julilili42/papers huggingface dataset:
Crosstalk of smooth muscle cell-derived fibronectin and cGMP signaling is atheroprotective
2024-03-27

<p class="first" dir="auto" id="d1262079e139">Rupture of unstable atherosclerotic plaques can lead to heart attack and stroke. Smooth muscle cells (SMCs) generate extracellular matrix (ECM) that contributes to plaque stability. Phenotypic switching of SMCs during atherogenesis may influence ECM composition and stability of plaques. cGMP signaling modulates SMC growth and phenotype, but how the ECM affects this process in atherosclerotic lesions is not well understood. Fibronectin (Fn1) is an abundant component of the plaque ECM and has been linked to coronary artery disease (CAD) risk in humans. To study the role of SMC-derived Fn1 in SMC phenotypic switching, we generated conditional knockout mice lacking Fn1 in SMCs on an ApoE-deficient background (Fn-smko mice). As compared to control mice, Fn‐smko mice had larger lesions with less Acta2+ cells and reduced collagen content in the fibrous cap indicative of decreased plaque stability. A combination of scRNA-seq, SMC lineage tracing and immunostaining showed that Fn-smko lesions contained more modulated SMCs than control plaques. Interestingly, the shift in SMC phenotypes was associated with increased expression of the NO-sensitive guanylyl cyclase (NO-GC) in modulated plaque cells. Like Fn1, NO-GC has been linked to CAD risk in humans. Real-time analyses of primary aortic SMCs revealed increased growth of Fn-smko cells associated with high activity of the NO-cGMP pathway. Collectively, our findings provide strong evidence that SMC-derived Fn1 promotes an atheroprotective SMC phenotype associated with reduced NO-cGMP signaling. This study also reveals a link between two CAD risk genes, Fn1 and NO-GC.
Characterization of CNP-induced cGMP signaling in the murine hippocampus
2024-03-27

<p class="first" dir="auto" id="d6654666e102">C-type natriuretic peptide (CNP) induced cGMP signaling is mediated by particulate guanylyl cyclase B (GC-B) and regulates endochondral ossification, oocyte maturation and sensory axon bifurcation. In contrast to cGMP produced by nitric oxide-activated guanylyl cyclase, not much is known about the role of CNP-induced cGMP signaling in the central nervous system. Therefore, we used the lacZ reporter mouse lines we developed to investigate the expression pattern of CNP and GC-B in the brain. Thereby, we detected a joint distribution of the ligand-receptor pair in the dentate granule neurons (DGNs) of the hippocampus, a brain structure involved in memory formation and adult neurogenesis. Additionally, CNP expression was observed in pyramidal neurons of the CA1-CA3 region and in some hilar cells. Biochemical analysis of hippocampal tissue extracts showed an increase in cGMP levels after CNP administration. Real-time FRET measurements of cGMP in DGNs expressing a genetically encoded cGMP sensor also showed robust cGMP generation in response to CNP as well as nitric oxide, suggesting the presence of both types of cGMP generators in DGNs. While analyzing specific phosphodiesterase (PDE) inhibitors, we found that PDE2A, similar to sensory neurons, is involved in modulating CNP-induced cGMP signaling in DGNs. Finally, we investigated the functional effects of CNP-induced cGMP generation in DGNs and observed an increase in neurite length, suggesting enhanced neuronal growth and plasticity. Our results provide new insights into cGMP signaling that may not only have implications for understanding hippocampal functions but also highlight potential avenues for therapeutic augmentation of cGMP signaling.
Mechanosensitive cGMP signaling in vascular smooth muscle cells
2024-03-27

<p class="first" dir="auto" id="d15870589e162">Hypertension is an important risk factor for the development of vascular diseases. NO/NO-sensitive guanylyl cyclase (NO-GC)/cGMP signaling, a major mechanism of vasodilatation, affects blood pressure by regulating the relaxation of vascular smooth muscle cells (VSMCs). Under (patho-)physiological conditions, VSMCs are exposed to mechanical forces such as shear stress and stretch. Based on our recent discovery of mechanosensitive NO/cGMP signaling in platelets, we hypothesized that mechanical forces may also affect the NO/cGMP axis in VSMCs and aid in maintaining appropriate cGMP levels, thereby contributing to vascular homeostasis. To investigate the mechano-modulation of cGMP in real time, we used cells and tissues isolated from transgenic mice that express a FRET-based cGMP sensor. Recording of NO-dependent cGMP signals in primary aortic VSMCs under flow and static conditions demonstrated a potentiation of cGMP signals by fluid shear stress in many but not all VSMCs. Similarly, pressure puffs, another type of mechanical force, increased NO-induced cGMP signals depending on the magnitude of the applied pressure. Moreover, an <i>exvivo</i> model of mounted carotid arteries showed concentration-dependent cGMP responses to NO under flow, which were further enhanced by increasing the intravascular pressure. Thus, different types of mechanical stress increase NO-induced cGMP concentrations in VSMCs in culture and intact vessels. Additional studies are needed to dissect the molecular make-up and mode of action of mechano-sensitive cGMP signalosomes in VSMCs. Together, our data demonstrate the presence of a mechano-sensitive NO/NO‐GC/cGMP axis in VSMCs, which might be a target for the treatment of vascular diseases.
Carbon footprint of maize-wheat cropping system after 40-year fertilization
2024-03-28

