Miracle-dz/UniFAR-FTUs huggingface dataset:
Guanine Holes Are Prominent Targets for Mutation in Cancer and Inherited Disease

Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G•C bp in the context of all 64 5′-NGNN-3′ motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.
Road Transport and Environmental Policies in Japan

This article reviews some of the important aspects of Japanese environmental problems caused by road transport and policies that have been proposed against them. We also report preliminary results of our research on the evaluation of various policy measures aimed at reducing CO2 emissions by automobiles. Our simulation results indicate that the ‘Green’ tax introduced in Japan in 2001 may not be effective in reducing CO2 emission while imposing large welfare costs on automobile users. The fuel tax is more cost effective than ownership and acquisition taxes. Furthermore, a revenue neutral tax policy that increases the fuel tax and reduces the ownership tax performs better than raising the ownership and the acquisition taxes.
Incidence of High-Amplitude δ Scuti-Type Variable Stars

An order-of-magnitude estimate for the incidence of high-amplitude i Scuti-type variable stars (HADS) in the i Scuti area of the H-R diagram was calculated. Using a model for the stellar distribution in the Milky Way, we calculated the number of stars that are expected to fall in the i Scuti area of the H-R diagram within the magnitude range and sky coverage of the ROTSE Survey for Variables I (RSV1). The incidence of the HADS phenomenon was then obtained by comparing the number of stars calculated by the model with the actual, observed number of HADS in the RSV1. We find that � 0.24% of the star st hatlie in the i Scuti area of the H-R diagram within the RSV1 observational limits exhibit the HADS phenomenon. This number is much lower than the incidence of low- amplitude i Scuti stars (LADS), & 1=3 ,i mplying that the HADS phenomenon takes place in a very small fraction of stars and/or its duration is very short, compared to the LADS.
Hierarchical Models in the Brain

This paper describes a general model that subsumes many parametric models for continuous data. The model comprises hidden layers of state-space or dynamic causal models, arranged so that the output of one provides input to another. The ensuing hierarchy furnishes a model for many types of data, of arbitrary complexity. Special cases range from the general linear model for static data to generalised convolution models, with system noise, for nonlinear time-series analysis. Crucially, all of these models can be inverted using exactly the same scheme, namely, dynamic expectation maximization. This means that a single model and optimisation scheme can be used to invert a wide range of models. We present the model and a brief review of its inversion to disclose the relationships among, apparently, diverse generative models of empirical data. We then show that this inversion can be formulated as a simple neural network and may provide a useful metaphor for inference and learning in the brain.
Delegation and Information Revelation

This paper addresses the question of delegation in an organization where there is an initial asymmetry of information between the principal and the agent. We assume that the principal cannot use revelation techniques a la Baron Myerson to elicit agent's superior information and in contrast, we posit that the decision and the state of the world parameter cannot be contracted for. With these simple contracts, we show that delegation is an alternative to contracting to elicit agent's information. We can show that delegated decisions completely reveal the state of the world to the principal. Therefore the principal can extract agent's information by giving up the control right over some decisions. As the organization takes a sequence of decisions, the information learned by the principal can be used for the other decisions. So delegation is only partial: the principal delegates some decisions and keeps control over other.
Edinburgh Research Explorer Associations between objectively measured physical activity and academic attainment in adolescents from a UK cohort.

Background To test for cross-sectional (at age 11) and longitudinal associations between objectively measured free-living physical activity (PA) and academic attainment in adolescents.Method Data from 4755 participants (45% male) with valid measurement of PA (total volume and intensity) by accelerometry at age 11 from the Avon Longitudinal Study of Parents and Children (ALSPAC) was examined. Data linkage was performed with nationally administered school assessments in English, Maths and Science at ages 11, 13 and 16. Results In unadjusted models, total volume of PA predicted decreased academic attainment. After controlling for total volume of PA, percentage of time spent in moderate-vigorous intensity PA (MVPA) predicted increased performance in English assessments in both sexes, taking into account confounding variables. In Maths at 16 years, percentage of time in MVPA predicted increased performance for males (standardised β =0.11, 95% CI 0.00 to 0.22) and females ( β =0.08, 95% CI 0.00 to 0.16). For females the percentage of time spent in MVPA at 11 years predicted increased Science scores at 11 and 16 years ( β =0.14 (95% CI 0.03 to 0.25) and 0.14 (0.07 to 0.21), respectively). The correction for regression dilution approximately doubled the standardised β coef ﬁ cients. Conclusions Findings suggest a long-term positive impact of MVPA on academic attainment in adolescence.
A Degenerate HLA-DR Epitope Pool of HER-2/neu Reveals a Novel In vivo Immunodominant Epitope, HER-2/neu88-102

Purpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell–activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu–specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas. Experimental Design: A combination of algorithms and HLA-DR–binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-γ enzyme-linked immunosorbent spot (ELIspot) assay. Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for ≥11 common HLA-DR molecules. A degenerate pool of four HLA-DR–restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in ∼84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu88-102 (p88). Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu–targeting, immune-based therapies such as vaccines. Clin Cancer Res; 16(3); 825–34
Genome-Wide Analysis of the AP2/ERF Family in Eucalyptus grandis: An Intriguing Over-Representation of Stress-Responsive DREB1/CBF Genes

Background The AP2/ERF family includes a large number of developmentally and physiologically important transcription factors sharing an AP2 DNA-binding domain. Among them DREB1/CBF and DREB2 factors are known as master regulators respectively of cold and heat/osmotic stress responses. Experimental Approaches The manual annotation of AP2/ERF family from Eucalyptus grandis, Malus, Populus and Vitis genomes allowed a complete phylogenetic study for comparing the structure of this family in woody species and the model Arabidopsis thaliana. Expression profiles of the whole groups of EgrDREB1 and EgrDREB2 were investigated through RNAseq database survey and RT-qPCR analyses. Results The structure and the size of the AP2/ERF family show a global conservation for the plant species under comparison. In addition to an expansion of the ERF subfamily, the tree genomes mainly differ with respect to the group representation within the subfamilies. With regard to the E. grandis DREB subfamily, an obvious feature is the presence of 17 DREB1/CBF genes, the maximum reported to date for dicotyledons. In contrast, only six DREB2 have been identified, which is similar to the other plants species under study, except for Malus. All the DREB1/CBF and DREB2 genes from E. grandis are expressed in at least one condition and all are heat-responsive. Regulation by cold and drought depends on the genes but is not specific of one group; DREB1/CBF group is more cold-inducible than DREB2 which is mainly drought responsive. Conclusion These features suggest that the dramatic expansion of the DREB1/CBF group might be related to the adaptation of this evergreen tree to climate changes when it expanded in Australia.
Alcoholism and Diabetes Mellitus

Chronic use of alcohol is considered to be a potential risk factor for the incidence of type 2 diabetes mellitus (T2DM), which causes insulin resistance and pancreatic β-cell dysfunction that is a prerequisite for the development of diabetes. However, alcohol consumption in diabetes has been controversial and more detailed information on the diabetogenic impact of alcohol seems warranted. Diabetes, especially T2DM, causes dysregulation of various metabolic processes, which includes a defect in the insulin-mediated glucose function of adipocytes, and an impaired insulin action in the liver. In addition, neurobiological profiles of alcoholism are linked to the effects of a disruption of glucose homeostasis and of insulin resistance, which are affected by altered appetite that regulates the peptides and neurotrophic factors. Since conditions, which precede the onset of diabetes that are associated with alcoholism is one of the crucial public problems, researches in efforts to prevent and treat diabetes with alcohol dependence, receives special clinical interest. Therefore, the purpose of this mini-review is to provide the recent progress and current theories in the interplay between alcoholism and diabetes. Further, the purpose of this study also includes summarizing the pathophysiological mechanisms in the neurobiology of alcoholism.
The Cyclicality of Mark-Ups and Profit Margins: Some Evidence for Manufacturing and Services

This paper uses industry and firm data to look at price cost mark-ups and firm profit margins in UK manufacturing and services. In particular it examines how they behave over the business cycle. It has two main findings. First, the estimated average mark-ups and the profit margin results both suggest that there is imperfect competition in manufacturing and services. Second, mark-ups are pro-cyclical, as are profit margins even after allowing for movements in their standard determinants. This suggests that price pressures may increase during recovery periods and decrease during recessions. One possible explanation for this is Kreps and Scheinkman's argument that the pro-cyclicality of capacity constraints means that firms move between Cournot and Bertrand competition over the cycle. The finding that mark-ups are pro- cyclical also raises doubts about macroeconomic models that assume that demand shocks may affect employment via counter-cyclical mark-ups.
Activities, affordances and attitude: how student-generated questions assist learning

