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Particle accelerators driven by laser-generated terahertz (THz) pulses promise unprecedented control over the energy–time phase space of particle bunches compared with conventional radiofrequency technology. Here we demonstrate acceleration of a relativistic electron beam in a THz-driven linear accelerator. Narrowband THz pulses were tuned to the phase-velocity-matched operating frequency of a rectangular dielectric-lined waveguide for extended collinear interaction with 35 MeV, 60 pC electron bunches, imparting multicycle energy modulation to chirped (6 ps) bunches and injection phase-dependent energy gain (up to 10 keV) to subcycle (2 ps) bunches. These proof-of-principle results establish a route to whole-bunch linear acceleration of subpicosecond particle beams, directly applicable to scaled-up and multistaged concepts capable of preserving beam quality, thus marking a key milestone for future THz-driven acceleration of relativistic beams.Relativistic 35 MeV electron bunches with charges of 60 pC are accelerated in a terahertz-wave-driven dielectric waveguide. When the terahertz pulse energy is 0.8 μJ, an accelerating gradient of 2 MeV m−1 and energy gain of 10 keV are achieved.

Dielectric structures driven by laser-generated terahertz (THz) pulses may hold the key to overcoming the technological limitations of conventional particle accelerators and with recent experimental demonstrations of acceleration, compression and streaking of low-energy (sub-100 keV) electron beams, operation at relativistic beam energies is now essential to realize the full potential of THz-driven structures. We present the first THz-driven linear acceleration of relativistic 35 MeV electron bunches, exploiting the collinear excitation of a dielectric-lined waveguide driven by the longitudinal electric field component of polarization-tailored, narrowband THz pulses. Our results pave the way to unprecedented control over relativistic electron beams, providing bunch compression for ultrafast electron diffraction, energy manipulation for bunch diagnostics, and ultimately delivering high-field gradients for compact THz-driven particle acceleration.

Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. ClinicalTrials.gov NCT01365065.

The solar wind temperature (T) and speed (V) are generally well correlated at ∼1 AU, except in Interplanetary Coronal Mass Ejections where this correlation breaks down. We perform a comprehensive analysis of both the temporal and radial variation in the temperature‐speed (T‐V) relationship of the non‐transient wind, and our analysis provides insight into both the causes of the T‐V relationship and the sources of the temperature variability. Often at 1 AU the speed‐temperature relationship is well represented by a single linear fit over a speed range spanning both the slow and fast wind. However, at times the fast wind from coronal holes can have a different T‐V relationship than the slow wind. A good example of this was in 2003 when there was a very large and long‐lived outward magnetic polarity coronal hole at low latitudes that emitted wind with speeds as fast as a polar coronal hole. The long‐lived nature of the hole made it possible to clearly distinguish that some holes can have a different T‐V relationship. In an earlier ACE study, we found that both the compressions and rarefactions T‐V curves are linear, but the compression curve is shifted to higher temperatures. By separating compressions and rarefactions prior to determining the radial profiles of the solar wind parameters, the importance of dynamic interactions on the radial evolution of the solar wind parameters is revealed. Although the T‐V relationship at 1 AU is often well described by a single linear curve, we find that the T‐V relationship continually evolves with distance. Beyond ∼2.5 AU the differences between the compressions and rarefactions are quite significant and affect the shape of the overall T‐V distribution to the point that a simple linear fit no longer describes the distribution well. Since additional heating of the ambient solar wind outside of interaction regions can be associated with Alfvénic fluctuations and the turbulent energy cascade, we also estimate the heating rate radial profile from the solar wind speed and temperature measurements. Key Points Solar wind speed‐temperature relationship systematically evolves with distance There is an overall decrease in the T‐V slope since 1972 In 2003 a long‐lived coronal hole extension emitted atypically fast wind