Two main challenges which human society faces for sustainable development goals are the maintenance of food security and mitigation of greenhouse gas (GHG) emissions. Here, we examined the impacts of six fertilization treatments including unfertilized control (CK), mineral nitrogen (N, 90 kg N ha<sup>-1</sup>), mineral N plus 30 kg P ha<sup>-1</sup> phosphorus (NP), NP combined with 3.75 Mg ha<sup>-1</sup> straw (NP + Str), farmyard manure (Man, 75 Mg ha<sup>-1</sup>), and NP combined with manure (NP + Man) on crop productivity and carbon emissions (soil GHG emission; GHGI, yield-based GHG intensity; NGHGB, net GHG balance; carbon footprint, CF) in a maize-wheat cropping system during two years (April 2018-June 2020) in a semi-arid continental climate after 40 years of fertilization in the Northwest China. Manure and straw increased total GHG by 38-60 % compared to the mineral fertilizers alone, which was mainly due to the 49-80 % higher direct emissions of carbon dioxide (CO<sub>2</sub>) rather than nitrous oxide (N<sub>2</sub>O). Compared to the N fertilizer alone, organic amendments and NP increased cumulative energy yield by 134-202 % but decreased GHGI by 38-55 %, indicating that organic fertilizers increased crop productivity at the cost of higher GHG emissions. When the soil organic carbon changes (ΔSOC) were accounted for in the C emission balance, manure application acted as a net C sink due to the NGHGB recorded with -123 kg CO<sub>2</sub>-eq ha<sup>-1</sup> year<sup>-1</sup>. When producing the same yield and economic benefits, the manure and straw addition decreased the CF by 59-85 % compared to N fertilization alone. Overall, the transition from mineral to organic fertilization in the semi-arid regions is a two-way independent solution to increase agricultural productivity along with the reduction of C emissions.
Profiling learning strategies of medical students: A person‐centered approach
2024-03-28

Abstract Background Students within a cohort might employ unique subsets of learning strategies (LS) to study. However, little research has aimed to elucidate subgroup‐specific LS usage among medical students. Recent methodological developments, particularly person‐centred approaches such as latent profile analysis (LPA), offer ways to identify relevant subgroups with dissimilar patterns of LS use. In this paper, we apply LPA to explore subgroups of medical students during preclinical training in anatomy and examine how these patterns are linked with learning outcomes. Methods We analysed the LS used by 689 undergraduate, 1st and 2nd‐year medical students across 6 German universities who completed the short version of the Learning Strategies of University Students (LIST‐K) questionnaire, and answered questions towards external criteria such as learning resources and performance. We used the thirteen different LS facets of the LIST‐K (four cognitive, three metacognitive, three management of internal and three management of external resources) as LPA indicators. Results Based on LPA, students can be grouped into four distinct learning profiles: Active learners (45% of the cohort), collaborative learners (17%), structured learners (29%) and passive learners (9%). Students in each of those latent profiles combine the 13 LS facets in a unique way to study anatomy. The profiles differ in both, the overall level of LS usage, and unique combinations of LS used for learning. Importantly, we find that the facets of LS show heterogeneous and subgroup‐specific correlations with relevant outcome criteria, which partly overlap but mostly diverge from effects observed on the population level. Conclusions The effects observed by LPA expand results from variable‐centered efforts and challenge the notion that LS operate on a linear continuum. These results highlight the heterogeneity between subgroups of learners and help generate a more nuanced interpretation of learning behaviour. Lastly, our analysis offers practical implications for educators seeking to tailor learning experiences to meet individual student needs.
Physician’s autonomy in the face of AI support: walking the ethical tightrope
2024-03-28

The introduction of AI support tools raises questions about the normative orientation of medical practice and the need to rethink its basic concepts. One of these concepts that is central to the discussion is the physician’s autonomy and its appropriateness in the face of high-powered AI applications. In this essay, a differentiation of the physician’s autonomy is made on the basis of a conceptual analysis. It is argued that the physician’s decision-making autonomy is a purposeful autonomy. The physician’s decision-making autonomy is fundamentally anchored in the medical ethos for the purpose to promote the patient’s health and well-being and to prevent him or her from harm. It follows from this purposefulness that the physician’s autonomy is not to be protected for its own sake, but only insofar as it serves this end better than alternative means. We argue that today, given existing limitations of AI support tools, physicians still need physician’s decision-making autonomy. For the possibility of physicians to exercise decision-making autonomy in the face of AI support, we elaborate three conditions: (1) sufficient information about AI support and its statements, (2) sufficient competencies to integrate AI statements into clinical decision-making, and (3) a context of voluntariness that allows, in justified cases, deviations from AI support. If the physician should fulfill his or her moral obligation to promote the health and well-being of the patient, then the use of AI should be designed in such a way that it promotes or at least maintains the physician’s decision-making autonomy.
FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion
2024-03-28

