julilili42/papers huggingface dataset:
Durlobactam, a Diazabicyclooctane β-Lactamase Inhibitor, Inhibits BlaC and Peptidoglycan Transpeptidases of Mycobacterium tuberculosis
2024-04-15

Peptidoglycan synthesis is an underutilized drug target in <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Diazabicyclooctanes (DBOs) are a class of broad-spectrum β-lactamase inhibitors that also inhibit certain peptidoglycan transpeptidases that are important in mycobacterial cell wall synthesis. We evaluated the DBO durlobactam as an inhibitor of BlaC, the <i>Mtb</i> β-lactamase, and multiple <i>Mtb</i> peptidoglycan transpeptidases (PonA1, Ldt<sub>Mt1</sub>, Ldt<sub>Mt2</sub>, Ldt<sub>Mt3</sub>, and Ldt<sub>Mt5</sub>). Timed electrospray ionization mass spectrometry (ESI-MS) captured acyl-enzyme complexes with BlaC and all transpeptidases except Ldt<sub>Mt5</sub>. Inhibition kinetics demonstrated durlobactam was a potent and efficient DBO inhibitor of BlaC (<i>K</i><sub>I app</sub> 9.2 ± 0.9 μM, <i>k</i><sub>2</sub>/<i>K</i> 5600 ± 560 M<sup>-1</sup> s<sup>-1</sup>) and similar to clavulanate (<i>K</i><sub>I app</sub> 3.3 ± 0.6 μM, <i>k</i><sub>2</sub>/<i>K</i> 8400 ± 840 M<sup>-1</sup> s<sup>-1</sup>); however, durlobactam had a lower turnover number (<i>t</i><sub>n</sub> = <i>k</i><sub>cat</sub>/<i>k</i><sub>inact</sub>) than clavulanate (1 and 8, respectively). <i>K</i><sub>I app</sub> values with durlobactam and clavulanate were similar for peptidoglycan transpeptidases, but ESI-MS captured durlobactam complexes at more time points. Molecular docking and simulation demonstrated several productive interactions of durlobactam in the active sites of BlaC, PonA1, and Ldt<sub>Mt2</sub>. Antibiotic susceptibility testing was conducted on 11 <i>Mtb</i> isolates with amoxicillin, ceftriaxone, meropenem, imipenem, clavulanate, and durlobactam. Durlobactam had a minimum inhibitory concentration (MIC) range of 0.5-16 μg/mL, similar to the ranges for meropenem (1-32 μg/mL) and imipenem (0.5-64 μg/mL). In β-lactam + durlobactam combinations (1:1 mass/volume), MICs were lowered 4- to 64-fold for all isolates except one with meropenem-durlobactam. This work supports further exploration of novel β-lactamase inhibitors that target BlaC and <i>Mtb</i> peptidoglycan transpeptidases.
Metacognitive monitoring in early elementary school-aged children: Task dependency in monitoring judgements, task consistency in monitoring behaviours.
2024-04-15

*This is a preprint and not yet published* Metacognitive monitoring is typically considered as a domain general skill that can be applied in different tasks and situations. However, this assumption lacks empirical evidence as few studies tested whether children’s accuracy of monitoring judgments as well as their monitoring behaviours are consistent across tasks. It is also not clear if children who provide more accurate monitoring judgments also show more frequent monitoring behaviours. In the current study 53 elementary school children’s metacognitive monitoring was assessed with four tasks: on the one hand, the accuracy of children’s monitoring judgments was assessed with two computer-based tasks (one task required monitoring of memory and the other task required monitoring of reaction times); on the other hand, the frequency with which they engaged in monitoring behaviours was assessed with two construction tasks. Correlational analysis showed that there was no significant association between children’s monitoring judgment accuracies. In turn, children’s monitoring behaviour on two construction tasks was significantly positively associated. Intercorrelations between children’s monitoring judgment accuracies and monitoring behaviours showed that children who more accurately monitored their reaction time showed significantly more monitoring behaviour when working on construction tasks. Conversely, children’s monitoring judgment accuracy on a memory task was not associated with their monitoring behaviour. These findings suggest that the processes underlying children’s monitoring judgments may be task specific, whereas their tendency to engage in monitoring behaviours may be domain general. Implications for promoting metacognitive monitoring are discussed.
From “Productivity Revolution” to “Digital Garden Cities”: Recent Shifts in the Dominant Political Discourse on Digitalisation in Japan
2024-04-15

Abstract This article investigates recent developments in the dominant political discourse on digitalisation in Japan with a particular focus on the suggested benefits and risks of digital technologies for workers and consumers. Whereas the discourse in the neoliberal Abe era (2012–2020) pushed for deregulation and flatly suggested economic benefits for “everybody,” there has been a recent shift that locates digitalisation in the countryside specifically with an emphasis on rural revitalisation and public infrastructure development. The analysis reveals a continued marginalisation of the risks of digitalisation and an overemphasis of its benefits. The findings further suggest that the dominant Liberal Democratic Party ( LDP ) deliberately creates vagueness which allows the presentation of digitalisation as a panacea for various societal issues depending on the party’s political exigencies. The end of the Abe era and the experience of the pandemic mark significant changes that might create more space for equality issues in the future. However, as “digitalisation for equality” pertains exclusively to the rural-urban divide, there is reasonable doubt that this might merely be the newest iteration of pork barrel politics. The analysis further suggests that benefits for workers as well as the dissemination of digitalisation in general might continue to be obstructed by lobby interests.
Human Placental Schistosomiasis – a Review of the Literature
2024-04-15

