Miracle-dz/UniFAR-FTUs huggingface dataset:
Powerful Cocktail Methods for Detecting Genome‐Wide Gene‐Environment Interaction

Identifying gene and environment interaction (G × E) can provide insights into biological networks of complex diseases, identify novel genes that act synergistically with environmental factors, and inform risk prediction. However, despite the fact that hundreds of novel disease‐associated loci have been identified from genome‐wide association studies (GWAS), few G × Es have been discovered. One reason is that most studies are underpowered for detecting these interactions. Several new methods have been proposed to improve power for G × E analysis, but performance varies with scenario. In this article, we present a module‐based approach to integrating various methods that exploits each method's most appealing aspects. There are three modules in our approach: (1) a screening module for prioritizing Single Nucleotide Polymorphisms (SNPs); (2) a multiple comparison module for testing G × E; and (3) a G × E testing module. We combine all three of these modules and develop two novel “cocktail” methods. We demonstrate that the proposed cocktail methods maintain the type I error, and that the power tracks well with the best existing methods, despite that the best methods may be different under various scenarios and interaction models. For GWAS, where the true interaction models are unknown, methods like our “cocktail” methods that are powerful under a wide range of situations are particularly appealing. Broadly speaking, the modular approach is conceptually straightforward and computationally simple. It builds on common test statistics and is easily implemented without additional computational efforts. It also allows for an easy incorporation of new methods as they are developed. Our work provides a comprehensive and powerful tool for devising effective strategies for genome‐wide detection of gene‐environment interactions.
Mereotopological reasoning about parts and (w)holes in bio-ontologies

We here deal with mereotopological properties of parts andassociated wholes, locations and empty spaces (holes), withparticular reference to biological structures. Our considerationslead to a basic ontology which contains 'solid object', 'hole' and'boundary' as mutually disjoint primitives. Formally, we embed therelations 'part-of' and 'location-of' into a parsimoniousdescription logic (ALC) and emulate partonomic and spatialreasoning involving these relations by terminological subsumption.In contrast to common conceptualizations, we do not distinguishbetween solids and the regions they occupy, as well as we allowsolids to have holes as proper parts. In order to support thesemodeling decisions, we discuss various concrete examples from humananatomy.
Association of plasma free fatty acids and left ventricular diastolic function in patients with clinically severe obesity.

BACKGROUND Obesity is an important contributor to many cardiovascular risk factors and has been associated with abnormalities in cardiac contractile function. Causes of impaired contractile function are not fully understood and may include an oversupply of substrates. OBJECTIVE We tested the hypothesis that metabolic dysregulation may adversely influence cardiac function. Specifically, we examined the effects of plasma free fatty acids and insulin sensitivity on left ventricular function in patients with clinically severe obesity. DESIGN We measured metabolic and cardiac variables in 64 obese patients [body mass index (BMI; in kg/m(2)) > 35], including 2-D complete echocardiogram with M-mode and tissue Doppler imaging, anthropometric measurements, and analysis of blood chemistries. RESULTS The median (25th and 75th percentile) age and BMI were 46 y (36, 53 y) and 51.5 (42.5, 56.5), respectively. The prevalence of diabetes, hypertension, and insulin resistance were 38%, 53%, and 90%, respectively. Plasma free fatty acid (FFA) concentrations were elevated in the cohort. No association was observed between insulin sensitivity or anthropometric measurements and left ventricular contractile function. However, FFA concentration was independently associated with diastolic function (r = -0.33, P = 0.01), and 40% of the cohort showed age-adjusted diastolic impairment as measured by tissue Doppler imaging. CONCLUSION The negative association between FFA and diastolic function, in the setting of insulin resistance, suggests that excess FFA may exert a lipotoxic effect on the heart.
Sex and menopausal status influence human dietary requirements for the nutrient choline.