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).
In situ incubation of iron(II)-bearing minerals and Fe(0) reveals insights into metabolic flexibility of chemolithotrophic bacteria in a nitrate polluted karst aquifer
2024-03-28

Groundwater nitrate pollution is a major reason for deteriorating water quality and threatens human and animal health. Yet, mitigating groundwater contamination naturally is often complicated since most aquifers are limited in bioavailable carbon. Since metabolically flexible microbes might have advantages for survival, this study presents a detailed description and first results on our modification of the BacTrap© method, aiming to determine the prevailing microbial community's potential to utilize chemolithotrophic pathways. Our microbial trapping devices (MTDs) were amended with four different iron sources and incubated in seven groundwater monitoring wells for ∼3 months to promote growth of nitrate-reducing Fe(II)-oxidizing bacteria (NRFeOxB) in a nitrate-contaminated karst aquifer. Phylogenetic analysis based on 16S rRNA gene sequences implies that the identity of the iron source influenced the microbial community's composition. In addition, high throughput amplicon sequencing revealed increased relative 16S rRNA gene abundances of OTUs affiliated to genera such as Thiobacillus, Rhodobacter, Pseudomonas, Albidiferax, and Sideroxydans. MTD-derived enrichments set up with Fe(II)/nitrate/acetate to isolate potential NRFeOxB, were dominated by e.g., Acidovorax spp., Paracoccus spp. and Propionivibrio spp. MTDs are a cost-effective approach for investigating microorganisms in groundwater and our data not only solidifies the MTD's capacity to provide insights into the metabolic flexibility of the aquifer's microbial community, but also substantiates its metabolic potential for anaerobic Fe(II) oxidation.
The art of seeing the elephant in the room: 2D embeddings of single-cell data do make sense
2024-03-28

A recent paper in PLOS Computational Biology (Chari and Pachter, 2023) claimed that t -SNE and UMAP embeddings of single-cell datasets fail to capture true biological structure. The authors argued that such embeddings are as arbitrary and as misleading as forcing the data into an elephant shape. Here we show that this conclusion was based on inadequate and limited metrics of embedding quality. More appropriate metrics quantifying neighborhood and class preservation reveal the elephant in the room: while t -SNE and UMAP embeddings of single-cell data do not preserve high-dimensional distances, they can nevertheless provide biologically relevant information.
Speeded classification of visual events is sensitive to crossmodal intensity correspondence.
2024-03-28

Crossmodal correspondences refer to systematic associations between stimulus attributes encountered in different sensory modalities. These correspondences can be probed in the speeded classification task where they tend to produce congruency effects. This study aimed to replicate and extend previous work conducted by Marks (1987, Experiment 3, <i>Journal of Experimental Psychology: Human Perception and Performance</i>, Vol. 13, No. 3, 384-394) which demonstrated a crossmodal correspondence between auditory and visual intensity attributes. Experiment 1 successfully replicates Marks' original finding that performance in a brightness classification task is affected by whether the loudness of a concurrently presented auditory distractor matches the brightness of the visual target. Furthermore, in line with the original study, we found that this effect was absent in a lightness classification task. In Experiment 2, we demonstrate that loudness-brightness correspondence is robust even when the exact stimulus input changes. This finding suggests that there is a context-dependent mapping between loudness and brightness levels, rather than an absolute mapping between any particular intensity levels. Finally, exploratory analysis using the diffusion model for conflict tasks indicated that evidence from the task-irrelevant modality generates a burst of weak, short-lived automatic activation that can bias decision-making in difficult tasks, but not in easy tasks. Our results provide further evidence for the existence of a flexible crossmodal correspondence between brightness and loudness, which might be helpful in determining one's distance to a stimulus source during the early stages of multisensory integration. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
ISTH bleeding assessment tool and platelet function analyzer in children with mild inherited platelet function disorders
2024-03-28

