Miracle-dz/UniFAR-FTUs huggingface dataset:
Pathophysiology and management of hemostatic alterations in cirrhosis and liver transplantation

In this thesis the results of several studies on the hemostasis prior to, during, and after OLT are discussed. Our studies show that various drugs and test work differently in patients with cirrhosis as compared to control groups. DDAVP has no effect on indices of hemostasis in contrast to patients with hemophilia type A, questioning its use as prohemostatic agent in cirrhotic patients. Various anticoagulant drug differ in efficacy as compared to healthy volunteers, indication dose adjustments in cirrhotic patients. Also, conventional coagulation assays are not reliable in measuring the efficacy of antithrombin dependent anticoagulant drugs. Bleeding complications during OLT occur frequently and are linked to the hemostasis, the surgical procedure and to portal hypertension. The pathophysiology, prevention and treatment of blood loss during OLT is discussed. Also we describe the study protocol of the PROTON-study, in which the hemostatic efficacy and safety of Cofact in decreasing blood loss during OLT is investigated. Retrospective research has revealed that blood loss and transfusion requirements during OLT have increased since discontinuation of prophylactic antifibrinolytic medication, prompting reconsideration of antifibrinolytic therapy during OLT. Also the role of hypertension in blood loss is confirmed in a study in which serum markers for portal hypertension prior to OLT were measured. Evidence for hypercoagulability in the liver transplant recipient is summarized and discussed. One year after OLT we found increased levels of endothelial derived coagulation factors, indicating the need for anticoagulant therapy in liver transplant recipients.
Understanding and Classifying Metabolite Space and Metabolite-Likeness

While the entirety of ‘Chemical Space’ is huge (and assumed to contain between 1063 and 10200 ‘small molecules’), distinct subsets of this space can nonetheless be defined according to certain structural parameters. An example of such a subspace is the chemical space spanned by endogenous metabolites, defined as ‘naturally occurring’ products of an organisms' metabolism. In order to understand this part of chemical space in more detail, we analyzed the chemical space populated by human metabolites in two ways. Firstly, in order to understand metabolite space better, we performed Principal Component Analysis (PCA), hierarchical clustering and scaffold analysis of metabolites and non-metabolites in order to analyze which chemical features are characteristic for both classes of compounds. Here we found that heteroatom (both oxygen and nitrogen) content, as well as the presence of particular ring systems was able to distinguish both groups of compounds. Secondly, we established which molecular descriptors and classifiers are capable of distinguishing metabolites from non-metabolites, by assigning a ‘metabolite-likeness’ score. It was found that the combination of MDL Public Keys and Random Forest exhibited best overall classification performance with an AUC value of 99.13%, a specificity of 99.84% and a selectivity of 88.79%. This performance is slightly better than previous classifiers; and interestingly we found that drugs occupy two distinct areas of metabolite-likeness, the one being more ‘synthetic’ and the other being more ‘metabolite-like’. Also, on a truly prospective dataset of 457 compounds, 95.84% correct classification was achieved. Overall, we are confident that we contributed to the tasks of classifying metabolites, as well as to understanding metabolite chemical space better. This knowledge can now be used in the development of new drugs that need to resemble metabolites, and in our work particularly for assessing the metabolite-likeness of candidate molecules during metabolite identification in the metabolomics field.
Continual online evolutionary planning for in-game build order adaptation in StarCraft

The real-time strategy game StarCraft has become an important benchmark for AI research as it poses a complex environment with numerous challenges. An important strategic aspect in this game is to decide what buildings and units to produce. StarCraft bots playing in AI competitions today are only able to switch between predefined strategies, which makes it hard to adapt to new situations. This paper introduces an evolutionary-based method to overcome this challenge, called Continual Online Evolutionary Planning (COEP), which is able to perform in-game adaptive build-order planning. COEP was added to an open source StarCraft bot called UAlbertaBot and is able to outperform the built-in bots in the game as well as being competitive against a number of scripted opening strategies. The COEP augmented bot can change its build order dynamically and quickly adapt to the opponent's strategy.
Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease

Genetic alterations in the alpha‐synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.
Modified Gravity Theories: Distinguishing from ΛCDM Model

