The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants' effect on gene ...expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.
Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring ...their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including an Alu insertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk.
Globally, urbanization constitutes one of the major underlying drivers of global ecological degradation. Hence, deurbanization, i.e., demographic shift from urban to distant rural areas in a way that ...increases quality of life (QoL), can be one of the key pathways to address this global challenge. In this study, we investigated the contribution of nature and other types of rural capital to QoL and to people’s decision to migrate from urban to rural areas by studying residents in Hokuto City, a popular urban-to-rural migration destination in Japan. An integrated analysis of the 414 responses to a questionnaire survey and open and commercial geospatial datasets representing natural, built, human, cultural, and financial capital revealed the contributions of specific elements of rural capital to people’s QoL. These included natural capital (farmland, symbolic natural sites, mountain peak view, lower temperature, and tranquility), built capital (highways, railway stations, shops, and restaurants), and financial capital (employment). Many of these are related to the reasons that migrants, including return and one-way migrants, chose their present home location in Hokuto City, indicating their intention to increase QoL by migration. Particularly, one-way migrant homes were located predominantly on higher up mountain slopes with lower temperatures, higher forest cover, near natural parks, and symbolic natural sites, and yet with easier access to railway stations and employment. These results provide a valuable evidence base for rural spatial planning for increased QoL and attracting migrants that considers ecological–social feedbacks, and hence supports deurbanization.
Abstract
The initial electrical properties of tantalum oxide resistive memory were investigated using four metal electrodes (TiN, Ti, Ta, and Al) and two kinds of tantalum oxide with different ...amounts of intrinsic oxygen vacancies. The initial resistance depended on the electrode material. This indicated that oxygen scavenging by the electrodes contributed to a reduction in the resistance. However, the resistance change depended on the intrinsic oxygen vacancy concentration introduced during the tantalum oxide deposition. The forming voltage also depended on the electrode metal. For the device with an Al electrode, a clear aluminum oxide layer was identified at the electrode–insulator interface, which was hypothesized to be the origin of the high forming voltage. All factors concerning the oxygen vacancies, i.e. intrinsic vacancies introduced via film deposition and extrinsic vacancies caused by the electrode scavenging effect, influenced the initial state of tantalum oxide, and thus, its switching performance as a resistive memory.
Acute kidney injury (AKI), with an increase in serum creatinine, is a common adverse drug event. Although various clinical studies have investigated whether a combination of two nephrotoxic drugs has ...an increased risk of AKI using traditional statistical models such as multivariable logistic regression (MLR), the evaluation metrics have not been evaluated despite the fact that traditional statistical models may over-fit the data. The aim of the present study was to detect drug-drug interactions with an increased risk of AKI by interpreting machine-learning models to avoid overfitting.
We developed six machine-learning models trained using electronic medical records: MLR, logistic least absolute shrinkage and selection operator regression (LLR), random forest, extreme gradient boosting (XGB) tree, and two support vector machine models (kernel = linear function and radial basis function). In order to detect drug-drug interactions, the XGB and LLR models that showed good predictive performance were interpreted by SHapley Additive exPlanations (SHAP) and relative excess risk due to interaction (RERI), respectively.
Among approximately 2.5 million patients, 65,667 patients were extracted from the electronic medical records, and assigned to case (
= 5,319) and control (
= 60,348) groups. In the XGB model, a combination of loop diuretic and histamine H
blocker mean (|SHAP|) = 0.011 was identified as a relatively important risk factor for AKI. The combination of loop diuretic and H
blocker showed a significant synergistic interaction on an additive scale (RERI 1.289, 95% confidence interval 0.226-5.591) also in the LLR model.
The present population-based case-control study using interpretable machine-learning models suggested that although the relative importance of the individual and combined effects of loop diuretics and H
blockers is lower than that of well-known risk factors such as older age and sex, concomitant use of a loop diuretic and histamine H
blocker is associated with increased risk of AKI.