Recent research has focused on tools that support the creation, review and sharing of student-generated content for peer learning. However, we know little about the student perspective of such activities. In this paper, we identify what students believe is most helpful for their learning by analysing open-ended comments from students engaged in creating, answering and reviewing exam-style questions generated by their peers. Students report learning about content and appropriate standards of work, both individually and through interaction with peer generated resources.
Slow GABA Transient and Receptor Desensitization Shape Synaptic Responses Evoked by Hippocampal Neurogliaform Cells

The kinetics of GABAergic synaptic currents can vary by an order of magnitude depending on the cell type. The neurogliaform cell (NGFC) has recently been identified as a key generator of slow GABAA receptor-mediated volume transmission in the isocortex. However, the mechanisms underlying slow GABAA receptor-mediated IPSCs and their use-dependent plasticity remain unknown. Here, we provide experimental and modeling data showing that hippocampal NGFCs generate an unusually prolonged (tens of milliseconds) but low-concentration (micromolar range) GABA transient, which is responsible for the slow response kinetics and which leads to a robust desensitization of postsynaptic GABAA receptors. This strongly contributes to the use-dependent synaptic depression elicited by various patterns of NGFC activity including the one detected during theta network oscillations in vivo. Synaptic depression mediated by NGFCs is likely to play an important modulatory role in the feedforward inhibition of CA1 pyramidal cells provided by the entorhinal cortex.
Biosimilars in rheumatology: out of the laboratory and into practice

In 2015, the rheumatology community saw the emergence of the first biosimilar products onto the market. Although biosimilars are not new to the medical community at large, their arrival into the field of rheumatology is new and comes with great anticipation. Infliximab (Remicade) first received a European license in August 1999. The patent on Remicade expired in February 2015. In March 2015, two infliximab biosimilars were launched in the UK simultaneously: Remsima (NAPP Pharmaceuticals) and Inflectra (Hospira). Both contain the same biological productmanufactured by Celltrion, the only difference being themarketing company. The National Health Service (NHS) list price for 100 mg vial of these compounds is £377.66 pence compared with Remicade, which is marketed at £419.62 pence [1]. Local agreements further reduced the cost, with discounts approaching 50% of the cost of the original Remicade price. In February 2016, the US Food and Drug Association (FDA) voted to approve Celltrion’s infliximab biosimilar in the US across all seven indications that Remicade holds a license for [2]. In the UK, the etanercept (Enbrel) patent expired in November 2015 and the first etanercept biosimilar was licensed in January 2016. The situation in the US is more complex. The original Enbrel patents were filed in 1995 but due to several delays were not approved until 2011. Previous legislation granted patent protection from the date of approval rather than the date of application. While this legislation has now changed, the Enbrel patents were filed under the old legislation. Roche, who own the patents, are claiming protection until 2028 but this is being contested by Novartis who have their own etanercept biosimilar currently awaiting FDA approval.
Geometric Cues Influence Head Direction Cells Only Weakly in Nondisoriented Rats

The influential hypothesis that environmental geometry is critical for spatial orientation has been extensively tested behaviorally, and yet findings have been conflicting. Head direction (HD) cells, the neural correlate of the sense of direction, offer a window into the processes underlying directional orientation and may help clarify the issue. In the present study, HD cells were recorded as rats foraged in enclosures of varying geometry, with or without simultaneous manipulation of landmarks and self-motion cues (path integration). All geometric enclosures had single-order rotational symmetry and thus completely polarized the environment. They also had unique features, such as corners, which could, in principle, act as landmarks. Despite these strongly polarizing geometric cues, HD cells in nondisoriented rats never rotated with these shapes. In contrast, when a cue card (white or gray) was added to one wall, HD cells readily rotated with the enclosure. When path integration was disrupted by disorienting the rat, HD cells rotated with the enclosure even without the landmark. Collectively, these findings indicate that geometry exerts little or no influence on heading computations in nondisoriented rats, but it can do so in disoriented rats. We suggest that geometric processing is only a weak influence, providing a backup system for heading calculations and recruited only under conditions of disorientation.
Identification of Subsets of Enteroaggregative Escherichia coli Associated with Diarrheal Disease among Under 5 Years of Age Children from Rural Gambia

