B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)
, and the diverse range of BCRs expressed by the ...total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.
After the domestication of animals and crops in the Near East some 11,000 years ago, farming had reached much of central Europe by 7500 years before the present. The extent to which these early ...European farmers were immigrants or descendants of resident hunter-gatherers who had adopted farming has been widely debated. We compared new mitochondrial DNA (mtDNA) sequences from late European hunter-gatherer skeletons with those from early farmers and from modern Europeans. We find large genetic differences between all three groups that cannot be explained by population continuity alone. Most (82%) of the ancient hunter-gatherers share mtDNA types that are relatively rare in central Europeans today. Together, these analyses provide persuasive evidence that the first farmers were not the descendants of local hunter-gatherers but immigrated into central Europe at the onset of the Neolithic.
Some forest plants adapt to shade by mixotrophy, i.e., they obtain carbon both from photosynthesis and from their root mycorrhizal fungi. Fully achlorophyllous species using exclusively fungal carbon ...(the so-called mycoheterotrophic plants) have repeatedly evolved from such mixotrophic ancestors. However, adaptations for this evolutionary transition, and the reasons why it has happened a limited number of times, remain unknown. We investigated this using achlorophyllous variants (i.e., albinos) spontaneously occurring in
Cephalanthera damasonium
, a mixotrophic orchid. In two populations, we compared albinos with co-occurring green individuals in situ. We investigated vegetative traits, namely, shoot phenology, dormancy, CO
2
and H
2
O leaf exchange, mycorrhizal colonization, degree of mycoheterotrophy (using
13
C abundance as a proxy), and susceptibility to pathogens and herbivores. We monitored seed production (in natural or experimental crosses) and seed germination. Albinos displayed (1) more frequent shoot drying at fruiting, possibly due to stomatal dysfunctions, (2) lower basal metabolism, (3) increased sensitivity to pathogens and herbivores, (4) higher dormancy and maladapted sprouting, and, probably due to the previous differences, (5) fewer seeds, with lower germination capacity. Over the growing season, green shoots shifted from using fungal carbon to an increasingly efficient photosynthesis at time of fruiting, when fungal colonization reached its minimum. Conversely, the lack of photosynthesis in fruiting albinos may contribute to carbon limitation, and to the above-mentioned trends. With a 10
3
× fitness reduction, albinos failed a successful transition to mycoheterotrophy because some traits inherited from their green ancestors are maladaptive. Conversely, mycoheterotrophy requires at least degeneration of leaves and stomata, optimization of the temporal pattern of fungal colonization and shoot sprouting, and new defenses against pathogens and herbivores. Transition to mycoheterotrophy likely requires progressive, joint evolution of these traits, while a sudden loss of photosynthesis leads to unfit plants. We provide explanations for the evolutionary stability of mixotrophic nutrition and for the rarity of emergence of carbon sinks in mycorrhizal networks. More broadly, this may explain what prevents the emergence of fully heterotrophic taxa in the numerous other mixotrophic plant or algal lineages recently described.
Control of mRNA translation adjusts protein production rapidly and facilitates local cellular responses to environmental conditions. Traditionally initiation of translation is considered to be a ...major translational control point, however, control of peptide elongation is also important. Here we show that the function of the elongation factor, eIF5a, is regulated dynamically in naïve CD8
T cells upon activation by post-translational modification, whereupon it facilitates translation of specific subsets of proteins. eIF5a is essential for long-term survival of effector CD8
T cells and sequencing of nascent polypeptides indicates that the production of proteins which regulate proliferation and key effector functions, particularly the production of IFNγ and less acutely TNF production and cytotoxicity, is dependent on the presence of functional eIF5a. Control of translation in multiple immune cell lineages is required to co-ordinate immune responses and these data illustrate that translational elongation contributes to post-transcriptional regulons important for the control of inflammation.
Summary
Background
The Harmonising Outcome Measures for Eczema (HOME) initiative has defined four core outcome domains for a core outcome set (COS) to be measured in all atopic eczema (AE) trials to ...ensure cross‐trial comparison: clinical signs, symptoms, quality of life and long‐term control.
Objectives
The aim of this paper is to report on the consensus process that was used to select the core instrument to consistently assess symptoms in all future AE trials.
Methods
Following the HOME roadmap, two systematic reviews were performed which identified three instruments that had sufficient evidence of validity, reliability and feasibility to be considered for the final COS.
Results
At the fourth international HOME meeting, there was broad consensus among all stakeholders that the Patient‐Oriented Eczema Measure (POEM) should be used as the core instrument (87·5% agreed, 9·4% unsure, 3·1% disagreed).
Conclusions
All relevant stakeholders are encouraged to use POEM as the chosen instrument to measure the core domain of symptoms in all future AE clinical trials. Other instruments of interest can be used in addition to POEM.
What's already known about this topic?
There is insufficient high‐quality evidence for many of the treatments of atopic eczema (AE), which is partly due to the heterogeneity in outcomes used in clinical trials.
The Harmonising Outcome Measures for Eczema initiative defined ‘symptoms’ as one of the core outcome domains that should be measured in AE clinical trials.
What does this study add?
Consensus was reached on the Patient‐Oriented Eczema Measure (POEM) as the core instrument to measure symptoms.
