julilili42/papers huggingface dataset:
Antitumor effects of curcumin in pediatric rhabdomyosarcoma in combination with chemotherapy and phototherapy in vitro
2020-12-10

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, has an unfavorable outcome in advanced tumor stages with less than 30% failure‐free survival. Curcumin (CUR) is a promising drug in complementary oncology with few side effects but proven efficacy in various adult oncological entities. The present study analyzed the effects of CUR on pediatric (RMS) cell lines in vitro. RMS cell lines (RD and RH30), and skeletal muscle cells (SKMC) were treated with different doses of CUR (1.5‐30 μM) alone, with phototherapy (PDT, 488 nm) or in combination with vincristine (VCR) or dactinomycin (DAC). MTT assays were used for analysis of RMS tumor cell viability. Clonal cell growth was assessed via colony forming assays and migration of the cells was analyzed with scratch tests. Annexin V staining was used to determine apoptosis in flow cytometry. Possible RMS resistance towards CUR after long‐term treatment was analyzed with MTT assays. CUR decreased cell viability in all assessed RMS cell lines in a concentration‐dependent manner with IC50=14‐20 μM. CUR enhanced the effects of the cytotoxic drugs VCR or DAC, and led to reduced migration and increased cell apoptosis. In combination with PDT, CUR decreased the cell viability in minute quantities with up to a 10‐fold lower IC50 than without PDT. CUR effectively inhibited the malignant properties of pediatric RMS cells and should be focused on as a useful additional agent in standard chemotherapy of RMS in children.
Approach to the Core Structure of Schweinfurthin B
2020-12-10

Abstract We investigated approaches to the xanthene part of schweinfurthin B. Starting from an exo ‐methylene cyclohexanone, an organocuprate addition led to a cyclohexanone featuring a functionalized benzyl substituent in the 2‐position. Ring‐closing reactions to the tetrahydroxanthene core (formation of the central ring) were possible in moderate yield by attack of a phenolic oxygen function on the keto group. More effective was the cyclization to the xanthene core structure after conversion of the cyclohexanone to the exo ‐methylene cyclohexane derivative and Lewis acid mediated addition of the phenolic OH to the double bond. In addition, we tried to form the xanthene ring system in a model study by cycloaddition reaction of a silyl enol ether with an ortho ‐quinone methide.
Adaptation to geometrically skewed moving images: An asymmetrical effect on the double-drift illusion
2020-12-10

Progressive addition lenses introduce distortions in the peripheral visual field that alter both form and motion perception. Here we seek to understand how our peripheral visual field adapts to complex distortions. The adaptation was induced across the visual field by geometrically skewed image sequences, and aftereffects were measured via changes in perception of the double-drift illusion. The double-drift or curveball stimulus contains both local and object motion. Therefore, the aftereffects induced by geometrical distortions might be indicative of how this adaptation interacts with the local and object motion signals. In the absence of the local motion components, the adaptation to skewness modified the perceived trajectory of object motion in the opposite direction of the adaptation stimulus skew. This effect demonstrates that the environment can also tune perceived object trajectories. Testing with the full double-drift stimulus, adaptation to a skew in the opposite direction to the local motion component induced a change in perception, reducing the illusion magnitude (when the stimulus was presented on the right side of the screen. A non-statistically significant shift, when stimuli were on the left side). However, adaptation to the other orientation resulted in no change in the strength of the double-drift illusion (for both stimuli locations). Thus, it seems that the adaptor's orientation and the motion statistics of the stimulus jointly define the perception of the measured aftereffect. In conclusion, not only size, contrast or drifting speed affects the double-drift illusion, but also adaptation to image distortions.
Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: a survey by the European Retinoblastoma group (EURbG)
2020-12-10

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond natural limits of the eye may lead to metastatic disease which is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma group (EURbG) network. Extended information were gathered via personal Email communication. Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.
Multipath Temporal Convolutional Network for Remaining Useful Life Estimation
2020-12-10

