julilili42/papers huggingface dataset:
Pharmacodynamics, Pharmacokinetics, and Antiviral Activity of BAY 81-8781, a Novel NF-κB Inhibiting Anti-influenza Drug
2017-11-02

Influenza is a respiratory disease that causes annual epidemics. Antiviral treatment options targeting the virus exist, but their efficiency is limited and influenza virus strains easily develop resistance. Thus, new treatment strategies are urgently needed. In the present study, we investigated the anti-influenza virus properties of D,L-lysine acetylsalicylate ⋅ glycine (BAY 81-8781; LASAG) that is approved as Aspirin i.v. for intravenous application. Instead of targeting the virus directly BAY 81-8781 inhibits the activation of the NF-κB pathway, which is required for efficient influenza virus propagation. Using highly pathogenic avian influenza virus strains we could demonstrate that BAY 81-8781 was able to control influenza virus infection <i>in vitro</i>. In the mouse infection model, inhalation of BAY 81-8781 resulted in reduced lung virus titers and protection of mice from lethal infection. Pharmacological studies demonstrated that the oral route of administration was not suitable to reach the sufficient concentrations of BAY 81-8781 for a successful antiviral effect in the lung. BAY 81-8781 treatment of mice infected with influenza virus started as late as 48 h after infection was still effective in protecting 50% of the animals from death. In summary, the data represent a successful proof of the novel innovative antiviral concept of targeting a host cell signaling pathway that is required for viral propagation instead of viral structures.
Methyl Fumarate‐Derived Iron Carbonyl Complexes (FumET‐CORMs) as Powerful Anti‐inflammatory Agents
2017-11-02

Abstract Autoimmune diseases are characterized by dendritic cell (DC)‐driven activation of pro‐inflammatory T cell responses. Therapeutic options for these severe diseases comprise small molecules such as dimethyl fumarate, or “gasotransmitters” such as CO. Herein we describe the synthesis of bifunctional enzyme‐triggered CO‐releasing molecules (ET‐CORMs) that allow the simultaneous intracellular release of both CO and methyl fumarate. Using bone‐marrow‐derived DCs the impressive therapeutic potential of these methyl fumarate‐derived compounds (FumET‐CORMs) is demonstrated by strong inhibition of lipopolysaccharide‐induced pro‐inflammatory signaling pathways and blockade of downstream interleukin‐12 or ‐23 production. The data also show that FumET‐CORMs are able to transform DCs into an anti‐inflammatory phenotype. Thus, these novel compounds have great clinical potential, for example, for the treatment of psoriasis or other inflammatory conditions of the skin.
MEASURING THE INTERDEPENDENCE OF MULTINATIONAL FIRMS' FOREIGN INVESTMENTS
2017-11-02

Earlier work found evidence for geographic linkages of aggregate foreign direct investment across countries and country‐pairs. From a theoretical point of view, such linkages at the macroeconomic level may root in between‐firm as well as within‐firm linkages and originate from information spillovers across or within firms in exploring unknown markets, and vertical linkages between production plants across different locations within the firm. We use data on the universe of German multinational enterprises (MNEs) to empirically explore how marginal investments at one foreign affiliate depend on investments at other affiliates within the same MNE. The empirical approach employs two channels or modes of cross‐affiliate interdependence: mere geography (capturing horizontal linkages through correlated learning and horizontal competition within the firm) and input–output relationships within or across industries (which capture vertical linkages ). Adding to earlier findings at the aggregate level, we find evidence of a significant interdependence of investments within the firm. In the firm‐level data at hand, vertical linkages appear to be more important than horizontal ones. Investments at one location tend to stimulate investments at other locations of the same MNE, particularly if input linkages are strong. The opposite seems to be true for output linkages. Beyond vertical linkages, mere geographic proximity matters only to a minor extent. This suggests that evidence of linkages through geographic closeness at aggregate data levels accrue mainly to reasons of vertical linkages within networks of affiliates. ( JEL C31, D22, F21, F23, F68, G31, H32)
Well-informed by national registers? A comparison of national ART registers in Germany, France and the United Kingdom
2017-11-02

Differences in the publications and the data collection methods of the three registers impact the opportunities of various stakeholders to access information about ART from their respective national registers.
Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation
2017-11-03