BACKGROUND Although humans require dietary choline for methyl donation, membrane function, and neurotransmission, choline can also be derived from the de novo synthesis of phosphatidylcholine, which is up-regulated by estrogen. A recommended Adequate Intake (AI) exists for choline; however, an Estimated Average Requirement has not been set because of a lack of sufficient human data. OBJECTIVE The objective of the study was to evaluate the dietary requirements for choline in healthy men and women and to investigate the clinical sequelae of choline deficiency. DESIGN Fifty-seven adult subjects (26 men, 16 premenopausal women, 15 postmenopausal women) were fed a diet containing 550 mg choline x 70 kg(-1) x d(-1) for 10 d followed by <50 mg choline x 70 kg(-1) x d(-1) with or without a folic acid supplement (400 microg/d per randomization) for up to 42 d. Subjects who developed organ dysfunction during this diet had normal organ function restored after incremental amounts of choline were added back to the diet. Blood and urine were monitored for signs of toxicity and metabolite concentrations, and liver fat was assessed by using magnetic resonance imaging. RESULTS When deprived of dietary choline, 77% of men and 80% of postmenopausal women developed fatty liver or muscle damage, whereas only 44% of premenopausal women developed such signs of organ dysfunction. Moreover, 6 men developed these signs while consuming 550 mg choline x 70 kg(-1) x d(-1), the AI for choline. Folic acid supplementation did not alter the subjects' response. CONCLUSION Subject characteristics (eg, menopausal status) modulated the dietary requirement for choline, and a daily intake at the current AI was not sufficient to prevent organ dysfunction in 19 of the subjects.
MKLN1 splicing defect in dogs with lethal acrodermatitis

Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.
Reminiscence in Everyday Conversations: A Naturalistic Observation Study of Older Adults.

OBJECTIVES We examined older adults' social reminiscence behavior in everyday life, and the relation between reminiscence functions and well-being. METHOD The sample included 2,164 sound snippets that included speech from 45 healthy older adults. We examined reminiscence in daily conversations using the Electronically Activated Recorder. Across four days, we collected a random sample of about 280 sound files (30 seconds long) per participant. Participants' utterances were coded for whether they included reminiscence, for their functions and conversation partners. Participants completed mood and life satisfaction measures. RESULTS Participants reminisced in 5% of their utterances (range: 0%-29%). They reminisced in 40% of cases with friends, 32.8% with their partner and 8% with their children/relatives. Three reminiscence functions were observed: identity, teaching/informing, and conversation. Participants' reminiscence served the identity function while they were reminiscing with their partner and children. Participants reminisced to teach/inform while reminiscing with their children and strangers. Reminiscing for conversation occurred mainly with partner and friends. We found positive relations between life satisfaction and identity, teach/inform, and conversation functions. Mood had a negative relation with identity and teach/inform functions. DISCUSSION This is the first study to take a naturalistic observation approach to reminiscence and to build on self-report data.
Degradation of phytic acid in cereal porridges improves iron absorption by human subjects.

BACKGROUND Phytic acid in cereal-based and legume-based complementary foods inhibits iron absorption. Low iron absorption from cereal porridges contributes to the high prevalence of iron deficiency in infants from developing countries. OBJECTIVE The objective was to measure the influence of phytic acid degradation on iron absorption from cereal porridges. DESIGN An exogenous phytase was used to fully degrade phytic acid during the manufacture of 9 roller-dried complementary foods based on rice, wheat, maize, oat, sorghum, and a wheat-soy blend. Iron absorption from the phytate-free and native phytate porridges prepared with water or milk (wheat only) was measured in adult humans with an extrinsic-label radioiron technique. Ascorbic acid was added to some porridges. RESULTS When the foods were reconstituted with water, dephytinization increased iron absorption from rice porridge from 1.73% to 5.34% (P < 0.001), from oat from 0.33% to 2.79% (P < 0.0001), from maize from 1.80% to 8.92% (P < 0.0001), from wheat from 0.99% to 11.54% (P < 0.0001), from the wheat-soy blend without ascorbic acid from 1.15% to 3.75% (P < 0.005), and from the wheat-soy blend with ascorbic acid from 2.40% to 8.46% (P < 0.005). Reconstituting wheat porridge with milk instead of water markedly decreased or completely removed the enhancing effect of dephytinization on iron absorption in the presence and absence of ascorbic acid. Dephytinization did not increase iron absorption from high-tannin sorghum porridge reconstituted with water but increased iron absorption from low-tannin sorghum porridge by approximately 2-fold (P < 0.01). CONCLUSIONS Phytate degradation improves iron absorption from cereal porridges prepared with water but not with milk, except from high-tannin sorghum.
Laser-based 3D cell printing for tissue engineering