Abstract Objectives To evaluate the diagnostic performance of platelet function analyzer (PFA) and The International Society on Thrombosis and Hemostasis bleeding‐assessment‐tool (ISTH‐BAT) in detecting mild inherited platelet function disorders (IPFDs) in children with suspected bleeding disorders. Methods Prospective single‐center diagnostic study including consecutive patients &lt;18 years with suspected bleeding disorder and performing a standardized workup for platelet function defects including ISTH‐BAT, PFA, platelet aggregation testing, blood smear‐based immunofluorescence, and next‐generation sequencing‐based genetic screening for IPFDs. Results We studied 97 patients, of which 34 von Willebrand disease (VWD, 22 type‐1, 11 type‐2), 29 IPFDs (including delta−/alpha‐storage pool disease, Glanzmann thrombasthenia, Hermansky–Pudlak syndrome) and 34 with no diagnosis. In a model combining PFA‐adenosine diphosphate (ADP), PFA‐epinephrine (EPI), and ISTH‐BAT overall performance to diagnose IPFDs was low with area under the curves of 0.56 (95% CI 0.44, 0.69) compared with 0.84 (95% CI 0.76, 0.92) for VWD. Correlation of PFA‐EPI/‐ADP and ISTH‐BAT was low with 0.25/0.39 Spearman's correlation coefficients. PFA were significantly prolonged in patients with VWD and Glanzmann thrombasthenia. ISTH‐BAT‐scores were only positive in severe bleeding disorders, but not in children with mild IPFDs or VWD. Conclusion Neither ISTH‐BAT nor PFA or the combination of both help diagnosing mild IPFDs in children. PFA is suited to exclude severe IPFDs or VWD and is in this regard superior to ISTH‐BAT in children.
Environmental conditions in the Massif Central during the Upper Palaeolithic using stable isotope tracking (13C, 15N) of bone collagen from large herbivores
2024-03-28

ABSTRACT The environmental conditions experienced by hunter‐gatherers during the second part of the Upper Palaeolithic (ca. 28 000–15 000 cal bp ) are poorly known in the mid‐elevation volcanic mountains of the Massif Central in southern France. The stable isotope ratios of carbon and nitrogen ( 13 C/ 12 C and 15 N/ 14 N expressed as δ 13 C and δ 15 N values) in bone collagen of large herbivores can track their diet and habitat, reflecting local abiotic conditions (temperature, aridity, altitude). Due to poor preservation of skeletal organic matter in the region, new radiocarbon dating was conducted on a limited number of quality‐controlled collagen samples, based on a minimum carbon content of 30%. They document three main phases of occupation corresponding to the Final Gravettian, the Badegoulian and the Magdalenian, each of which is represented in different regions of the Allier and Loire valleys. Over time, a decrease in horse δ 15 N values, the best documented species of large herbivores, is found between the Final Gravettian (ca. 26 700–25 600 cal bp ), around the Last Glacial Maximum and the Badegoulian (ca. 21 900–19 200 cal bp ), followed by an increase in δ 15 N and δ 13 C values during the Magdalenian (ca. 19 100–16 600 cal bp ). During the Badegoulian, the δ 15 N values of the horses were lower than those of their counterparts in southwestern France, testifying to harsh climatic conditions favourable to a tundra‐like landscape, also reflected in the higher horse and reindeer δ 13 C values in the Allier valley compared to those in southwestern France. The relatively high δ 13 C and low δ 15 N values of a Final Gravettian wolf from the Allier valley suggests reindeer as a preferred prey, in line with their high abundance in the archaeological sites. Game access, rather than climatic conditions or lithic resources, seems to have motivated human groups to occupy the Massif Central during the Upper Palaeolithic.
Conversational User Interfaces: Explanations and Interactivity Positively Influence Advice Taking from Generative Artificial Intelligence
2024-03-28

Generative artificial intelligence (GenAI) has surged in popularity with the implementation of conversational user interfaces. The possibility to engage in natural conversations with GenAI thus constitutes a promising countermeasure to algorithm aversion, or the general preference for humans over algorithms, which hinders the effective utilization of often superior algorithmic output. In this study, we experimentally test the influence of explanations and interactivity on advice taking from GenAIs. In a judge-advisor system, 472 participants (313 female, 154 male, 5 diverse; median age 23 years) solved a series of ten estimation tasks with access to pre-generated output from ChatGPT. In the control condition, only the numerical output was provided as advice. Participants in the treatment conditions were additionally provided with, or could request, a detailed explanation of the rationale underlying ChatGPT’s judgments. The weight of advice was positively influenced by both the opportunity to interact with the GenAI and the receipt of an explanation. Moreover, actively requesting an explanation significantly enhanced the positive effect of interactivity compared to trials on which this opportunity was forgone. However, there was no evidence that the weighting of algorithmic advice was influenced by whether an explanation was provided or requested. The inherent explanatory capabilities of GenAI and the opportunity to interactively engage with it independently increase users’ advice taking. This finding underscores the potential of conversational user interfaces to large language models such as ChatGPT to improve individuals’ augmented judgment and decision-making, but also poses a threat to human autonomy in interactions with conversational GenAI systems.