemodynamic properties of the conjunctival microcirculation were assessed with a validated iPhone and slit lamp-based imaging tool. Haemodynamic properties were extracted with semi-automated software and compared between groups. Biomarkers implicated in the development of CAD were assessed in combination with conjunctival microcirculatory parameters. The conjunctival blood vessel parameters and biomarkers were used to derive an algorithm to aid in the screening of patients for CAD. Conjunctival blood velocity measured in combination with the blood biomarkers (N-terminal pro-brain natriuretic peptide and adiponectin) had an area under receiver operator characteristic curve (AUROC) of 0.967, sensitivity 93.0%, specificity 91.5% for CAD. This study demonstrated that the novel algorithm which included a combination of conjunctival blood vessel haemodynamic properties, and blood-based biomarkers could be used as a potential screening tool for CAD and should be validated for potential utility in asymptomatic individuals.
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