Abstract Currently, different 3D printing techniques are investigated for printing biomaterials and living cells. An ambitious aim is the printing of fully functional tissue or organs. Furthermore, for manifold applications in biomedical research and in testing of pharmaceuticals or cosmetics, printed tissue could be a new method, partly substituting test animals. Here we describe a laser-based printing technique applied for the arrangement of vital cells in two and three-dimensional patterns and for tissue engineering. First printed tissue, tested in vitro and in vivo, and printing of cell patterns for investigating cell-cell interactions are presented.
Genetic variants linked to education predict longevity

Significance Individuals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including >130,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents; compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity. Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members’ polygenic profile score for education to predict their parents’ longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼2.4% lower risk for fathers (total ndeaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.
Proof-Relevant Logical Relations for Name Generation

Pitts and Stark’s ν-calculus is a paradigmatic total language for studying the problem of contextual equivalence in higher-order languages with name generation. Models for the ν-calculus that validate basic equivalences concerning names may be constructed using functor categories or nominal sets, with a dynamic allocation monad used to model computations that may allocate fresh names. If recursion is added to the language and one attempts to adapt the models from (nominal) sets to (nominal) domains, however, the direct-style construction of the allocation monad no longer works. This issue has previously been addressed by using a monad that combines dynamic allocation with continuations, at some cost to abstraction.
Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration, and survival in many cell types. Here, the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: noninvasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt, and metM-Wntliver cells, 12, 29, and 25 metabolites, respectively, were significantly different (P < 0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration, and invasion occurred in M-Wnt and metM-Wntliver cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype. Implications: Metabolic reprogramming driven by folate restriction represents a therapeutic target for reducing the burden of breast cancer. Mol Cancer Res; 15(2); 189–200. ©2016 AACR.
Systematic Reviews andMeta-and Pooled Analyses Leukocyte Telomere Length andAll-Cause , Cardiovascular Disease , and Cancer Mortality : Results From Individual-Participant-Data Meta-Analysis of 2 Large Prospective Cohort Studies

We studied the associations of leukocyte telomere length (LTL) with all-cause, cardiovascular disease, and cancer mortality in 12,199 adults participating in 2 population-based prospective cohort studies from Europe (ESTHER) and the United States (Nurses’ Health Study). Blood samples were collected in 1989–1990 (Nurses’ Health Study) and 2000–2002 (ESTHER). LTL was measured by quantitative polymerase chain reaction. We calculated z scores for LTL to standardize LTL measurements across the cohorts. Cox proportional hazards regression models were used to calculate relative mortality according to continuous levels and quintiles of LTL z scores. The hazard ratios obtained from each cohort were subsequently pooled by meta-analysis. Overall, 2,882 deaths were recorded during follow-up (Nurses’ Health Study, 1989–2010; ESTHER, 2000–2015). LTL was inversely associated with age in both cohorts. After adjustment for age, a significant inverse trend of LTL with all-cause mortality was observed in both cohorts. In random-effects meta-analysis, age-adjusted hazard ratios for the shortest LTL quintile compared with the longest were 1.23 (95% confidence interval (CI): 1.04, 1.46) for all-cause mortality, 1.29 (95% CI: 0.83, 2.00) for cardiovascular mortality, and 1.10 (95% CI: 0.88, 1.37) for cancer mortality. In this study population with an age range of 43–75 years, we corroborated previous evidence suggesting that LTL predicts all-causemortality beyond its association with age.
BioTop: An upper domain ontology for the life sciencesA description of its current structure, contents and interfaces to OBO ontologies

