Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are a defining feature of ANCA-associated vasculitides (AAV). They play a ...pivotal role in disease pathophysiology and have strongly improved early diagnosis and treatment of these infrequent, but potentially fatal diseases. Neutrophils and their products are major players in initiating the autoimmune response and tissue destruction in vasculitic as well as granulomatous inflammation. This review highlights recent findings on old and novel players (ANCA, neutrophils, neutrophil extracellular traps, fibroblasts, immune cells and complement) and puts them into context with the current understanding of disease mechanisms in AAV.
Advances in communication technologies have made the interaction of small devices, such as smartphones, wearables, and sensors, scattered on the Internet, bringing a whole new set of complex ...applications with ever greater task processing needs. These Internet of things (IoT) devices run on batteries with strict energy restrictions. They tend to offload task processing to remote servers, usually to cloud computing (CC) in datacenters geographically located away from the IoT device. In such a context, this work proposes a dynamic cost model to minimize energy consumption and task processing time for IoT scenarios in mobile edge computing environments. Our approach allows for a detailed cost model, with an algorithm called TEMS that considers energy, time consumed during processing, the cost of data transmission, and energy in idle devices. The task scheduling chooses among cloud or mobile edge computing (MEC) server or local IoT devices to achieve better execution time with lower cost. The simulated environment evaluation saved up to 51.6% energy consumption and improved task completion time up to 86.6%.
Room-temperature ionic liquids are useful as solvents for organic synthesis, electrochemical studies, and separations. We wished to examine whether their high solubalizing power, negligible vapor ...pressure, and broad liquid temperature range are advantageous if they are used as matrixes for UV-MALDI. Several different ionic matrixes were synthesized and tested, using peptides, proteins, and poly(ethylene glycol) (PEG-2000). All ionic liquids tested have excellent solubilizing properties and vacuum stability compared to other commonly used liquid and solid matrixes. However, they varied widely in their ability to produce analyte gas-phase ions. Certain ionic matrixes, however, produce homogeneous solutions of greater vacuum stability, higher ion peak intensity, and equivalent or lower detection limits than currently used solid matrixes. Clearly, ionic liquids and their more amorphous solid analogues merit further investigation as MALDI matrixes.
Protein structures are dynamic and can explore a large conformational landscape
. Only some of these structural substates are important for protein function (such as ligand binding, catalysis and ...regulation)
. How evolution shapes the structural ensemble to optimize a specific function is poorly understood
. One of the constraints on the evolution of proteins is the stability of the folded 'native' state. Despite this, 44% of the human proteome contains intrinsically disordered peptide segments greater than 30 residues in length
, the majority of which have no known function
. Here we show that the entropic force produced by an intrinsically disordered carboxy terminus (ID-tail) shifts the conformational ensemble of human UDP-α-D-glucose-6-dehydrogenase (UGDH) towards a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the intrinsically disordered segment, and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface
. Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of UGDH to favour inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of intrinsic disorder in the proteome.
The German Lung Cancer Screening Intervention Trial (LUSI) is one of the European randomized trials investigating the efficacy of low-dose multislice computed tomography (MSCT) as a screening tool ...for lung cancer. In the evaluation of the first (prevalence) screening round, we observed exceptionally high early recall rates, which made the routine application of MSCT screening questionable. Because screening may behave differently in subsequent (incidence) screening rounds, we analyzed (a) basic characteristics for the annual rounds 2 to 4, which have now also been completed, and (b) the first 3 years with complete follow-up since time of randomization.
Data material was the data record of LUSI after the fourth screening round and the 3-year follow-up had been completed. Basic characteristics of screening, e.g., early recall rate, detection rate, and interval cancers as well of proportion of advanced cancers, were descriptively evaluated and, if informative, group differences were tested for statistical significance.
Early recall rates were significantly lower in the subsequent screening rounds than in the first one if the MSCT information from the previous screening rounds was available. Detection and biopsy rates were approximately 1% or lower, ratio of benign:malignant biopsies: 1:1.6 to 1:3.
Our recent data may not only settle one concern regarding high recall rates in routine MSCT screening but also indicate that screening must be strictly organized to be effective. Performance indicators are similar to those in mammography screening. Nevertheless, possible consequences for the participants (diagnostic workup of suspicious findings, biopsies) are more invasive than in mammography screening.
We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody ...associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV.
Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified.
A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months.
used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender.
Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.
Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients ...exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3–7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.
Significance Glaucoma is a leading cause of blindness, associated with elevated intraocular pressure (IOP) and progressive loss of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit diffuse loss of visual sensitivity, but the cellular origins of such sensitivity loss is unknown. In this study, we present evidence showing that elevated IOP decreases the efficacy of the rod bipolar cell to the AII amacrine cell synapse, resulting in reduction of RGC sensitivity. These findings, for the first time to our knowledge, identify the synaptic loci mediating visual sensitivity loss in early glaucoma, and can be used to develop new diagnostic tools and treatments for this blinding disease.
Objectives: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. Methods: An expert consensus group ...was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. Results: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. Conclusions: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.
Declines in species richness due to fertilization are typically rapid and associated with increases in aboveground production. However, in a long-term experiment examining the impacts of ...fertilization in an early successional community, we found it took 14 years for plant species richness to significantly decline in fertilized plots, despite fertilization causing a rapid increase in aboveground production. To determine what accounted for this lag in the species richness response, we examined several potential mechanisms. We found evidence suggesting the abundance of one functional group–tall species with long-distance (runner) clonality–drove changes in species richness, and we found little support for other mechanisms. Tall runner species initially increased in abundance due to fertilization, then declined dramatically and were not abundant again until later in the experiment, when species richness and the combined biomass of all other functional groups (non-tall runner) declined. Over 86 % of the species found throughout the course of our study are non-tall runner, and there is a strong negative relationship between non-tall runner and tall runner biomass. We therefore suggest that declines in species richness in the fertilized treatment are due to high tall runner abundance that decreases the abundance and richness of non-tall runner species. By identifying the functional group that drives declines in richness due to fertilization, our results help to elucidate how fertilization decreases plant richness and also suggest that declines in richness due to fertilization can be lessened by controlling the abundance of species with a tall runner growth form.
Pain related to many age-related chronic conditions is a burdensome problem in elderly adults and may also interfere with cognitive functioning. The purpose of this study was to examine the ...cross-sectional relationship between measures of pain severity and pain interference and cognitive performance in community-living older adults.
We studied 765 participants in the Maintenance of Balance Independent Living Intellect and Zest (MOBILIZE) Boston Study, a population-based study of persons aged 70 and older. Global pain severity and interference were measured using the Brief Pain Inventory subscales. The neuropsychological battery included measures of attentional capacity (Trail Making Test A, WORLD Test), executive function (Trail Making Test B and Delta, Clock-in-a-Box, Letter Fluency), memory (Hopkins Verbal Learning Test), and a global composite measure of cognitive function. Multivariable linear regression models were used to analyze the relationship between pain and cognitive functioning.
Elderly adults with more severe pain or more pain interference had poorer performance on memory tests and executive functioning compared to elders with none or less pain. Pain interference was also associated with impaired attentional capacity. Additional adjustment for chronic conditions, behaviors, and psychiatric medication resulted in attenuation of many of the observed associations. However, the association between pain interference and general cognitive function persisted.
Our findings point to the need for further research to understand how chronic pain may contribute to decline in cognitive function and to determine strategies that may help in preventing or managing these potential consequences of pain on cognitive function in older adults.
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