julilili42/papers huggingface dataset:
Effects of Diminished NADPH:cytochrome P450 Reductase in Human Hepatocytes on Lipid and Bile Acid Homeostasis
2021-11-15

NADPH:cytochrome P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450 (CYP) enzymes involved in the biosynthesis of endogenous substances like bile acids and other steroids as well as in the oxidative metabolism of xenobiotics. P450 oxidoreductase also supports other redox enzymes in fatty acid and cholesterol pathways. Recently, we have established CRISPR/Cas9-mediated POR knockdown in a human hepatic cell model, HepaRG, and demonstrated the differential effects of limited POR expression on CYP activity. The aim of the present work was to systematically investigate the impact of POR knockdown with a focus on the expression of ADME (absorption, distribution, metabolism, and excretion) genes and related regulators. Functional consequences have been assessed using quantitative mass spectrometry for targeted metabolomics covering bile acids, and cholesterol and its precursors, and for untargeted proteomics. In addition to the previously described alteration of RNA expression of CYP genes, we showed significant downregulation of transcriptional regulators of drug metabolism and transport, including NR1I3 (CAR), NR1I2 (PXR), NR1H4 (FXR), and NR1H3 (LXRα) in cells with POR gene disruption. Furthermore, POR knockdown resulted in deregulated bile acid and cholesterol biosynthesis demonstrated by low levels of cholic acid derivates and increased concentrations of chenodeoxycholic acid derivates, respectively. Systemic effects of POR knockdown on global protein expression were indicated by downregulation of several metabolic pathways including lipid metabolism and biological oxidation reactions. The deduced protein network map corroborates CYP enzymes as direct interaction partners, whereas changes in lipid metabolism and homeostasis are the result of indirect effects. In summary, our results emphasize a widespread role of POR in various metabolic pathways and provide the first human data on the effects of diminished POR expression on drug and endogenous metabolism in a genomeedited HepaRG cell model.
Synthesis, Structure, and Thermoelastic Properties of LiSn2Br3(CN2) and Sn4Br2(CN2)3
2021-11-15

Abstract Tin carbodiimides have been reported with various compositions, prepared via solid‐state metathesis reactions by heating tin halides and lithium carbodiimide at moderate temperatures. The formations of two new compounds, LiSn 2 Br 3 (CN 2 ) and Sn 4 Br 2 (CN 2 ) 3 are monitored by differential thermal analysis (DTA), and crystal structures are reported as refined on basis of X‐ray diffraction studies. The structure of LiSn 2 Br 3 (CN 2 ) can be described by two interpenetrating frameworks of corner‐linked coordination polyhedra, raising the possibility of negative thermal expansion (NTE) as investigated by density functional perturbation theory (DFPT). Like some previously reported tin carbodiimide compounds, LiSn 2 Br 3 (CN 2 ) was also found to be a semiconductor with an indirect band gap of 2.5 eV, as determined by DFT calculations.
The Lithium Iodostannate LiSn3I7: Synthesis, Properties and its Relationship to SnI2
2021-11-15

Abstract The mixed lithium tin iodide LiSn 3 I 7 was prepared by reacting LiI and SnI 2 at 300 °C. Single‐crystal X‐ray diffraction revealed a crystal structure related to that of SnI 2 , with nearly identical coordination environments of tin atoms. The lithium ion in the structure of LiSn 3 I 7 shares one crystallographic position with a tin atom in octahedral voids of (LiSn)Sn 2 I 7 , as confirmed by solid‐state 7 Li, 119 Sn and 127 I MAS NMR spectra. DFT band structure calculations show LiSn 3 I 7 to be a semiconductor with an indirect bandgap on the order of 2 eV.
Sponging of glutamate at the outer plasma membrane surface reveals roles for glutamate in development
2021-11-16

SUMMARY Plants use electrical and chemical signals for systemic communication. Herbivory, for instance, appears to trigger local apoplasmic glutamate accumulation, systemic electrical signals, and calcium waves that travel to report insect damage to neighboring leaves and initiate defense. To monitor extra‐ and intracellular glutamate concentrations in plants, we generated Arabidopsis lines expressing genetically encoded fluorescent glutamate sensors. In contrast to cytosolically localized sensors, extracellularly displayed variants inhibited plant growth and proper development. Phenotypic analyses of high‐affinity display sensor lines revealed that root meristem development, particularly the quiescent center, number of lateral roots, vegetative growth, and floral architecture were impacted. Notably, the severity of the phenotypes was positively correlated with the affinity of the display sensors, intimating that their ability to sequester glutamate at the surface of the plasma membrane was responsible for the defects. Root growth defects were suppressed by supplementing culture media with low levels of glutamate. Together, the data indicate that sequestration of glutamate at the cell surface either disrupts the supply of glutamate to meristematic cells and/or impairs localized glutamatergic signaling important for developmental processes.
You gotta fight! – Why norm-violations and outgroup criticism lead to confrontational reactions
2021-11-16

