julilili42/papers huggingface dataset:
Capillary electrophoresis applied for the determination of acidity constants and limiting electrophoretic mobilities of ionizable herbicides including glyphosate and its metabolites and for their simultaneous separation
2022-01-05

Abstract Thermodynamic acidity constants and limiting ionic mobilities were determined for polyprotic non‐chromophore analytes using capillary electrophoresis with capacitively coupled contactless conductivity detection. It was not necessary to work with buffers of identical ionic strength as ionic strength effects on effective electrophoretic mobilities were corrected by modeling during data evaluation (software AnglerFish). The mobility data from capillary electrophoresis coupled to conductivity detection were determined in the pH range from 1.25 to 12.02 with a high resolution (36 pH steps). With this strategy, thermodynamic acidity constants and limiting ionic mobilities for various acidic herbicides were determined, sometimes for the first time. The model analytes included glyphosate, its metabolites, and its acetylated derivates (aminomethyl phosphonic acid, glyoxylic acid, sarcosine, glycine, N ‐acetyl glyphosate, N‐ acetyl aminomethyl phosphonic acid, hydroxymethyl phosphonic acid). The obtained data were used in simulations to optimize separations by capillary electrophoresis. Simulations correlated very well to experimental results. With the new method, the separation of glyphosate from interfering components like phosphate in beer samples was possible.
DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family
2022-01-05

Abstract DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients’ frontal cortex, THAP1 patients’ induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients’ iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.
A Naturalistic, European Multi-Center Clinical Study of Electrodermal Reactivity and Suicide Risk Among Patients With Depression
2022-01-05

Background: Electrodermal hyporeactivity has been proposed as a marker of suicidal risk. The EUDOR-A study investigated the prevalence of electrodermal hyporeactivity among patients with depression and its association with attempted and completed suicide. Methods: Between August 2014 and March 2016, 1,573 in- and outpatients with a primary diagnosis of depression (active or remission phase) were recruited at 15 European psychiatric centers. Each patient was followed-up for 1 year. Electrodermal activity was assessed at baseline with the ElectroDermal Orienting Reactivity Test. Data on the sociodemographic characteristics, clinical diagnoses, and treatment of the subjects were also collected. The severity of the depressive symptoms was assessed through the Montgomery–Asberg Depression Rating Scale. Information regarding number, time, and method of suicide attempts was gathered at baseline and at the end of the 1-year follow-up. The same data were collected in case of completed suicide. Results: Hyporeactive patients were shown to be significantly more at risk of suicide attempt compared to reactive patients, both at baseline and follow-up. A sensitivity of 29.86% and a positive predictive value (PPV) of 46.77% were found for attempted suicide at baseline, while a sensitivity of 35.36% and a PPV of 8.92% were found for attempted suicide at follow-up. The sensitivity and PPV for completed suicide were 25.00 and 0.61%, respectively. However, when controlled for suicide attempt at baseline, the association between hyporeactivity and follow-up suicide attempt was no longer significant. The low number of completed suicides did not allow any analysis.
Feeding to satiation induces mild oxidative/carbonyl stress in the brain of young mice
2022-01-05

Intermittent fasting as a dietary intervention can prevent overweight and obesity in adult organisms. Nevertheless, information regarding consequences of intermittent fasting for redox status and reactive metabolite-mediated processes that are crucial for the normal functioning of organisms is limited. Since the information on effects of intermittent fasting on parameters of oxidative/carbonyl stress in the brains of young mice was absent, the present study addressed these questions using an every-other-day fasting (EODF) protocol. The levels of carbonyl proteins were ~28 %, 22 % and 18 % lower in the cerebral cortex of EODF males and females and middle parts of the brain of EODF males, respectively, as compared to their ad libitum fed counterparts. Lipid peroxides and α-dicarbonyl compounds were lower only in the cortex and medulla part of EODF male brain. The EODF regimen resulted in higher total non-specific antioxidant capacity in different parts of male brain and a tendency to be higher this parameter in females. At the same time, EODF regimen had no effect on the activities of the defensive antioxidant enzymes, namely superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, glyoxylase 1 and glucose-6-phosphate dehydrogenase in the cortex of both sexes, but even decreased activities of these enzymes in medulla and middle part of the brain. In general, the results suggest that in the brain of young mice ad libitum feeding induces mild oxidative/carbonyl stress which may be partially alleviated by the EODF regimen. The effect of EODF regimen is more pronounced in the medulla part than in the cortex.
Patient views on genetics and functional imaging for precision medicine: a willingness-to-pay analysis
2022-01-05