No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (<i>P</i><0.001), advanced disease (<i>P</i>=0.001), older age (<i>P</i>=0.007), unrelated donor (<i>P</i>=0.008) and acute graft-<i>versus</i>-host disease before relapse (<i>P</i><0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation (<i>P</i><0.001) and younger age (<i>P</i>=0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation (<i>P</i><0.001), complete remission at second transplant (<i>P</i>=0.008), no prior chronic graft-<i>versus</i>-host disease (<i>P</i><0.001) and change to a new donor (<i>P</i>=0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials.
Microbially Mediated Coupling of Fe and N Cycles by Nitrate-Reducing Fe(II)-Oxidizing Bacteria in Littoral Freshwater Sediments
2017-11-03

ABSTRACT Nitrate-reducing iron(II)-oxidizing bacteria have been known for approximately 20 years. There has been much debate as to what extent the reduction of nitrate and the oxidation of ferrous iron are coupled via enzymatic pathways or via abiotic processes induced by nitrite formed by heterotrophic denitrification. The aim of the present study was to assess the coupling of nitrate reduction and iron(II) oxidation by monitoring changes in substrate concentrations, as well as in the activity of nitrate-reducing bacteria in natural littoral freshwater sediment, in response to stimulation with nitrate and iron(II). In substrate-amended microcosms, we found that the biotic oxidation of ferrous iron depended on the simultaneous microbial reduction of nitrate. Additionally, the abiotic oxidation of ferrous iron by nitrite in sterilized sediment was not fast enough to explain the iron oxidation rates observed in microbially active sediment. Furthermore, the expression levels of genes coding for enzymes crucial for nitrate reduction were in some setups stimulated by the presence of ferrous iron. These results indicate that there is a direct influence of ferrous iron on bacterial denitrification and support the hypothesis that microbial nitrate reduction is stimulated by biotic iron(II) oxidation. IMPORTANCE The coupling of nitrate reduction and Fe(II) oxidation affects the environment at a local scale, e.g., by changing nutrient or heavy metal mobility in soils due to the formation of Fe(III) minerals, as well as at a global scale, e.g., by the formation of the primary greenhouse gas nitrous oxide. Although the coupling of nitrate reduction and Fe(II) oxidation was reported 20 years ago and has been studied intensively since then, the underlying mechanisms still remain unknown. One of the main knowledge gaps is the extent of enzymatic Fe(II) oxidation coupled to nitrate reduction, which has frequently been questioned in the literature. In the present study, we provide evidence for microbially mediated nitrate-reducing Fe(II) oxidation in freshwater sediments. This evidence is based on the rates of nitrate reduction and Fe(II) oxidation determined in microcosm incubations and on the effect of iron on the expression of genes required for denitrification.
Different shades of default mode disturbance in schizophrenia: Subnodal covariance estimation in structure and function
2017-11-03

Abstract Schizophrenia is a devastating mental disease with an apparent disruption in the highly associative default mode network (DMN). Interplay between this canonical network and others probably contributes to goal‐directed behavior so its disturbance is a candidate neural fingerprint underlying schizophrenia psychopathology. Previous research has reported both hyperconnectivity and hypoconnectivity within the DMN, and both increased and decreased DMN coupling with the multimodal saliency network (SN) and dorsal attention network (DAN). This study systematically revisited network disruption in patients with schizophrenia using data‐derived network atlases and multivariate pattern‐learning algorithms in a multisite dataset ( n = 325). Resting‐state fluctuations in unconstrained brain states were used to estimate functional connectivity, and local volume differences between individuals were used to estimate structural co‐occurrence within and between the DMN, SN, and DAN. In brain structure and function, sparse inverse covariance estimates of network coupling were used to characterize healthy participants and patients with schizophrenia, and to identify statistically significant group differences. Evidence did not confirm that the backbone of the DMN was the primary driver of brain dysfunction in schizophrenia. Instead, functional and structural aberrations were frequently located outside of the DMN core, such as in the anterior temporoparietal junction and precuneus. Additionally, functional covariation analyses highlighted dysfunctional DMN‐DAN coupling, while structural covariation results highlighted aberrant DMN‐SN coupling. Our findings reframe the role of the DMN core and its relation to canonical networks in schizophrenia. We thus underline the importance of large‐scale neural interactions as effective biomarkers and indicators of how to tailor psychiatric care to single patients.
WRINKLED1 and ACYL‐COA:DIACYLGLYCEROL ACYLTRANSFERASE1 regulate tocochromanol metabolism in Arabidopsis
2017-11-03

