Observation of the effect of gravity on the motion of antimatter.

Einstein's general theory of relativity from 19151 remains the most successful description of gravitation. From the 1919 solar eclipse2 to the observation of gravitational waves3, the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Dirac's theory4 appeared in 1928; the positron was observed5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter7-10. In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive 'antigravity' is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP.

Laser cooling of antihydrogen atoms.

The photon-the quantum excitation of the electromagnetic field-is massless but carries momentum. A photon can therefore exert a force on an object upon collision1. Slowing the translational motion of atoms and ions by application of such a force2,3, known as laser cooling, was first demonstrated 40 years ago4,5. It revolutionized atomic physics over the following decades6-8, and it is now a workhorse in many fields, including studies on quantum degenerate gases, quantum information, atomic clocks and tests of fundamental physics. However, this technique has not yet been applied to antimatter. Here we demonstrate laser cooling of antihydrogen9, the antimatter atom consisting of an antiproton and a positron. By exciting the 1S-2P transition in antihydrogen with pulsed, narrow-linewidth, Lyman-α laser radiation10,11, we Doppler-cool a sample of magnetically trapped antihydrogen. Although we apply laser cooling in only one dimension, the trap couples the longitudinal and transverse motions of the anti-atoms, leading to cooling in all three dimensions. We observe a reduction in the median transverse energy by more than an order of magnitude-with a substantial fraction of the anti-atoms attaining submicroelectronvolt transverse kinetic energies. We also report the observation of the laser-driven 1S-2S transition in samples of laser-cooled antihydrogen atoms. The observed spectral line is approximately four times narrower than that obtained without laser cooling. The demonstration of laser cooling and its immediate application has far-reaching implications for antimatter studies. A more localized, denser and colder sample of antihydrogen will drastically improve spectroscopic11-13 and gravitational14 studies of antihydrogen in ongoing experiments. Furthermore, the demonstrated ability to manipulate the motion of antimatter atoms by laser light will potentially provide ground-breaking opportunities for future experiments, such as anti-atomic fountains, anti-atom interferometry and the creation of antimatter molecules.

Observation of the 1S-2P Lyman-α transition in antihydrogen.

In 1906, Theodore Lyman discovered his eponymous series of transitions in the extreme-ultraviolet region of the atomic hydrogen spectrum1,2. The patterns in the hydrogen spectrum helped to establish the emerging theory of quantum mechanics, which we now know governs the world at the atomic scale. Since then, studies involving the Lyman-α line-the 1S-2P transition at a wavelength of 121.6 nanometres-have played an important part in physics and astronomy, as one of the most fundamental atomic transitions in the Universe. For example, this transition has long been used by astronomers studying the intergalactic medium and testing cosmological models via the so-called 'Lyman-α forest'3 of absorption lines at different redshifts. Here we report the observation of the Lyman-α transition in the antihydrogen atom, the antimatter counterpart of hydrogen. Using narrow-line-width, nanosecond-pulsed laser radiation, the 1S-2P transition was excited in magnetically trapped antihydrogen. The transition frequency at a field of 1.033 tesla was determined to be 2,466,051.7 ± 0.12 gigahertz (1σ uncertainty) and agrees with the prediction for hydrogen to a precision of 5 × 10-8. Comparisons of the properties of antihydrogen with those of its well-studied matter equivalent allow precision tests of fundamental symmetries between matter and antimatter. Alongside the ground-state hyperfine4,5 and 1S-2S transitions6,7 recently observed in antihydrogen, the Lyman-α transition will permit laser cooling of antihydrogen8,9, thus providing a cold and dense sample of anti-atoms for precision spectroscopy and gravity measurements10. In addition to the observation of this fundamental transition, this work represents both a decisive technological step towards laser cooling of antihydrogen, and the extension of antimatter spectroscopy to quantum states possessing orbital angular momentum.

Characterization of the 1S-2S transition in antihydrogen.

