julilili42/papers huggingface dataset:
The dominantly expressed class II molecule from a resistant MHC haplotype presents only a few Marek’s disease virus peptides by using an unprecedented binding motif
2021-04-26

Viral diseases pose major threats to humans and other animals, including the billions of chickens that are an important food source as well as a public health concern due to zoonotic pathogens. Unlike humans and other typical mammals, the major histocompatibility complex (MHC) of chickens can confer decisive resistance or susceptibility to many viral diseases. An iconic example is Marek’s disease, caused by an oncogenic herpesvirus with over 100 genes. Classical MHC class I and class II molecules present antigenic peptides to T lymphocytes, and it has been hard to understand how such MHC molecules could be involved in susceptibility to Marek’s disease, given the potential number of peptides from over 100 genes. We used a new in vitro infection system and immunopeptidomics to determine peptide motifs for the 2 class II molecules expressed by the MHC haplotype B2, which is known to confer resistance to Marek’s disease. Surprisingly, we found that the vast majority of viral peptide epitopes presented by chicken class II molecules arise from only 4 viral genes, nearly all having the peptide motif for BL2*02, the dominantly expressed class II molecule in chickens. We expressed BL2*02 linked to several Marek’s disease virus (MDV) peptides and determined one X-ray crystal structure, showing how a single small amino acid in the binding site causes a crinkle in the peptide, leading to a core binding peptide of 10 amino acids, compared to the 9 amino acids in all other reported class II molecules. The limited number of potential T cell epitopes from such a complex virus can explain the differential MHC-determined resistance to MDV, but raises questions of mechanism and opportunities for vaccine targets in this important food species, as well as providing a basis for understanding class II molecules in other species including humans.
Physiological Role and Use of Thyroid Hormone Metabolites - Potential Utility in COVID-19 Patients
2021-04-26

Thyroxine and triiodothyronine (T3) are classical thyroid hormones and with relatively well-understood actions. In contrast, the physiological role of thyroid hormone metabolites, also circulating in the blood, is less well characterized. These molecules, namely, reverse triiodothyronine, 3,5-diiodothyronine, 3-iodothyronamine, tetraiodoacetic acid and triiodoacetic acid, mediate both agonistic (thyromimetic) and antagonistic actions additional to the effects of the classical thyroid hormones. Here, we provide an overview of the main factors influencing thyroid hormone action, and then go on to describe the main effects of the metabolites and their potential use in medicine. One section addresses thyroid hormone levels in corona virus disease 19 (COVID-19). It appears that i) the more potently-acting molecules T3 and triiodoacetic acid have shorter half-lives than the less potent antagonists 3-iodothyronamine and tetraiodoacetic acid; ii) reverse T3 and 3,5-diiodothyronine may serve as indicators for metabolic dysregulation and disease, and iii) Nanotetrac may be a promising candidate for treating cancer, and resmetirom and VK2809 for steatohepatitis. Further, the use of L-T3 in the treatment of severely ill COVID-19 patients is critically discussed.
LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
2021-04-26

Abstract While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analyzed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.
Association between language and early numerical development – The case of quantifiers
2021-04-26

Language and numerical development are associated in early childhood. In the present study, we focused on the association of the development of children's cardinality understanding of small numbers and their knowledge on unspecific quantifiers (i.e., many, a few). In a longitudinal study, we pursued the research question whether children's knowledge on quantifiers facilitated the acquisition of specific cardinality understanding. Therefore, we followed a total of 76 (34 boys and 42 girls) monolingual German-speaking children aged between 3;6 and 4;6 years at the first measurement time point for two more measurement time points 6 months and one year later. Children's cardinality understanding of small numbers and their quantifier knowledge were assessed using a give-N task. Results indicated a full mediation effect of children's quantifier knowledge at time point 2 on the development of their cardinality understanding from time point 2 to time point 3. This indicates a significant contribution of children's knowledge on unspecific quantifiers to the development of their specific cardinality understanding.
Beyond the tracked line of sight - Evaluation of the peripheral usable field of view in a simulator setting
2021-04-26

