julilili42/papers huggingface dataset:
Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
2021-07-02

There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh porcine eyes obtained from the local slaughterhouse as a model for testing the intravitreal biodistribution and retention of liposomes with or without polyethylene glycol (PEG) conjugation and with different surface charges. The histology of the eyes was analyzed to localize the liposomes, and it was found that liposomes with PEG absorbed rapidly on the retina (within 1 h), with positively charged and PEG-coated liposomes being retained for at least 24 h. In parallel, fluorophotometry was employed on intact eyes, to determine the pharmacokinetics of the fluorophore calcein, as a substitute for a small hydrophilic therapeutic compound. We found a 4.5-fold increase in the vitreous half-life of calcein loaded in liposomes, compared with the free solution. Retinal toxicity was addressed using murine-derived retinal explant cultures. Liposomes were non-toxic up to 500 μg/mL. Toxicity was observed at 5 mg/mL for anionic and cationic liposomes, with 2-fold and 2.5-fold increased photoreceptor cell death, respectively. Overall, we could show that important ocular drug delivery considerations such as pharmacokinetics and biodistribution can be estimated in ex vivo porcine eyes, and may guide subsequent in vivo experiments.
Assessing language indicators across the lifespan within the German National Educational Panel Study (NEPS)
2021-07-02

Based on a brief review of models and empirical results concerning the acquisition of language, a conceptual framework for assessing language competencies within the German National Educational Panel Study (NEPS) is outlined. Language-component-oriented approaches and functional-integrative perspectives on language competencies are compared, and their importance for the investigation of language development as well as for the measurement of language competencies is highlighted. Further, implications for a comprehensive assessment and design for measuring language competencies within a large-scale educational study will be presented, and the concrete measures of the NEPS will be mentioned. Finally, results of a small preliminary study are reported to show a theoretical and data-driven approach to select instruments for the NEPS surveys. (DIPF/Orig.)
Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3β Inhibitors
2021-07-02

In small molecule binding, water is not a passive bystander but rather takes an active role in the binding site, which may be decisive for the potency of the inhibitor. Here, by addressing a high-energy water, we improved the IC<sub>50</sub> value of our co-crystallized glycogen synthase kinase-3β (GSK-3β) inhibitor by nearly two orders of magnitude. Surprisingly, our results demonstrate that this high-energy water was not displaced by our potent inhibitor (<i>S</i>)-3-(3-((7-ethynyl-9<i>H</i>-pyrimido[4,5-<i>b</i>]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (<b>(<i>S</i>)</b>-<b>15</b>, IC<sub>50</sub> value of 6 nM). Instead, only a subtle shift in the location of this water molecule resulted in a dramatic decrease in the energy of this high-energy hydration site, as shown by the WaterMap analysis combined with microsecond timescale molecular dynamics simulations. <b>(<i>S</i>)</b>-<b>15</b> demonstrated both a favorable kinome selectivity profile and target engagement in a cellular environment and reduced GSK-3 autophosphorylation in neuronal SH-SY5Y cells. Overall, our findings highlight that even a slight adjustment in the location of a high-energy water can be decisive for ligand binding.
Beyond Takai's Olefination Reagent: Persistent Dehalogenation Emerges in a Chromium(III)‐μ3‐Methylidyne Complex
2021-07-02