In 1928, Dirac published an equation 1 that combined quantum mechanics and special relativity. Negative-energy solutions to this equation, rather than being unphysical as initially thought, represented a class of hitherto unobserved and unimagined particles-antimatter. The existence of particles of antimatter was confirmed with the discovery of the positron 2 (or anti-electron) by Anderson in 1932, but it is still unknown why matter, rather than antimatter, survived after the Big Bang. As a result, experimental studies of antimatter3-7, including tests of fundamental symmetries such as charge-parity and charge-parity-time, and searches for evidence of primordial antimatter, such as antihelium nuclei, have high priority in contemporary physics research. The fundamental role of the hydrogen atom in the evolution of the Universe and in the historical development of our understanding of quantum physics makes its antimatter counterpart-the antihydrogen atom-of particular interest. Current standard-model physics requires that hydrogen and antihydrogen have the same energy levels and spectral lines. The laser-driven 1S-2S transition was recently observed 8 in antihydrogen. Here we characterize one of the hyperfine components of this transition using magnetically trapped atoms of antihydrogen and compare it to model calculations for hydrogen in our apparatus. We find that the shape of the spectral line agrees very well with that expected for hydrogen and that the resonance frequency agrees with that in hydrogen to about 5 kilohertz out of 2.5 × 1015 hertz. This is consistent with charge-parity-time invariance at a relative precision of 2 × 10-12-two orders of magnitude more precise than the previous determination 8 -corresponding to an absolute energy sensitivity of 2 × 10-20 GeV.

Fluorescent IGF-II analogues for FRET-based investigations into the binding of IGF-II to the IGF-1R.

The interaction of IGF-II with the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-1R) has recently been identified as potential therapeutic target for the treatment of cancer. Understanding the interactions of IGF-II with these receptors is required for the development of potential anticancer therapeutics. This work describes an efficient convergent synthesis of native IGF-II and two non-native IGF-II analogues with coumarin fluorescent probes incorporated at residues 19 and 28. These fluorescent analogues bind with nanomolar affinities to the IGF-1R and are suitable for use in fluorescence resonance energy transfer (FRET) studies. From these studies the F19Cou IGF-II and F28Cou IGF-II proteins were identified as good probes for investigating the binding interactions of IGF-II with the IGF-1R and its other high affinity binding partners.

Socioeconomic status and lifestyle behaviours in cancer survivors: smoking and physical activity.

PURPOSE: Smoking cessation and increased physical activity (pa) have been linked to better outcomes in cancer survivors. We assessed whether socioeconomic factors influence changes in those behaviours after a cancer diagnosis. METHODS: As part of a cross-sectional study, a diverse group of cancer survivors at the Princess Margaret Cancer Centre (Toronto, ON), completed a questionnaire about past and current lifestyle behaviours and perceptions about the importance of those behaviours with respect to their health. The influence of socioeconomic indicators on smoking status and physical inactivity at 1 year before and after diagnosis were assessed using multivariable logistic regression with adjustment for clinico-demographic factors. RESULTS: Of 1222 participants, 1192 completed the smoking component. Of those respondents, 15% smoked before diagnosis, and 43% of those smokers continued to smoke after. The proportion of survivors who continued to smoke increased with lower education level (p = 0.03). Of the 1106 participants answering pa questions, 39% reported being physically inactive before diagnosis, of whom 82% remained inactive afterward. Survivors with a lower education level were most likely to remain inactive after diagnosis (p = 0.003). Lower education level, household income, and occupation were associated with the perception that pa had no effect or could worsen fatigue and quality of life (p ≤ 0.0001). CONCLUSIONS: In cancer survivors, education level was a major modifier of smoking and pa behaviours. Lower socioeconomic status was associated with incorrect perceptions about pa. Targeting at-risk survivors by education level should be evaluated as a strategy in cancer survivorship programs.

Bone health management in men undergoing ADT: examining enablers and barriers to care.

UNLABELLED: The study determined prostate cancer specialists' knowledge and concordance to guidelines regarding the diagnosis, management, and prevention of androgen deprivation therapy-induced osteoporosis. Despite high knowledge regarding bone health, most respondents did not routinely measure bone mineral density or use fracture risk assessment tools, suggesting a significant gap in the screening/monitoring of bone health. INTRODUCTION: The purpose of this study was to determine prostate cancer specialists' knowledge, practices, self-perceived competencies and barriers to providing guideline-concordant care in the diagnosis, prevention, and management of androgen deprivation therapy (ADT)-induced osteoporosis (OP). METHODS: A number of 73 Canadian radiation oncologists and 83 urologists completed questionnaires assessing (i) knowledge regarding OP and consensus guidelines for bone health management in men receiving ADT, (ii) self-assessed competencies regarding bone health management, (iii) current practices regarding OP prevention and management, and (iv) self-perceived barriers to providing guideline-concordant care. RESULTS: The majority of respondents were able to correctly identify the guideline-concordant frequency of repeat dual-energy X-Ray absorptiometry (DXA) scans (76.3%), vitamin D (70.3%), and calcium (53.2%) intake and that bisphosphonates/denosumab should always be considered for patients with a history of one low-trauma fracture (57.6%). Just under 1/3 (32.5%) reported routinely measuring bone mineral density (BMD) prior to starting ADT and routinely measuring BMD 1-2 years following the initiation of ADT (36.6%). Only 4.6% of respondents routinely used a validated fracture risk assessment tool. Lowest self-assessed competency levels were reported in providing self-management education to patients to foster the uptake of healthy bone behaviors (HBBs) and managing patients who present with or develop osteopenia and OP. The most significant barriers to providing OP prevention and management were lack of time and lack of supporting structures. CONCLUSIONS: Despite high knowledge about appropriate bone health care among prostate cancer specialists, there remain significant gaps in screening and monitoring of bone health, suggesting the need to develop innovative strategies to overcome barriers to implementation.

Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration.

FIG4 is a ubiquitously expressed phosphatase that, in complex with FAB1/PIKFYVE and VAC14, regulates the biosynthesis of the signaling lipid PI(3,5)P(2). Null mutation of Fig4 in the mouse results in spongiform degeneration of brain and peripheral ganglia, defective myelination and juvenile lethality. Partial loss-of-function of human FIG4 results in a severe form of Charcot-Marie-Tooth neuropathy. Neurons from null mice contain enlarged vacuoles derived from the endosome/lysosome pathway, and astrocytes accumulate proteins involved in autophagy. Other cellular defects include astrogliosis and microgliosis. To distinguish the contributions of neurons and glia to spongiform degeneration in the Fig4 null mouse, we expressed Fig4 under the control of the neuron-specific enolase promoter and the astrocyte-specific glial fibrillary acidic protein promoter in transgenic mice. Neuronal expression of Fig4 was sufficient to rescue cellular and neurological phenotypes including spongiform degeneration, gliosis and juvenile lethality. In contrast, expression of Fig4 in astrocytes prevented accumulation of autophagy markers and microgliosis but did not prevent spongiform degeneration or lethality. To confirm the neuronal origin of spongiform degeneration, we generated a floxed allele of Fig4 and crossed it with mice expressing the Cre recombinase from the neuron-specific synapsin promoter. Mice with conditional inactivation of Fig4 in neurons developed spongiform degeneration and the full spectrum of neurological abnormalities. The data demonstrate that expression of Fig4 in neurons is necessary and sufficient to prevent spongiform degeneration. Therapy for patients with FIG4 deficiency will therefore require correction of the deficiency in neurons.

Frequency ratio of two optical clock transitions in 171Yb+ and constraints on the time variation of fundamental constants.

Singly ionized ytterbium, with ultranarrow optical clock transitions at 467 and 436 nm, is a convenient system for the realization of optical atomic clocks and tests of present-day variation of fundamental constants. We present the first direct measurement of the frequency ratio of these two clock transitions, without reference to a cesium primary standard, and using the same single ion of 171Yb+. The absolute frequencies of both transitions are also presented, each with a relative standard uncertainty of 6×10(-16). Combining our results with those from other experiments, we report a threefold improvement in the constraint on the time variation of the proton-to-electron mass ratio, µ/µ=0.2(1.1)×10(-16) yr(-1), along with an improved constraint on time variation of the fine structure constant, α/α=-0.7(2.1)×10(-17) yr(-1).

Norwegian survival prediction model in trauma: modelling effects of anatomic injury, acute physiology, age, and co-morbidity.

INTRODUCTION: Anatomic injury, physiological derangement, age, and injury mechanism are well-founded predictors of trauma outcome. We aimed to develop and validate the first Scandinavian survival prediction model for trauma. METHODS: Eligible were patients admitted to Oslo University Hospital Ullevål within 24 h after injury with Injury Severity Score ≥ 10, proximal penetrating injuries or received by a trauma team. The derivation dataset comprised 5363 patients (August 2000 to July 2006); the validation dataset comprised 2517 patients (August 2006 to July 2008). Exclusion because of missing data was < 1%. Outcome was 30-day mortality. Logistic regression analysis incorporated fractional polynomial modelling and interaction effects. Model validation included a calibration plot, Hosmer-Lemeshow test and receiver operating characteristic (ROC) curves. RESULTS: The new survival prediction model included the anatomic New Injury Severity Score (NISS), Triage Revised Trauma Score (T-RTS, comprising Glascow Coma Scale score, respiratory rate, and systolic blood pressure), age, pre-injury co-morbidity scored according to the American Society of Anesthesiologists Physical Status Classification System (ASA-PS), and an interaction term. Fractional polynomial analysis supported treating NISS and T-RTS as linear functions and age as cubic. Model discrimination between survivors and non-survivors was excellent. Area (95% confidence interval) under the ROC curve was 0.966 (0.959-0.972) in the derivation and 0.946 (0.930-0.962) in the validation dataset. Overall, low mortality and skewed survival probability distribution invalidated model calibration using the Hosmer-Lemeshow test. CONCLUSIONS: The Norwegian survival prediction model in trauma (NORMIT) is a promising alternative to existing prediction models. External validation of the model in other trauma populations is warranted.

Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'.

The mouse neurological mutant 'motor endplate disease' (med) is characterized by early onset progressive paralysis of the hind limbs, severe muscle atrophy, degeneration of Purkinje cells and juvenile lethality. We have isolated a voltage-gated sodium channel gene, Scn8a, from the flanking region of a transgene-induced allele of med. Scn8a is expressed in brain and spinal cord but not in skeletal muscle or heart, and encodes a predicted protein of 1,732 amino acids. An intragenic deletion at the transgene insertion site results in loss of expression. Scn8a is closely related to other sodium channel alpha subunits, with greatest similarity to a brain transcript from the pufferfish Fugu rubripes. The human homologue, SCN8A, maps to chromosome 12q13 and is a candidate gene for inherited neurodegenerative disease.

Sympathetic cooling of positrons to cryogenic temperatures for antihydrogen production.

The positron, the antiparticle of the electron, predicted by Dirac in 1931 and discovered by Anderson in 1933, plays a key role in many scientific and everyday endeavours. Notably, the positron is a constituent of antihydrogen, the only long-lived neutral antimatter bound state that can currently be synthesized at low energy, presenting a prominent system for testing fundamental symmetries with high precision. Here, we report on the use of laser cooled Be+ ions to sympathetically cool a large and dense plasma of positrons to directly measured temperatures below 7 K in a Penning trap for antihydrogen synthesis. This will likely herald a significant increase in the amount of antihydrogen available for experimentation, thus facilitating further improvements in studies of fundamental symmetries.

Antibody response of immunodeficient (xid) CBA/N mice to Escherichia coli 0113 lipopolysaccharide, a thymus-independent antigen.

CBA/N mice, which possess an X-linked immunodeficiency (xid), produce a convincing antibody response to lipopolysaccharide derived from Escherichia coli 0113 (LPS 0113), a thymus-independent antigen. The antibody response produced was shown to be specific for the O-polysaccharide moiety of LPS 0113, rather than lipid A or lipid-A-associated protein. The relevance of this finding to the nature of the genetic defect of xid-mice is discussed.

The most influential papers in mitral valve surgery; a bibliometric analysis.

This study is an analysis of the 100 most cited articles in mitral valve surgery. A bibliometric analysis is a tool to evaluate research performance in a given field. It uses the number of times a publication is cited by others as a proxy marker of its impact. The most cited paper Carpentier et al. discusses mitral valve repair in terms of restoring the geometry of the entire valve rather than simply narrowing the annulus (Carpentier, J Thorac Cardiovasc Surg 86:23-37, 1983). The first successful mitral valve repair was performed by Elliot Cutler at Brigham and Women's Hospital in 1923 (Cohn et al., Ann Cardiothorac Surg 4:315, 2015). More recently percutaneous and minimally invasive techniques that were originally designed as an option for high risk patients are being trialled in other patient groups (Hajar, Heart Views 19:160-3, 2018). Comparison of percutaneous method with open repair represents an expanding area of research (Hajar, Heart Views 19:160-3, 2018). This study will analyse the top 100 cited papers relevant to mitral valve surgery, identifying the most influential papers that guide current management, the institutions that produce them and the authors involved.

Multiple distinct targeting signals in integral peroxisomal membrane proteins.

