julilili42/papers huggingface dataset:
Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells
2023-10-17

Abstract Therapy-resistant leukemia stem and progenitor cells (LSC) are a main cause of acute myeloid leukemia (AML) relapse. LSC-targeting therapies may thus improve outcome of patients with AML. Here we demonstrate that LSCs present HLA-restricted antigens that induce T-cell responses allowing for immune surveillance of AML. Using a mass spectrometry–based immunopeptidomics approach, we characterized the antigenic landscape of patient LSCs and identified AML- and AML/LSC-associated HLA-presented antigens absent from normal tissues comprising nonmutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. Functional relevance of shared AML/LSC antigens is illustrated by presence of their cognizant memory T cells in patients. Antigen-specific T-cell recognition and HLA class II immunopeptidome diversity correlated with clinical outcome. Together, these antigens shared among AML and LSCs represent prime targets for T cell–based therapies with potential of eliminating residual LSCs in patients with AML. Significance: The elimination of therapy-resistant leukemia stem and progenitor cells (LSC) remains a major challenge in the treatment of AML. This study identifies and functionally validates LSC-associated HLA class I and HLA class II–presented antigens, paving the way to the development of LSC-directed T cell–based immunotherapeutic approaches for patients with AML. See related commentary by Ritz, p. 430 . This article is featured in Selected Articles from This Issue, p. 419
Quantum trajectories of dissipative time crystals
2023-10-17

The authors address the boundary time-crystal transition at the level of individual quantum trajectories that result from continuous monitoring. Signatures of critical behavior and of the time-crystal phase are identified for the photon count signal and homodyne current, while each monitoring scheme is shown to imprint its own characteristic features.
Critical incidents, nocturnal supervision, and caregiver knowledge on SUDEP in patients with Dravet syndrome: A prospective multicenter study in Germany
2023-10-17

Abstract Objective The aim was to investigate the monitoring, interventions, and occurrence of critical, potentially life‐threatening incidents in patients with Dravet syndrome (DS) and caregivers’ knowledge about sudden unexpected death in epilepsy (SUDEP). Methods This multicenter, cross‐sectional study of patients with DS and their caregivers in Germany consisted of a questionnaire and prospective diary querying the disease characteristics and demographic data of patients and caregivers. Results Our analysis included 108 questionnaires and 82 diaries. Patients with DS were 49.1% male ( n = 53), with a mean age of 13.5 (SD ± 10.0 years) and primary caregivers were 92.6% ( n = 100) female, with a mean age of 44.7 (SD ± 10.6 years). Monitoring devices were used regularly by 75.9% ( n = 82) of caregivers, and most monitored daily/nightly. Frequently used devices were pulse oximeters (64.6%), baby monitors (64.6%), thermometers (24.1%), and Epi‐Care (26.8%). Younger caregiver and patient age and history of status epilepticus were associated with increased use of monitoring, and 81% of monitor users reported having avoided a critical incident with nocturnal monitoring. The need for resuscitation due to cardiac or respiratory arrest was reported by 22 caregivers (20.4%), and most cases (72.7%) were associated with a seizure. Caregivers reported frequently performing interventions at night, including oropharyngeal suction, oxygenation, personal hygiene, and change of body position. Most caregivers were well informed about SUDEP ( n = 102; 94%) and monitored for a lateral or supine body position; however, only 39.8% reported receiving resuscitation training, whereas 52.8% ( n = 57) knew what to do in case the child's breathing or heart activity failed. Significance Critical incidents and the need for resuscitation are reported frequently by caregivers and may be related to high mortality and SUDEP rates in DS. Resuscitation training is welcomed by caregivers and should be continuously provided. Oxygen monitoring devices are frequently used and considered useful by caregivers.
The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
2023-10-17

Hereditary retinal degeneration (RD) is often associated with excessive cGMP signalling in photoreceptors. Previous research has shown that inhibition of cGMP-dependent protein kinase G (PKG) can reduce photoreceptor loss in two different RD animal models. In this study, we identified a PKG inhibitor, the cGMP analogue CN238, which preserved photoreceptor viability and functionality in rd1 and rd10 mutant mice. Surprisingly, in explanted retinae, CN238 also protected retinal ganglion cells from axotomy-induced retrograde degeneration and preserved their functionality. Furthermore, kinase activity-dependent protein phosphorylation of the PKG target Kv1.6 was reduced in CN238-treated rd10 retinal explants. Ca2+-imaging on rd10 acute retinal explants revealed delayed retinal ganglion cell repolarization with CN238 treatment, suggesting a PKG-dependent modulation of Kv1-channels. Together, these results highlight the strong neuroprotective capacity of PKG inhibitors for both photoreceptors and retinal ganglion cells, illustrating their broad potential for the treatment of retinal diseases and possibly neurodegenerative diseases in general.
Reframing dopamine: A controlled controller at the limbic-motor interface
2023-10-17

