Miracle-dz/UniFAR-FTUs huggingface dataset:
CHARACTERIZATION OF ASPHALT-FILLER MORTARS WITH SUPERPAVE BINDER TESTS

Within hot mix asphalt (HMA), the potential stiffening effect of a filler on an asphalt cement is limited by a filler-to-asphalt ratio (sometimes referred to as dust-to-asphalt ratio). However, this method does not account for variations in properties of different fillers nor is it based on changes in fundamental binder or mixture properties. A test originally designed by Rigden (1) and later modified by anderson (2) (dry compaction test) has been shown to related the stiffening potential of a filler in an asphalt-filler mortar. This test uses the compaction characteristics of a filler to estimate the particle size distribution, particle shape, and surface texture of a filler. A property derived from this test (percent bulk volume) has been shown in previous research to be an indicator of the stiffening potential of a filler. Based on this previous research and testing accomplished within this study, a limiting value of bulk volume was selected as 55 percent. To evaluate the stiffening potential of fillers on an asphalt binder, the Superpave binder tests were used. This research found that a limiting bulk volume value of 55 percent corresponded to increases in the Superpave binder test properties. These increases ranged between three and four times over that of the neat asphalt binders.
Influence of changes in the intestinal microflora on the immune function in mice

The composition of the intestinal microbiota is related to the health and immune function of the host. Administration of antibiotics affects the composition of the intestinal microbiota. However, the effects of immune function on the composition of the intestinal microbiota are still unclear. In this study, we investigated the lymphocyte composition and determined the relationships between lymphocyte function and the intestinal microbiota following antibiotic treatment in mice. To change the composition of the intestinal microbiota, mice were treated with or without antibiotics. Analysis of intestinal microbiota was performed by metagenomic analysis targeting 16S rRNA. Lymphocyte subsets of splenocytes were measured by flow cytometry. For functional analysis of T cells, splenocytes were stimulated with concanavalin (Con A), and cytokine gene expression was measured by real-time polymerase chain reaction. Firmicutes were predominant in the control group, whereas Bacteroidetes predominated in the antibiotic-treated group, as determined by metagenomic analysis. The diversity of the microbiota decreased in the antibiotic-treated group. Analysis of lymphocyte subsets showed that CD3+ cells decreased, whereas CD19+ cells increased in the antibiotic-treated group. All cytokine genes in splenocytes treated with Con A were downregulated in the antibiotic-treated group; in particular, genes encoding interferon-γ, interleukin (IL)-6, and IL-13 significantly decreased. Taken together, these results revealed that changes in the composition of the intestinal microbiota by antibiotic treatment influenced the population of lymphocytes in splenocytes and affected the immune response.
On Interpolation and Symbol Elimination in Theory Extensions

In this paper we study possibilities of interpolation and symbol elimination in extensions of a theory $${\mathcal T}_0$$ with additional function symbols whose properties are axiomatised using a set of clauses. We analyze situations in which we can perform such tasks in a hierarchical way, relying on existing mechanisms for symbol elimination in $${\mathcal T}_0$$. This is for instance possible if the base theory allows quantifier elimination. We analyze possibilities of extending such methods to situations in which the base theory does not allow quantifier elimination but has a model completion which does. We illustrate the method on various examples.
optPBN: An Optimisation Toolbox for Probabilistic Boolean Networks

Background There exist several computational tools which allow for the optimisation and inference of biological networks using a Boolean formalism. Nevertheless, the results from such tools yield only limited quantitative insights into the complexity of biological systems because of the inherited qualitative nature of Boolean networks. Results We introduce optPBN, a Matlab-based toolbox for the optimisation of probabilistic Boolean networks (PBN) which operates under the framework of the BN/PBN toolbox. optPBN offers an easy generation of probabilistic Boolean networks from rule-based Boolean model specification and it allows for flexible measurement data integration from multiple experiments. Subsequently, optPBN generates integrated optimisation problems which can be solved by various optimisers. In term of functionalities, optPBN allows for the construction of a probabilistic Boolean network from a given set of potential constitutive Boolean networks by optimising the selection probabilities for these networks so that the resulting PBN fits experimental data. Furthermore, the optPBN pipeline can also be operated on large-scale computational platforms to solve complex optimisation problems. Apart from exemplary case studies which we correctly inferred the original network, we also successfully applied optPBN to study a large-scale Boolean model of apoptosis where it allows identifying the inverse correlation between UVB irradiation, NFκB and Caspase 3 activations, and apoptosis in primary hepatocytes quantitatively. Also, the results from optPBN help elucidating the relevancy of crosstalk interactions in the apoptotic network. Summary The optPBN toolbox provides a simple yet comprehensive pipeline for integrated optimisation problem generation in the PBN formalism that can readily be solved by various optimisers on local or grid-based computational platforms. optPBN can be further applied to various biological studies such as the inference of gene regulatory networks or the identification of the interaction's relevancy in signal transduction networks.
Study books on ADHD genetics: balanced or biased?