Peroxisomal proteins are synthesized on free polysomes and then transported from the cytoplasm to peroxisomes. This process is mediated by two short well-defined targeting signals in peroxisomal matrix proteins, but a well-defined targeting signal has not yet been described for peroxisomal membrane proteins (PMPs). One assumption in virtually all prior studies of PMP targeting is that a given protein contains one, and only one, distinct targeting signal. Here, we show that the metabolite transporter PMP34, an integral PMP, contains at least two nonoverlapping sets of targeting information, either of which is sufficient for insertion into the peroxisome membrane. We also show that another integral PMP, the peroxin PEX13, also contains two independent sets of peroxisomal targeting information. These results challenge a major assumption of most PMP targeting studies. In addition, we demonstrate that PEX19, a factor required for peroxisomal membrane biogenesis, interacts with the two minimal targeting regions of PMP34. Together, these results raise the interesting possibility that PMP import may require novel mechanisms to ensure the solubility of integral PMPs before their insertion in the peroxisome membrane, and that PEX19 may play a central role in this process.

PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.

Peroxisomes are components of virtually all eukaryotic cells. While much is known about peroxisomal matrix protein import, our understanding of how peroxisomal membrane proteins (PMPs) are targeted and inserted into the peroxisome membrane is extremely limited. Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes. Furthermore, mislocalization of PEX19 to the nucleus leads to nuclear accumulation of newly synthesized PMPs. At steady state, PEX19 is bimodally distributed between the cytoplasm and peroxisome, with most of the protein in the cytoplasm. We propose that PEX19 may bind newly synthesized PMPs and facilitate their insertion into the peroxisome membrane. This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion.

Embryonic stem cell lines derived from human blastocysts.

Human blastocyst-derived, pluripotent cell lines are described that have normal karyotypes, express high levels of telomerase activity, and express cell surface markers that characterize primate embryonic stem cells but do not characterize other early lineages. After undifferentiated proliferation in vitro for 4 to 5 months, these cells still maintained the developmental potential to form trophoblast and derivatives of all three embryonic germ layers, including gut epithelium (endoderm); cartilage, bone, smooth muscle, and striated muscle (mesoderm); and neural epithelium, embryonic ganglia, and stratified squamous epithelium (ectoderm). These cell lines should be useful in human developmental biology, drug discovery, and transplantation medicine.

Two lipocortin-like proteins, endonexin II and anchorin CII, may be alternate splices of the same gene.

The annexins are a family of phospholipid- and Ca2+-binding proteins that are structurally related. Two members of this family, human endonexin II and chicken anchorin CII, may arise from the same gene by alternative splicing of two structurally unrelated segments.

Classification of macroalgae as fuel and its thermochemical behaviour.

A preliminary classification of five macroalgae from the British Isles; Fucus vesiculosus, Chorda filum, Laminaria digitata, Fucus serratus, Laminaria hyperborea, and Macrocystis pyrifera from South America, has been presented in terms of a Van Krevelen diagram. The macroalgae have been characterised for proximate and ultimate analysis, inorganic content, and calorific value. The different options for thermal conversion and behaviour under combustion and pyrolysis have been evaluated and compared to several types of terrestrial biomass including Miscanthus, short rotation Willow coppice and Oat straw. Thermal treatment of the macroalgae has been investigated using thermogravimetry (TGA) and pyrolysis-gc-ms. Combustion behaviour is investigated using TGA in an oxidising atmosphere. The suitability of macroalgae for the different thermal processing routes is discussed. Ash chemistry restricts the use of macroalgae for direct combustion and gasification. Pyrolysis produces a range of pentosans and a significant proportion of nitrogen containing compounds. High char yields are produced.

Exploring cancer centres for physical activity and sedentary behaviour support for breast cancer survivors.

Background: Up to 90% of breast cancer survivors report low levels of physical activity (pa) and spend approximately 70% of the day in sedentary behaviour. Survivors might not be receiving information about the health benefits of pa and the consequences of sedentary behaviour in the context of their cancer. The primary purpose of the present study was to evaluate cancer centres for pa and sedentary behaviour information and infrastructure. A secondary aim was to evaluate the quality of the information that is accessible to breast cancer survivors in cancer centres. Methods: A built-environment scan of the 14 regional cancer centres in Ontario and an evaluation of the text materials about pa available at the cancer centres were completed. Data analyses included descriptive statistics, proportions, and inter-rater reliability. Results: The infrastructure of the cancer centres provided few opportunities for dissemination of information related to pa through signs and printed notices. Televisions were present in all waiting rooms, which could provide a unique opportunity for dissemination of information about pa and sedentary behaviour. Text materials were rated as trustworthy, used some behaviour change techniques (for example, information about the consequences of lack of pa, barrier identification, and setting graded tasks), and were aesthetically pleasing. Conclusions: These findings represent areas for knowledge dissemination both for the centre and for resources that could be further improved.