Abstract. Enteroaggregative Escherichia coli (EAEC) cause acute and persistent diarrhea, mostly in children worldwide. Outbreaks of diarrhea caused by EAEC have been described, including a large outbreak caused by a Shiga toxin expressing strain. This study investigated the association of EAEC virulence factors with diarrhea in children less than 5 years. We characterized 428 EAEC strains isolated from stool samples obtained from moderate-to-severe diarrhea cases (157) and healthy controls (217) children aged 0–59 months recruited over 3 years as part of the Global Enteric Multicenter Study (GEMS) in The Gambia. Four sets of multiplex polymerase chain reaction were applied to detect 21 EAEC-virulence genes from confirmed EAEC strains that target pCVD432 (aatA) and AAIC (aaiC). In addition, Kirby-Bauer disc diffusion antimicrobial susceptibility testing was performed on 88 EAEC strains following Clinical Laboratory Standard Institute guidelines. We observed that the plasmid-encoded enterotoxin [odds ratio (OR): 6.9, 95% confidence interval (CI): 2.06–29.20, P < 0.001], aggregative adherence fimbriae/I fimbriae (aggA) [OR: 2.2, 95% CI: 1.16–4.29, P = 0.008], and hexosyltransferase (capU) [OR: 1.9, 95% CI 1.02–3.51, P = 0.028] were associated with moderate-to-severe diarrhea among children < 12 months old but not in the older age strata (> 12 months). Our data suggest that some EAEC-virulent factors have age-specific associations with moderate-to-severe diarrhea in infants. Furthermore, our study showed that 85% and 72% of EAEC strains tested were resistant to sulphamethoxazole-trimethoprim and ampicillin, respectively. Sulphamethoxazole-trimethoprim and ampicillin are among the first-line antibiotics used for the treatment of diarrhea in The Gambia.
Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance

The ardA gene, found in many prokaryotes including important pathogenic species, allows associated mobile genetic elements to evade the ubiquitous Type I DNA restriction systems and thereby assist the spread of resistance genes in bacterial populations. As such, ardA contributes to a major healthcare problem. We have solved the structure of the ArdA protein from the conjugative transposon Tn916 and find that it has a novel extremely elongated curved cylindrical structure with defined helical grooves. The high density of aspartate and glutamate residues on the surface follow a helical pattern and the whole protein mimics a 42-base pair stretch of B-form DNA making ArdA by far the largest DNA mimic known. Each monomer of this dimeric structure comprises three alpha–beta domains, each with a different fold. These domains have the same fold as previously determined proteins possessing entirely different functions. This DNA mimicry explains how ArdA can bind and inhibit the Type I restriction enzymes and we demonstrate that 6 different ardA from pathogenic bacteria can function in Escherichia coli hosting a range of different Type I restriction systems.
An Approach for Cost Eeectiveness Analysis of Multiversion Software Using Software Reliability Models

For a software system, there are two clear methods to achieve a target reliability. One is to increase the reliability of a given software to the desired level by spending more resources in testing, and the other is to use multiversion software to increase the reliability. In this paper we propose an approach based on software reliability models, to analyze the cost eeectiveness of multiversion software for achieving a given target reliability as compared to achieving it by using a single version system. By using software reliability models the cost of raising the reliability of a software from a given reliability to the desired reliability can be estimated as the testing time needed to achieve the target. Total time for software development can be estimated as a function of this testing time. Total estimated development time is then used as the cost metric for comparison. As an example of this approach, we have used a few of the well known software reliability models to perform the cost eeectiveness analysis. The analysis shows that a three version system is cost eeective only if the testing cost is very high and even then when the mission time for software usage is a small fraction of the mean time to failure of the software.
Tannase Production by Penicillium Atramentosum KM under SSF and its Applications in Wine Clarification and Tea Cream Solubilization

Tannin acyl hydrolase commonly known as tannase is an industrially important enzyme having a wide range of applications, so there is always a scope for novel tannase with better characteristics. A newly isolated tannase-yielding fungal strain identified as Penicillium atramentosum KM was used for tannase production under solid-state fermentation (SSF) using different agro residues like amla (Phyllanthus emblica), ber (Zyzyphus mauritiana), jamun (Syzygium cumini), Jamoa (Eugenia cuspidate) and keekar (Acacia nilotica) leaves. Among these substrates, maximal extracellular tannase production i.e. 170.75 U/gds and 165.56 U/gds was obtained with jamun and keekar leaves respectively at 28ºC after 96 h. A substrate to distilled water ratio of 1:2 (w/v) was found to be the best for tannase production. Supplementation of sodium nitrate (NaNO3) as nitrogen source had enhanced tannase production both in jamun and keekar leaves. Applications of the enzyme were studied in wine clarification and tea cream solubilization. It resulted in 38.05% reduction of tannic acid content in case of jamun wine, 43.59% reduction in case of grape wine and 74% reduction in the tea extract after 3 h at 35°C.