The remaining useful life (RUL) estimation of a component is a core aspect in the implementation of a predictive maintenance policy for mechanical systems. Several novel deep learning approaches have already been developed to forecast the failure of a particular system or element. Most of them focus only on the improvement of the accuracy and thus, very complex deep architectures are generated to solve the RUL prediction task. However, such complex models can hardly be implemented in an embedded system. Thus, they could not be suitable for applications such as the condition monitoring of vehicles or mobile robots. On the other hand, we propose a new architecture named Multipath Temporal Convolutional Network (MTCN), which is based on residual networks. This novel architecture enables an accurate prediction of the time to failure (TTF) of a system and simultaneously reduces the computation complexity. Moreover, the hyperparameters of the network are optimized with a genetic algorithm (GA). We validate the efficiency of our approach by using the C-MAPSS database and perform a direct comparison with the state of the art approaches for failure prognosis. The experimental study validates the high performance of MTCNs to solve the RUL prediction task with a minimal computational complexity in comparison to other published approaches. This will enable the deployment of MTCN for on-board monitoring applications of mobile systems in future research.
Uncovering the Organization of Neural Circuits with Generalized Phase Locking Analysis
2020-12-10

Abstract Despite the considerable progress of in vivo neural recording techniques, inferring the biophysical mechanisms underlying large scale coordination of brain activity from neural data remains challenging. One obstacle is the difficulty to link high dimensional functional connectivity measures to mechanistic models of network activity. We address this issue by investigating spike-field coupling (SFC) measurements, which quantify the synchronization between, on the one hand, the action potentials produced by neurons, and on the other hand a mesoscopic “field” signals, reflecting subthreshold activities at possibly multiple recording sites. As the number of recording sites gets large, the amount of pairwise SFC measurements becomes overwhelmingly challenging to interpret. We develop Generalized Phase Locking Analysis (GPLA) as a dimensionality reduction of this multivariate SFC. GPLA describes the dominant coupling between field activity and neural ensembles across space and frequencies, thereby providing rich yet interpretable information. In particular, we show that GPLA features are biophysically interpretable when used in conjunction with appropriate network models, such that we can identify the influence of underlying circuit properties on these features. We demonstrate the statistical benefits and interpretability of this approach in various computational models and Utah array recordings. The results suggest that GPLA used jointly with biophysical modeling can help uncover the contribution of recurrent microcircuits to the spatio-temporal dynamics observed in multi-channel experimental recordings.
Investigating the mini and giant radio flare episodes of Cygnus X-3
2020-12-10

The microquasar Cygnus X-3 underwent a giant radio flare in April 2017, reaching a maximum flux of ∼16.5 Jy at 8.5 GHz. We present results from a long monitoring campaign carried out with Medicina at 8.5, 18.6 and 24.1 GHz, in parallel to the Metsähovi radio telescope at 37 GHz, from 4 to 11 April 2017. We observe a spectral steepening from α=0.2 to 0.5 (with Sν∝ν−α) within 6 h around the epoch of the peak maximum of the flare, and rapid changes in the spectral slope in the following days during brief enhanced emission episodes while the general trend of the radio flux density indicated the decay of the giant flare. We further study the radio orbital modulation of Cyg X-3 emission associated with the 2017 giant flare and with six mini-flares observed in 1983, 1985, 1994, 1995, 2002 and 2016. The enhanced emission episodes observed during the decline of the giant flare at 8.5 GHz coincide with the orbital phase φ∼0.5 (orbital inferior conjunction). On the other hand the light curves of the mini-flares observed at 15−22 GHz peak at φ∼0, except for the 2016 light curve which is shifted of 0.5 w.r.t. the other ones. We attribute the apparent phase shift to the variable location of the emitting region along the bent jet. This might be explained by the different accretion states of the flaring episodes (the 2016 mini-flare occurred in the hypersoft X-ray state).
Lexical encoding of multiword expressions in XMG
2020-12-10

Multiword expressions (MWEs) exhibit both regular and idiosyncratic properties. Their idiosyncrasy requires lexical encoding in parallel with their component words. Their (at times intricate) regularity, on the other hand, calls for means of flexible factorization to avoid redundant descriptions of shared properties. However, so far, non-redundant general-purpose lexical encoding of MWEs has not received a satisfactory solution. We offer a proof of concept that this challenge might be effectively addressed within eXtensible MetaGrammar (XMG), an object-oriented metagrammar framework. We first make an existing metagrammatical resource, the FrenchTAG grammar, MWE-aware. We then evaluate the factorization gain during incremental implementation with XMG on a dataset extracted from an MWE-annotated reference corpus.
Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent 9H-pyrimido[4,5-b]indole-based GSK-3β inhibitors.
2020-12-10