Summary Photosynthetic organisms such as plants, algae and some cyanobacteria synthesize tocochromanols, a group of compounds that encompasses tocopherols and tocotrienols and that exhibits vitamin E activity in animals. While most vitamin E biosynthetic genes have been identified in plant genomes, regulatory genes controlling tocopherol accumulation are currently unknown. We isolated by forward genetics Arabidopsis enhanced vitamin E ( eve ) mutants that overaccumulate the classic tocopherols and plastochromanol‐8, and a tocochromanol unknown in this species. We mapped eve1 and eve4 , and identified the unknown Arabidopsis tocochromanol by using a combination of analytical tools. In addition, we determined its biosynthetic pathway with a series of tocochromanol biosynthetic mutants and transgenic lines. eve1 and eve4 are two seed lipid mutants affecting the WRINKLED 1 ( WRI1 ) and ACYL‐COA:DIACYLGLYCEROL ACYLTRANSFERASE 1 ( DGAT1 ) genes, respectively. The unknown tocochromanol is 11′‐12′ γ‐tocomonoenol, whose biosynthesis is VITAMIN E 1 ( VTE 1) ‐ and VTE 2‐dependent and is initiated by the condensation of homogentisate ( HGA ) and tetrahydrogeranylgeranyl pyrophosphate. This study identifies the first two regulatory genes, WRI 1 and DGAT 1 , that control the synthesis of all tocochromanol forms in seeds, and shows the existence of a metabolic trade‐off between lipid and tocochromanol metabolisms. Moreover, it shows that Arabidopsis possesses a tocomonoenol biosynthetic pathway that competes with tocopherol synthesis.
The BACHD Rat Model of Huntington Disease Shows Specific Deficits in a Test Battery of Motor Function
2017-11-03

<b>Rationale</b>: Huntington disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and neuropsychiatric symptoms. HD is usually diagnosed by the appearance of motor deficits, resulting in skilled hand use disruption, gait abnormality, muscle wasting and choreatic movements. The BACHD transgenic rat model for HD represents a well-established transgenic rodent model of HD, offering the prospect of an in-depth characterization of the motor phenotype. <b>Objective</b>: The present study aims to characterize different aspects of motor function in BACHD rats, combining classical paradigms with novel high-throughput behavioral phenotyping. <b>Methods</b>: Wild-type (WT) and transgenic animals were tested longitudinally from 2 to 12 months of age. To measure fine motor control, rats were challenged with the pasta handling test and the pellet reaching test. To evaluate gross motor function, animals were assessed by using the holding bar and the grip strength tests. Spontaneous locomotor activity and circadian rhythmicity were assessed in an automated home-cage environment, namely the PhenoTyper. We then integrated existing classical methodologies to test motor function with automated home-cage assessment of motor performance. <b>Results</b>: BACHD rats showed strong impairment in muscle endurance at 2 months of age. Altered circadian rhythmicity and locomotor activity were observed in transgenic animals. On the other hand, reaching behavior, forepaw dexterity and muscle strength were unaffected. <b>Conclusions</b>: The BACHD rat model exhibits certain features of HD patients, like muscle weakness and changes in circadian behavior. We have observed modest but clear-cut deficits in distinct motor phenotypes, thus confirming the validity of this transgenic rat model for treatment and drug discovery purposes.
Processing the Scientific Tentativeness of Medical Research: An Experimental Study on the Effects of Research News and User Comments in Online Media
2017-11-03

When people read medical research news on the Internet, they are confronted not only with information from the article itself but often also with comments written by other users about the article. Moreover, Internet users have the opportunity to write their own comments. In an experimental study we found that the actual scientific tentativeness of the research findings reported in a health news article as well as the empirical and the anecdotal evidence provided in other users’ skeptical comments influenced how the participants perceived scientific tentativeness and, in turn, how much they addressed this tentativeness in their own comments.
Multimodal interaction in classrooms: implementation of tangibles in integrated music and math lessons
2017-11-03