<b>Purpose:</b> Willingness-to-pay (WTP) analyses can support allocation processes considering the patients preferences in personalized medicine. However, genetic testing especially might imply ethical concerns that have to be considered. <b>Methods:</b> A WTP questionnaire was designed to compare preferences for imaging and genetic testing in cancer patients and to evaluate potential ethical concerns. <b>Results:</b> Comparing the options of imaging and genetics showed comparable WTP values. Ethical concerns about genetic testing seemed to be minor. Treatment success was the top priority irrespective of the diagnostic modality. In general, the majority of patients considered personalized medicine to be beneficial. <b>Conclusion:</b> Most patients valued personalized approaches and rated the benefits of precision medicine of overriding importance irrespective of modality or ethical concerns.
‘When most I wink, then’ – what? Assessing the comprehension of literary texts in university students of English as a second language
2022-01-05

This article introduces a test for literary text comprehension in university students of English as a second language. Poetry is especially suited for our purpose since it frequently shows features that offer challenges to comprehension in a limited space. An example is Shakespeare’s Sonnet 43, on which our test is based: it is suited for assessing not only if a text has been understood but also the ability of respondents to reflect on their own comprehension skills. We show that the test’s psychometric properties are satisfactory, and we demonstrate its validity by analysing relevant external indicators. Thus, we can show a direct link between general reading experience and text comprehension as tested: the more students read, the better do they perform. The collaboration of literary studies with psychometrics moreover allows for a statistically valid identification of specific challenges to comprehension and thus advance our knowledge of what readers find difficult. This will be of interest not only in a hermeneutic and linguistic perspective but also with a view to addressing those difficulties in an educational context. For example, asking someone whether they have understood an utterance (in this case: a line of poetry) does not elicit reliable answers. Being able to say how one has established the meaning of a line seems to be a more reliable indicator of actually having understood it.
Multi-surveyor detection-mark-redetection as a powerful tool for butterfly population monitoring in the pre-imaginal stage
2022-01-05

1. For many elusive insect species, which are difficult to cover by standard monitoring schemes, innovative monitoring methods are needed to gain robust data on population trends. We suggest a monitoring of overwintering larvae for the endangered nymphalid butterfly Limenitis reducta. 2. We tested one removal and three detection-mark-redetection (DMR) approaches in a field study in the “Alb-Donau” region, Germany. We replaced movement of the study organisms by random movement of multiple different surveyors, and we examined the model assumption of equal detectability using simulations. 3. Our results indicate that multi-surveyor removal/DMR techniques are suitable for estimating abundance of overwintering L. reducta larvae. Detection probabilities varied with surveyor experience and the uncertainty of population estimates increased with a decrease in personnel expenditure. Estimated larval densities on a spruce clear-cut ranged between one and three individuals per 100 m2. 4. We suggest a detection-mark-redetection (DMR) approach with three trained surveyors for the monitoring of L. reducta populations in the pre-imaginal stage. Besides L. reducta, the proposed method is likely to be suitable for other insect taxa with specific immobile life-stages and some sessile organisms, e.g. corals, elusive plants, or fungi.
Early Reconstitution of Antibody Secreting Cells after Allogeneic Stem Cell Transplantation
2022-01-05

