Identification of diagnostic biomarkers in Alzheimer’s disease by integrated bioinformatic analysis and machine learning strategies

BackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia, and is becoming one of the most burdening and lethal diseases. More useful biomarkers for diagnosing AD and reflecting the disease progression are in need and of significance.MethodsThe integrated bioinformatic analysis combined with machine-learning strategies was applied for exploring crucial functional pathways and identifying diagnostic biomarkers of AD. Four datasets (GSE5281, GSE131617, GSE48350, and GSE84422) with samples of AD frontal cortex are integrated as experimental datasets, and another two datasets (GSE33000 and GSE44772) with samples of AD frontal cortex were used to perform validation analyses. Functional Correlation enrichment analyses were conducted based on Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Reactome database to reveal AD-associated biological functions and key pathways. Four models were employed to screen the potential diagnostic biomarkers, including one bioinformatic analysis of Weighted gene co-expression network analysis (WGCNA)and three machine-learning algorithms: Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) analysis. The correlation analysis was performed to explore the correlation between the identified biomarkers with CDR scores and Braak staging.ResultsThe pathways of the immune response and oxidative stress were identified as playing a crucial role during AD. Thioredoxin interacting protein (TXNIP), early growth response 1 (EGR1), and insulin-like growth factor binding protein 5 (IGFBP5) were screened as diagnostic markers of AD. The diagnostic efficacy of TXNIP, EGR1, and IGFBP5 was validated with corresponding AUCs of 0.857, 0.888, and 0.856 in dataset GSE33000, 0.867, 0.909, and 0.841 in dataset GSE44770. And the AUCs of the combination of these three biomarkers as a diagnostic tool for AD were 0.954 and 0.938 in the two verification datasets.ConclusionThe pathways of immune response and oxidative stress can play a crucial role in the pathogenesis of AD. TXNIP, EGR1, and IGFBP5 are useful biomarkers for diagnosing AD and their mRNA level may reflect the development of the disease by correlation with the CDR scores and Breaking staging

Cannabinoids help to unravel etiological aspects in common and bring hope for the treatment of autism and epilepsy

Desde 1843 que as propriedades anticonvulsivantes da Cannabis são conhecidas pela ciência ocidental. Em 1980, ensaios clínicos demonstraram que canabidiol possui atividade antiepilética em pacientes de epilepsia refratária, sendo sonolência o único efeito colateral. O embargo imposto pela proibição do uso medicinal da Cannabis, no entanto, prejudicou imensamente o desenvolvimento científico e a exploração dessas propriedades. Multiplicam-se, contudo, os casos bem sucedidos de uso ilegal e sem orientação para o tratamento de síndromes caracterizadas por epilepsia e autismo regressivo. Os resultados corroboram evidências científicas que indicam a existência de processos etiológicos comuns entre o autismo e a epilepsia. Estudos em modelos animais confirmam envolvimento do sistema endocanabinoide. Esses avanços apontam o início de uma revolução no entendimento e tratamento desses transtornos.Since 1843 the anticonvulsant properties of Cannabis are known by the Western science. In 1980, clinical trials have shown that cannabidiol has antiepileptic activity in refractory epilepsy patients, with drowsiness as the only side effect. The embargo imposed by banning medicinal Cannabis use, however, harmed scientific development and the exploration of these properties. However, there is a growing number of successful cases of illegal use without guidance for the treatment of syndromes characterized by epilepsy and regressive autism. The results corroborate scientific evidence that indicates the existence of common etiological aspects between autism and epilepsy. Studies in animal models have confirmed involvement of the endocannabinoid system. These advances indicate the beginning of a revolution in the understanding and treatment of these disorders

Kenya: West Kenya postmarks

HiWATER: The Multi-Scale Observation Experiment on Evapotranspiration over heterogeneous land surfaces (MUSOEXE) Dataset - Flux Observation Matrix (stable isotopic observations

The time-depth of Corded Ware burial landscapes: A comparative study of Single Grave and Battle Axe burial alignments in Denmark, The Netherlands and Sweden

Barrow landscapes appeared in the third and second millennia BC throughout North-Western Europe; these first barrows were constructed by people of the Corded Ware culture and placed in alignments. This thesis is an interregional comparative study, to determine whether there is a pattern in the time-depths of the burial alignments of Trehuse-Sjørup-Dollerup in Denmark, Angelso-Emmerhout in The Netherlands and Lilla Beddinge in Sweden. The analysis is conducted by means of a literature study and the application of typochronologies. In recent research, the Corded Ware ‘culture’ is still seen as a widespread, unified social phenomenon that is the result of migration, but more emphasis is placed on the regional variability of this phenomenon. Regional variability is also what we see in the three case-studies; in fact, perhaps one may better speak of ‘local variability’, as each case-study reveals a remarkable variety even within one alignment. Even though there do seem to be interregionally shared traits, these are expressed in local practices. Despite the limitations of establishing a time-depth by means of typochronologies, all three alignments reveal a long use-life; even in the Bronze and Iron Ages, prehistoric people buried their dead here. Temporality seems to have been an important aspect of the ‘Corded Ware’ burial landscape

Collaborative mental health care : changing the landscape of mental health care?