ABSTRACT Academic textbooks are essential assets for disseminating knowledge about ADHD to future healthcare professionals. This study examined if they are balanced with regard to genetics. We selected and analyzed textbooks (N=43) used in (pre) master’s programmes at 10 universities in the Netherlands. Because the mere behaviourally informed quantitative genetics give a much higher effect size of the genetic involvement in ADHD, it is important that textbooks contrast these findings with molecular genetics’ outcomes. The latter studies use real genetic data, and their low effect sizes expose the potential weaknesses of quantitative genetics, like underestimating the involvement of the environment. Only a quarter of books mention both effect sizes and contrast these findings, while another quarter does not discuss any effect size. Most importantly, however, roughly half of the books in our sample mention only the effect sizes from quantitative genetic studies without addressing the low explained variance of molecular genetic studies. This may confuse readers by suggesting that the weakly associated genes support the quite spectacular, but potentially flawed estimates of twin, family and adoption studies, while they actually contradict them.
Calciprotein particles as potential etiologic agents of idiopathic preterm birth

Aggregation of calciprotein particles in amniotic fluid may play a pathogenic role in idiopathic preterm birth. A particular trigger for preterm birth Preterm birth is a common cause of neonatal death and disability worldwide. It is often triggered by premature rupture of membranes, but in most cases, it is not clear what causes this rupture, and there is no specific way to treat or prevent it. Shook et al. have shed some light on this mystery by identifying mineral-protein complexes called calciprotein particles in the amniotic fluid and fetal membranes from women with this condition. Although it is not yet clear how the particles promote membrane rupture and how this condition can be treated, the findings of this study suggest that it may be possible to interfere with this process through interventions that maintain a normal protein-mineral balance. Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality and is often preceded by preterm premature rupture of the membranes (PPROM) without an identifiable cause. Pathological calcification, the deposition of hydroxyapatite (HA) in nonskeletal tissues, has been implicated in degenerative diseases including atherosclerosis and aneurism rupture. Among pathogenic mechanisms, the aberrant aggregation of HA into calciprotein particles (CPPs) and the HA-induced differentiation of mesenchymal cells into osteoblasts (ectopic osteogenesis) have been implicated. We explored the hypothesis that CPPs form in human amniotic fluid (AF), deposit in fetal membranes, and are linked mechanistically to pathogenic pathways favoring PTB. We demonstrated that fetal membranes from women with idiopathic PPROM frequently show evidence of ectopic calcification and expression of osteoblastic differentiation markers. Concentrations of fetuin-A, an endogenous inhibitor of ectopic calcification, were decreased in AF of idiopathic PPROM cases, which reflected their reduced functional capacity to inhibit calcification. Using long-term cultures of sterile AF, we demonstrated coaggregation of HA with endogenous proteins, including fetuin-A. The fetuin-HA aggregates exhibited progressive growth in vitro in a pattern similar to CPPs. When applied to amniochorion explants, AF-derived CPPs induced structural and functional pathological effects recapitulating those noted for PPROM. Our results demonstrate that disruption of protein-mineral homeostasis in AF stimulates the formation and deposition of CPPs, which may represent etiologic agents of idiopathic PPROM. Therapeutic or dietary interventions aimed at maintaining the balance between endogenous HA formation and fetuin reserve in pregnant women may therefore have a role in preventing PTB.
Trajectories in Physical Activity and Sedentary Time Among Women Veterans in the Women's Health Initiative.