Immune cell reconstitution after stem cell transplantation is allocated over several stages. Whereas cells mediating innate immunity recover rapidly, adaptive immune cells, including T and B cells, recover slowly over several months. In this study we investigated kinetics and reconstitution of de novo B cell formation in patients receiving CD3 and CD19 depleted haploidentical stem cell transplantation with additional in vivo T cell depletion with monoclonal anti-CD3 antibody. This model enables a detailed in vivo evaluation of hierarchy and attribution of defined lymphocyte populations without skewing by mTOR- or NFAT-inhibitors. As expected CD3+ T cells and their subsets had delayed reconstitution (&lt;100 cells/μL at day +90). Well defined CD19+ B lymphocytes of naïve and memory phenotype were detected at day +60. Remarkably, we observed a very early reconstitution of antibody-secreting cells (ASC) at day +14. These ASC carried the HLA-haplotype of the donor and secreted the isotypes IgM and IgA more prevalent than IgG. They correlated with a population of CD19− CD27− CD38low/+ CD138− cells. Of note, reconstitution of this ASC occurred without detectable circulating T cells and before increase of BAFF or other B cell stimulating factors. In summary, we describe a rapid reconstitution of peripheral blood ASC after CD3 and CD19 depleted haploidentical stem cell transplantation, far preceding detection of naïve and memory type B cells. Incidence before T cell reconstitution and spontaneous secretion of immunoglobulins allocate these early ASC to innate immunity, eventually maintaining natural antibody levels.
Inflammasome activation in neutrophils of patients with severe COVID-19
2022-01-06

Abstract Infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-CoV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation (ie, apoptosis-associated speck-like protein containing a CARD [ASC] speck assembly) and timing relative to NETosis in stimulated neutrophils by real-time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that ∼2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was observed in neutrophils with an intact poly-lobulated nucleus, suggesting early formation during neutrophil activation. Additionally, 40% of nuclei were positive for citrullinated histone H3, and there was a significant correlation between speck formation and nuclear histone citrullination. Time-lapse microscopy in lipopolysaccharide -stimulated neutrophils from fluorescent ASC reporter mice showed that ASC speck formed transiently and at the microtubule organizing center long before NET release. Our study shows that ASC speck is present in neutrophils from COVID-19 patients with respiratory failure and that it forms early in NETosis. Our findings suggest that inhibition of neutrophil inflammasomes may be beneficial in COVID-19.
Molecular Mechanisms of Staphylococcus and Pseudomonas Interactions in Cystic Fibrosis
2022-01-06

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that is characterized by recurrent and chronic infections of the lung predominantly by the opportunistic pathogens, Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. While S. aureus is the main colonizing bacteria of the CF lungs during infancy and early childhood, its incidence declines thereafter and infections by P. aeruginosa become more prominent with increasing age. The competitive and cooperative interactions exhibited by these two pathogens influence their survival, antibiotic susceptibility, persistence and, consequently the disease progression. For instance, P. aeruginosa secretes small respiratory inhibitors like hydrogen cyanide, pyocyanin and quinoline N -oxides that block the electron transport pathway and suppress the growth of S. aureus . However, S. aureus survives this respiratory attack by adapting to respiration-defective small colony variant (SCV) phenotype. SCVs cause persistent and recurrent infections and are also resistant to antibiotics, especially aminoglycosides, antifolate antibiotics, and to host antimicrobial peptides such as LL-37, human β-defensin (HBD) 2 and HBD3; and lactoferricin B. The interaction between P. aeruginosa and S. aureus is multifaceted. In mucoid P. aeruginosa strains, siderophores and rhamnolipids are downregulated thus enhancing the survival of S. aureus . Conversely, protein A from S. aureus inhibits P. aeruginosa biofilm formation while protecting both P. aeruginosa and S. aureus from phagocytosis by neutrophils. This review attempts to summarize the current understanding of the molecular mechanisms that drive the competitive and cooperative interactions between S. aureus and P. aeruginosa in the CF lungs that could influence the disease outcome.
Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition
2022-01-06

Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity is associated with numerous forms of hearing loss, including noise damage, age-dependent hearing loss, and deafness, as well as tinnitus or auditory processing deficits in autism spectrum disorder (ASD). In most cases, the reduced central inhibitory activity and the accompanying hyperexcitability are interpreted as an active compensatory response to the absence of synaptic activity, linked to increased central neural gain control (increased output activity relative to reduced input). We here suggest that hyperexcitability also could be related to an immaturity or impairment of tonic inhibitory strength that typically develops in an activity-dependent process in the ascending auditory pathway with auditory experience. In these cases, high-SR auditory nerve fibers, which are critical for the shortest latencies and lowest sound thresholds, may have either not matured (possibly in congenital deafness or autism) or are dysfunctional (possibly after sudden, stressful auditory trauma or age-dependent hearing loss linked with cognitive decline). Fast auditory processing deficits can occur despite maintained basal hearing. In that case, tonic inhibitory strength is reduced in ascending auditory nuclei, and fast inhibitory parvalbumin positive interneuron (PV-IN) dendrites are diminished in auditory and frontal brain regions. This leads to deficits in central neural gain control linked to hippocampal LTP/LTD deficiencies, cognitive deficits, and unbalanced extra-hypothalamic stress control. Under these conditions, a diminished inhibitory strength may weaken local neuronal coupling to homeostatic vascular responses required for the metabolic support of auditory adjustment processes. We emphasize the need to distinguish these two states of excitatory/inhibitory imbalance in hearing disorders: (i) Under conditions of preserved fast auditory processing and sustained tonic inhibitory strength, an excitatory/inhibitory imbalance following auditory deprivation can maintain precise hearing through a memory linked, transient disinhibition that leads to enhanced spiking fidelity (central neural gain⇑) (ii) Under conditions of critically diminished fast auditory processing and reduced tonic inhibitory strength, hyperexcitability can be part of an increased synchronization over a broader frequency range, linked to reduced spiking reliability (central neural gain⇓). This latter stage mutually reinforces diminished metabolic support for auditory adjustment processes, increasing the risks for canonical dementia syndromes.
Hydrodynamics of quantum entropies in Ising chains with linear dissipation
2022-01-06

Abstract We study the dynamics of quantum information and of quantum correlations after a quantum quench, in transverse field Ising chains subject to generic linear dissipation. As we show, in the hydrodynamic limit of long times, large system sizes, and weak dissipation, entropy-related quantities—such as the von Neumann entropy, the Rényi entropies, and the associated mutual information—admit a simple description within the so-called quasiparticle picture. Specifically, we analytically derive a hydrodynamic formula, recently conjectured for generic noninteracting systems, which allows us to demonstrate a universal feature of the dynamics of correlations in such dissipative noninteracting system. For any possible dissipation, the mutual information grows up to a time scale that is proportional to the inverse dissipation rate, and then decreases, always vanishing in the long time limit. In passing, we provide analytic formulas describing the time-dependence of arbitrary functions of the fermionic covariance matrix, in the hydrodynamic limit.
Discovery of a Cryptic Nitro Intermediate in the Biosynthesis of the 3-(trans-2′-Aminocyclopropyl)alanine Moiety of Belactosin A
2022-01-06

Belactosin A, a β-lactone proteasome inhibitor, contains a unique 3-(<i>trans</i>-2'-aminocyclopropyl)alanine moiety. We recently identified the biosynthetic gene cluster of the belactosin series from <i>Streptomyces</i> sp. UCK14. To shed light on the formation of the aminocyclopropylalanine, we established a heterologous pathway expression, constructed a set of gene deletion mutants, and performed feeding studies for a chemical complementation that include the incorporation of stable isotope-labeled precursors. We thereby show that, in the biosynthesis of this building block, a cryptic nitrocyclopropylalanine intermediate is generated from l-lysine. The subsequent reduction of the N-oxygenated precursor to the corresponding amine is mediated by the molybdopterin-dependent enzyme BelN.
Clinico‐radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency
2022-01-06

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.