Abstract Reaction of CHI 3 with six equivalents of CrCl 2 in THF at low temperatures affords [Cr 3 Cl 3 (μ 2 ‐Cl) 3 (μ 3 ‐CH)(thf) 6 ] as the first isolable high‐yield Cr III μ 3 ‐methylidyne complex. Substitution of the terminal chlorido ligands via salt metathesis with alkali‐metal cyclopentadienides generates isostructural half‐sandwich chromium(III)‐μ 3 ‐methylidynes [Cp R 3 Cr 3 (μ 2 ‐Cl) 3 (μ 3 ‐CH)] (Cp R =C 5 H 5 , C 5 Me 5 , C 5 H 4 SiMe 3 ). Side and decomposition products of the Cl/Cp R exchange reactions were identified and structurally characterized for [Cr 4 (μ 2 ‐Cl) 4 (μ 2 ‐I) 2 (μ 4 ‐O)(thf) 4 ] and [(η 5 ‐C 5 H 4 SiMe 3 )CrCl(μ 2 ‐Cl) 2 Li(thf) 2 ]. The Cl/Cp R exchange drastically changed the ambient‐temperature effective magnetic moment μ eff from 9.30/9.11 μ B (solution/solid) to 3.63/4.32 μ B (Cp R =C 5 Me 5 ). Reactions of [Cr 3 Cl 3 (μ 2 ‐Cl) 3 (μ 3 ‐CH)(thf) 6 ] with aldehydes and ketones produce intricate mixtures of species through oxy/methylidyne exchange, which were partially identified as radical recombination products through GC/MS analysis and 1 H NMR spectroscopy.
Overabundance and inflectional classification: Quantitative evidence from Czech
2021-07-02

Overabundance is the situation where two or more distinct word forms fill the same cell in an inflectional paradigm (Thornton 2011). While this topic has received renewed attention in recent years, there are still several open questions regarding its properties and status. In this paper we present a new take on the matter. On the basis of a case study of the locative singular and instrumental plural of Czech nouns, we argue that there are at least two kinds of overabundance phenomena which should be distinguished, depending on whether overabundant behavior integrates in the inflection system or is orthogonal to it. The evidence for the distinction comes from a quantitative study of the way phonological, morphosyntactic, semantic, and sociolinguistic factors contribute to partially predicting whether a lexeme is overabundant and which form is used in different contexts.
New findings in gluon TMD physics
2021-07-02

We revisit the model-independent decomposition of the gluon correlator,\\nproducing T-even and T-odd gluon transverse momentum distributions (TMDs), at\\nleading twist. We propose an expansion of the gluon correlator, using a basis\\nof four tensors (one antisymmetric and three symmetric), which are expressed\\nthrough generators of the group acting in the two-dimensional transverse\\nplane. One can do clear interpretations of the two transversity T-odd TMDs with\\nlinear polarization of gluons: symmetric and asymmetric under permutation of\\nthe transverse spin of the nucleon and the transverse momentum of the gluon.\\nUsing light-front wave function (LFWF) representation, we also derive T-even\\nand T-odd gluon TMDs in the nucleon at leading twist. The gluon-three-quark\\nFock component in the nucleon is considered as bound state of gluon and\\nthree-quark core (spectator). The TMDs are constructed as factorized product of\\ntwo LFWFs and gluonic matrix encoding information about both T-even and T-odd\\nTMDs. In particular, T-odd TMDs arise due to gluon rescattering between the\\ngluon and three-quark spectator. Gluon rescattering effects are parametrized by\\nunknown scalar functions depending on the and variables.\\nOur gluon TDMs obey the model-independent Mulders-Rodrigues inequalities. We\\nalso derive new sum rules (SRs) involving T-even TMDs. One of the SRs states\\nthat the square of the unpolarized TMD is equal to a sum of the squares of\\nthree polarized TMDs. Based on the SR derived for T-even gluon TMDs, we make a\\nconjecture that there should two additional SRs involving T-odd gluon TMDs,\\nvalid at orders and . Then, we check these SRs at small\\nand large values of . We think that our study could serve as useful input\\nfor future phenomenological studies of TMDs.\\n
Be water my friend: mesh assimilation
2021-07-02