Current enhancement without increasing the input power is a critical issue to be pursued for electronic circuits. However, drivability of metal-oxide-semiconductor (MOS) transistors is limited by the ...source-injection current, and electrons that have passed through the source unavoidably waste their momentum to the phonon bath. Here, we propose the Si electron-aspirator, a nanometer-scaled MOS device with a T-shaped branch, to go beyond this limit. The device utilizes the hydrodynamic nature of electrons due to the electron-electron scattering, by which the injected hot electrons transfer their momentum to cold electrons before they relax with the phonon bath. This momentum transfer induces an electron flow from the grounded side terminal without additional power sources. The operation is demonstrated by observing the output-current enhancement by a factor of about 3 at 8 K, which reveals that the electron-electron scattering can govern the electron transport in nanometer-scaled MOS devices, and increase their effective drivability.
Pharmacoepidemiology is the study of the utilization and effects of drugs in clinical and population settings, and the outcomes of drug therapy. The growing trend of recording computerized data that ...will increasingly be automated into health care delivery is making the use of large datasets more and more common in pharmacoepidemiologic research. Most retrospective databases offer large populations and longer observation periods with real-world practice and can answer a variety of research questions quickly and cost-effectively. Observational studies, specifically using large databases, can complement findings from randomized clinical trials (RCTs) by assessing treatment effectiveness in patients encountered in daily clinical practice, although they are more exposed to bias and certainly are lower on the hierarchy of evidence than RCTs. Furthermore, careful defining of the research question with appropriate design and application of advanced statistical techniques, e.g., propensity-score analysis or marginal structural models, can yield findings with validity and improve causal inference of treatment effects. Some existing guidelines for comparative effectiveness help decision makers to evaluate the quality of observational studies comparing the effectiveness of various medical products and services. Thus, the trend for utilization of databases for pharmacoepidemiology will continue to grow in coming years.
Switching of Cu/MoOx/TiN CBRAM at MoOx/TiN interface Arita, Masashi; Ohno, Yuuki; Takahashi, Yasuo
Physica status solidi. A, Applications and materials science,
February 2016, Letnik:
213, Številka:
2
Journal Article
Recenzirano
Odprti dostop
For dynamical observation of CBRAM microstructure, in situ transmission electron microscopy (in situ TEM) was performed on Cu/MoOx/TiN during the resistive switching. It was confirmed that the local ...area near the MoOx/TiN interface contributes to resistive switching. The Cu deposit at the bottom of the MoOx layer swelled into the oxidized thin layer of the TiN bottom electrode, and a thin filament of 3–5 nm diameter was formed in the Set process. The reversal change was seen in the Reset process. On increasing the switching power, a microstructural change in the MoOx layer was also seen, and the CBRAM film was finally destroyed.
Drug-induced liver injury (DILI) is a common adverse drug reaction, with abnormal elevation of serum alanine aminotransferase (ALT). Several clinical studies have investigated whether a combination ...of two drugs alters the reporting frequency of DILI using traditional statistical methods such as multiple logistic regression (MLR), but this model may over-fit the data. This study aimed to detect a synergistic interaction between two drugs on the risk of abnormal elevation of serum ALT in Japanese adult patients using three machine-learning algorithms: MLR, logistic least absolute shrinkage and selection operator (LASSO) regression, and extreme gradient boosting (XGBoost) algorithms. A total of 58,413 patients were extracted from Nihon University School of Medicine’s Clinical Data Warehouse and assigned to case (
N
= 4,152) and control (
N
= 54,261) groups. The MLR model over-fitted a training set. In the logistic LASSO regression model, three combinations showed relative excess risk due to interaction (RERI) for abnormal elevation of serum ALT: diclofenac and famotidine (RERI 2.427, 95% bootstrap confidence interval 1.226–11.003), acetaminophen and ambroxol (0.540, 0.087–4.625), and aspirin and cilostazol (0.188, 0.135–3.010). Moreover, diclofenac (adjusted odds ratio 1.319, 95% bootstrap confidence interval 1.189–2.821) and famotidine (1.643, 1.332–2.071) individually affected the risk of abnormal elevation of serum ALT. In the XGBoost model, not only the individual effects of diclofenac (feature importance 0.004) and famotidine (0.016), but also the interaction term (0.004) was included in important predictors. Although further study is needed, the combination of diclofenac and famotidine appears to increase the risk of abnormal elevation of serum ALT in the real world.
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