Combining advanced gaze tracking systems with the latest vehicle environment sensors opens up new fields of applications for driver assistance. Gaze tracking enables researchers to determine the location of a fixation, and under consideration of the visual saliency of the scene, to predict visual perception of objects. The perceptual limits, for stimulus identification, found in literature have mostly been determined in laboratory conditions using isolated stimuli, with a fixed gaze point, on a single screen with limited coverage of the field of view. The found limits are usually reported as hard limits. Such commonly used limits are therefore not applicable to settings with a wide field of view, natural viewing behavior and multi-stimuli. As handling of sudden, potentially critical driving maneuvers heavily relies on peripheral vision, the peripheral limits for feature perception need to be included in the determined perceptual limits. To analyze the human visual perception of different, simultaneously occurring, object changes (shape, color, movement) we conducted a study with 50 participants, in a driving simulator and we propose a novel way to determine perceptual limits, which is more applicable to driving scenarios.
Freedom in amina wadud's Tawḥīdic Hermeneutics and Mouhanad Khorchide's Theology of Mercy
2021-04-26

Western Islamology often regards liberal Islamic intellectuals as the exotics among the exotics. However, contemporary freethinkers from within academia employ concepts already prominent among the first generation of postcolonial Muslim emancipators, and they also refer to philosophical thought not only from the Islamic heritage but also from other traditions. In the following description and comparison of amina wadud and Mouhanad Khorchide, we trace their ideas on hermeneutics and freedom. With an individual confessional outlook on a cosmopolitan and essentially humanistic Islam, both authors provide authentic versions of a profoundly anthropocentric faith. Their aim is to do justice to the dynamism of life by actively safeguarding Islam's relevance for today. It is time to give these alternative voices the weight they deserve within the rich landscapes of Islamic philosophies.
In vitroeffects of S-Licarbazepine as a potential precision therapy onSCN8Avariants causing neuropsychiatric disorders
2021-04-26

Abstract Background and Purpose Among genetic epilepsies, variants in sodium channel coding genes constitute a major subgroup. Variants in SCN8A , the coding gene for Na V 1.6 channels, are characterized by a variety of symptoms including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, and others such as autistic features, ataxia or dystonia. Standard anticonvulsant treatment has only limited impact on the course of disease. Experimental Approach Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome intractability. Toward this aim, we investigated in vitro in neuroblastoma cells the effects of S-Licarbazepine, a third-generation dibenzazepine and enhancer of slow inactivation of voltage gated sodium channels, on three gain-of-function Na V 1.6 variants linked to representative phenotypes of mild epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results S-Licarbazepine strongly enhances the slow and - less pronounced – the fast inactivation of Na V 1.6 wildtype channels. It acts similarly on all tested variants and irrespective of their particular biophysical dysfunction mechanism. Beyond that S-Licarbazepine has variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D, M1760I) and a trend to reduce the enhanced persistent Na + current by A1622D variant channels. Conclusion and Implications These data bring out that S-Licarbazepine not only owns substance-specific effects, but also holds variant-specific effects, which can variably contribute to functional compensation of distinct channel-specific biophysical properties and thereby highlighting the role of personalized approaches, which likely will be key to improved and successful treatment not only of SCN8A -related disease. Bullet points What is already known? S-Lic strongly modulates slow and - to a less extend - fast inactivation of wild-type Na V 1.6 channels. What this study adds? Differential modulatory effects of S-Lic extend to Na V 1.6 A1622D, M1760I and G1475R variant channels irrespective of their leading biophysical mode of gain-of-function and variably contribute to variant-specific functional compensation of their altered biophysical properties. Clinical significance: These data suggest therapeutic potential of S-Lic for SCN8A neuropsychiatric disorders and highlight the role of personalized approaches aimed at increasingly precise correction of underlying pathophysiological mechanisms.
Hybridization of Alkali Basaltic Magmas: a Case Study of the Ogol Lavas from the Laetoli Area, Crater Highlands (Tanzania)
2021-04-26