This statement should promote awareness among all stakeholders.
What are the clinical implications of this work?
Not only itch and sleeplessness are symptoms important for patients with AE.
All relevant stakeholders are encouraged to use POEM as the chosen instrument to measure the core domain of symptoms in all future AE clinical trials.
Respond to this article
Linked Comment: Naldi. Br J Dermatol 2017; 176:852–853
Plain language summary available online
Injectable biomimetic hydrogels have great potential for use in regenerative medicine as cellular delivery vectors. However, they can suffer from issues relating to hypoxia, including poor cell ...survival, differentiation, and functional integration owing to the lack of an established vascular network. Here we engineer a hybrid myoglobin:peptide hydrogel that can concomitantly deliver stem cells and oxygen to the brain to support engraftment until vascularisation can occur naturally. We show that this hybrid hydrogel can modulate cell fate specification within progenitor cell grafts, resulting in a significant increase in neuronal differentiation. We find that the addition of myoglobin to the hydrogel results in more extensive innervation within the host tissue from the grafted cells, which is essential for neuronal replacement strategies to ensure functional synaptic connectivity. This approach could result in greater functional integration of stem cell-derived grafts for the treatment of neural injuries and diseases affecting the central and peripheral nervous systems.
High-power lasers that fit into a university-scale laboratory can now reach focused intensities of more than 1019 W cm-2 at high repetition rates. Such lasers are capable of producing beams of ...energetic electrons, protons and γ-rays. Relativistic electrons are generated through the breaking of large-amplitude relativistic plasma waves created in the wake of the laser pulse as it propagates through a plasma, or through a direct interaction between the laser field and the electrons in the plasma. However, the electron beams produced from previous laser-plasma experiments have a large energy spread, limiting their use for potential applications. Here we report high-resolution energy measurements of the electron beams produced from intense laser-plasma interactions, showing that-under particular plasma conditions-it is possible to generate beams of relativistic electrons with low divergence and a small energy spread (less than three per cent). The monoenergetic features were observed in the electron energy spectrum for plasma densities just above a threshold required for breaking of the plasma wave. These features were observed consistently in the electron spectrum, although the energy of the beam was observed to vary from shot to shot. If the issue of energy reproducibility can be addressed, it should be possible to generate ultrashort monoenergetic electron bunches of tunable energy, holding great promise for the future development of 'table-top' particle accelerators.
We present high angular resolution (∼80 mas) ALMA continuum images of the SN 1987A system, together with CO J = 2 1, J = 6 5, and SiO J = 5 4 to J = 7 6 images, which clearly resolve the ejecta (dust ...continuum and molecules) and ring (synchrotron continuum) components. Dust in the ejecta is asymmetric and clumpy, and overall the dust fills the spatial void seen in H images, filling that region with material from heavier elements. The dust clumps generally fill the space where CO J = 6 5 is fainter, tentatively indicating that these dust clumps and CO are locationally and chemically linked. In these regions, carbonaceous dust grains might have formed after dissociation of CO. The dust grains would have cooled by radiation, and subsequent collisions of grains with gas would also cool the gas, suppressing the CO J = 6 5 intensity. The data show a dust peak spatially coincident with the molecular hole seen in previous ALMA CO J = 2 1 and SiO J = 5 4 images. That dust peak, combined with CO and SiO line spectra, suggests that the dust and gas could be at higher temperatures than the surrounding material, though higher density cannot be totally excluded. One of the possibilities is that a compact source provides additional heat at that location. Fits to the far-infrared-millimeter spectral energy distribution give ejecta dust temperatures of 18-23 K. We revise the ejecta dust mass to Mdust = 0.2-0.4 for carbon or silicate grains, or a maximum of <0.7 for a mixture of grain species, using the predicted nucleosynthesis yields as an upper limit.
Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to ...nearly full estrogen suppression in previous studies.
We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II EM-I and EM-II) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.
A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.
Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).
Rapid Arctic climate warming, amplified relative to lower-latitude regions, has led to permafrost thaw and associated thermokarst processes. Recent work has shown permafrost is a rich source of ...ice-nucleating particles (INPs) that can initiate ice formation in supercooled liquid clouds. Since the phase of Arctic clouds strongly affects the surface energy budget, especially over ice-laden surfaces, characterizing INP sources in this region is critical. For the first time, we provide a large-scale survey of potential INP sources in tundra terrain where thermokarst processes are active and relate to INPs in the air. Permafrost, seasonally thawed active layer, ice wedge, vegetation, water, and aerosol samples were collected near Utqiaġvik, Alaska, in late summer and analyzed for their INP contents. Permafrost was confirmed as a rich source of INPs that was enhanced near the coast. Sensitivity to heating revealed differences in INPs from similar sources, such as the permafrost and active layer. Water, vegetation, and ice wedge INPs had the highest heat-labile percentage. The aerosol likely contained a mixture of known and unsurveyed INP types that were inferred as biological. Arctic water bodies were shown to be potential important links of sources to the atmosphere in thermokarst regions. Therefore, a positive relationship found with total organic carbon considering all water bodies gives a mechanism for future parameterization as permafrost continues to thaw and drive regional landscape shifts.
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