Abstract Inspired by the ability of water to assimilate any shape, if being poured into it, regardless if flat, round, sharp, or pointy, we present a novel, high-quality meshing method. Our algorithm creates a triangulated mesh, which automatically refines where necessary and accurately aligns to any target, given as mesh, point cloud, or volumetric function. Our core optimization iterates over steps for mesh uniformity, point cloud projection, and mesh topology corrections, always guaranteeing mesh integrity and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>ε</mml:mi> </mml:math> -close surface reconstructions. In contrast with similar approaches, our simple algorithm operates on an individual vertex basis. This allows for automated and seamless transitions between the optimization phases for rough shape approximation and fine detail reconstruction. Therefore, our proposed algorithm equals established techniques in terms of accuracy and robustness but supersedes them in terms of simplicity and better feature reconstruction, all controlled by a single parameter, the intended edge length. Due to the overall increased versatility of input scenarios and robustness of the assimilation, our technique furthermore generalizes multiple established approaches such as ballooning or shrink wrapping.
Dynamics of glucose metabolism after liver transplantation: prediabetes as a window of opportunity for patient survival and long‐term kidney function
2021-07-02

Post-transplantation diabetes mellitus (PTDM) is a relevant complication following liver transplantation with profound impact on morbidity and mortality. To date, little is known about the evolution and dynamics of glucose metabolism and the impact of prediabetes in long-term follow-up. To address this issue, all consecutive adult liver transplant recipients (n = 429) from a European university hospital transplant center between 2007 and 2017 were analyzed retrospectively. In patients without pre-existing diabetes (n = 327), we conducted a longitudinal characterization of glucose metabolism. Median follow-up was 37 [9-64, IQR] months. Median prevalence of prediabetes was 39 [37-39]% and of PTDM 21 [17-22]%. Throughout follow-up, intra-individual glucose regulation of patients was highly variable, continuously fluctuating between different states of glucose metabolism (normal glucose tolerance, prediabetes, PTDM). Whereas overall survival and long-term kidney function of patients with PTDM were significantly lower than that of patients with normal glucose metabolism, prediabetes was not associated with adverse outcome. This study provides new insight into the dynamics and impact of glucose metabolism after liver transplantation. Unlike PTDM, prediabetes is not associated with adverse outcome, providing a window of opportunity for targeted intervention. The results underline the need for constant screening and intervention in posttransplant care of liver allograft recipients.
Overidentification of learning disorders among language-minority students. Implications for the standardization of school achievement tests
2021-07-02

This German prevalence study examined disproportionate representation of language- minority students among children identified with learning disorder (LD) according to ICD-10 (WHO, 1992). Most German school achievement tests used in LD diagnostics do not provide separate norms for language-minority students, and thus do not take these children’s second language status into account when evaluating their academic performance. Although this is likely to result in an LD over identification of language-minority students, little is known about the magnitude of this effect. Therefore, we compared the estimation of LD prevalence between native German speaking students (n = 566) and language-minority students (n = 478) when pooled versus group-specific achievement norms were used for LD classification. Three important findings emerged from our study: Firstly, and as expected, significant disproportionality effects occurred under pooled norms. Specifically, the likelihood of being diagnosed with LD amounted to 14–18 % among native German speakers and nearly doubled to 25–30 % among language-minority students. Secondly, disproportionality varied as a function of LD subtype: Whereas no disproportionate representation was revealed for arithmetic LD (F81.2), overidentification of language-minority students was found for verbal LD subtypes (namely, reading disorder [F81.0], spelling disorder [F81.1], and mixed disorder of scholastic skills [F81.3]). Thirdly, disproportionality effects were absent when group-specific norms were used for LD classification that controlled for second-language issues. Challenges that have to be met when testing language-minority students for LD are discussed. (DIPF/Orig.)
The Genetic Architecture of Amygdala Nuclei
2021-07-02