PURPOSE OF THE STUDY Trajectories of physical activity (PA) and sedentary time (ST) after military separation are likely important determinants of women's health outcomes later in life, because low PA and high ST are known contributors to premature mortality risk. Our objective was to compare longitudinal trajectories of recreational PA and ST between Veteran and non-Veteran postmenopausal women from the Women's Health Initiative (WHI). DESIGN AND METHODS Women Veteran (n = 3,719) and non-Veteran (n = 141,800) WHI participants were included. Self-reported participation in recreational PA, converted to metabolic equivalent (MET)-hours/week, was prospectively assessed over 8 years. Self-reported ST, defined as hours/day sitting or lying down, was collected at baseline and at Years 3 and 6. Generalized estimating equations were used to compare trajectories of PA and ST between Veterans and non-Veterans, adjusted for demographics and lifestyle behaviors. RESULTS Veterans had higher baseline PA than non-Veterans (13.2 vs 12.5 MET-hours/week, p = .03). PA declined for both groups, with a steeper decline among Veterans (change/visit year -0.19 vs -0.02 MET-hours/week; interaction p < .001). At baseline, Veterans and non-Veterans had similar levels of ST (107.2 vs 105.9 hours/week, p = 0.42). Over time, ST remained stable among Veterans but declined slightly among non-Veterans (change/visit year -0.19 vs -0.49 hours/week; interaction p = .01). IMPLICATIONS The less favorable longitudinal trajectories of PA and ST we observed for women Veterans may contribute to worse health among these individuals later in life. Understanding barriers to enhancing PA and reducing ST in women Veterans could lead to more effective approaches to intervening on these health behaviors.
Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

Resolving TYK2 locus genotype-to-phenotype differences reveals an immune signaling optimum that may be exploited therapeutically for treating autoimmune diseases. TYK2’s balancing act Determining the biological consequences of the thousands of genetic variants that contribute to common diseases for the purpose of improving health care is challenging. Genetic variants that influence autoimmune diseases have been identified in the tyrosine kinase 2 (TYK2) gene, but conflicting evidence regarding their biological impact obscures the therapeutic potential of TYK2. By resolving this conflict, Dendrou et al. have revealed a genetic effect that drives an optimal degree of immune signaling: low enough to be protective against autoimmunity but high enough to prevent immunodeficiency. These findings indicate that TYK2 may be a potential drug target in a number of autoimmune conditions. Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for certain common autoimmune disorders.
Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade

Immunotherapy success depends on inflamed tumor microenvironments. In tumor models, inflammation induced by chemotherapy, combined with CTLA-4 blockade, improved survival rates. In a clinical trial, patients with melanoma showed a durable response to such combined therapy. Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade–based immunotherapy results in a durable response to cancer therapy. Cancer Immunol Res; 6(2); 189–200. ©2018 AACR.
Hidden Talents of the Variational Autoencoder.

Variational autoencoders (VAE) represent a popular, flexible form of deep generative model that can be stochastically fit to samples from a given random process using an information-theoretic variational bound on the true underlying distribution. Once so-obtained, the model can be putatively used to generate new samples from this distribution, or to provide a low-dimensional latent representation of existing samples. While quite effective in numerous application domains, certain important mechanisms which govern the behavior of the VAE are obfuscated by the intractable integrals and resulting stochastic approximations involved. Moreover, as a highly non-convex model, it remains unclear exactly how minima of the underlying energy relate to original design purposes. We attempt to better quantify these issues by analyzing a series of tractable special cases of increasing complexity. In doing so, we unveil interesting connections with more traditional dimensionality reduction models, as well as an intrinsic yet underappreciated propensity for robustly dismissing sparse outliers when estimating latent manifolds. With respect to the latter, we demonstrate that the VAE can be viewed as the natural evolution of recent robust PCA models, capable of learning nonlinear manifolds of unknown dimension obscured by gross corruptions.
The relationship between loading history and proximal femoral diaphysis cross‐sectional geometry

We investigated the relationship between loading history and bone biomechanical properties used in physical activity reconstructions. These bone properties included bone bending and torsional strength (J), cortical area (CA), the direction of the major axis (theta angle), and element shape ratios determined from cross sections of standardized bone length. In addition, we explored the applicability of anatomically determined cross sections.
Designing allostery-inspired response in mechanical networks