Raw concatenated trajectories&amp;nbsp;of the molecular dynamics simulations related to publication:\\n\\n\\n\\n\\nAddressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent 9H-pyrimido[4,5-b]indole-based GSK-3&amp;beta; inhibitors.\\n\\n\\n\\nCompounds (S)-5c and (S)-15 trajectories are provided in a single concatenated Desmond&amp;nbsp;trajectory file\\n\\n\\n(Both: 1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s +&amp;nbsp;1 &amp;micro;s =&amp;nbsp;10 &amp;micro;s in total)&amp;nbsp;\\n\\n\\n(S)-5c = Files named: M_CL_all-out.cms; M_CL_all_trj/\\n\\n\\n(S)-15&amp;nbsp;= Files named: M_CC_all-out.cms; M_CC_all_trj/
Coronavirus disease 2019 (COVID-19), human erythrocytes and the PKC-alpha/-beta inhibitor chelerythrine –possible therapeutic implication
2020-12-11

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. Until now, diverse drugs have been used for the treatment of COVID-19. These drugs are associated with severe side effects, e.g. induction of erythrocyte death, named eryptosis. This massively affects the oxygen (O<sub>2</sub>) supply of the organism. Therefore, three elementary aspects should be considered simultaneously: (1) a potential drug should directly attack the virus, (2) eliminate virus-infected host cells and (3) preserve erythrocyte survival and functionality. It is known that PKC-α inhibition enhances the vitality of human erythrocytes, while it dose-dependently activates the apoptosis machinery in nucleated cells. Thus, the use of chelerythrine as a specific PKC-alpha and -beta (PKC-α/-β) inhibitor should be a promising approach to treat people infected with SARS-CoV-2.
Inclusion/exclusion: Educational closure and social differentiation in world society
2020-12-11

Niklas Luhmann’s late concept of inclusion/exclusion in world society compensates for the lack of a systems theory of social differentiation, but ultimately remains incomplete. Moreover, it is remarkable that Luhmann apparently never linked the inclusion/exclusion concept to his late theory of the education system. The following considerations seek this missing link, assuming that both functional and social differentiation constitute a double-sided form of societal structuring generated by the polycontextural operation of social closure mechanisms. The term ‘educational closure’ refers to the autopoietic form of inclusion/exclusion processed by an education system internally coupling operational and social closure. The article argues that organised education worldwide operates as an observing system autopoietically generating categorical differences, as well as inequalities between persons. While grouping, sorting, and tracking pupils, the education system seeks to maintain the recursion of educational communication, but also generates unequal social differentiation as a far-reaching side effect. Finally, reconstructing Weber’s theory of social closure as an earlier inclusion/exclusion concept may provide a theoretical basis for further empirical research into the social consequences of educational inclusion/exclusion in a world society.
Physiologically Based Pharmacokinetic Modeling of Metoprolol Enantiomers and α-Hydroxymetoprolol to Describe CYP2D6 Drug-Gene Interactions
2020-12-11

The beta-blocker metoprolol (the sixth most commonly prescribed drug in the USA in 2017) is subject to considerable drug–gene interaction (DGI) effects caused by genetic variations of the CYP2D6 gene. CYP2D6 poor metabolizers (5.7% of US population) show approximately five-fold higher metoprolol exposure compared to CYP2D6 normal metabolizers. This study aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to predict CYP2D6 DGIs with metoprolol. The metoprolol (R)- and (S)-enantiomers as well as the active metabolite α-hydroxymetoprolol were implemented as model compounds, employing data of 48 different clinical studies (dosing range 5–200 mg). To mechanistically describe the effect of CYP2D6 polymorphisms, two separate metabolic CYP2D6 pathways (α-hydroxylation and O-demethylation) were incorporated for both metoprolol enantiomers. The good model performance is demonstrated in predicted plasma concentration–time profiles compared to observed data, goodness-of-fit plots, and low geometric mean fold errors of the predicted AUClast (1.27) and Cmax values (1.23) over all studies. For DGI predictions, 18 out of 18 DGI AUClast ratios and 18 out of 18 DGI Cmax ratios were within two-fold of the observed ratios. The newly developed and carefully validated model was applied to calculate dose recommendations for CYP2D6 polymorphic patients and will be freely available in the Open Systems Pharmacology repository.
Intra‐amygdala metaplasticity modulation of fear extinction learning
2020-12-11

Abstract The amygdala is a key brain region involved in emotional memory formation. It is also responsible for memory modulation in other brain areas. Under extreme conditions, amygdala modulation may lead to the generation of abnormal plasticity and trauma‐related psychopathologies. However, the amygdala itself is a dynamic brain region, which is amenable to long‐term plasticity and is affected by emotional experiences. These alterations may modify the way the amygdala modulates activity and plasticity in other related brain regions, which in turn may alter the animal's response to subsequent challenges in what could be termed as “Behavioral metaplasticity.”Because of the reciprocal interactions between the amygdala and other emotion processing regions, such as the medial prefrontal cortex (mPFC) or the hippocampus, experience‐induced intra‐amygdala metaplasticity could lead to alterations in mPFC‐dependent or hippocampus‐dependent behaviors. While initiated by alterations within the basolateral amygdala (BLA), such alterations in other brain regions may come to be independent of BLA modulation, thus establishing what may be termed “Trans‐regional metaplasticity.” In this article, we review evidence supporting the notions of intra‐BLA metaplasticity and how this may develop into “Trans‐regional metaplasticity.” Future research is needed to understand how such dynamic metaplastic alterations contribute to developing psychopathologies, and how this knowledge may be translated into promoting novel interventions in psychopathologies associated with fear, stress, and trauma.
Utility-Value Intervention in School: Students’ Migration and Parental Educational Backgrounds as Moderators
2020-12-11

A growing body of research suggests that utility-value interventions can promote students' academic motivation and achievement. Moreover, there is evidence that minimal interventions are particularly useful for ethnic minority and first-generation students at college. Whether this is also the case with high school students belonging to minorities and having low parental educational background, is unclear. In a double-blind randomized field experiment with N = 439 academic-track students from 9th grade in Germany, we investigated whether a short version of an established utility-value intervention (i.e., quotations evaluation intervention) would promote the students' utility, attainment, and intrinsic values in math and their math test performance after the intervention. Moreover, we investigated if such short-term intervention effects were moderated by students' migration background and parental educational background. We found significant positive main effects of the intervention on the students' utility and attainment values in math compared to a control group. The effect on attainment value was especially pronounced for students with migration background whose parents held no university entrance certificate. We discuss the practical relevance of these findings and highlight challenges for future research in this field.
Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis
2020-12-11

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell–specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.
Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening
2020-12-11

Alexander disease (AxD) is a rare astrogliopathy caused by heterozygous mutations, either inherited or arising de novo, on the glial fibrillary acid protein (GFAP) gene (17q21). Mutations in the GFAP gene make the protein prone to forming aggregates which, together with heat-shock protein 27 (HSP27), αB-crystallin, ubiquitin, and proteasome, contribute to form Rosenthal fibers causing a toxic effect on the cell. Unfortunately, no pharmacological treatment is available yet, except for symptom reduction therapies, and patients undergo a progressive worsening of the disease. The aim of this study was the production of a zebrafish model for AxD, to have a system suitable for drug screening more complex than cell cultures. To this aim, embryos expressing the human GFAP gene carrying the most severe p.R239C under the control of the zebrafish gfap gene promoter underwent functional validation to assess several features already observed in in vitro and other in vivo models of AxD, such as the localization of mutant GFAP inclusions, the ultrastructural analysis of cells expressing mutant GFAP, the effects of treatments with ceftriaxone, and the heat shock response. Our results confirm that zebrafish is a suitable model both to study the molecular pathogenesis of GFAP mutations and to perform pharmacological screenings, likely useful for the search of therapies for AxD.
Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile
2020-12-11

Sclerosing spindle cell rhabdomyosarcoma (SSRMS) is a rare rhabdomyosarcomas (RMS) subtype. Especially cases bearing a myogenic differentiation 1 (MYOD1) mutation are characterized by a high recurrence and metastasis rate, often leading to a fatal outcome. SSRMS cell lines are valuable in vitro models for studying disease mechanisms and for the preclinical evaluation of new therapeutic approaches. In this study, a cell line established from a primary SSRMS tumor of a 24-year-old female after multimodal chemotherapeutic pretreatment has been characterized in detail, including immunohistochemistry, growth characteristics, cytogenetic analysis, mutation analysis, evaluation of stem cell marker expression, differentiation potential, and tumorigenicity in mice. The cell line which was designated SRH exhibited a complex genomic profile, including several translocations and deletions. Array-comparative genomic hybridization (CGH) revealed an overall predominating loss of gene loci. The mesenchymal tumor origin was underlined by the expression of mesenchymal markers and potential to undergo adipogenic and osteogenic differentiation. Despite myogenic marker expression, terminal myogenic differentiation was inhibited, which might be elicited by the MYOD1 hotspot mutation. In vivo tumorigenicity could be confirmed after subcutaneous injection into NOD/SCID/γcnull mice. Summarized, the SRH cell line is the first adult SSRMS cell line available for preclinical research on this rare RMS subtype.