Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work-up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence-based recommendations have improved neonatal survival and short-term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post-translational short-chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short-chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising

‘Getting inside the wicket’: strategies for the social inclusion of British Pakistani Muslim cricketers

The England and Wales Cricket Board (ECB) are keen to increase the participation of British Asian groups, including those of British Pakistani Muslim (BPM) backgrounds, at mainstream levels of the game in order to meet their twin strategic aims of raising participation levels and fostering elite development. We argue that the potential to include BPM men in and through cricket is achievable, but strategies to engage them must address their social needs and circumstances rather than be superficial and tokenistic. Cricket agencies and bodies must be willing to adapt and change to become more inclusive, and indeed supportive of real meritocracy. Using research testimonies garnered from interviews with BPM men who play cricket at amateur mainstream and/or alternative formats of the game, we identify and forward strategies that can be activated by cricket development officers in order to create new possibilities for the social inclusion of BPM men

Premature Discontinuation of Prospective Clinical Studies Approved by a Research Ethics Committee - A Comparison of Randomised and Non-Randomised Studies.

Premature discontinuation of clinical studies affects about 25% of randomised controlled trials (RCTs) which raises concerns about waste of scarce resources for research. The risk of discontinuation of non-randomised prospective studies (NPSs) is yet unclear. To compare the proportion of discontinued studies between NPSs and RCTs that received ethical approval. We systematically surveyed prospective longitudinal clinical studies that were approved by a single REC in Freiburg, Germany between 2000 and 2002. We collected study characteristics, identified subsequent publications, and surveyed investigators to elucidate whether a study was discontinued and, if so, why. Of 917 approved studies, 547 were prospective longitudinal studies (306 RCTs and 241 NPSs). NPSs were on average smaller than RCTs, more frequently single centre and pilot studies, and less frequently funded by industry. NPSs were less frequently discontinued than RCTs: 32/221 (14%) versus 78/288 (27%, p<0.001, missing data excluded). Poor recruitment was the most frequent reason for discontinuation in both NPSs (36%) and RCTs (37%). Compared to RCTs, NPSs were at lower risk for discontinuation. Measures to reliably predict, sustain, and stimulate recruitment could prevent discontinuation of many RCTs but also of some NPSs

Efimov physics from the functional renormalization group

Few-body physics related to the Efimov effect is discussed using the functional renormalization group method. After a short review of renormalization in its modern formulation we apply this formalism to the description of scattering and bound states in few-body systems of identical bosons and distinguishable fermions with two and three components. The Efimov effect leads to a limit cycle in the renormalization group flow. Recently measured three-body loss rates in an ultracold Fermi gas $^6$Li atoms are explained within this framework. We also discuss briefly the relation to the many-body physics of the BCS-BEC crossover for two-component fermions and the formation of a trion phase for the case of three species.Comment: 28 pages, 13 figures, invited contribution to a special issue of "Few-Body Systems" devoted to Efimov physics, published versio

Towards a macroscope : leveraging technology to transform the breadth, scale and resolution of macroecological data

M.D. is grateful for support from the Templeton Foundation (grant #60501, “Putting the Extended Evolutionary Synthesis to the Test”) and from a Leverhulme Trust Fellowship.The problem Earth‐based observations of the biosphere are spatially biased in ways that can limit our ability to detect macroecological patterns and changes in biodiversity. To resolve this problem, we need to supplement the ad hoc data currently collected with planned biodiversity monitoring, in order to approximate global stratified random sampling of the planet. We call this all‐encompassing observational system ‘the macroscope’. The solution With a focus on the marine realm, we identify seven main biosphere observation tools that compose the macroscope: satellites, drones, camera traps, passive acoustic samplers, biologgers, environmental DNA and human observations. By deploying a nested array of these tools that fills current gaps in monitoring, we can achieve a macroscope fit for purpose and turn these existing powerful tools into more than the sum of their parts. An appeal Building a macroscope requires commitment from many fields, together with coordinated actions to attract the level of funding required for such a venture. We call on macroecologists to become advocates for the macroscope and to engage with existing global observation networks.PostprintPeer reviewe