In this thesis two major changes in the organization of mental health care delivery are explored. The first is collaborative mental health care in primary care, developed as an alternative way to treat common mental health disorders compared to the traditional referral and treatment practice. The collaborative care program followed the principles of stepped care. The first and least intensive treatment step was provided within the collaborative care program in the primary care setting. Treatment intensity was only stepped up through referral to specialized mental health care for patients who did not sufficiently respond to the first step. The traditional practice was direct referral and treatment within specialized care. In several studies we investigated effectiveness, short- and long-term efficiency, cost-effectiveness and whether the stepped care approach was appropriate for all patients instead of the matched care approach. The second change was the integration of eHealth in the collaborative care treatment model. In this study, implementation factors that could either inhibit or promote the uptake and utilization of blended collaborative care by mental health professionals and patients were assessed

Simultaneous Quantification of γ-Hydroxybutyrate, γ-Butyrolactone, and 1,4-Butanediol in Four Kinds of Beverages

γ-Hydroxybutyrate (GHB) is a neurotransmitter, which exhibits a strong central nervous system depressant effect. The abuse of GHB or its precursor substances (γ-butyrolactone (GBL) and 1,4-butanediol (1,4-BD)) may cause serious problems. This study developed a fast and effective UHPLC-MS/MS method for the simultaneous quantification of GHB, GBL, and 1,4-BD in four popular beverages, including carbonated drinks, tea, apple cider vinegar, and coffee. The established method overcomes the influence of the in-source collision-induced dissociation of unstable compounds during quantification. The limits of detection were 0.2 μg/mL for GBL and 0.5 μg/mL for GHB and 1,4-BD with excellent linearity in the range of 0.2–50 μg/mL. The recoveries of the three compounds at three spiked levels (2.5, 5.0, and 10.0 μg/mL) in the four kinds of beverages studied were between 90 and 110%, while the relative standard deviations (RSDs) were all <10%. The matrix effect was negligible using this simple and appropriate preprocessed procedure. The method established in this study can quickly and reliably detect the GHB content and its analogues in beverages

Analytical study on abnormal change in time-variable gravity at Yichang seismostation before the M5.1 Badong earthquake

An M5.1 earthquake occurred in Badong County, only 66 km from the Three Gorges Dam, on December 16, 2013. The continuous gravity observation data obtained at Yichang seismostation nearest to the epicenter (96 km) were analyzed, and it was found that the continuous gravity observation data obtained in this rainy season did not exhibit a characteristic of seasonal change in gravity identical to that in the past years, and thereafter the M5.1 Badong earthquake occurred. Numerical simulation revealed that the water storage and discharge of the Three Gorges reservoir generated seasonal change in gravity, and the changes in atmospheric pressure and gravity load were not the main sources of the seasonal change of continuous gravity observation data whether in respect of magnitude or phase and did not have obvious breaking change on annual variation before the earthquake. Through analysis of the seasonal change data observed on the same site including cavern temperature, rainfall data and global terrestrial water model (CPC) simulated water load, it was thought that, in the observation room with cavern temperature change of only −0.11 °C/a at Yichang seismostation, the seasonal change of continuous gravity observation result mainly originated from the seasonal change in rainfall. In the case that the changes in rainfall and its water load did not have evident breaking change on annual variation law before the earthquake, if the M5.1 Badong earthquake was the cause of the breaking change on annual variation law in Yichang this time, then it was believed through analysis of crust expansion ratio that similar anomaly should occur at a crust expansion and compression intersection, no more than 100 km away from the epicenter

A Strategy for Sample Preparation: Using Egg White Gel to Promote the Determination of Aflatoxin M1 Content in Milk Samples

The analysis of food samples is a challenging task. The high complexity of food matrices hinders the extraction and detection of analytes from them. Therefore, the correct preparation of food samples is a crucial step for their subsequent analysis, as it achieves the proper isolation and preconcentration of analytes and removes the interfering proportion of the food matrix before instrumental analysis. We aimed to develop a method that not only satisfies the requirement of detecting trace compounds in complex matrices but also achieves a “greener” approach by reducing the use of organic solvents and non-degradable materials to minimize the health hazards posed to the operators as well as pollution to the environment. In this study, we prepared egg white as a concentrated gel and used this material for the biological purification of milk samples. After the milk protein was removed by acidification and salting, the residual amount of aflatoxin M1 in milk samples was quantitatively determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The results showed that the novel egg white purification method possessed advantages over the immunoaffinity technique used as the reference method in extraction recovery, sensitivity, repeatability, and operability. The limit of detection (LOD) was 0.001 μg/kg. In spiked samples containing 0.01 μg/kg to 2 μg/kg of AFM1, the average recovery was 88.3–94.7%, with a precision of 6.1–11.0%. Improved repeatability was obtained by significantly reducing the operation time and resource requirements compared with the immunoaffinity technique currently used internationally. This study provides a reference for the further improvement of the relevant international standards in place for the detection of aflatoxin M1 in milk

Effective thermal control techniques for liquid-cooled 3D multi-core processors

Microchannel liquid cooling shows great potential in cooling 3D processors. However, the cooling of 3D processors is limited due to design-time and run-time challenges. Moreover, in new technologies, the processor power density is continually increasing and this will bring more serious challenges to liquid cooling. In this paper, we propose two thermal control techniques: 1) Core Vertically Placed (CVP) technique. According to the architecture of a processor core, two schemes are given for placing a core vertically onto multilayers. The 3D processor with the CVP technique can be better cooled since its separate hotspot blocks have a larger total contact area with the cooler surroundings. 2) Thermoelectric cooling (TEC) technique. We propose to incorporate the TEC technique into the liquid-cooled 3D processor to enhance the cooling of hotspots. Our experiments show the CVP technique reduces the maximum temperature up to 29.58 °C, and 16.64 °C on average compared with the baseline design. Moreover, the TEC technique effectively cools down a hotspot from 96.86 °C to 78.60 °C. © 2013 IEEE