This demo presents the multidisciplinary development of the enrichment program "Listening to Math: Kids compose with LEGO", that aims at fostering the math and music skills of gifted primary school students. In this program LEGO bricks are used as tangible representation of music notes. The so called LEGO-Table, a tabletop computer, translates patterns made out of bricks into piano melodies. We will present the finished program, address our experiences made during the project, and we will also give some insights on the implementation and evaluation of the program. Functions of the LEGO-Table will be demonstrated interactively on a tablet.
Hominid butchers and biting crocodiles in the African Plio–Pleistocene
2017-11-06

Significance The idea that early Australopithecus shaped stone tools to butcher large mammals before the emergence of Homo around 2 million years ago has excited both primatologists and archaeologists. Such claims depend on interpreting modifications found on the surfaces of fossil bones. Recent experiments involving the feeding of mammal carcasses to modern crocodiles have revealed that equifinality—the creation of similar products by different processes—is more important than previously appreciated by zooarchaeologists. Application of these findings to Ethiopian fossils casts doubt on claims for the earliest large mammal butchery and indicates the need for reassessment of all Oldowan-associated bone assemblages to determine the degree to which equifinality compromises earlier interpretations of hominid subsistence activities and their role in human evolution.
Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma
2017-11-06

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.
Toward a methodical framework for comprehensively assessing forest multifunctionality
2017-11-06

Abstract Biodiversity–ecosystem functioning ( BEF ) research has extended its scope from communities that are short‐lived or reshape their structure annually to structurally complex forest ecosystems. The establishment of tree diversity experiments poses specific methodological challenges for assessing the multiple functions provided by forest ecosystems. In particular, methodological inconsistencies and nonstandardized protocols impede the analysis of multifunctionality within, and comparability across the increasing number of tree diversity experiments. By providing an overview on key methods currently applied in one of the largest forest biodiversity experiments, we show how methods differing in scale and simplicity can be combined to retrieve consistent data allowing novel insights into forest ecosystem functioning. Furthermore, we discuss and develop recommendations for the integration and transferability of diverse methodical approaches to present and future forest biodiversity experiments. We identified four principles that should guide basic decisions concerning method selection for tree diversity experiments and forest BEF research: (1) method selection should be directed toward maximizing data density to increase the number of measured variables in each plot. (2) Methods should cover all relevant scales of the experiment to consider scale dependencies of biodiversity effects. (3) The same variable should be evaluated with the same method across space and time for adequate larger‐scale and longer‐time data analysis and to reduce errors due to changing measurement protocols. (4) Standardized, practical and rapid methods for assessing biodiversity and ecosystem functions should be promoted to increase comparability among forest BEF experiments. We demonstrate that currently available methods provide us with a sophisticated toolbox to improve a synergistic understanding of forest multifunctionality. However, these methods require further adjustment to the specific requirements of structurally complex and long‐lived forest ecosystems. By applying methods connecting relevant scales, trophic levels, and above‐ and belowground ecosystem compartments, knowledge gain from large tree diversity experiments can be optimized.
Are local plants the best for ecosystem restoration? It depends on how you analyze the data
2017-11-06

Abstract One of the key questions in ecosystem restoration is the choice of the seed material for restoring plant communities. The most common strategy is to use local seed sources, based on the argument that many plants are locally adapted and thus local seed sources should provide the best restoration success. However, the evidence for local adaptation is inconsistent, and some of these inconsistencies may be due to different experimental approaches that have been used to test for local adaptation. We illustrate how conclusions about local adaptation depend on the experimental design and in particular on the method of data analysis. We used data from a multispecies reciprocal transplant experiment and analyzed them in three different ways: (1) comparing local vs. foreign plants within species and sites, corresponding to tests of the “local is best” paradigm in ecological restoration, (2) comparing sympatric vs. allopatric populations across sites but within species, and (3) comparing sympatric and allopatric populations across multiple species. These approaches reflect different experimental designs: While a local vs. foreign comparison can be done even in small experiments with a single species and site, the other two approaches require a reciprocal transplant experiment with one or multiple species, respectively. The three different analyses led to contrasting results. While the local/foreign approach indicated lack of local adaptation or even maladaptation, the more general sympatric/allopatric approach rather suggested local adaptation, and the most general cross‐species sympatric/allopatric test provided significant evidence for local adaptation. The analyses demonstrate how the design of experiments and methods of data analysis impact conclusions on the presence or absence of local adaptation. While small‐scale, single‐species experiments may be useful for identifying the appropriate seed material for a specific restoration project, general patterns can only be detected in reciprocal transplant experiments with multiple species and sites.