julilili42/papers huggingface dataset:
Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia
2019-03-28

Platelet autoantibody-induced platelet clearance represents a major pathomechanism in immune thrombocytopenia (ITP). There is growing evidence for clinical differences between anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib/IX mediated ITP. Glycoprotein V is a well characterized target antigen in Varicella-associated and drug-induced thrombocytopenia. We conducted a systematic study assessing the prevalence and functional capacity of autoantibodies against glycoprotein V. A total of 1140 patients were included. In one-third of patients, platelet-bound autoantibodies against glycoproteins Ib/IX, IIb/IIIa, or V were detected in a monoclonal antibody immobilization of platelet antigen assay; platelet-bound autoantiglycoprotein V was present in the majority of samples (222 out of 343, 64.7%). Investigation of patient sera revealed the presence of free autoantibodies against glycoprotein V in 13.5% of these patients by an indirect monoclonal antibody immobilization of platelet antigen assay, but in 39.6% by surface plasmon resonance technology. These antibodies showed significantly lower avidity (association/dissociation ratio 0.32±0.13 <i>vs</i> 0.73±0.14; <i>P</i><0.001). High- and low-avidity antibodies induced comparable amounts of platelet uptake in a phagocytosis assay using CD14<sup>+</sup> positively-selected human macrophages [mean phagocytic index, 6.81 (range, 4.75-9.86) <i>vs</i> 6.01 (range, 5.00-6.98); <i>P</i>=0.954]. In a NOD/SCID mouse model, IgG prepared from both types of anti-glycoprotein V autoantibodies eliminated human platelets with no detectable difference between the groups from the murine circulation [mean platelet survival at 300 minutes, 40% (range, 27-55) <i>vs</i> 35% (16-46); <i>P</i>=0.025]. Our data establish glycoprotein V as a relevant immune target in immune thrombocytopenia. We would suggest that further studies including glycoprotein V will be required before ITP treatment can be tailored according to platelet autoantibody specificity.
Comparison of Dynamic International Prognostic Scoring System and MYelofibrosis SECondary to PV and ET Prognostic Model for Prediction of Outcome in Polycythemia Vera and Essential Thrombocythemia Myelofibrosis after Allogeneic Stem Cell Transplantation
2019-03-28

We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
Evidence for Recent Polygenic Selection on Educational Attainment and Intelligence Inferred from Gwas Hits: A Replication of Previous Findings Using Recent Data
2019-03-28

Genetic variants identified by three large genome-wide association studies (GWAS) of educational attainment (EA) were used to test a polygenic selection model. Weighted and unweighted polygenic scores (PGS) were calculated and compared across populations using data from the 1000 Genomes (n = 26), HGDP-CEPH (n = 52) and gnomAD (n = 8) datasets. The PGS from the largest EA GWAS was highly correlated to two previously published PGSs (r = 0.96–0.97, N = 26). These factors are both highly predictive of average population IQ (r = 0.9, N = 23) and Learning index (r = 0.8, N = 22) and are robust to tests of spatial autocorrelation. Monte Carlo simulations yielded highly significant p values. In the gnomAD samples, the correlation between PGS and IQ was almost perfect (r = 0.98, N = 8), and ANOVA showed significant population differences in allele frequencies with positive effect. Socioeconomic variables slightly improved the prediction accuracy of the model (from 78–80% to 85–89%), but the PGS explained twice as much of the variance in IQ compared to socioeconomic variables. In both 1000 Genomes and gnomAD, there was a weak trend for lower GWAS significance SNPs to be less predictive of population IQ. Additionally, a subset of SNPs were found in the HGDP-CEPH sample (N = 127). The analysis of this sample yielded a positive correlation with latitude and a low negative correlation with distance from East Africa. This study provides robust results after accounting for spatial autocorrelation with Fst distances and random noise via an empirical Monte Carlo simulation using null SNPs.
Landslide Hazard Zonation in Sri Lanka: An Assessment of Manual and GIS Based Automated Procedure in Preparation of Geology Weight Map
2019-03-28

Many techniques have been proposed for landslide hazard zonation (LHZ). They can generally be divided into two groups : direct or semi direct hazard mapping in which the degree of hazard is determined by the mapping expert and indirect hazard mapping in which either statistical or deterministic models are used to predict landslide prone areas based on information obtained from the interrelation between terrain factors and the landslide distribution. With the introduction of GIS, in particular indirect methods gained enormously due to its capacity to handle and analyze data with high spatial variability.
Mesons in a soft-wall AdS-Schwarzschild approach at low temperature
2019-03-28