In the life sciences, there is an ample need for semantic interoperability of data. Thus shared vocabularies are needed for consistently expressing metadata in terms of semantic annotations as well as for querying bibliographic information systems. In the past years, lots of highly specialized, yet also fragmented terminologies have evolved. However, they lack principled forms of conceptual interlinkage. In order to provide an ontological basis for a seamless integration of such isolated parts of biological knowledge, we here introduce BioTop, an upper domain ontology for molecular biology. We describe its structure and contents, as well as its current interfaces to a selected set of OBO ontologies, which contain more detailed terminological knowledge about specific areas of molecular biology, e.g., cell types, molecular functions, biological processes and chemical compounds.
Reward deficits in behavioural variant frontotemporal dementia include insensitivity to negative stimuli

During reward processing individuals weigh positive and negative features of a stimulus to determine whether they will pursue or avoid it. Though patients with behavioural variant frontotemporal dementia display changes in their pursuit of rewards, such as food, alcohol, money, and sex, the basis for these shifts is not clearly established. In particular, it is unknown whether patients' behaviour results from excessive focus on rewards, insensitivity to punishment, or to dysfunction in a particular stage of reward processing, such as anticipation, consumption, or action selection. Our goal was to determine the nature of the reward deficit in behavioural variant frontotemporal dementia and its underlying anatomy. We devised a series of tasks involving pleasant, unpleasant, and neutral olfactory stimuli, designed to separate distinct phases of reward processing. In a group of 25 patients with behavioural variant frontotemporal dementia and 21 control subjects, diagnosis by valence interactions revealed that patients with behavioural variant frontotemporal dementia rated unpleasant odours as less aversive than did controls and displayed lower skin conductance responses when anticipating an upcoming aversive odour. Subjective pleasantness ratings and skin conductance responses did not differ between behavioural variant frontotemporal dementia and controls for pleasant or neutral smells. In a task designed to measure the effort subjects would expend to smell or avoid smelling a stimulus, patients with behavioural variant frontotemporal dementia were less motivated, and therefore less successful than control subjects, at avoiding what they preferred not to smell, but had equivalent success at obtaining stimuli they found rewarding. Voxel-based morphometry of patients with behavioural variant frontotemporal dementia revealed that the inability to subjectively differentiate the valence of pleasant and unpleasant odours correlated with atrophy in right ventral mid-insula and right amygdala. High pleasantness ratings of unpleasant stimuli correlated with left dorsal anterior insula and frontal pole atrophy. These findings indicate that insensitivity to negative information may be a key component of the reward-seeking behaviours in behavioural variant frontotemporal dementia, and may relate to degeneration of structures that are involved in representing the emotional salience of sensory information.
Victim Disk First: An Asymmetric Cache to Boost the Performance of Disk Arrays under Faulty Conditions

The buffer cache plays an essential role in smoothing the gap between the upper-level computational components and the lower-level storage devices. A good buffer cache management scheme should be beneficial to not only the computational components, but also to the storage components by reducing disk I/Os. Existing cache replacement algorithms are well optimized for disks in normal mode, but inefficient under faulty scenarios, such as a parity-based disk array with faulty disk(s). To address this issue, we propose a novel asymmetric buffer cache replacement strategy, named Victim (or faulty) Disk(s) First (VDF) cache, to improve the reliability and performance of a storage system consisting of a buffer cache and disk arrays. The basic idea is to give higher priority to cache the blocks on the faulty disks when the disk array fails, thus reducing the I/Os directed to the faulty disks. To verify the effectiveness of the VDF cache, we have integrated VDF into two popular cache algorithms LFU and LRU, named VDF-LFU and VDF-LRU, respectively. We have conducted extensive simulations as well as a prototype implementation. The simulation results show that VDF-LFU can reduce disk I/Os to surviving disks by up to 42.3% and VDF-LRU can reduce those by up to 36.2%. Our measurement results also show that VDF-LFU can speed up the online recovery by up to 46.3% under a spare-rebuilding mode with online reconstruction, or improve the maximum system service rate by up to 47.7% under a degraded mode without a reconstruction workload. Similarly, VDF-LRU can speed up the online recovery by up to 34.6%, or improve the system service rate by up to 28.4%.