Abstract Background Whereas a number of genetic variants influencing total amygdala volume have been identified in previous research, genetic architecture of its distinct nuclei have yet to be thoroughly explored. We aimed to investigate whether increased phenotypic specificity through segmentation of the nuclei aids genetic discoverability and sheds light on the extent of shared genetic architecture and biological pathways between the nuclei and disorders associated with the amygdala. Methods T1-weighted brain MRI scans (n=36,352, mean age= 64.26 years, 52% female) of trans-ancestry individuals from the UK Biobank were segmented into nine amygdala nuclei with FreeSurfer v6.1, and genome-wide association analyses were performed on the full sample and a European-only subset (n=31,690). We estimated heritability using Genome-wide Complex Trait Analysis, derived estimates of polygenicity, discoverability and power using MiXeR, and determined genetic correlations and shared loci between the nuclei using Linkage Disequilibrium Score Regression, followed by functional annotation using FUMA. Results The SNP-based heritability of the nuclei ranged between 0.17-0.33, and the central nucleus had the greatest statistical power for discovery. Across the whole amygdala and the nuclei volumes, 38 novel significant (p &lt; 5×10 −9 ) loci were identified, with most loci mapped to the central nucleus. The mapped genes and associated pathways revealed both unique and shared effects across the nuclei, and immune-related pathways were particularly enriched across several nuclei. Conclusions These findings indicate that the amygdala nuclei volumes have significant genetic heritability, increased power for discovery compared to whole amygdala volume, may have unique and shared genetic architectures, and a significant immune component to their aetiology.
Investigation of new biomarkers of kidney injury in renal transplant recipients undergoing graft biopsy
2021-07-02

ABSTRACT Aim Urinary and blood kidney biomarkers (BM) remain insufficient for early kidney injury detection. We aimed to compare new kidney BM with histopathological data in kidney allograft recipients. Methods Blood and urine samples were collected from consecutive adult patients just before graft biopsy. All kidney samples were classified according to the Banff 2007 classification. The diagnostic performance of 16 new BM was compared to those of urinary proteins, blood urea nitrogen, eGFR, and serum creatinine to identify histopathological groups. Results Two hundred and twenty‐three patients were analyzed. Microalbuminuria and urinary proteins performed well to discriminate glomerular injury from slightly modified renal parenchyma (SMRP). Urinary neutrophil gelatinase‐associated lipocalin (NGAL) had the best performance relative to SMRP (AUROC .93) for acute tubular necrosis (ATN) diagnosis. Other BM had a slightly lower AUROC (.89). For the comparison of ATN to acute rejection, several new urinary BM (NGAL, cystatin C, MCP1) and classical BM (eGFR, serum creatinine) gave similar AUROC values (from .80 to .85). Urinary NGAL values in patients with ATN were 10‐time higher than those with acute rejection ( P =.0004). Conclusion The new BM did not outperform classical BM in the context of renal transplantation. Urinary NGAL may be useful for distinguishing between ATN and acute rejection.
Feasibility of a Geriatric Assessment to Detect and Quantify Sarcopenia and Physical Functioning in German Nursing Home Residents—A Pilot Study
2021-07-02

Background: Entering into a nursing home leads to increased immobility and further reductions in physical and cognitive functioning. As a result, there is a risk of sarcopenia, which is characterized by loss of muscle strength, muscle mass and physical functioning. To our knowledge, the feasibility of sarcopenia screening has not yet been performed in the German nursing home setting. Methods: For sarcopenia screening, the specifications of EWGSOP2 were applied. The quantification of sarcopenia was performed according to the corresponding cut-off values. The collection of anthropometric data and the morbidity status were recorded. SARC-F, mini-mental state examination, Barthel Index, Short Physical Performance Battery and Timed Up and Go tests were implemented. Results: In one participant, severe sarcopenia could be identified. The quantification was not possible for four participants. A suspicion of sarcopenia was not confirmed in five participants. Only one person was able to perform all assessments. Conclusions: Sarcopenia screening according to EWGSOP2 presented satisfactory feasibility by nursing home residents. However, further tests to assess the physical functioning of the participants often could not be performed. Moreover, inconsistencies in individual assessments became apparent, leading to inconclusive analyses. The recording of sarcopenia prevalence in German nursing homes should be the goal of further research.
Why education should engage in the inner curriculum of the mind
2021-07-02