The method and probability of distinguishing between the Λ cold dark matter ( Λ CDM) model and modified gravity are studied from future observations for the growth rate of cosmic structure (Euclid redshift survey). We compare the mock observational data to the theoretical cosmic growth rate by modified gravity models, including the extended Dvali – Gabadadze – Porrati (DGP) model, kinetic gravity braiding model, and Galileon model. In the original DGP model, the growth rate f σ 8 is suppressed in comparison with that in the Λ CDM model in the setting of the same value of the today ’ s energy density of matter Ω m ; 0 , due to suppression of the effective gravitational constant. In the case of the kinetic gravity braiding model and the Galileon model, the growth rate f σ 8 is enhanced in comparison with the Λ CDM model in the same value of Ω m ; 0 , due to enhancement of the effective gravitational constant. For the cosmic growth rate data from the future observation (Euclid), the compatible value of Ω m ; 0 differs according to the model. Fur- thermore, Ω m ; 0 can be stringently constrained. Thus, we find the Λ CDM model is distinguishable from modified gravity by combining the growth rate data of Euclid with other observations.
Comparing optical to digital metrics: What is the optimal defocus in a rotationally symmetric system?

We address the problem of finding the optimal focus of an optical system with spherical aberration, under three optimization criteria: the classical optical root-mean-square second order moment minimization, the expected mean square error on the sensor, and the expected mean square error at the output of a Wiener restoration filter. We observe that these three criteria may behave very differently, and, particularly, the classical optical criterion typically provides very poor results in comparison. This has a direct impact on the design of new hybrid optical-digital imaging systems, which account for the image quality after an optics-aware embedded digital restoration stage. We present some very encouraging results for simulations under different noise and aberration levels.
ESSENTIALS: Software for Rapid Analysis of High Throughput Transposon Insertion Sequencing Data

High-throughput analysis of genome-wide random transposon mutant libraries is a powerful tool for (conditional) essential gene discovery. Recently, several next-generation sequencing approaches, e.g. Tn-seq/INseq, HITS and TraDIS, have been developed that accurately map the site of transposon insertions by mutant-specific amplification and sequence readout of DNA flanking the transposon insertions site, assigning a measure of essentiality based on the number of reads per insertion site flanking sequence or per gene. However, analysis of these large and complex datasets is hampered by the lack of an easy to use and automated tool for transposon insertion sequencing data. To fill this gap, we developed ESSENTIALS, an open source, web-based software tool for researchers in the genomics field utilizing transposon insertion sequencing analysis. It accurately predicts (conditionally) essential genes and offers the flexibility of using different sample normalization methods, genomic location bias correction, data preprocessing steps, appropriate statistical tests and various visualizations to examine the results, while requiring only a minimum of input and hands-on work from the researcher. We successfully applied ESSENTIALS to in-house and published Tn-seq, TraDIS and HITS datasets and we show that the various pre- and post-processing steps on the sequence reads and count data with ESSENTIALS considerably improve the sensitivity and specificity of predicted gene essentiality.
Performance Analysis for Partial Feedback Downlink MIMO with Unitary Codebook Beamforming for LTE

Until recently, mobile communication tasks have been grouped into different layers in a hierarchical layer approach. In this conventional approach, layer-specific protocols are developed and optimised independently. As new wireless applications emerge, requiring high data rates and flexibility for supporting applications with significantly varying QoS requirements, it has become imperative that a higher level of communication between adjacent layers needs to be established. A unitary codebook based beamforming approach has been proposed for LTE that incorporates an improved cross-layer interface in order to improve service to users according to specified QoS criteria. This paper examines this beamforming approach under partial feedback conditions for different MIMO configurations. It is shown that non-obvious precoding matrix selection strategies and scheduling policies for the DLC, can achieve superior performance for LTE system, whilst meeting the QoS requirements of urgent users. I.INDRODUCTION
Social Disequilibrium and the Risk of HIV Acquisition: A Multilevel Study in Rural KwaZulu-Natal Province, South Africa