Abstract The southern part of the eastern branch of the East African Rift is characterized by extensive volcanic activity since the late Miocene. In the Crater Highlands, part of the North Tanzanian Divergence zone, effusive and pyroclastic rocks reflect nephelinitic and basaltic compositions that formed between 4·6 and 0·8 Ma. The former are best represented by the Sadiman volcano (4·6–4·0 Ma) and the latter occur in the giant Ngorongoro crater (2·3–2·0 Ma), the Lemagarut volcano (2·4–2·2 Ma) and as a small volcanic field in the Laetoli area (2·3 Ma), where basaltic rocks known as Ogol lavas were erupted through fissures and several cinder cones. Compositionally, they are alkaline basalts with 46·0–47·9 wt% SiO2, 3·0–4·3 wt% of Na2O + K2O, Mg# of 61 to 55, and high Cr and Ni content (450–975 and 165–222 ppm respectively). Detailed textural and compositional analysis of the major minerals (olivine, clinopyroxene, plagioclase and spinel-group minerals) reveals the heterogeneity of the rocks. The primary mineral assemblage that crystallized from the Ogol magmas comprises macro- and microcrysts of olivine (Fo89·5–84·2), Cr-bearing diopside to augite, magnesiochromite–chromitess, magnetite–ulvöspinelss, andesine–oligoclasess and fluorapatite, with glass of phonolitic composition in the groundmass. All samples contain appreciable proportions of xenocrystic minerals of macro- and microcryst size, with large variations in both concentration and mineral populations between samples. Xenocrysts include olivine with reverse zonation (Fo84·1–72·5), rounded and embayed clinopyroxene cores of variable composition, anhedral Cr-free magnetite–ulvöspinelss and embayed oligoclase. These xenocrysts as well as variations in major and trace element contents, 87Sr/86Sr(i) (0·70377–0·70470) and 143Nd/144Nd(i) (0·51246–0·51261) ratios provide evidence of multi-stage magma mixing and mingling between Ogol and adjacent Lemagarut volcano basaltic melts with only very minor contamination by Precambrian granite–gneisses. Elevated alkalinity of Ogol lavas, which positively correlates with isotope ratios, and the presence of xenocrystic green core clinopyroxene, perovskite, schorlomite and titanite indicate additional mixing and mingling with evolved nephelinitic magmas and/or assimilation of nephelinitic Laetolil tuffs or foidolitic rocks related to the Sadiman volcano. Owing to their heterogeneity, estimates on the crystallization conditions for the Ogol rocks are difficult. Nevertheless, clinopyroxene–liquid thermobarometry indicates crystallization temperatures of around 1150–1220 °C and records upper-crustal depths of 3–12 km (1–4 kbar). Despite the fact that Ogol basalts are hybrid rocks that formed under open-system conditions with well-documented mixing and mingling processes, they seem to be the best examples closest to primary basaltic melts within the Crater Highlands.
Is large-scale rapid CoV-2 testing a substitute for lockdowns?
2021-04-26

BACKGROUND Various forms of contact restrictions have been adopted in response to the Covid-19 pandemic. Around February 2021, rapid testing appeared as a new policy instrument. Some claim it may serve as a substitute for contact restrictions. OBJECTIVES/METHODS We evaluate the effects of a unique policy experiment: In March and April 2021, the city of Tübingen set up a testing scheme while relaxing contact restrictions. We compare case rates in Tübingen county to an appropriately identified control unit. CONCLUSIONS The experiment led to an increase in the reported case rate. This increase is robust across alternative statistical specifications. An epidemiological model that corrects for ‘more cases due to more testing’ and ‘reduced testing and reporting during the Easter holiday’ also confirms the finding.
Predicting the end of Covid-19 infection for various countries using a stochastic agent-based model taking into account vaccination rates and the new mutant
2021-04-26