Pavlovian influences notoriously interfere with operant behaviour. Evidence suggests this interference sometimes coincides with the release of the neuromodulator dopamine in the nucleus accumbens. Suppressing such interference is one of the targets of cognitive control. Here, using the examples of active avoidance and omission behaviour, we examine the possibility that direct manipulation of the dopamine signal is an instrument of control itself. In particular, when instrumental and Pavlovian influences come into conflict, dopamine levels might be affected by the controlled deployment of a reframing mechanism that recasts the prospect of possible punishment as an opportunity to approach safety, and the prospect of future reward in terms of a possible loss of that reward. We operationalize this reframing mechanism and fit the resulting model to rodent behaviour from two paradigmatic experiments in which accumbens dopamine release was also measured. We show that in addition to matching animals’ behaviour, the model predicts dopamine transients that capture some key features of observed dopamine release at the time of discriminative cues, supporting the idea that modulation of this neuromodulator is amongst the repertoire of cognitive control strategies.
Long-Term Follow-Up of COVID-19 Convalescents—Immune Response Associated with Reinfection Rate and Symptoms
2023-10-17

SARS-CoV-2 has spread worldwide, causing millions of deaths and leaving a significant proportion of people with long-term sequelae of COVID-19 (“post-COVID syndrome”). Whereas the precise mechanism of post-COVID syndrome is still unknown, the immune response after the first infection may play a role. Here, we performed a long-term follow-up analysis of 110 COVID-19 convalescents, analyzing the first SARS-CoV-2-directed immune response, vaccination status, long-term symptoms (approximately 2.5 years after first infection), and reinfections. A total of 96% of convalescents were vaccinated at least once against SARS-CoV-2 after their first infection. A reinfection rate of 47% was observed, and lower levels of anti-spike IgG antibodies after the first infection were shown to associate with reinfection. While T-cell responses could not be clearly associated with persistent postinfectious symptoms, convalescents with long-term symptoms showed elevated SARS-CoV-2-specific antibody levels at the first infection. Evaluating the immune response after the first infection might be a useful tool for identifying individuals with increased risk for re-infections and long-term symptoms.
Hominin Tool Evolution and Its (Surprising) Relation to Language Origins
2023-10-17

Culture and communication are widespread in the animal kingdom. However, among apes, only the human line has evolved these into something altogether different. Moreover, our extraordinary cultural and communicative capacities underlie much else of what makes our species stand out among apes. Thus, understanding the how and why of the process by which these capacities were transformed from their great ape-like precursors into their modern human equivalents is of fundamental importance to the challenge of understanding the evolution of our species more generally. In this chapter, we take up these questions using a novel framework for thinking about social learning. We hypothesize that human apes show a unique propensity for a certain type of social learning, which we call “know-how copying.” Know-how copying is considered foundational to our species’ well-known capacity to culturally evolve both behaviour and artifact forms that can far exceed anything a single individual could realistically invent on his or her own. This copying is therefore also foundational to our species’ capacity to construct, maintain and expand the large lexicons of (often) arbitrary signs that underlie human languages. After discussing the various methodologies that are available for testing whether a given type of human or animal culture is demanding of know-how copying, we turn to the archaeological record with an eye towards identifying plausible signatures of the origins of know-how copying in the human line. In particular, we examine the course of hominin technological evolution – as the most visible and most frequent data. We suggest a much later date for the origins of know-how copying than is typically assumed. But this poses a deep puzzle, namely: there is good reason to think that hominins had considerably expanded their communicative repertoire prior to the evolution of know-how copying. How was this possible in the seeming absence of know-how copying? We sketch a solution to this puzzle which we think provides an additional argument in support of a gestural-iconic origins scenario for language.
Sustainable Silt Management in the Lower Kosi River, North Bihar, India: Demand Assessment, Investment Model and Socio-Economic Development
2023-10-17

The Kosi River, draining through Nepal and north Bihar, India, has been known for excessive sediment (commonly called silt) deposition—a primary cause of several hazards. However, there are still no good estimates of the volume of silt accumulated in the Kosi River channel, which makes removal and utilization of silt a major challenge, both technically as well as economically. In this work, we first present a novel method to estimate sediment volume on a reach scale using hydrological and channel planform data mapped from satellite images. We then identify various commercial uses of the Kosi River sediments such as embankment construction, backfilling, land reclamation, landscaping, agricultural applications, industrial applications, and geotextile silt walls. In consultation with various stakeholders, backfilling and embankment construction were identified as potentially the best solutions shortlisted for the development of a business case and investment model. Therefore, we prepared an investment model based on economic viability, cost-to-benefit ratio, and stakeholder consultations for two districts. We performed a SWOT analysis by breaking down the opportunities and risks into political, economic, social, technological, environmental, and legal (PEST-EL) factors to identify the pros and cons within the sector and of the ecosystem in which the stakeholders operate.
Towards More Accurate Pharmacogenomic Variant Effect Predictions
2023-10-17