Background: Few population-based multilevel studies have quantified the risks that social context poses in rural communities with high HIV incidence across South Africa. We investigated the individual, social, and community challenges to HIV acquisition risk in areas with high and low incidence of HIV infection (hotspots/coldspots). Methods: The cohort (N = 17,376) included all HIV-negative adults enrolled in a population-based HIV surveillance study from 2004 to 2015 in a rural South African community with large labor migrancy. Multilevel survival models were fitted to examine the social determinants (ie, neighborhood migration intensity), community traits (ie, HIV prevalence), and individual determinants of HIV acquisition risk in identified hotspots/coldspots. Results: The HIV acquisition risk (adjusted hazard ratio [aHR] = 1.05, 95% confidence interval [CI]: 1.01 to 1.09) was greater in hotspots with higher neighborhood migration intensity among men. In women, higher neighborhood migration intensity (aHR = 1.02, 95% CI: 1.01 to 1.02) was associated with a greater HIV acquisition risk, irrespective of whether they lived in hotspot/coldspot communities. HIV acquisition risk was greater in communities with a higher prevalence of HIV in both men (aHR = 1.07, 95% CI: 1.03 to 1.12) and women (aHR = 1.03, 95% CI: 1.01 to 1.05), irrespective of hotspot/coldspot locations. Conclusion: HIV acquisition risk was strongly influenced by gender (ie, young women), behavior (ie, sexual debut, contraception, circumcision), and social determinants. Certain challenges (ie, community disease prevalence) for HIV acquisition risk impacted both sexes, regardless of residence in hotspot/coldspot communities, whereas social determinants (ie, neighborhood migration intensity) were pronounced in hotspots among men. Future intervention scale-up requires addressing the social context that contributes to HIV acquisition risk in rural areas with high migration.
Genomic evidence that resource‐based trade‐offs limit host‐range expansion in a seed beetle

Trade‐offs have often been invoked to explain the evolution of ecological specialization. Phytophagous insects have been especially well studied, but there has been little evidence that resource‐based trade‐offs contribute to the evolution of host specialization in this group. Here, we combine experimental evolution and partial genome resequencing of replicate seed beetle selection lines to test the trade‐off hypothesis and measure the repeatability of evolution. Bayesian estimates of selection coefficients suggest that rapid adaptation to a poor host (lentil) was mediated by standing genetic variation at multiple genetic loci and involved many of the same variants in replicate lines. Sublines that were then switched back to the ancestral host (mung bean) showed a more gradual and variable (less repeatable) loss of adaptation to lentil. We were able to obtain estimates of variance effective population sizes from genome‐wide differences in allele frequencies within and between lines. These estimates were relatively large, which suggests that the contribution of genetic drift to the loss of adaptation following reversion was small. Instead, we find that some alleles that were favored on lentil were selected against during reversion on mung bean, consistent with the genetic trade‐off hypothesis.
Endometrial cancer invasion depends on cancer‐derived tumor necrosis factor‐α and stromal derived hepatocyte growth factor

Cancer invasion is an outcome of interactions of the cancer and the host cell. It is now becoming increasingly clear that ovarian hormones have a huge influence on such intercommunications in various types of cancers. Estrogen is known to aggravate the aggressiveness of the endometrial cancer whereas progesterone seems to act as a negative factor. Insight into the mode of ovarian hormonal actions could come from the studies of its regulation of the paracrine interactions between the endometrial cancer and the normal stromal cells during the cancer invasion. In this context, we report here that estrogen promotes the endometrial cancer invasion by inducing humoral interactions between the cancer and the stromal cells, i.e., estrogen stimulates tumor necrosis factor‐α expression from the endometrial cancer cells, which, in turn, induces the stromal expression of hepatocyte growth factor (HGF), conferring the enhanced NK4 (HGF‐antagonist/angiogenesis inhibitor)‐sensitive invasion characteristic of the endometrial cancer cells. Additionally, we demonstrate a close correlation of the invasion of endometrial cancer cells with the expression and dimerization of integrin αvβ5 as well as the activation of focal adhesion kinase as the consequences of paracrine interactions. Thus, understanding of paracrine interactions of cancer cells with host stromal cells can yield new insight into the architecture and function of cancer invasion and metastasis, leading to a development of a new cancer therapeutic intervention. © 2008 Wiley‐Liss, Inc.
Causation or selection – examining the relation between education and overweight/obesity in prospective observational studies: a meta‐analysis