Abstract Using a stochastic, agent-based model, the course of infection since the first occurrence of a Covid-19 infection is simulated for various countries, taking into account the new, more infectious mutant and the vaccinations. The simulation shows that the course of infection for the United Kingdom (UK) and Israel is surprisingly good. For the other countries, an end date for the infection can be predicted based on the course of the simulation. For Germany, the course is calculated in a second scenario, assuming a higher vaccination rate.
Faculty Opinions recommendation of Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.
2021-04-26

BACKGROUND AND AIMS: Heterogeneity in Crohn's disease [CD] provides a challenge for the development of effective therapies. Our goal was to define a unique molecular signature for severe, refractory CD to enable precision therapy approaches to disease treatment and to facilitate earlier intervention in complicated disease.METHODS: We analysed clinical metadata, genetics, and transcriptomics from uninvolved ileal tissue from CD patients who underwent a single small bowel resection. We determined transcriptional risk scores, cellular signatures, and mechanistic pathways that define patient subsets in refractory CD.RESULTS: Within refractory CD, we found three CD patient subgroups [CD1, CD2, and CD3]. Compared with CD1, CD3 was enriched for subjects with increased disease recurrence after first surgery [OR = 6.78, p = 0.04], enhanced occurrence of second surgery [OR = 5.07, p = 0.016], and presence of perianal CD [OR = 3.61, p = 0.036]. The proportion of patients with recurrence-free survival was smaller in CD3 than in CD1 (p = 0.02, median survival time [months] in CD1 = 10 and CD3 = 6). Overlaying differential gene expression between CD1 and CD3 on CD subgroup-associated genetic polymorphisms identified 174 genes representing both genetic and biological differences between the CD subgroups. Pathway analyses using this unique gene signature indicated eukaryotic initiation factor 2 [eIF2] and cyclic adenosine monophosphate [cAMP] signalling to be dominant pathways associated with CD3. Furthermore, the severe, refractory subset, CD3, was associated with a higher transcriptional risk score and enriched with eosinophil and natural killer T [NKT] cell gene signatures.CONCLUSION: We characterized a subset of severe, refractory CD patients who may need more aggressive treatment after first resection and who are likely to benefit from targeted therapy based on their genotype and tissue gene expression signature.Copyright © 2019 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. PMID: 30877309 Funding information This work was supported by: NIDDK NIH HHS, United States Grant ID: U01 DK062413 NIDDK NIH HHS, United States Grant ID: P01 DK046763 NIDDK NIH HHS, United States Grant ID: K01 DK109081
Spatio-Temporal Analysis of Heavy Metals in Arid Soils at the Catchment Scale Using Digital Soil Assessment and a Random Forest Model
2021-04-27

Predicting the spatio-temporal distribution of absorbable heavy metals in soil is needed to identify the potential contaminant sources and develop appropriate management plans to control these hazardous pollutants. Therefore, our aim was to develop a model to predict soil adsorbable heavy metals in arid regions of Iran from 1986 to 2016. Soil adsorbable heavy metals were measured in 201 samples from locations selected using the Latin hypercube sampling method in 2016. A random forest (RF) model was used to determine the relationship between a suite of geospatial predictors derived from remote sensing and digital elevation model data with georeferenced measurements of soil absorbable heavy metals. The trained RF model from 2016 was used to reconstruct the spatial distribution of soil absorbable heavy metals at three historical timesteps (1986, 1999, and 2010). Results indicated that the RF model was effective at predicting the distribution of heavy metals with coefficients of determination of 0.53, 0.59, 0.41, 0.45, and 0.60 for Fe, Mn, Ni, Pb, and Zn, respectively. The predicted maps showed high spatio-temporal variability; for example, there were substantial increases in Pb (the 1.5–2 mg/kg−1 class) where its distribution increased by ~25% from 1988 to 2016—similar trends were observed for the other heavy metals. This study provides insights into the spatio-temporal trends and the potential causes of soil heavy metal contamination to facilitate appropriate planning and management strategies to prevent, control, and reduce the impact of heavy metal contamination in soils.
Redox control on the tungsten isotope composition of seawater
2021-04-27