Group members frequently face group-related discrepancies, such as other group members violating group norms or outgroup members criticising the ingroup. In response, they often engage in confrontational reactions like expressing disapproval or excluding the person causing the discrepancy. The present work tests the often voiced but rarely studied idea that group-related discrepancies are met with such confrontational responses because discrepancies elicit <i>feelings</i> of threat. Our approach is inspired by research on threat-regulation, which links certain negative emotions to the activation of specific threat-regulatory systems. Three experiments (<i>N</i><sub>total</sub> = 680) provide evidence suggesting that group-related discrepancies foster emotions consistent with an activation of the Fight-Flight-Freeze-System (especially anger-related emotions tied to fight-tendencies), emotions consistent with an activation of the Behavioural Inhibition System (i.e. anxiety-related emotions), and confrontational intentions. The effect of discrepancies on confrontational intentions was mediated by heightened anger-related emotions. This supports the idea that confrontational reactions are driven by experienced threat and that these reactions are rightfully called confrontational. We discuss our results in relation to research on ingroup norm-violations, outgroup criticism, and threat perception.
Pathophysiological interplay between O -GlcNAc transferase and the Machado–Joseph disease protein ataxin-3
2021-11-16

Significance Machado–Joseph disease (MJD) is an incurable neurodegenerative disorder caused by a mutation in the ataxin-3 protein, which becomes toxic and induces cerebellar degeneration and motor impairments. Disturbances in the protein modification O -GlcNAcylation, catalyzed by the enzyme O -GlcNAc transferase (OGT), have been linked to neurodegeneration, but its potential involvement in MJD remains elusive. By analyzing MJD cells and animal models, we demonstrate altered levels of OGT in MJD, further identifying this enzyme as a substrate of ataxin-3. Targeting OGT reduced ataxin-3 toxicity, improving the motor phenotype of an MJD animal model. Our results unveiled a physiological interplay between ataxin-3 and OGT, highlighting OGT as a potential therapeutic target in this deadly condition.
Trait Response to Nitrogen and Salinity in Rhizophora mangle Propagules and Variation by Maternal Family and Population of Origin
2021-11-16

Many coastal foundation plant species thrive across a range of environmental conditions, often displaying dramatic phenotypic variation in response to environmental variation. We characterized the response of propagules from six populations of the foundation species Rhizophora mangle L. to full factorial combinations of two levels of salinity (15 ppt and 45 ppt) reflecting the range of salinity measured in the field populations, and two levels of nitrogen (N; no addition and amended at approximately 3 mg N per pot each week) equivalent to comparing ambient N to a rate of addition of 75 kg per hectare per year. The response to increasing salinity included significant changes, i.e., phenotypic plasticity, in succulence and root to shoot biomass allocation. Propagules also showed plasticity in maximum photosynthetic rate and root to shoot allocation in response to N amendment, but the responses depended on the level of salinity and varied by population of origin. In addition, propagules from different populations and maternal families within populations differed in survival and all traits measured except photosynthesis. Variation in phenotypes, phenotypic plasticity and propagule survival within and among R. mangle populations may contribute to adaptation to a complex mosaic of environmental conditions and response to climate change.
Laser‐evoked potentials recover gradually when using dorsal root ganglion stimulation, and this influences nociceptive pathways in neuropathic pain patients
2021-11-16

Abstract Objective Dorsal root ganglion stimulation (DRGS) is able to relieve chronic neuropathic pain. There seems evidence that DRGS might achieve this by gradually influencing pain pathways. We used laser‐evoked potentials (LEP) to verify our hypothesis that the recovery of the LEP may reflect DRGS‐induced changes within the nociceptive system. Methods Nine patients (mean age 56.8 years, range 36–77 years, two females) diagnosed with chronic neuropathic pain in the knee or groin were enrolled in the study. We measured each patient's LEP at the painful limb and contralateral control limb on the first, fourth, and seventh day after implantation of the DRGS system. We used the numeric rating scale (NRS) for the simultaneous pain assessment. Results The LEP amplitude of the N2–P2 complex showed a significant increase on day 7 when compared to day 1 ( Z = −2.666, p = 0.008) and to day 4 ( Z = −2.547, p = 0.011), respectively. There was no significant difference in the N2–P2 complex amplitude between ON and OFF states during DRGS. The patients’ NRS significantly decreased after 1 day ( p = 0.007), 4 days ( p = 0.007), and 7 days ( p = 0.007) when compared to the baseline. Conclusions The results show that with DRGS, the LEP recovered gradually within 7 days in neuropathic pain patients. Therefore, reduction of the NRS in patients with chronic neuropathic pain might be due to DRGS‐induced processes within the nociceptive system. These processes might indicate neuroplasticity mediated recovery of the LEP.
Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome
2021-11-16

