Establishing In-House Cutoffs of CSF Alzheimer’s Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort

Background: Clinical diagnosis of Alzheimer’s disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. Methods: We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST^® ELISA and Lumipulse G^® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer’s disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aβ1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aβ1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aβ1-42/Aβ1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). Results: Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing–Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland–Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42/Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan–Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815⁻²⁷). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.     

Arabinoxylan and Pectin Metabolism in Crohn’s Disease Microbiota: An In Silico Study

Inflammatory bowel disease is a chronic disorder including ulcerative colitis and Crohn’s disease (CD). Gut dysbiosis is often associated with CD, and metagenomics allows a better understanding of the microbial communities involved. The objective of this study was to reconstruct in silico carbohydrate metabolic capabilities from metagenome-assembled genomes (MAGs) obtained from healthy and CD individuals. This computational method was developed as a mean to aid rationally designed prebiotic interventions to rebalance CD dysbiosis, with a focus on metabolism of emergent prebiotics derived from arabinoxylan and pectin. Up to 1196 and 1577 MAGs were recovered from CD and healthy people, respectively. MAGs of Akkermansia muciniphila, Barnesiella viscericola DSM 18177 and Paraprevotella xylaniphila YIT 11841 showed a wide range of unique and specific enzymes acting on arabinoxylan and pectin. These glycosidases were also found in MAGs recovered from CD patients. Interestingly, these arabinoxylan and pectin degraders are predicted to exhibit metabolic interactions with other gut microbes reduced in CD. Thus, administration of arabinoxylan and pectin may ameliorate dysbiosis in CD by promoting species with key metabolic functions, capable of cross-feeding other beneficial species. These computational methods may be of special interest for the rational design of prebiotic ingredients targeting at CD.     

Loxin Reduced the Inflammatory Response in the Liver and the Aortic Fatty Streak Formation in Mice Fed with a High-Fat Diet

Oxidized low-density lipoprotein (ox-LDL) is the most harmful form of cholesterol associated with vascular atherosclerosis and hepatic injury, mainly due to inflammatory cell infiltration and subsequent severe tissue injury. Lox-1 is the central ox-LDL receptor expressed in endothelial and immune cells, its activation regulating inflammatory cytokines and chemotactic factor secretion. Recently, a Lox-1 truncated protein isoform lacking the ox-LDL binding domain named LOXIN has been described. We have previously shown that LOXIN overexpression blocked Lox-1-mediated ox-LDL internalization in human endothelial progenitor cells in vitro. However, the functional role of LOXIN in targeting inflammation or tissue injury in vivo remains unknown. In this study, we investigate whether LOXIN modulated the expression of Lox-1 and reduced the inflammatory response in a high-fat-diet mice model. Results indicate that human LOXIN blocks Lox-1 mediated uptake of ox-LDL in H4-II-E-C3 cells. Furthermore, in vivo experiments showed that overexpression of LOXIN reduced both fatty streak lesions in the aorta and inflammation and fibrosis in the liver. These findings were associated with the down-regulation of Lox-1 in endothelial cells. Then, LOXIN prevents hepatic and aortic tissue damage in vivo associated with reduced Lox-1 expression in endothelial cells. We encourage future research to understand better the underlying molecular mechanisms and potential therapeutic use of LOXIN.     

A metaheuristic-based downlink power allocation for LTE/LTE-A cellular deployments

The explosive growth of cellular networks makes their deployment and maintenance more and more complex, time consuming, and expensive. Self-Organizing Networks have been recognized as a promising way to alleviate this problem by minimizing human intervention in such processes. This paper introduces a novel multiobjective framework, based on evolutionary optimization, aiming at improving network performance and users Quality of Service. By tuning the transmitted power at each cell, average intercell interference levels are minimized. The design of the proposed scheme is feasible for distributed implementations in Long Term Evolution (LTE) and LTE-Advanced networks and its operation is compatible with current specifications. The framework is able to provide effective network-specific optimization and obtained results show that gains in terms of network capacity and cell edge performance are 5 and 10 %, respectively. Energy savings always accompanied such enhancements with reductions up to 35 %.     

Characterization of pellets from industrial tomato residues

Large volumes of residual biomass (mainly peels and seeds) are generated by tomato industrial processing plants. After adequate drying and densification operations, those biomass wastes might be used for livestock food production, for lycopene extraction or even as fuel supply for thermal applications.The process described in the present paper is the manufacturing of 6 mm diameter pellets from tomato waste samples obtained from industrial processing plants. As a previous step, the samples were dehydrated to five different values of moisture content (20, 25, 29, 34 and 38 wt% w.b. approximately). Bulk and particle densities, hardness and durability of pellets were significantly influenced by the initial moisture content of the biomass raw materials, as well as by the subsequent reductions of such moisture content after pelletizing operations and storage periods. Increases of 21%, 41% and 67% in moisture content of the feeding biomass material – with respect to the lower value of the operating range, i.e. 20 wt% w.b. – were observed to yield the following percentage increments in a series of physical properties of pellets, respectively: 14%, 25% and 50% in bulk density; 6%, 16% and 18% in particle density; 225%, 1737% and 3575% in hardness; 8%, 44% and 88% in durability. Nevertheless, higher increments in moisture content of feeding material led to significantly lower values of the aforementioned properties – not to mention technical operating problems due to roller skidding in the pelletizing device.Pellets obtained from raw biomass (peels and seeds) with 34 wt% initial moisture content (9% final moisture content of pellets) were regarded as those with the most suitable configuration: durability 91.2%, hardness up to 88 N and energy density approaching 8 GJ/m³.     

An energy efficient middleware for an ad-hoc AAL wireless sensor network

DIA (Dispositivo Inteligente de Alarma, in Spanish) is an AAL (Ambient Assisted Living) system that allows to infer a potential dangerous action of an elderly person living alone at home. This inference is obtained by a specific sensorisation with sensor nodes (portables and fixes) and a reasoning layer embedded in a PC that learns of the users behaviour patterns and advices when actual one differs significantly of the normal patterns. In AAL systems, energy is a limited resource therefore sensor devices need to be properly managed to conserve energy. In this paper, we introduce the design and implementation of innovative and specific mechanisms at the sensory layer middleware which is capable of, first to discriminate spurious motion detections assuming that these signals do not resemble the patterns of real motion detections and, second to reduce the dynamics of messages by a sensor signal processing in order to compress the whole information in one single event. The middleware achieves power saving by modifying the raw information from sensors and adapting it to the predefined semantic of the reasoning layer. It manages the important task of data processing from sensors (raw information), and transfers the pre-processed information into the top layer of reasoning in a more energy efficient way. We also address the trade-off between reducing power consumption and reducing delay for incoming data. We present results from experiments using our implementation of these mechanisms at the middleware that comprises from node firmware to the PC driver. The number of messages of the proposed method with respect to the raw data is reduced by approximately 98.5%. The resources used in the PIR signal processing is reduced by approximately 85%. The resulting delay introduced is small (10–19 s) but system dynamics is slow enough to avoid contextualisation errors or reduction of system performance. We consider these results as very satisfactory.