Significance We show that removal of a small number of bonds in a random elastic network can dramatically change its mechanical response. Our theoretical approach precisely and efficiently controls the local strain at one point in such a network in response to a strain applied elsewhere in the system. The responses we create are inspired by the long-range-correlated deformations that often characterize allostery in proteins. The ubiquity of allostery in biological molecules suggests that it is relatively easy to develop through evolution. Our nearly 100% success rate in designing these responses by removing a very small fraction of bonds shows that it is similarly easy to create these types of elastic responses in disordered mechanical networks. Recent advances in designing metamaterials have demonstrated that global mechanical properties of disordered spring networks can be tuned by selectively modifying only a small subset of bonds. Here, using a computationally efficient approach, we extend this idea to tune more general properties of networks. With nearly complete success, we are able to produce a strain between any two target nodes in a network in response to an applied source strain on any other pair of nodes by removing only ∼1% of the bonds. We are also able to control multiple pairs of target nodes, each with a different individual response, from a single source, and to tune multiple independent source/target responses simultaneously into a network. We have fabricated physical networks in macroscopic 2D and 3D systems that exhibit these responses. This work is inspired by the long-range coupled conformational changes that constitute allosteric function in proteins. The fact that allostery is a common means for regulation in biological molecules suggests that it is a relatively easy property to develop through evolution. In analogy, our results show that long-range coupled mechanical responses are similarly easy to achieve in disordered networks.
Clinicopathological correlation of tumor-associated macrophages in Ewing sarcoma.

AIMS Tumor-associated macrophages (TAMs) are known markers playing complex roles in tumorigenesis. However, the function of TAMs in a variety of malignancies is not yet fully understood. The aim of this pilot study was to quantify the density of TAMs in Ewing sarcoma and to determine the correlation between TAMs and clinicopathological parameters. METHODS Using immunohistochemistry, the expressions of CD68 and CD163 were examined in 24 tissue samples of Ewing sarcoma of bone. The density of CD68 and CD163-positive TAMs was analyzed quantitatively and semi-quantitatively and statistically correlated with clinical parameters. RESULTS CD163-positive TAMs outnumbered CD68-positive cells (median of 130 vs 96, respectively). No statistically significant relatio nship was found between density of CD68-positive cells, clinical parameters or prognosis. However, high levels of CD163-positive TAMs were associated with localized disease (P=0.008). In cases with a higher density of CD163-positive cells, a trend toward longer survival was revealed (P=0.063). CONCLUSION This is the first study that has quantified CD163 expression in TAMs in Ewing sarcoma and showed its possible prognostic value. CD163 was confirmed to be a more specific marker of macrophages than CD68. CD163 is not an exclusive hallmark of M2 macrophages.
A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney. Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene. Clin Cancer Res; 24(9); 2044–9. ©2018 AACR.
Sprint Interval Training Decreases Circulating MicroRNAs Important for Muscle Development

Abstract Small non-coding RNAs, such as microRNAs (miRNAs), have emerged as powerful post-transcriptional regulators of gene expression that play important roles in many developmental and biological processes. In this study, we assessed the abundance of circulating microRNAs important for skeletal muscle and heart adaptations to exercise (miR-1, miR-133a, miR-133b and miR-486), following acute exercise and short-term sprint interval training (SIT). Twenty-eight individuals completed four all-out efforts on a cycle ergometer, and donated blood before and 30 min after the cessation of exercise. A subset of 10 untrained men completed 4-6 efforts of SIT, three times a week for 6 weeks, and donated resting blood samples before and after the intervention. MiRNA TaqMan qPCR was performed and whilst no changes were observed after a single session of SIT (all p>0.05), the 6-wk SIT intervention significantly reduced the whole blood content of all four miRNAs (mean fold-changes: 0.37–0.48, all p<0.01). Our data suggests that circulating miRNAs are responsive to short-term SIT and could have roles in SIT-induced health and performance adaptations. Further work is required to establish whether circulating miRNAs could serve as biomarkers for predicting exercise training responses and monitoring exercise interventions.