We derive a holographic soft-wall approach in five dimensional\\nAdS-Schwarzschild space for the description of mesons at finite temperature. In\\nthis first application we consider the small temperature limit and derive\\nanalytical expression for the mass spectrum of mesons with adjustable quantum\\nnumbers (radial number), (angular orbital momentum) and (total\\nangular momentum). We explicitly separate the contribution at zero temperature\\nand the leading order temperature correction. The temperature corrections arise\\nfrom the temperature dependence of the dilaton parameter (which is the\\nparameter of spontaneous breaking of chiral symmetry related to the\\npseudoscalar meson decay constant) and the warping of the AdS metric due to\\ntemperature. We extend our results to any hadron with integer spin\\n(tetraquarks, dibaryons, etc.). We present numerical analysis for the\\ntemperature dependence of meson masses and form factors.\\n
Blister-Actuated LIFT Printing for Multiparametric Functionalization of Paper-Like Biosensors
2019-03-28

Laser induced forward transfer (LIFT) is a flexible digital printing process for maskless, selective pattern transfer, which uses single laser pulses focused through a transparent carrier substrate onto a donor layer to eject a tiny volume of the donor material towards a receiver substrate. Here, we present an advanced method for the high-resolution micro printing of bio-active detection chemicals diluted in a viscous buffer solution by transferring droplets with precisely controllable volumes using blister-actuated LIFT (BA-LIFT). This variant of the LIFT process makes use of an intermediate polyimide layer partially ablated by the laser pulses. The expanding gaseous ablation products lead to blisters in the polyimide and ejection of droplets from the subjacent viscous solution layer. A relative movement of donor and receiver substrates for the transfer of partially overlapping pixels is realized with a custom-made positioning system. Using a specially developed donor ink containing bio-active components presented method allows to transfer droplets with well controllable volumes between 20 fL and 6 pL, which is far more precise than other methods like inkjet or contact printing. The usefulness of the process is demonstrated by locally functionalizing laser-structured nitrocellulose paper-like membranes to form a multiparametric lateral flow test. The recognition zones localized within parallel micro channels exhibit a well-defined and homogeneous color change free of coffee-ring patterns, which is of utmost importance for reliable optical readout in miniature multiparametric test systems.
The Scavenger Receptor CD68 Regulates Platelet Mediated Oxidized Low-Density Lipoprotein (oxLDL) Deposition in Atherosclerotic Vessels at an Early Stage of Atherosclerosis in LDLR-/-/ApoBec-/- Mice
2019-03-28

Platelets contribute to increased tissue oxLDL in the aortic wall but not in peripheral blood. CD68 seems to play a role in the oxLDL metabolism in the vessel wall at early stages of atherosclerosis. FcIgG2-FL-CD68 could serve as a novel therapeutic option to modify the oxLDL content in the vessel wall.
Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides
2019-03-28

Abstract The paper is focused on the synthesis and screening of the antiplasmodial activity of novel fumardiamides 5–10 with the mefloquine pharmacophore and a Michael acceptor motif. Multi-step reactions leading to the title compounds included two amide bond formations. The first amide bond was achieved by the reaction of ( E )-ethyl 4-chloro-4-oxobut-2-enoate ( 1 ) and N 1 -(2,8-bis(trifluoromethyl)quinolin-4-yl) butane-1,4-diamine ( 2 ). The obtained ester 3 was hydrolyzed and gave acid 4 , which then reacted with the selected halogenanilines in the presence of HATU/DIEA and formed products 5–10 . Title compounds showed marked, dose dependent activity in vitro against hepatic stages of Plasmodium berghei. IC 50 values of the most active compounds 5 , 7 and 9 bearing 3-fluoro, 3-chloro and 3-trifluoromethyl substituents were 3.04–4.16 μmol L −1 , respectively. On the other hand, the compounds exerted only weak activity against the erythrocytic stages of two P. falciparum strains ( Pf 3D7 and Pf Dd2) in vitro , with the exception of compound 5 ( IC 50 = 2.9 μmol L −1 ).
Noncoding variations in Cyp24a1 gene are associated with Klotho‐mediated aging phenotypes in different strains of mice
2019-03-28