Summary Background Acute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. Methods We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12 th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. Findings Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0·17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0·04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. Interpretation Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.
Abstract 10165: The Correlation of Age and Extension Length in Debakey Type I Aortic Dissection: Are Septuagenarians at a Lower Risk?
2021-11-16

Introduction: Elderly patients have been suggested to be more prone to acute aortic dissection due to a higher incidence of age-related atherosclerosis and stiffness of the thoracic aorta. Hypothesis: Younger patients suffer more extensive DeBakey type I dissections due to aortic wall integrity, potentially allowing unhindered extension. The study's aim was to correlate age and dissection extension length in a large contemporary multi-center cohort. Methods: The perioperative data of 3385 patients with acute aortic dissection were retrospectively analyzed with regard to postoperative outcome and dissection extent. DeBakey type I aortic dissections (n=2510) were identified and divided into two groups: &lt;70 years (n=1741) and &gt;70 years (n=769). Patients with DeBakey type II and connective tissue disease were excluded (n=875). Results: Septuagenarians (&gt;70 yrs) had a higher incidence of atherosclerosis (32.0% vs. 18.9%; p&lt;0.001) and showed significantly more often a limitation of dissection extension until the aortic arch level (40.9% vs. 29.2%; p&lt;0.001). In younger patients, aortic dissections involved the supraaortic vessels more often (52.0% vs. 40.1%; p&lt;0.001) and extended significantly further downstream the aorta: descending aorta (68.5% vs. 57.1%; p&lt;0.001), abdominal aorta (54.7% vs. 42.0%; p&lt;0.001) and iliac bifurcation (36.6% vs. 26.0%; p&lt;0.001) ( Fig.1 ). Clinically, younger patients presented with significantly higher incidences of preoperative cerebral (p=0.002), spinal (p=0.003), visceral (p=0.002) and peripheral (p&lt;0.001) malperfusion. In-hospital mortality rates in patients &lt;70 yrs and &gt;70 yrs were 18.9% and 22.2% (p=0.067), respectively. Conclusions: Extensive DeBakey type I aortic dissection is less frequent in septuagenarians. Conversely, younger patients suffer significantly more often from preoperative organ malperfusion and associated complications. Postoperative mortality remains high irrespective of age groups.
Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia
2021-11-16

Abstract Recent studies have suggested that cerebellar and subcortical structures are impacted early in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau ( MAPT ), progranulin ( GRN ) and chromosome 9 open reading frame 72 ( C9orf72 ). However, the clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the C9orf72 group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity for each genetic group. The biggest differences were in the extent of the cerebellar involvement (larger extent in C9orf72 group) and more prominent amygdalar contribution in the MAPT group. Finally, our findings demonstrated that C9orf72 and MAPT brain scores were related to estimated years before the age of symptom onset (EYO) in a second order relationship highlighting a steeper brain score decline 20 years before expected symptom onset, while GRN brain scores were related to age and not EYO. Overall, these results demonstrated the important role of the subcortical structures and especially of the cerebellum in genetic FTD symptom expression.
Boethius
2021-11-16

For a long time, Boethius (b. between 475 and 480, d. between 524 and 526) has only been considered a mediator between classical ancient thought and the Middle Ages. Nowadays, this view is increasingly changing and Boethius is more and more recognized as an independent and creative thinker who made significant contributions to philosophy and theology. The entry sheds some light on the peculiarities of Boethius's theological and philosophical methods, on his rather innovative position on the relationship between faith and reason and on the lasting impact Boethius's thought has had on the development of rational theology, especially in the Middle Ages.
Bridging the Gap between Autonomous and Predetermined Paradigms: The Role of Sampling in Evaluative Learning
2021-11-16