Both contemporary naturalist and deconstructivist theories share the suspicion of invoking an emphatic subject in education while not being able to address the question of what education is for in a constructive and value-based way. However, while naturalist theory also focuses on the human mind and its evolutionary origins, deconstructivism is preoccupied with the social constraints of subjectivation. The following takes up the idea that a core value of education is the enhancement of human wellbeing by referring to Ergas’s call for a contemplative turn towards mindful education and relating it to naturalist evolutionary theory about the human mind. This attempt turns out to be promising because mindful education addresses the problem of wellbeing without postulating a non-naturalist realm of emphatic subjectivity. To take up the deconstructivist critique, socio-cultural problems that arise from the idea of mindful education and its relation to naturalist thinking are discussed.
How Do Hospital Pharmacists Approach Substitution of Nanomedicines? Insights from a Qualitative Pilot Study and a Quantitative Market Research Analysis in Five European Countries
2021-07-02

We conducted research to assess hospital pharmacists’ familiarity with/interpretation of data requirements for the different regulatory approval frameworks and the impact of this on their approach to substitution in the formulary. The online questionnaire included a small molecule (acetylsalicylic acid—follow-ons approved via the generic pathway), two biologic drugs (insulin glargine and etanercept—follow-ons approved via the biosimilar pathway), a non-biologic complex drug (NBCD; glatiramer acetate—follow-ons approved via the hybrid pathway) and a nanomedicine, ferric carboxymaltose (no follow-ons approved as yet). The study was conducted in two phases: an initial qualitative pilot study with 30 participants, followed by a quantitative stage involving 201 pharmacists from five European countries. Most expected negligible safety/efficacy differences between reference and follow-on products. Head-to-head clinical data showing therapeutic equivalence as a prerequisite for reference product/follow-on substitution was perceived to be needed most for biologics (47%), followed by NBCDs (44%)/nanomedicines (39%) and small molecules (23%). Overall, 28% did not know the data requirements for follow-on approval via the hybrid pathway; 16% were familiar with this pathway, compared with 50% and 55% for the generic and biosimilar pathways, respectively. Overall, 19% of respondents thought the European Medicines Agency (EMA) was responsible for defining the substitutability of follow-ons. Education is required to increase hospital pharmacist’s knowledge of regulatory approval frameworks and their relevance to substitution practices.
A decomposition of local labour-market conditions and their relevance for inequalities in transitions to vocational training
2021-07-02

We investigate to what extent individual transitions to vocational training in Germany have been affected by local labour-market conditions. A statistical decomposition approach is developed and applied, allowing for a systematic differentiation between long-term change, short-term fluctuations, and structural regional differences in labour-market conditions. To study individual-level consequences for transitions to vocational training, regionalized labour-market data are merged with longitudinal data from the National Educational Panel Study, and multivariate transition-rate models are fitted. The results indicate that structural differences between regions have had significant effects on the transition behavior of school leavers, whereas temporary crises have been of only minor relevance. Moreover, different groups have been affected to different degrees by varying labour-market conditions. We also highlight the usefulness of our decomposition approach for a broader set of applications. (DIPF/Orig.)
Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma
2021-07-03

In malignant disease, CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Tregs) hamper antitumor immune responses and may provide a target for immunotherapy. Although immune checkpoint blockade (ICB) has become an established therapy for several cancer entities including lymphoma, its mechanisms have not been entirely uncovered. Using endogenously arising λ-MYC-transgenic mouse B-cell lymphomas, which can effectively be suppressed by either Treg ablation or ICB, we investigated which mechanisms are used by Tregs to suppress antitumor responses and how ICB affects these pathways. During tumor development, Tregs up-regulated Foxp3, CD25, CTLA-4 and IL-10, which correlated with enhanced immunosuppressive functions. Thus, in contrast to other tumors, Tregs did not become dysfunctional despite chronic stimulation in the tumor microenvironment and progressive up-regulation of PD-1. Immunosuppression was mediated by direct contacts between Tregs and effector T cells and by IL-10. When λ-MYC mice were treated with ICB antibodies, Tregs revealed a less profound up-regulation of Foxp3, CD25 and IL-10 and a decreased suppressive capacity. This may be due to the shift towards a pro-inflammatory milieu fostered by ICB. In summary, an ICB-induced interference with Treg-dependent immunosuppression may contribute to the success of ICB.