Abstract In mutant mice, reduced levels of Klotho promoted high levels of active vitamin D in the serum. Genetic or dietary manipulations that diminished active vitamin D alleviated aging‐related phenotypes caused by Klotho down‐regulation. The hypomorphic Klotho [ kl/kl ] allele that decreases Klotho expression in C3H, BALB/c, 129, and C57BL/6 genetic backgrounds substantially increases 1,25(OH)2D3 levels in the sera of susceptible C3H, BALB/c, and 129, but not C57BL/6 mice. This may be attributed to increased basal expression of Cyp24a1 in C57BL/6 mice, which promotes inactivation of 1,25(OH)2D3. Decreased expression of Cyp24a1 in susceptible strains was associated with genetic alterations in noncoding regions of Cyp24a1 gene, which were strongly reminiscent of super‐enhancers that regulate gene expression. These observations suggest that higher basal expression of an enzyme required for catabolizing vitamin D renders B6‐kl/kl mice less susceptible to changes in Klotho expression, providing a plausible explanation for the lack of aging phenotypes on C57BL/6 strain.
Gibbs and boltzmann entropy in classical and quantum mechanics
2019-03-28

The Gibbs entropy of a macroscopic classical system is a function of a probability distribution over phase space, i.e., of an ensemble. In contrast, the Boltzmann entropy is a function on phase space, and is thus defined for an individual system. Our aim is to discuss and compare these two notions of entropy, along with the associated ensemblist and individualist views of thermal equilibrium. Using the Gibbsian ensembles for the computation of the Gibbs entropy, the two notions yield the same (leading order) values for the entropy of a macroscopic system in thermal equilibrium. The two approaches do not, however, necessarily agree for non-equilibrium systems. For those, we argue that the Boltzmann entropy is the one that corresponds to thermodynamic entropy, in particular in connection with the second law of thermodynamics. Moreover, we describe the quantum analog of the Boltzmann entropy, and we argue that the individualist (Boltzmannian) concept of equilibrium is supported by the recent works on thermalization of closed quantum systems.
Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures
2019-03-29

Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel "sibling" 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients.
Chasing Multiple Bonding Interactions between Alkaline‐Earth Metals and Main‐Group Fragments
2019-03-30

Abstract Formally dianionic ligands such as alkylidenes or organoimidos play a major role in the organometallic chemistry of transition metals and are an emerging topical area of f‐element chemistry. The pursuit and development of main‐group‐metal congeners has been tackled sporadically but is clearly lacking behind. The pronounced ionic bonding in particular, prevailing in alkali and alkaline‐earth (Ae) metal derivatives, proved cumbersome. Recent substantial progress in the respective field of divalent Ae chemistry has been triggered by the implementation of new synthesis strategies involving new Ae II precursors and tailor‐made ligands. The main emphasis of this Minireview will be on the synthesis and reactivity of well‐defined Group 2 alkylidenes, organoimides, silylenes, and phosphandiides.
Reforming promeity: Feuerbach’s misreading of Luther
2019-03-30

This article is a consideration of Feuerbach’s appropriation of Luther’s theology towards constructive ends. Special attention is given to the way in which Luther’s emphasis on divine promeity furnishes Feuerbach with philosophical resources to advance his claim that discourse about ‘God’ (theology) is ultimately discourse about ‘man’ (anthropology). Following a consideration of Feuerbach’s use of Luther, an account of Karl Barth’s efforts to respond to Feuerbach are considered. A final section argues that Feuerbach has misunderstood the systematic connections in Luther’s thought and that his efforts to present Luther as support for his provocative theological and anthropological claims are undermined by Luther’s contention that divine aseity provides the grounds for divine promeity.
A novel phyllosphere residentProtomycesspecies that interacts with theArabidopsisimmune system
2019-03-31

ABSTRACT We describe the genome contents of six Protomyces spp. that are pathogenic within the typical host range of the genus and a novel Protomyces strain (SC29) that was previously isolated from the phylloplane of wild Arabidopsis thaliana ( Arabidopsis ), an atypical or possible alternate host. Genome-wide phylogenetic analysis defined SC29 as a distinct Protomyces sp. Analysis of gene family expansions, gene retention, and gene loss patterns among these Protomyces spp. lead us to hypothesize that SC29 may have undergone a host jump. The role of phyllosphere residency in the lifecycle of Protomyces spp. was previously unknown. Genomic changes in SC29 and all other Protomyces spp. were consistent with adaptations to the plant phylloplane. As predicted by our analysis of its mating locus, SC29 did not cause disease on Arabidopsis as a single strain, but could persist in its phylloplane, while the closely related P. inouyei does not. SC29 treated Arabidopsis exhibited enhanced immunity against Botrytis cinerea infection, associated with activation of MAPK3/6, camalexin, and SA-signalling pathways. We conclude that SC29 is a novel Protomyces sp. able to survive in the Arabidopsis phylloplane and that phylloplane residency is an important element in the lifecycle of Protomyces spp.
A set of Arabidopsis genes involved in the accommodation of the downy mildew pathogen Hyaloperonospora arabidopsidis
2019-03-31