Significance The fate and transport of tungsten (W) in aquatic environments is still poorly constrained. To identify the processes that control the abundance of dissolved W, we applied a sophisticated analytical approach that enables the accurate determination of the seawater W isotopic composition. Our results indicate that the removal of W from seawater mainly occurs via adsorption onto oxide minerals. The marine inventory of W is therefore intimately linked to the areal extension of oxic marine conditions. Concurrently, the limited scavenging of W in anoxic marine settings seems a unique characteristic of W, highlighting that W isotopes can help to reconstruct the earliest rise of oceanic oxygen in Earth’s history.
Obtaining deeper insights into microbiome diversity using a simple method to block host and nontargets in amplicon sequencing
2021-04-27

Abstract Profiling diverse microbiomes is revolutionizing our understanding of biological mechanisms and ecologically relevant problems, including metaorganism (host + microbiome) assembly, functions and adaptation. Amplicon sequencing of multiple conserved, phylogenetically informative loci has therefore become an instrumental tool for many researchers. Investigations in many systems are hindered, however, since essential sequencing depth can be lost by amplification of nontarget DNA from hosts or overabundant microorganisms. Here, we introduce “blocking oligos”, a low‐cost and flexible method using standard oligonucleotides to block amplification of diverse nontargets and software to aid their design. We apply them primarily in leaves, where exceptional challenges with host amplification prevail. A . thaliana ‐specific blocking oligos applied in eight different target loci reduce undesirable host amplification by up to 90%. To expand applicability, we designed universal 16S and 18S rRNA gene plant blocking oligos for targets that are conserved in diverse plant species and demonstrate that they efficiently block five plant species from five orders spanning monocots and dicots ( Bromus erectus , Plantago lanceolata , Lotus corniculatus , Amaranth sp., Arabidopsis thaliana ). These can increase alpha diversity discovery without biasing beta diversity patterns and do not compromise microbial load information inherent to plant‐derived 16S rRNA gene amplicon sequencing data. Finally, we designed and tested blocking oligos to avoid amplification of 18S rRNA genes of a sporulating oomycete pathogen, demonstrating their effectiveness in applications well beyond plants. Using these tools, we generated a survey of the A . thaliana leaf microbiome based on eight loci targeting bacterial, fungal, oomycete and other eukaryotic microorganisms and discuss complementarity of commonly used amplicon sequencing regions for describing leaf microbiota. This approach has potential to make questions in a variety of study systems more tractable by making amplicon sequencing more targeted, leading to deeper, systems‐based insights into microbial discovery. For fast and easy design for blocking oligos for any nontarget DNA in other study systems, we developed a publicly available R package.
CeCl3/n‐BuLi: Unraveling Imamoto's Organocerium Reagent
2021-04-27

Abstract CeCl 3 (thf) reacts at low temperatures with MeLi, t‐BuLi, and n‐BuLi to isolable organocerium complexes. Solvent‐dependent extensive n‐BuLi dissociation is revealed by 7 Li NMR spectroscopy, suggesting “Ce( n‐ Bu) 3 (thf) x ” or solvent‐separated ion pairs like “[Li(thf) 4 ][Ce( n‐ Bu) 4 (thf) y ]” as the dominant species of the Imamoto reagent. The stability of complexes Li 3 Ln(n‐Bu) 6 (thf) 4 increases markedly with decreasing Ln III size. Closer inspection of the solution behavior of crystalline Li 3 Lu(n‐Bu) 6 (thf) 4 and mixtures of LuCl 3 (thf) 2 /n‐BuLi in THF indicates occurring n‐BuLi dissociation only at molar ratios of &lt;1:3. n‐BuLi‐depleted complex LiLu(n‐Bu) 3 Cl(tmeda) 2 was obtained by treatment of Li 2 Lu(n‐Bu) 5 (tmeda) 2 with ClSiMe 3 , at the expense of LiCl incorporation. Imamoto's ketone/tertiary alcohol transformation was examined with 1,3‐diphenylpropan‐2‐one, affording 99 % of alcohol.