4,869 research outputs found

    Biomolecular imaging and electronic damage using X-ray free-electron lasers

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    Proposals to determine biomolecular structures from diffraction experiments using femtosecond X-ray free-electron laser (XFEL) pulses involve a conflict between the incident brightness required to achieve diffraction-limited atomic resolution and the electronic and structural damage induced by the illumination. Here we show that previous estimates of the conditions under which biomolecular structures may be obtained in this manner are unduly restrictive, because they are based on a coherent diffraction model that is not appropriate to the proposed interaction conditions. A more detailed imaging model derived from optical coherence theory and quantum electrodynamics is shown to be far more tolerant of electronic damage. The nuclear density is employed as the principal descriptor of molecular structure. The foundations of the approach may also be used to characterize electrodynamical processes by performing scattering experiments on complex molecules of known structure.Comment: 16 pages, 2 figure

    Synovial cell metabolism and chronic inflammation in rheumatoid arthritis

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    Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes to nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principle site of inflammation in RA. Here the resident cells are the fibroblast-like synoviocytes (FLS) and the synovial tissue macrophages (STM), which are transformed toward overproduction of enzymes which degrade cartilage and bone, and cytokines which promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients and these may be therapeutically targetable. However, as the origins and subset specific functions of synoviocytes are poorly understood and the signaling modules which control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings toward clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers (SLC) in their membranes, to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and are yet to be explored. Finally, it is not yet known whether metabolic change is a consequence of disease or if primary changes to cellular metabolism might underlie or contribute to early stage disease pathogenesis. This article collates what is known about metabolism in synovial tissue cells and highlights future research directions in this area

    Formidable females and the power trajectories of socially integrated male vervet monkeys

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    Sexual conflict theory expects females to avoid nonoptimal mating attempts by males. Although female vervet monkeys, Chlorocebus pygerythrus, can resist direct mating attempts, higher-ranking males still have more mating opportunities than lower-ranking ones. We presume that rank-related access reflects maleemale competition that may conflict with female reproductive objectives. We extend an earlier report of codominance in this species to show that powerful females can undermine the restrictions imposed through maleemale competition by improving the dominance rank of preferred male associates. We found that the dominance hierarchies of the sexes were comprehensively interdigitated and that males who had more female spatial associates, and who groomed with well-connected females, were more likely improve their Elo-ratings, which we use as an index of male power. The effects of partner number and integration, which predicted the probability of the initiation of aggression by lower-ranking males, suggest that association with females offered the prospect of protected threat if this likelihood increased. Although female rank and aggression were not directly consequential for males, we argue that female power and influence are intertwined and that both stem from the strength of female reproductive control

    Enhanced flight performance by genetic manipulation of wing shape in Drosophila

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    Insect wing shapes are remarkably diverse and the combination of shape and kinematics determines both aerial capabilities and power requirements. However, the contribution of any specific morphological feature to performance is not known. Using targeted RNA interference to modify wing shape far beyond the natural variation found within the population of a single species, we show a direct effect on flight performance that can be explained by physical modelling of the novel wing geometry. Our data show that altering the expression of a single gene can significantly enhance aerial agility and that the Drosophila wing shape is not, therefore, optimized for certain flight performance characteristics that are known to be important. Our technique points in a new direction for experiments on the evolution of performance specialities in animals

    Recommendations for the transition of patients with ADHD from child to adult healthcare services:a consensus statement from the UK adult ADHD network

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    The aim of this consensus statement was to discuss transition of patients with ADHD from child to adult healthcare services, and formulate recommendations to facilitate successful transition. An expert workshop was convened in June 2012 by the UK Adult ADHD Network (UKAAN), attended by a multidisciplinary team of mental health professionals, allied professionals and patients. It was concluded that transitions must be planned through joint meetings involving referring/receiving services, patients and their families. Negotiation may be required to balance parental desire for continued involvement in their child’s care, and the child’s growing autonomy. Clear transition protocols can maintain standards of care, detailing relevant timeframes, responsibilities of agencies and preparing contingencies. Transition should be viewed as a process not an event, and should normally occur by the age of 18, however flexibility is required to accommodate individual needs. Transition is often poorly experienced, and adherence to clear recommendations is necessary to ensure effective transition and prevent drop-out from services

    Social feasibility assessments in conservation translocations

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    This is the final version. Available on open access from Cell Press via the DOI in this recordImproving the effectiveness of conservation translocations could contribute to reversing global biodiversity loss. Although evaluations of ecological factors affecting translocation outcomes are commonplace, consideration of human social factors remains rare, hindering improvements to this conservation practice. We analysed 550 translocation case studies to explore the inclusion of social factors in project feasibility assessments. Reviewed projects often failed to assess social feasibility, and assessments, where attempted, tended to be narrow in scope. Consequently, challenges such as proactively addressing conflict often remained unaddressed. Insufficient knowledge sharing and prioritisation of ecological feasibility, to the detriment of social feasibility, remain barriers to effective planning. Successful outcomes of translocations are linked to early assessment of social feasibility and to the establishment of long-term commitments between people, places, and partners.Vincent Wildlife TrustDurrell Wildlife Conservation TrustUniversity of Exete

    Onasemnogene abeparvovec preserves bulbar function in infants with presymptomatic spinal muscular atrophy: a post-hoc analysis of the SPR1NT trial

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    Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function
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