Tweetable abstract Accurate variant interpretation has become a key bottleneck for the translation of an individual's pharmacogenome into actionable recommendations. We recommend an integrated use of multiplexed assays, structure-based predictions and biobank data to develop more accurate effect predictors.
Realism about tense and atemporality
2023-10-17

Abstract Realists about tense, or A-theorists of time, believe that some of the facts that fundamentally constitute reality are tensed, and most of them seem to think that those tensed facts are to be understood as fixing the way things are, absolutely speaking , or simpliciter . But there is a simple yet powerful argument, the argument from atemporality , to the effect that realists should reject the absolutist conception of reality’s constitution by facts because, despite appearances to the contrary, that conception is in fact inconsistent with realism about tense. After presenting the argument, I investigate why the relevant inconsistency has not been recognised so far and point to one possible explanation.
Medicago truncatulaSOBIR1 controls specificity in the Rhizobium-legume symbiosis
2023-10-17

Summary Medicago truncatula Nod Factor Perception (MtNFP) is a lysin-domain Receptor-Like Kinase (LysM-RLK) that plays a key role in the Rhizobium-legume symbiosis, and is involved in plant immunity. MtNFP also has an inactive kinase domain, suggesting that the protein is involved in different receptor complexes. Using the MtNFP pseudo-kinase domain as a bait in a Yeast two Hybrid screen, we identified M. truncatula SUPPRESSOR OF BIR1 (MtSOBIR1) as a new interactor of MtNFP. We showed that an interaction between the two RLKs can occur in planta and that the kinase domain of MtSOBIR1 is active and can transphosphorylate the pseudo-kinase domain of MtNFP. Like in other plants, our data suggest a positive role of MtSOBIR1 in immunity; MtSOBIR1 could functionally complement an Atsobir1 mutant for defence activation, and a Mtsobir1 mutant was defective in pathogen-induced defence gene expression. We also showed that MtSOBIR1 has a symbiotic role with Mtsobir1 mutants showing a strong symbiotic phenotype in a plant genotype- and rhizobial strain-specific manner. The symbiotic role was apparent both at an early stage of rhizobial infection and in nodules. Together, these data suggest that, like MtNFP, MtSOBIR1 has a dual role, and can control immunity in both pathogenic and beneficial situations, with positive or negative roles, respectively.
A mechanistic study on the tolerance of PAM distal end mismatch by SpCas9
2023-10-17

Abstract CRISPR-Cas9 is the newest technology available for targeted genome editing. It is very efficient and cheap compared to other genome editing techniques. However, its therapeutic application is limited due to its off-target activity. To have a better understanding of this off-target effect, we concentrated our efforts on its mismatch-prone PAM distal end. Current off-target prediction algorithms use RNA-DNA complementation derived energy as a major factor in predicting off-target effect. RNA-DNA complementation derived energy drives Cas9 conformational change, which in turn drives its functional activity. In the case of lower RNA-DNA complementarity, a partial conformational change occurs resulting in a slower reaction rate and partial activity. However, extensive mismatches are often tolerated despite lower complementation derived energy available from RNA: DNA duplex formation. Thus, the off-target activity of Cas9 depends directly on the nature of mismatches which in turn result in deviation of the active site of the enzyme due to structural instability in the duplex strand. In order to test the hypothesis, we have designed an array of mismatched target sites and performed in vitro and cell line-based experiments to assess the effects of PAM distal mismatches in Cas9 activity. For further mechanistic validation, Molecular dynamics simulation was performed and it revealed that certain mismatch mutations induced pronounced conformational instability within the RNA-DNA duplex, leading to elevated root mean square deviation (RMSD) values. We found that, target sites having mismatches in the 18th to 16th position upstream of the PAM showed no to little activity.
Metacognition, public health compliance, and vaccination willingness
2023-10-18

Metacognition, our ability to reflect on our own beliefs, manifests itself in the confidence we have in these beliefs, and helps us guide our behavior in complex and uncertain environments. Here, we provide empirical tests of the importance of metacognition during the pandemic. Bayesian and frequentist analyses demonstrate that citizens with higher metacognitive sensitivity—where confidence differentiates correct from incorrect COVID-19 beliefs—reported higher willingness to vaccinate against COVID-19, and higher compliance with recommended public health measures. Notably, this benefit of accurate introspection held controlling for the accuracy of COVID-19 beliefs. By demonstrating how vaccination willingness and compliance may relate to insight into the varying accuracy of beliefs, rather than only the accuracy of the beliefs themselves, this research highlights the critical role of metacognitive ability in times of crisis. However, we do not find sufficient evidence to conclude that citizens with higher metacognitive sensitivity were more likely to comply with recommended public health measures when controlling for the absolute level of the confidence citizens had in their COVID-19 beliefs.
Interrelated effects of age and parenthood on whole-brain controllability: protective effects of parenthood in mothers
2023-10-18