Numerous studies have investigated the association between education and overweight/obesity. Yet less is known about the relative importance of causation (i.e. the influence of education on risks of overweight/obesity) and selection (i.e. the influence of overweight/obesity on the likelihood to attain education) hypotheses. A systematic review was performed to assess the linkage between education and overweight/obesity in prospective studies in general populations. Studies were searched within five databases, and study quality was appraised with the Newcastle–Ottawa scale. In total, 31 studies were considered for meta‐analysis. Regarding causation (24 studies), the lower educated had a higher likelihood (odds ratio: 1.33, 1.21–1.47) and greater risk (risk ratio: 1.34, 1.08–1.66) for overweight/obesity, when compared with the higher educated. However, these associations were no longer statistically significant when accounting for publication bias. Concerning selection (seven studies), overweight/obese individuals had a greater likelihood of lower education (odds ratio: 1.57, 1.10–2.25), when contrasted with the non‐overweight or non‐obese. Subgroup analyses were performed by stratifying meta‐analyses upon different factors. Relationships between education and overweight/obesity were affected by study region, age groups, gender and observation period. In conclusion, it is necessary to consider both causation and selection processes in order to tackle educational inequalities in obesity appropriately.
Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia

The importance of epigenetic dysregulation to acute myeloid leukemia (AML) pathophysiology has become increasingly apparent in recent years. Epigenetic regulators, including readers, writers, and erasers, are recurrently dysregulated by way of chromosomal translocations, somatic mutations, or genomic amplification in AML and many of these alterations are directly implicated in AML pathogenesis. Mutations in epigenetic regulators are often discovered in founder clones and persist after therapy, indicating that they may contribute to a premalignant state poised for the acquisition of cooperating mutations and frank malignancy. Apart from the proto-oncogenic impact of these mutations, the AML epigenome is also shaped by other epigenetic factors that are not mutated but co-opted by AML oncogenes, presenting with actionable vulnerabilities in this disease. Targeting the AML epigenome might also be important for eradicating AML leukemia stem cells, which can be critical for disease maintenance and resistance to therapy. In this review, we describe the importance of epigenetic regulators in AML. We also summarize evidence implicating specific epigenetic regulators in AML pathobiology and discuss emerging epigenome-based therapies for the treatment of AML in the clinic.
Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer.

PURPOSE This article discusses osteonecrosis of the jaw (ONJ) and offers health care professionals practical guidelines and recommendations for the prevention, diagnosis, and management of ONJ in cancer patients receiving bisphosphonate treatment. METHODS A panel of experts representing oral and maxillofacial surgery, oral medicine, endocrinology, and medical oncology was convened to review the literature and clinical evidence, identify risk factors for ONJ, and develop clinical guidelines for the prevention, early diagnosis, and multidisciplinary treatment of ONJ in patients with cancer. The guidelines are based on experience and have not been evaluated within the context of controlled clinical trials. RESULTS ONJ is a clinical entity with many possible etiologies; historically identified risk factors include corticosteroids, chemotherapy, radiotherapy, trauma, infection, and cancer. With emerging concern for potential development of ONJ in patients receiving bisphosphonates, the panel recommends a dental examination before patients begin therapy with intravenous bisphosphonates. Dental treatments and procedures that require bone healing should be completed before initiating intravenous bisphosphonate therapy. Patients should be instructed on the importance of maintaining good oral hygiene and having regular dental assessments. For patients currently receiving bisphosphonates who require dental procedures, there is no evidence to suggest that interrupting bisphosphonate therapy will prevent or lower the risk of ONJ. Frequent clinical assessments and conservative dental management are suggested for these patients. For treatment of patients who develop ONJ, a conservative, nonsurgical approach is strongly recommended. CONCLUSION An increased awareness of the potential risk of ONJ in patients receiving bisphosphonate therapy is needed. Close coordination between the treating physician and oral surgeon and/or a dental specialist is strongly recommended in making treatment decisions.
Multidecadal Variability of North Atlantic Temperature and Salinity during the Twentieth Century

Abstract Substantial changes occurred in the North Atlantic during the twentieth century. Here the authors demonstrate, through the analysis of a vast collection of observational data, that multidecadal fluctuations on time scales of 50–80 yr are prevalent in the upper 3000 m of the North Atlantic Ocean. Spatially averaged temperature and salinity from the 0–300- and 1000–3000-m layers vary in opposition: prolonged periods of cooling and freshening (warming and salinification) in one layer are generally associated with opposite tendencies in the other layer, consistent with the notion of thermohaline overturning circulation. In the 1990s, widespread cooling and freshening was a dominant feature in the 1000–3000-m layer, whereas warming and salinification generally dominated in the upper 300 m, except for the subpolar North Atlantic where complex exchanges with the Arctic Ocean occur. The single-signed basin-scale pattern of multidecadal variability is evident from decadal 1000–3000-m temperature and salin.