Background: Schistosome egg deposition in pregnant women may affect the placenta of infected mothers and cause Placental Schistosomiasis (PS). Histopathological examination of placental tissue is an inadequate detection method due to low sensitivity. So far, there has not been any sys-tematic review on PS. Methods: We conducted a systematic literature search on PubMed and in-cluded relevant secondary literature found in the citations of the primarily included publications. Results: We found a total of 8 publications describing PS with a total of 92 cases, describing egg deposition of dead and/or viable eggs and worms of S. haematobium and S. mansoni in placental tissue. One cross-sectional study investigating the prevalence of PS and its association to adverse birth outcomes, found 22% of placentas to be infested using a maceration technique but only &amp;lt; 1% using histologic examination. Additionally, no direct link to deleterious pregnancy outcomes could be shown. Conclusions: PS is a highly unattended and underdiagnosed condition in en-demic populations, due to a lack of awareness as well as low sensitivity of histopathological examinations. However, PS may play an important role in mediating or reinforcing adverse birth outcomes (ABO) such as fetal growth restriction (FGR) in maternal schistosomiasis, possibly by placental inflammation.
Rise of Populism: Identity Threats as an Explanation in Relation With Deprivation and Cultural Fear
2024-04-15

This article introduces the thesis of threatened social identities as a new explanatory approach to the emergence of populist attitudes and tests it explicitly for the first time using quantitative data. We examine whether SIT indicators explain populist attitudes directly and influence effects of indicators of two established approaches: the losers of modernization thesis (LOM) and the cultural backlash thesis (CBT). We use a sample representative for the German labor force. Furthermore, we developed items to quantify the recognition of social identities for the first time with respect to social class and occupational identities. All four of our SIT indicators—recognition of social class, recognition of an East or West German identity, political recognition of occupational groups, and identity insecurity—are significant predictors of populist attitudes. Based on SEMs, we also conclude that these variables are important antecedents of previously established indicators of LOM and CBT on populist attitudes. Overall, we conclude that SIT adds to the literature on the emergence of populism as another complementary explanatory approach. In addition to being effective as an explanation in its own right, this thesis can also fill theoretical and empirical gaps of the established LOM and CBT.
GDPR Overreach?
2024-04-15

After Meta introduced this model for its social networking services Facebook and Instagram in November 2023, several national data protection authorities called on the EDPB to clarify the compatibility of this model with the GDPR. Data protection law is to be used as a lever to prohibit media companies or online service providers from offering a service that is more data-minimalist than the traditional business model. Data protection authorities are therefore faced with the question of whether the GDPR should address "social justice" concerns.
Removing scanner effects with a multivariate latent approach: A RELIEF for the ABCD imaging data?
2024-04-15

Abstract Scan site harmonization is a crucial part of any neuroimaging analysis when data have been pooled across different study sites. Zhang and colleagues recently introduced the multivariate harmonization method RELIEF (REmoval of Latent Inter-scanner Effects through Factorization), aiming to remove explicit and latent scan site effects. Their initial validation in an adult sample showed superior performance compared to established methods. We here sought to investigate utility of RELIEF in harmonizing data from the Adolescent Brain and Cognitive Development (ABCD) study, a widely used resource for developmental brain imaging. We benchmarked RELIEF against unharmonized, ComBat, and CovBat harmonized data and investigated the impact of manufacturer type, sample size, and a narrow sample age range on harmonization performance. We found that in cases where sites with sufficiently large samples were harmonized, RELIEF outperformed other techniques, yet in cases where sites with very small samples were included there was substantial performance variation unique to RELIEF. Our results therefore highlight the need for careful quality control when harmonizing data sets with imbalanced samples like the ABCD cohort. Our comment alongside shared scripts may provide guidance for other scholars wanting to integrate best practices in their ABCD related work.
Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to Burkholderia pseudomallei , a lung-tropic pathogen
2024-04-15

ABSTRACT Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen Burkholderia pseudomallei . The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in B. pseudomallei infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of B. pseudomallei infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that B. pseudomallei infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that B. pseudomallei likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of B. pseudomallei are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to B. pseudomallei is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to B. pseudomallei infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.
Non-invasive vagus nerve stimulation conditions increased invigoration and wanting in depression
2024-04-16

Our study replicates the invigorating effects of taVNS in Session 1 and reveals its generalizability to depression. Furthermore, we expand upon previous research by showing taVNS-induced conditioning effects on invigoration and wanting within Session 1 in patients that were largely sustained. While enduring motivational improvements present challenges for crossover designs, they are highly desirable in interventions and warrant further follow-up research.
Quantum thermodynamics of boundary time-crystals
2024-04-16