Abstract The intracellular accommodation structures formed by plant cells to host arbuscular mycorrhiza fungi and biotrophic hyphal pathogens are cytologically similar but it remains unclear whether these interactions build on an overlapping genetic framework. In legumes, the malectin-like domain leucine-rich repeat receptor kinase SYMRK, the cation channel POLLUX and members of the nuclear pore NUP107-160 subcomplex are essential for symbiotic signal transduction and arbuscular mycorrhiza development. Here we identified members of these three groups in Arabidopsis thaliana and explored their impact on the interaction with the oomycete downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa). We report that mutations in the corresponding genes reduced the reproductive success of Hpa as determined by sporangiophore and spore counts. We discovered that a developmental transition of haustorial shape occurred significantly earlier and at higher frequency in the mutants. Analysis of the multiplication of extracellular bacterial pathogens, Hpa-induced cell death or callose accumulation, as well as Hpa- or flg22-induced defence marker gene expression, did not reveal any traces of constitutive or exacerbated defence responses. These findings point towards an overlap between the plant genetic toolboxes involved in the interaction with biotrophic intracellular hyphal symbionts and pathogens in terms of the gene families involved. Author Summary Our work reveals genetic commonalities between biotrophic intracellular interactions with symbiotic and pathogenic hyphal microbes. The majority of land plants engages in arbuscular mycorrhiza (AM) symbiosis with phosphate-acquiring arbuscular mycorrhizal fungi to avoid phosphate starvation. Nutrient exchange in this interaction occurs via arbuscules, tree-shaped fungal structures, hosted within plant root cells. A series of plant genes including the Symbiosis Receptor-like kinase (SYMRK), members of the NUP107-160 subcomplex and nuclear envelope localised cation channels are required for a signalling process leading to the development of AM. The model plant Arabidopsis thaliana lost the ability to form AM. Although the ortholog of SYMRK was deleted during evolution, members of the malectin-like domain leucine-rich repeat receptor kinases (MLD-LRR-RKs) gene family, components of the NUP107-160 subcomplex, and an ortholog of the nuclear envelope-localized cation channel POLLUX, are still present in the Arabidopsis genome, and Arabidopsis leaf cells retained the ability to accommodate haustoria, presumed feeding structures of the obligate biotrophic downy mildew pathogen Hyaloperonospora arabidopsidis. We discovered that both of these plant-microbe interactions utilize a corresponding set of genes including the ortholog of POLLUX, members of the NUP107-160 subcomplex and members of the MLD-LRR-RK gene family, thus revealing similarities in the plant program for the intracellular accommodation of biotrophic organisms in symbiosis and disease.
Going back to Einstein 1907 in the modern Computer Age
2019-03-31

Einstein’s equivalence principle of 1907 amounts to a mental analog computer that is ready for simulation in the modern computer age. Several new fundamental implications do already come to the fore in the process of merely preparing to do so. They are as revolutionary as one is used to from Einstein’s brain children.
Going Back to Einstein's 1907 in the Modern Computer Age
2019-03-31

Einstein’s equivalence principle of 1907 amounts to a mental analog computer that is ready for simulation in the modern computer age. Several new fundamental implications do already come to the fore in the process of merely preparing to do so. They are as revolutionary as one is used to from Einstein’s brain children.
Constraints on the Spacetime Metric around Seven “Bare” AGNs Using X-Ray Reflection Spectroscopy
2019-04-01

Abstract We present the study of a sample of seven “bare” active galactic nuclei observed with Suzaku . We interpret the spectrum of these sources with a relativistic reflection component and we employ our model relxill _ nk to test the Kerr nature of their supermassive black holes. We constrain the Johannsen deformation parameters α 13 and α 22 , in which the Kerr metric is recovered when α 13 = α 22 = 0. All our measurements are consistent with the hypothesis that the spacetime geometry around these supermassive objects is described by the Kerr solution. For some sources, we obtain quite strong constraints on α 13 and α 22 when compared to those found in our previous studies. We discuss the systematic uncertainties in our tests and the implications of our results.