A Graphical Null Model for Scaling Biodiversity–Ecosystem Functioning Relationships

Global biodiversity is declining at rates faster than at any other point in human history. Experimental manipulations at small spatial scales have demonstrated that communities with fewer species consistently produce less biomass than higher diversity communities. Understanding the consequences of the global extinction crisis for ecosystem functioning requires understanding how local experimental results are likely to change with increasing spatial and temporal scales and from experiments to naturally assembled systems. Scaling across time and space in a changing world requires baseline predictions. Here, we provide a graphical null model for area scaling of biodiversity–ecosystem functioning relationships using observed macroecological patterns: the species–area curve and the biomass–area curve. We use species–area and biomass–area curves to predict how species richness–biomass relationships are likely to change with increasing sampling extent. We then validate these predictions with data from two naturally assembled ecosystems: a Minnesota savanna and a Panamanian tropical dry forest. Our graphical null model predicts that biodiversity–ecosystem functioning relationships are scale-dependent. However, we note two important caveats. First, our results indicate an apparent contradiction between predictions based on measurements in biodiversity–ecosystem functioning experiments and from scaling theory. When ecosystem functioning is measured as per unit area (e.g. biomass per m2), as is common in biodiversity–ecosystem functioning experiments, the slope of the biodiversity ecosystem functioning relationship should decrease with increasing scale. Alternatively, when ecosystem functioning is not measured per unit area (e.g. summed total biomass), as is common in scaling studies, the slope of the biodiversity–ecosystem functioning relationship should increase with increasing spatial scale. Second, the underlying macroecological patterns of biodiversity experiments are predictably different from some naturally assembled systems. These differences between the underlying patterns of experiments and naturally assembled systems may enable us to better understand when patterns from biodiversity–ecosystem functioning experiments will be valid in naturally assembled systems. Synthesis. This paper provides a simple graphical null model that can be extended to any relationship between biodiversity and any ecosystem functioning across space or time. Furthermore, these predictions provide crucial insights into how and when we may be able to extend results from small-scale biodiversity experiments to naturally assembled regional and global ecosystems where biodiversity is changing

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

The impact of mental health recovery narratives on recipients experiencing mental health problems: Qualitative analysis and change model.

BACKGROUND: Mental health recovery narratives are stories of recovery from mental health problems. Narratives may impact in helpful and harmful ways on those who receive them. The objective of this paper is to develop a change model identifying the range of possible impacts and how they occur. METHOD: Semi-structured interviews were conducted with adults with experience of mental health problems and recovery (n = 77). Participants were asked to share a mental health recovery narrative and to describe the impact of other people's recovery narratives on their own recovery. A change model was generated through iterative thematic analysis of transcripts. RESULTS: Change is initiated when a recipient develops a connection to a narrator or to the events descripted in their narrative. Change is mediated by the recipient recognising experiences shared with the narrator, noticing the achievements or difficulties of the narrator, learning how recovery happens, or experiencing emotional release. Helpful outcomes of receiving recovery narratives are connectedness, validation, hope, empowerment, appreciation, reference shift and stigma reduction. Harmful outcomes are a sense of inadequacy, disconnection, pessimism and burden. Impact is positively moderated by the perceived authenticity of the narrative, and can be reduced if the recipient is experiencing a crisis. CONCLUSIONS: Interventions that incorporate the use of recovery narratives, such as peer support, anti-stigma campaigns and bibliotherapy, can use the change model to maximise benefit and minimise harms from narratives. Interventions should incorporate a diverse range of narratives available through different mediums to enable a range of recipients to connect with and benefit from this material. Service providers using recovery narratives should preserve authenticity so as to maximise impact, for example by avoiding excessive editing

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation