julilili42/papers huggingface dataset:
Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics
2022-03-01

Non-clinical models to study metabolism including animal models and cell assays are often limited in terms of species translatability and predictability of human biology. This field urgently requires a push towards more physiologically accurate recapitulations of drug interactions and disease progression in the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), are an emerging technology that is well suited to providing a species-specific platform to study the various types of metabolism (glucose, lipid, protein and drug) by recreating organ-level function. This review provides a resource for scientists aiming to study human metabolism by providing an overview of MOCs recapitulating aspects of metabolism, by addressing the technical aspects of MOC development and by providing guidelines for correlation with in silico models. The current state and challenges are presented for two application areas: (i) disease modelling and (ii) pharmacokinetics/pharmacodynamics. Additionally, the guidelines to integrate the MOC data into in silico models could strengthen the predictive power of the technology. Finally, the translational aspects of metabolizing MOCs are addressed, including adoption for personalized medicine and prospects for the clinic. Predictive MOCs could enable a significantly reduced dependence on animal models and open doors towards economical non-clinical testing and understanding of disease mechanisms.
Consensus statement for treatment protocols in pressurized intraperitoneal aerosol chemotherapy (PIPAC)
2022-03-01

Abstract Objectives Safe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics. Methods The expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance). Results Twenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m 2 ) and cisplatin (10.5 mg/m 2 ) was endorsed by 20/22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m 2 (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of ≥8/10. Conclusions The current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research.
A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL
2022-03-01

Background In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Common targets in AML such as CD33, CD123, and CLEC12A are highly expressed on both AML blasts and on normal myeloid cells and hematopoietic stem cells (HSCs), thereby raising toxicity concerns. In B-cell acute lymphoblastic leukemia (B-ALL), bsAbs and CAR-T therapy targeting CD19 and CD22 have demonstrated clinical success, but resistance via antigen loss is common, motivating the development of agents focused on alternative targets. An attractive emerging target is FLT3, a proto-oncogene expressed in both AML and B-ALL, with low and limited expression on myeloid dendritic cells and HSCs. Methods We developed and characterized CLN-049, a T cell-activating bsAb targeting CD3 and FLT3, constructed as an IgG heavy chain/scFv fusion. CLN-049 binds the membrane proximal extracellular domain of the FLT3 protein tyrosine kinase, which facilitates the targeting of leukemic blasts regardless of FLT3 mutational status. CLN-049 was evaluated for preclinical safety and efficacy in vitro and in vivo. Results CLN-049 induced target-restricted activation of CD4+ and CD8+ T cells. AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed on treatment with subnanomolar concentrations of CLN-049, whereas FLT3-expressing hematopoietic progenitor cells and dendritic cells were not sensitive to CLN-049 killing. Treatment with CLN-049 also induced lysis of AML and B-ALL patient blasts by autologous T cells at the low effector-to-target ratios typically observed in patients with overt disease. Lysis of leukemic cells was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft models, CLN-049 was highly active against human leukemic cell lines and patient-derived AML and B-ALL blasts. Conclusions CLN-049 has a favorable efficacy and safety profile in preclinical models, warranting evaluation of its antileukemic activity in the clinic.
miRNAs as markers for the development of individualized training regimens: A pilot study
2022-03-01

Small, non-coding RNAs (microRNAs) have been shown to regulate gene expression in response to exercise in various tissues and organs, thus possibly coordinating their adaptive response. Thus, it is likely that differential microRNA expression might be one of the factors that are responsible for different training responses of different individuals. Consequently, determining microRNA patterns might be a promising approach toward the development of individualized training strategies. However, little is known on (1) microRNA patterns and their regulation by different exercise regimens and (2) possible correlations between these patterns and individual training adaptation. Here, we present microarray data on skeletal muscle microRNA patterns in six young, female subjects before and after six weeks of either moderate-intensity continuous or high-intensity interval training on a bicycle ergometer. Our data show that n = 36 different microRNA species were regulated more than twofold in this cohort (n = 28 upregulated and n = 8 downregulated). In addition, we correlated baseline microRNA patterns with individual changes in VO<sub>2</sub> max and identified some specific microRNAs that might be promising candidates for further testing and evaluation in the future, which might eventually lead to the establishment of microRNA marker panels that will allow individual recommendations for specific exercise regimens.
Core fragmentation and Toomre stability analysis of W3(H2O): A case study of the IRAM NOEMA large program CORE
2022-03-01

The fragmentation mode of high-mass molecular clumps and the properties of the central rotating structures surrounding the most luminous objects have yet to be comprehensively characterised. Using the IRAM NOrthern Extended Millimeter Array (NOEMA) and the IRAM 30-m telescope, the CORE survey has obtained high-resolution observations of 20 well-known highly luminous star-forming regions in the 1.37 mm wavelength regime in both line and dust continuum emission. We present the spectral line setup of the CORE survey and a case study for W3(H2O). At ~0.35" (700 AU at 2 kpc) resolution, the W3(H2O) clump fragments into two cores (West and East), separated by ~2300 AU. Velocity shifts of a few km/s are observed in the dense-gas tracer, CH3CN, across both cores, consistent with rotation and perpendicular to the directions of two bipolar outflows, one emanating from each core. The kinematics of the rotating structure about W3(H2O) W shows signs of differential rotation of material, possibly in a disk-like object. The observed rotational signature around W3(H2O) E may be due to a disk-like object, an unresolved binary (or multiple) system, or a combination of both. We fit the emission of CH3CN (12-11) K = 4-6 and derive a gas temperature map with a median temperature of ~165 K across W3(H2O). We create a Toomre Q map to study the stability of the rotating structures against gravitational instability. The rotating structures appear to be Toomre unstable close to their outer boundaries, with a possibility of further fragmentation in the differentially-rotating core W3(H2O) W. Rapid cooling in the Toomre-unstable regions supports the fragmentation scenario. Combining millimeter dust continuum and spectral line data toward the famous high-mass star-forming region W3(H2O), we identify core fragmentation on large scales, and indications for possible disk fragmentation on smaller spatial scales.
Chasing discs around O-type (proto)stars - ALMA evidence for an SiO disc and disc wind from G17.64+0.16
2022-03-01

We present high angular resolution 0.2 arcsec continuum and molecular emission line Atacama Large Millimeter/sub-millimeter Array (ALMA) observations of G17.64+0.16 in Band 6 (220GHz) taken as part of a campaign in search of circumstellar discs around (proto)-O-stars. At a resolution of 400au the main continuum core is essentially unresolved and isolated from other strong and compact emission peaks. At a resolution of 400au the main continuum core is essentially unresolved and isolated from other strong and compact emission peaks. We detect SiO (5-4) emission that is marginally resolved and elongated in a direction perpendicular to the large-scale outflow seen in the 13CO (2-1) line using the main ALMA array in conjunction with the Atacama Compact Array (ACA). Morphologically, the SiO appears to represent a disc-like structure. Using parametric models we show that the position-velocity profile of the SiO is consistent with the Keplerian rotation of a disc around an object between 10-30Mo in mass, only if there is also radial expansion from a separate structure. The radial motion component can be interpreted as a disc wind from the disc surface. Models with a central stellar object mass between 20 and 30Mo are the most consistent with the stellar luminosity (100000 Lo) and indicative of an O-type star. The H30a millimetre recombination line (231.9GHz) is also detected, but spatially unresolved, and is indicative of a very compact, hot, ionised region co-spatial with the dust continuum core. Accounting for all observables, we suggest that G17.64 is consistent with a O-type young stellar object in the final stages of protostellar assembly, driving a wind, but that has not yet developed into a compact HII region. The existance and detection of the disc in G17.64 is likely related to its isolated and possibly more evolved nature, traits which may underpin discs in similar sources.
Cognitive and Motivational Person Characteristics as Predictors of Diagnostic Performance: Combined Effects on Pre-Service Teachers’ Diagnostic Task Selection and Accuracy
2022-03-01

Abstract The acquisition of diagnostic competences is an essential goal of teacher education. Thus, evidence on how learning environments facilitate pre-service teachers’ acquisition of corresponding competences is important. In teacher education, approximations of practice (such as simulations) are discussed as being learning environments that can support learners in activating acquired knowledge in authentic situations. Simulated diagnostic interviews are recommended to foster teachers’ diagnostic competences. The conceptualization of diagnostic competences highlights the importance of cognitive and motivational characteristics. Motivational learning theories predict that the activation of acquired knowledge in learning situations may be influenced by motivational characteristics such as individual interest. Although teachers’ diagnostic competences constitute an increasing research focus, how cognitive and motivational characteristics interact when shaping the diagnostic process and accuracy in authentic learning situations remains an open question. To address this question, we report on data from 126 simulated diagnostic one-on-one interviews conducted by 63 pre-service secondary school mathematics teachers (students simulated by research assistants), studying the combined effects of interest and professional knowledge on the diagnostic process and accuracy. In addition to the main effect of content knowledge, interaction effects indicate that participants’ interest plays the role of a “door-opener” for the activation of knowledge during simulation-based learning. Thus, the results highlight the importance of both, cognitive and motivational characteristics. This implies that simulation-based learning environments should be designed to arouse participants’ interest to support their learning or to support less interested learners in activating relevant knowledge.
Accreting on the Edge: A Luminosity-dependent Cyclotron Line in the Be/X-Ray Binary 2S 1553-542 Accompanied by Accretion Regimes Transition
2022-03-01

Abstract Accreting X-ray pulsars undergo luminous X-ray outbursts during which the luminosity-dependent spectral and timing features of the neutron star’s emission can be analyzed in detail, thus shedding light on the accretion regime at work. We took advantage of a monitoring campaign that was performed with NuSTAR, Swift/XRT, AstroSat and NICER to follow the Be/X-ray Binary 2S 1553-542 along one of its rare outbursts, and thus trace its spectral and timing evolution. We report the discovery of a luminosity-dependent cyclotron line energy for the first time in this source. The pulse profiles and pulsed fraction also show variability along the outburst, which is consistent with the interpretation that the source transitions from the subcritical to the supercritical accretion regime, separated by a critical luminosity of L crit ≈ 4 × 10 37 erg s −1 .
The differential association between local neurotransmitter levels and whole‐brain resting‐state functional connectivity in two distinct cingulate cortex subregions
2022-03-01

Abstract Reproducible resting‐state functional connectivity (rsFC) patterns and their alterations play an increasing role in neuropsychiatric research. Studies that limit the analysis of metabolites and rsFC strengths to a predefined canonical network suggest that the rsFC strength positively correlates with the local glutamate (Glu) levels and negatively correlates with the gamma‐aminobutyric acid (GABA) levels. The contribution of regional neurotransmitter activity to rsFC strengths from a given seed to the whole‐brain remains unclear. In this study, 121 healthy participants (50 female/71 male) underwent multimodal resting‐state functional magnetic resonance imaging (rsfMRI) and magnetic resonance spectroscopy (MRS) at 7 T, allowing for acquisition of multiple, neuroanatomically well‐defined MRS voxels in the same session. We examined the association between rsFC and local neurotransmitter levels in the pregenual anterior cingulate cortex (pgACC) and the anterior mid‐cingulate cortex (aMCC) by varying rsFC strengths at the whole‐brain level. Our results showed that both glutamatergic and GABAergic edge weights (defined as the across‐participants partial correlation coefficients between the local metabolite levels and the rsFC of the seed region to each target parcel) were positively correlated with the rsFC strengths in the pgACC and negatively correlated with the rsFC strengths in the aMCC. The region‐dependent directionality of associations may indicate that region‐specific microscale properties, such as neurotransmitter receptor architecture, modulate the interaction between brain regions at the macroscale level.
The Ever-Expanding Scope of Animation Historiography: A Discussion of Interdisciplinary Approaches and Methods
2022-03-01

Accounting for animation’s pervasiveness, heterogeneity and intermediality, this article reflects conceptions of animation historiography. It brings together contemporary perspectives and methods in the research of animation history/historiography, and considers tangible approaches outside animation studies. Particular attention is paid to materials and aspects that are overlooked and non-canonical. The authors conceptualize animation historiography in the shape of a rhizome, enabling a better understanding of the relations between canonical aspects and fringes, and enriching the dialogue between the various disciplines, actors and institutions writing the histories of animation. Following a look at the current state of debate about animation history/histories and historiography in animation studies, the article surveys pertinent debates in film studies, art history and media art history. It then discusses historical research in performance studies and in the history of science, both concerned with fields where animation is often marginalized, as well as animation-related research on motion graphics and useful cinema, themselves under-researched topics, for perspectives to reconceptualize animation history. Media archaeology, its approaches and methodology, will be addressed repeatedly from the perspectives of the different disciplines and areas. The article is conceived as an ‘open paper’, understood as an invitation to further discuss animation historiography on a metalevel.
Stability of the co-orbital resonance under dissipation: Application to its evolution in protoplanetary discs
2022-03-01