While most evaluative learning paradigms remove participants’ autonomy over the information they receive, other research traditions have demonstrated that information sampling has an important role in learning. We investigate the impact of information sampling on a central evaluative learning paradigm: evaluative conditioning. We compare a traditional evaluative conditioning paradigm with a paradigm in which participants have autonomy over the stimulus pairings they receive. Participants in the high-autonomy condition show a strong preference for positively paired CSs. Nevertheless, the strength of evaluative conditioning effects was independent of autonomy. Moreover, high-autonomy participants, but not their low-autonomy counterparts, demonstrate a relationship between sampling frequency and evaluations, in line with the interpretation that sampled stimuli become more positive, whereas ignored stimuli become more negative over the course of the learning phase. The present research provides a cornerstone for integrating several research traditions within and beyond the evaluative learning literature, providing a foundation for new insights and more comprehensive theories of evaluative learning.
Statistical bias control in typology
2021-11-17

Abstract In this paper, we propose two new statistical controls for genealogical and areal bias in typological samples. Our test case being the effect of VO-order effect on affix position (prefixation vs. suffixation), we show how statistical modeling including a phylogenetic regression term (phylogenetic control) and a two-dimensional Gaussian Process (areal control) can be used to capture genealogical and areal effects in a large but unbalanced sample. We find that, once these biases are controlled for, VO-order has no effect on affix position. Another important finding, which is in line with previous studies, is that areal effects are as important as genealogical effects, emphasizing the importance of areal or contact control in typological studies built on language samples. On the other hand, we also show that strict probability sampling is not required with the statistical controls that we propose, as long as the sample is a variety sample large enough to cover different areas and families. This has the crucial practical consequence that it allows us to include as much of the available information as possible, without the need to artificially restrict the sample and potentially lose otherwise available information.
Surface Transient Storage Under Low‐Flow Conditions in Streams With Rough Bathymetry
2021-11-17

Abstract In natural and restored rivers, protruding river‐bed elements can cause complex flow patterns. We hypothesize that, particularly at very low flows, solute spreading in such streams is controlled by different mechanisms than at high flows, questioning existing parameterizations. We investigate two‐dimensional flow and transport in a synthetic channel with rough bathymetry under low‐flow conditions with a numerical model solving the full shallow‐water equations. Recirculation cells form behind protruding bed elements and trap water, macroscopically acting as transient‐storage domain. We fit the one‐dimensional mobile‐immobile transport model to the concentration breakthrough curves of the two‐dimensional model and relate the fitted parameters to easy‐to‐measure properties of the stream. The velocity in the mobile domain undergoes a power‐law relation with the discharge and the channel slope, differing from the relationship expected for normal flow in streams with large water depths. Both the fitted dispersion coefficient and the mass‐transfer coefficient between the mobile and immobile domains scale linearly with the velocity in the mobile domain. The ratio of immobile to mobile storage volumes β first increases then decreases with increasing discharge. We suggest measuring the surface area of bed elements protruding the water surface and that of the open water. The product of the corresponding area ratio with the velocity exerts a power‐law control on β . Altogether, we can relate the coefficients of the mobile‐immobile transport model to a few easy‐to‐measure properties of the stream. The findings of the present work contribute to the understanding of surface transient storage in natural and restored streams.
Prevalence of Candida species in Psoriasis
2021-11-17

Abstract Background Psoriasis patients are more frequently colonised with Candida species . The correlation between fungal colonisation and clinical severity is unclear, but may exacerbate psoriasis and the impact of antipsoriatic therapies on the prevalence of Candida is unknown. Objectives To examine the prevalence of C species in psoriasis patients compared to an age‐ and sex‐matched control population, we investigated the influence of Candida colonisation on disease severity, immune cell activation and the interplay on psoriatic treatments. Methods The prevalence of C species was examined in 265 psoriasis patients and 200 control subjects by swabs and stool samples for fungal cultures. Peripheral mononuclear blood cells (PBMCs) were collected from 20 fungal colonised and 24 uncolonised patients and stimulated. The expression of interferon (IFN)‐γ, IL‐17A, IL‐22 and tumour necrosis factor (TNF)‐α from stimulated PBMCs was measured by quantitative real‐time polymerase chain reaction (qPCR). Results A significantly higher prevalence for Candida was detected in psoriatic patients (p ≤ .001) compared to the control subjects; most abundant in stool samples, showing Candida albicans . Older participants (≥51 years) were more frequent colonised, and no correlation with gender, disease severity or systemic treatments like IL‐17 inhibitors was found. Conclusions Although Candida colonisation is significantly more common in patients with psoriasis, it does not influence the psoriatic disease or cytokine response. Our study showed that Candida colonisation is particularly more frequent in patients with psoriasis ≥51 years of age. Therefore, especially this group should be screened for symptoms of candidiasis during treatment with IL‐17 inhibitors.