Background Controllability is a measure of the brain’s ability to orchestrate neural activity which can be quantified in terms of properties of the brain’s network connectivity. Evidence from the literature suggests that aging can exert a general effect on whole-brain controllability. Mounting evidence, on the other hand, suggests that parenthood and motherhood in particular lead to long-lasting changes in brain architecture that effectively slow down brain aging. We hypothesize that parenthood might preserve brain controllability properties from aging. Methods In a sample of 814 healthy individuals (aged 33.9 ± 12.7 years, 522 females), we estimate whole-brain controllability and compare the aging effects in subjects with vs. those without children. We use diffusion tensor imaging (DTI) to estimate the brain structural connectome. The level of brain control is then calculated from the connectomic properties of the brain structure. Specifically, we measure the network control over many low-energy state transitions (average controllability) and the network control over difficult-to-reach states (modal controllability). Results and conclusion In nulliparous females, whole-brain average controllability increases, and modal controllability decreases with age, a trend that we do not observe in parous females. Statistical comparison of the controllability metrics shows that modal controllability is higher and average controllability is lower in parous females compared to nulliparous females. In men, we observed the same trend, but the difference between nulliparous and parous males do not reach statistical significance. Our results provide strong evidence that parenthood contradicts aging effects on brain controllability and the effect is stronger in mothers.
Image Quality and Diagnostic Performance of Accelerated 2D Hip MRI with Deep Learning Reconstruction Based on a Deep Iterative Hierarchical Network
2023-10-18

Objectives: Hip MRI using standard multiplanar sequences requires long scan times. Accelerating MRI is accompanied by reduced image quality. This study aimed to compare standard two-dimensional (2D) turbo spin echo (TSE) sequences with accelerated 2D TSE sequences with deep learning (DL) reconstruction (TSEDL) for routine clinical hip MRI at 1.5 and 3 T in terms of feasibility, image quality, and diagnostic performance. Material and Methods: In this prospective, monocentric study, TSEDL was implemented clinically and evaluated in 14 prospectively enrolled patients undergoing a clinically indicated hip MRI at 1.5 and 3T between October 2020 and May 2021. Each patient underwent two examinations: For the first exam, we used standard sequences with generalized autocalibrating partial parallel acquisition reconstruction (TSES). For the second exam, we implemented prospectively undersampled TSE sequences with DL reconstruction (TSEDL). Two radiologists assessed the TSEDL and TSES regarding image quality, artifacts, noise, edge sharpness, diagnostic confidence, and delineation of anatomical structures using an ordinal five-point Likert scale (1 = non-diagnostic; 2 = poor; 3 = moderate; 4 = good; 5 = excellent). Both sequences were compared regarding the detection of common pathologies of the hip. Comparative analyses were conducted to assess the differences between TSEDL and TSES. Results: Compared with TSES, TSEDL was rated to be significantly superior in terms of image quality (p ≤ 0.020) with significantly reduced noise (p ≤ 0.001) and significantly improved edge sharpness (p = 0.003). No difference was found between TSES and TSEDL concerning the extent of artifacts, diagnostic confidence, or the delineation of anatomical structures (p &gt; 0.05). Example acquisition time reductions for the TSE sequences of 52% at 3 Tesla and 70% at 1.5 Tesla were achieved. Conclusion: TSEDL of the hip is clinically feasible, showing excellent image quality and equivalent diagnostic performance compared with TSES, reducing the acquisition time significantly.
State investigative interest varies across daily life and predicts academic engagement: Replication and extension of the nomological network
2023-10-18

Recent contributions propose to integrate a state perspective into the conceptualization of vocational interests. Such integration addresses in-the-moment expressions of interests and allows to track relations to distal outcomes of vocational interests more closely. To further the trait-state integration of vocational interests, insights into the nomological network of state vocational interests are necessary. In this preregistered experience sampling study of 217 university students, we studied state investigative interest in daily life and the relations with theory-derived person- and situation-related constructs. Results from 5631 observations across 3.5 weeks showed that specific situation characteristics, openness, happiness, and current social student role were associated with state investigative interest. Furthermore, person-aggregated state investigative interest and the reactivity of investigative interest in situations related with their academic studies predicted individuals’ overall academic engagement in some cases. Generally, the relations in the nomological network were stronger when state investigative interest and hypothesized constructs were more closely aligned. Overall, the results underline the systematic nature and psychological relevance of state vocational interests. We discuss how integrating a state perspective into research on vocational interests implies novel approaches for capitalizing on the power of vocational interests.