Abstract Time-translation symmetry breaking is a mechanism for the emergence of non-stationary many-body phases, so-called time-crystals, in Markovian open quantum systems. Dynamical aspects of time-crystals have been extensively explored over the recent years. However, much less is known about their thermodynamic properties, also due to the intrinsic nonequilibrium nature of these phases. Here, we consider the paradigmatic boundary time-crystal system, in a finite-temperature environment, and demonstrate the persistence of the time-crystalline phase at any temperature. Furthermore, we analyze thermodynamic aspects of the model investigating, in particular, heat currents, power exchange and irreversible entropy production. Our work sheds light on the thermodynamic cost of sustaining nonequilibrium time-crystalline phases and provides a framework for characterizing time-crystals as possible resources for, e.g. quantum sensing. Our results may be verified in experiments, for example with trapped ions or superconducting circuits, since we connect thermodynamic quantities with mean value and covariance of collective (magnetization) operators.
Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis
2024-04-16

Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary 'Pseudomonas aeruginosa' infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived, cells, cell cultures and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified bi-allelic pathogenic variants in 'WFDC2' in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of 'WFDC2' was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from 'WFDC2-deficient' individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and thus secretion of mature WFDC2. Conclusions: 'WFDC2' dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis.
Simulating vision impairment in virtual reality: a comparison of visual task performance with real and simulated tunnel vision
2024-04-16

Abstract In this work, we explore the potential and limitations of simulating gaze-contingent tunnel vision conditions using Virtual Reality (VR) with built-in eye tracking technology. This approach promises an easy and accessible way of expanding study populations and test groups for visual training, visual aids, or accessibility evaluations. However, it is crucial to assess the validity and reliability of simulating these types of visual impairments and evaluate the extend to which participants with simulated tunnel vision can represent real patients. Two age-matched participant groups were acquired: The first group (n = 8, aged 20–60, average 49.1 ± 13.2) consisted of patients diagnosed with Retinitis pigmentosa (RP). The second group (n = 8, aged 27–59, average 46.5 ± 10.8) consisted of visually healthy participants with simulated tunnel vision. Both groups carried out different visual tasks in a virtual environment for 30 min per day over the course of four weeks. Task performances as well as gaze characteristics were evaluated in both groups over the course of the study. Using the ’two one-sided tests for equivalence’ method, the two groups were found to perform similar in all three visual tasks. Significant differences between groups were found in different aspects of their gaze behavior, though most of these aspects seem to converge over time. Our study evaluates the potential and limitations of using Virtual Reality technology to simulate the effects of tunnel vision within controlled virtual environments. We find that the simulation accurately represents performance of RP patients in the context of group averages, but fails to fully replicate effects on gaze behavior.
Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results
2024-04-16

Abstract INTRODUCTION Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72 , 70 GRN , and 31 MAPT presymptomatic carriers and 158 non‐carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. DISCUSSION Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. Highlights Gray matter perfusion declines in at‐risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at‐risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non‐converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.
Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade
2024-04-16

<b>Rationale:</b> Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. <b>Objectives:</b> To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. <b>Methods:</b> The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. <b>Measurements and Main Results:</b> Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4<sup>+</sup> IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. <b>Conclusions:</b> Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4<sup>+</sup> T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.
A life span perspective on competencies for a healthy, physically active lifestyle: Findings of a data pooling initiative with over 7000 individuals
2024-04-16

Abstract Individuals are recommended to lead active lifestyles throughout the life course. The model of physical activity‐related health competence (PAHCO) adopts a competence approach by integrating physical, cognitive, and motivational determinants for health‐enhancing PA (movement competence, control competence, self‐regulation competence). Drawing on a comprehensive dataset pooling, the goal of the present study was to model the idiosyncratic courses of 10 PAHCO indicators over the life span. We identified studies that empirically operationalized PAHCO, combining data of 7134 individuals (age range: 15–97 years; 61% female) from 18 different populations (prevention and rehabilitation sectors). We applied a stepwise multilevel analysis approach with disjunct sub‐samples ( n = 48) to examine linear and quadratic associations between age and PAHCO. Indicators of movement competence (i.e., manageability of endurance, strength, and balance demands; task‐specific self‐efficacy) congruently showed negative associations with age (0.054 ≤ ≤ 0.211). However, parameters of control competence remained stable across the life span (−0.066 ≤ β ≤ 0.028). The three indicators of self‐regulation competence revealed an inconsistent relationship with age, though uncovering positive associations for self‐control ( β = 0.106) and emotional attitude toward PA ( β = 0.088). The associations of some indicators varied significantly across sub‐samples. The results suggest differential analyses for associations between PAHCO and age. While the physically determined PAHCO indicators (movement competence) probably decline across the life span, the ability to ensure regularity of PA (self‐regulation competence) or align PAs with an individual's health (control competence) appear to remain constant or improve with increasing age. The findings reinforce a de‐stigmatizing approach for PA promotion practices with considerable space for aligning activities with health also in the elderly.