Despite the existence of co-orbital bodies in the solar system, and the prediction of the formation of co-orbital planets by planetary system formation models, no co-orbital exoplanets (also called trojans) have been detected thus far. In this paper we investigate how a pair of co-orbital exoplanets would fare during their migration in a protoplanetary disc. To this end, we computed a stability criterion of the Lagrangian equilibria L4 and L5 under generic dissipation and slow mass evolution. Depending on the strength and shape of these perturbations, the system can either evolve towards the Lagrangian equilibrium, or tend to increase its amplitude of libration, possibly all the way to horseshoe orbits or even exiting the resonance. We estimated the various terms of our criterion using a set of hydrodynamical simulations, and show that the dynamical coupling between the disc perturbations and both planets have a significant impact on the stability: the structures induced by each planet in the disc perturb the dissipative forces applied on the other planets over each libration cycle. Amongst our results on the stability of co-orbitals, several are of interest to constrain the observability of such configurations: long-distance inward migration and smaller leading planets tend to increase the libration amplitude around the Lagrangian equilibria, while leading massive planets and belonging to a resonant chain tend to stabilise it. We also show that, depending on the strength of the dissipative forces, both the inclination and the eccentricity of the smaller of the two co-orbitals can be significantly increased during the inward migration of the co-orbital pair, which can have a significant impact on the detectability by transit of such configurations.
Building blocks for developing a research question: The ABC‐model
2022-03-01

Abstract A precisely formulated research question is becoming increasingly important within the humanities. This applies not only to research funding applications, but also to articles, papers, and student theses. This article presents a tool allowing students to develop research questions on their own, which is open enough to allow for a wide variety of research questions, while still giving users sufficient guidance to formulate a precise question. It also offers a concrete roadmap for students to use in developing their research question.
Empirical evidence to the nonmonotonic relationship between public health expenditure and economic growth
2022-03-01

Government spending does not have a monotonic relationship with economic growth. The growth impacts of government spending differ owning to several factors. This paper has examined the relationship empirically. The empirical analysis has been carried out separately for developed and developing economies. The analysis has been performed with panel datasets of 36 developed and 88 developing countries over the period of 2000-2018. Fixed Effects (FE) model and Panel Error Correction Model (PECM) were used for estimation. The long-run cointegrating relationship was estimated using a PDOLS estimator. The FE estimation showed negative impacts of public expenditure on growth in developed economies whereas no causal relationship for the case of less developed economies. In the dynamic estimation analysis, it was found that public health expenditure negatively affected growth in developed economies and positively in the less developed economies, in the long run. In the short-run, no causal relationships could be established for both the cases.
Anonymity, fidelity to law, and digital Civil disobedience
2022-03-01

Making use of the liberal concept of civil disobedience, this paper assesses, under which circumstances instances of illegal digital protest—called “hacktivism”—can be justified vis-à-vis the pro tanto political obligation to obey the law. For this, the paper draws on the three main criteria for liberal civil disobedience—publicity, nonviolence, and fidelity to law—and examines how these can be transferred to the realm of the digital. One of the main disanalogies between street and cyberspace protests is the tendency of hacktivists to remain anonymous, which in turn calls into question their fidelity to law (the third criterion). The paper argues that there are functionally equivalent alternatives to what can be called the “acceptance-of-legal-consequences-condition” (ALCC) associated with the fidelity to law. As a result, the ALCC is not a necessary condition for hacktivists to showcase their fidelity to law, thereby resolving the apparent disanalogy.
Comprehensive clinical and virological characterization of three cases of fulminant liver failure owing to HSV1 primary infection
2022-03-01

Abstract Herpes simplex virus 1 (HSV‐1) is a frequently unrecognized, yet deadly cause of acute liver failure (ALF). We, therefore, analysed three cases of fatal HSV‐1‐induced ALF. All patients shared clinical (extremely elevated transaminases, LDH and AST/LDH ratio &lt; 1) and virological characteristics (ratio of viral load in plasma versus throat swabs: 60–700‐fold, lack of anti‐HSV‐1‐IgG antibodies or low IgG‐avidity during primary infection), which may help to identify patients at risk. Additionally, in vitro chemosusceptibility assays revealed high efficacy of the helicase‐primase inhibitors (HPI), pritelivir and drug‐candidate IM‐250 compared to acyclovir (ACV) using HSV‐1‐isolates from two patients; hence, ACV/HPI‐combinations might offer new therapeutic options for HSV‐induced ALF.