This paper documents the biogeochemistry configuration of the Energy Exascale Earth System Model (E3SM), E3SMv1.1‐BGC. The model simulates historical carbon cycle dynamics, including carbon losses predicted in response to land use and land cover change, and the responses of the carbon cycle to changes in climate. In addition, we introduce several innovations in the treatment of soil nutrient limitation mechanisms, including explicit dependence on phosphorus availability. The suite of simulations described here includes E3SM contributions to the Coupled Climate‐Carbon Cycle Model Intercomparison Project and other projects, as well as simulations to explore the impacts of structural uncertainty in representations of nitrogen and phosphorus limitation. We describe the model spin‐up and evaluation procedures, provide an overview of results from the simulation campaign, and highlight key features of the simulations. Cumulative warming over the twentieth century is similar to observations, with a midcentury cold bias offset by stronger warming in recent decades. Ocean biomass production and carbon uptake are underpredicted, likely due to biases in ocean transport leading to widespread anoxia and undersupply of nutrients to surface waters. The inclusion of nutrient limitations in the land biogeochemistry results in weaker carbon fertilization and carbon‐climate feedbacks than exhibited by other Earth System Models that exclude those limitations. Finally, we compare with an alternative representation of terrestrial biogeochemistry, which differs in structure and in initialization of soil phosphorus. While both configurations agree well with observational benchmarks, they differ significantly in their distribution of carbon among different pools and in the strength of nutrient limitations. Plain Language Summary A new state‐of‐the‐art Earth System Model has been funded by the United States Department of Energy (DOE) to explore questions relevant to DOE's mission. The Energy Exascale Earth System Model version 1.1 (E3SMv1.1) represents nitrogen and phosphorous controls on the carbon cycle and extends the recently released E3SMv1 to include active biogeochemistry in the land, ocean, and ice components. E3SMv1.1 also includes an alternative representation of terrestrial carbon and nutrient cycles that is used to explore model structural uncertainties. E3SMv1.1's capabilities are demonstrated through a set of experiments described by the Coupled Climate‐Carbon Cycle Model Intercomparison Project, aimed at understanding the influence of changes in climate and CO2 on the carbon cycle. Simulations of the land surface properties and terrestrial carbon cycle compare well with observations, as does the simulated global and regional climate. Nutrient limitations result in less land carbon uptake compared to models that exclude these limitations. However, variations in model structure and initialization influence the magnitude of those limitations and carbon cycle dynamics. The ocean biogeochemistry in E3SMv1.1 simulates less biomass and slightly lower anthropogenic carbon uptake than is observed. Future efforts will aim to reduce model biases as well as to include additional aspects of global carbon cycle dynamics. Key Points Introduces the U.S. DOE's Energy Exascale Earth System Model‐Biogeochemistry version, E3SMv1.1‐BGC, is introduced Ecosystem‐climate responses are characterized in a standard set of C4MIP‐type simulations The impacts of terrestrial nitrogen and phosphorus limitations and their structural uncertainties are explored

SIRT1 activators in diabetes SIRT1, an NAD + -dependent deacetylase that acts on proteins involved in cellular regulation, has been implicated in longevity and as a mediator of the beneficial effects of calorie restriction. A new screening programme has identified a series of small-molecule SIRT1 activators that are structurally unlike, and 1,000-fold more potent than, resveratrol, the well-known SIRT1 activator found in red wine. These new compounds improve metabolic function in animal models of diabetes and obesity, suggesting that they may have therapeutic potential in type 2 diabetes and insulin resistance. This work describes the identification and characterization of novel small molecule activators of SIRT1, an NAD + -dependent deacetylase that mediates the beneficial effects of caloric restriction. These small molecules are structurally unrelated to, and much more potent than, resveratrol, and improve metabolic function in animal models of diabetes and obesity. Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes 1 , 2 . SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity 3 , 4 , 5 , 6 , 7 , 8 , 9 . Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival 10 , 11 , 12 , 13 , 14 . Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18 , play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K + channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 ( KCNK10 ) K2P K + channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains. K2P channels are important regulators of cellular electrical activity. Here the authors show how nanobody fragments can be used to detect and modulate TREK2 K2P channel activity to provide insight into the mechanism of gating.

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB , which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings. Sickle cell disease includes genetic conditions that are caused by mutations in one of the genes encoding haemoglobin. Mutant haemoglobin molecules can polymerize, causing the red blood cells to acquire a characteristic crescent shape that gives the disease its name.

Ecological applications of compound-specific stable isotope analysis (CSIA) of amino acids (AAs) include 1) tracking carbon pathways in food webs using essential AA (AA ESS ) δ 13 C values, and 2) estimating consumer trophic position (TP) by comparing relative differences of ‘trophic’ and ‘source’ AA δ 15 N values. Despite the significance of these applications, few studies have examined AA-specific SI patterns among tissues with different AA compositions and metabolism/turnover rates, which could cause differential drawdown of body AA pools and impart tissue-specific isotopic fractionation. To address this knowledge gap, especially in the absence of controlled diet studies examining this issue in captive marine mammals, we used a paired-sample design to compare δ 13 C and δ 15 N values of 11 AAs in commonly sampled tissues (skin, muscle, and dentine) from wild beluga whales ( Delphinapterus leucas ). δ 13 C of two AAs, glutamic acid/glutamine (Glx, a non-essential AA) and, notably, threonine (an essential AA), differed between skin and muscle. Furthermore, δ 15 N of three AAs (alanine, glycine, and proline) differed significantly among the three tissues, with glycine δ 15 N differences of approximately 10 ‰ among tissues supporting recent findings it is unsuitable as a source AA. Significant δ 15 N differences in AAs such as proline, a trophic AA used as an alternative to Glx in TP estimation, highlight tissue selection as a potential source of error in ecological applications of CSIA-AA. Amino acids that differed among tissues play key roles in metabolic pathways (e.g., ketogenic and gluconeogenic AAs), pointing to potential physiological applications of CSIA-AA in studies of free-ranging animals. These findings underscore the complexity of isotopic dynamics within tissues and emphasize the need for a nuanced approach when applying CSIA-AA in ecological research.

A year-long, phase 3, randomized trial involving patients with sickle cell disease showed that the median number of pain crises was 25% lower and the median number of hospitalizations was 33% lower with l -glutamine supplementation than with placebo.