julilili42/papers huggingface dataset:
Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure
2024-05-29

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local βAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different βAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by β<sub>1</sub>AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca<sup>2+</sup>) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β<sub>1</sub>AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β<sub>1</sub>AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with β<sub>1</sub>AR were observed. Stimulating β<sub>1</sub>AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β<sub>1</sub>AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca<sup>2+</sup> cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.
mitoBKCa is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming
2024-05-29

Alterations in the function of K + channels such as the voltage- and Ca 2+ -activated K + channel of large conductance (BK Ca ) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BK Ca splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBK Ca ). Through a combination of genetic knockdown and knockout along with a cell permeable BK Ca channel blocker, we show that mitoBK Ca modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the ‘Warburg effect’, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBK Ca and BK Ca transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBK Ca could represent a treatment strategy for selected BC patients in future.
Approach to the Core Structure of Signermycin B
2024-05-29

Abstract Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis ‐decalin. In this paper, we demonstrate that the cis ‐decalin section of signermycin B can be accessed by an anionic oxy‐Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels‐Alder reaction of a masked ortho ‐benzoquinone, generated by oxidation of an α‐methoxyphenol in presence of cis ‐2‐hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy‐Cope rearrangement to a cis ‐decalinone. While we could show, that introduction of the 4‐ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4‐ epi ‐isomer was formed.
How values relate to student achievement in upper secondary education: Integrating interdisciplinary perspectives on value beliefs in the school context
2024-05-29

Abstract Educational research often refers to the subjective values assigned to aspects of education. Theoretical frameworks from the related disciplines of psychology and sociology applied to the context of education aim to better describe why some students are more motivated in school than others to understand differences in academic outcomes. In the current study, we followed an interdisciplinary approach that aimed to integrate psychological views regarding domain-specific value beliefs (i.e., intrinsic, attainment, utility, cost) and sociological views regarding domain-general values of education (i.e., stimulation, comfort, status, behavioral confirmation) and to investigate how they relate to academic success in upper secondary education. In a sample of 3,775 upper secondary school students in Germany, we found evidence that combining the two perspectives had incremental effects when predicting domain-specific achievement and GPA. We discuss how integrating interdisciplinary theoretical perspectives could foster communication between scientific disciplines and benefit future research in the field of motivation.
Reactivation strength during cued recall is modulated by graph distance within cognitive maps
2024-05-29

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8 min consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms, with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps.
Successful treatment of Sneddon Syndrome with high dose intravenous immunoglobulin
2024-05-29

Abstract Sneddon Syndrome is an orphan disease characterized by the clinical presence of livedo racemosa and cerebrovascular ischaemia. Its pathophysiology remains inadequately understood and no validated treatment modality has been established. In this case report of a 37‐year‐old woman, we present high‐dose intravenous immunoglobulin (IVIg) as a potential successful treatment option. The diagnosis was confirmed through a deep spindle biopsy, revealing the typical intima proliferation. Furthermore, we found a positive medical history concerning neurological symptoms. The commonly applied high‐dose anticoagulation had previously not resulted in improvement of the ulcers or pain reduction. The initiated therapy with IVIg significantly alleviated the pain after a single cycle and led to the complete healing of the ulcers 12 weeks later. This case of a patient with subsequent long‐term responsiveness to IVIg supports the approach as a promising therapy alternative.
Natural variation of immune epitopes reveals intrabacterial antagonism
2024-05-30

Plants and animals detect biomolecules termed microbe-associated molecular patterns (MAMPs) and induce immunity. Agricultural production is severely impacted by pathogens which can be controlled by transferring immune receptors. However, most studies use a single MAMP epitope and the impact of diverse multicopy MAMPs on immune induction is unknown. Here, we characterized the epitope landscape from five proteinaceous MAMPs across 4,228 plant-associated bacterial genomes. Despite the diversity sampled, natural variation was constrained and experimentally testable. Immune perception in both Arabidopsis and tomato depended on both epitope sequence and copy number variation. For example, Elongation Factor Tu is predominantly single copy, and 92% of its epitopes are immunogenic. Conversely, 99.9% of bacterial genomes contain multiple cold shock proteins, and 46% carry a nonimmunogenic form. We uncovered a mechanism for immune evasion, intrabacterial antagonism, where a nonimmunogenic cold shock protein blocks perception of immunogenic forms encoded in the same genome. These data will lay the foundation for immune receptor deployment and engineering based on natural variation.
Environment-induced heritable variations are common in Arabidopsis thaliana
2024-05-30

Abstract Parental or ancestral environments can induce heritable phenotypic changes, but whether such environment-induced heritable changes are a common phenomenon remains unexplored. Here, we subject 14 genotypes of Arabidopsis thaliana to 10 different environmental treatments and observe phenotypic and genome-wide gene expression changes over four successive generations. We find that all treatments caused heritable phenotypic and gene expression changes, with a substantial proportion stably transmitted over all observed generations. Intriguingly, the susceptibility of a genotype to environmental inductions could be predicted based on the transposon abundance in the genome. Our study thus challenges the classic view that the environment only participates in the selection of heritable variation and suggests that the environment can play a significant role in generating of heritable variations.
Improving assessment of lesions in longitudinal CT scans: a bi-institutional reader study on an AI-assisted registration and volumetric segmentation workflow
2024-05-30

Abstract Purpose AI-assisted techniques for lesion registration and segmentation have the potential to make CT-based tumor follow-up assessment faster and less reader-dependent. However, empirical evidence on the advantages of AI-assisted volumetric segmentation for lymph node and soft tissue metastases in follow-up CT scans is lacking. The aim of this study was to assess the efficiency, quality, and inter-reader variability of an AI-assisted workflow for volumetric segmentation of lymph node and soft tissue metastases in follow-up CT scans. Three hypotheses were tested: (H1) Assessment time for follow-up lesion segmentation is reduced using an AI-assisted workflow. (H2) The quality of the AI-assisted segmentation is non-inferior to the quality of fully manual segmentation. (H3) The inter-reader variability of the resulting segmentations is reduced with AI assistance. Materials and methods The study retrospectively analyzed 126 lymph nodes and 135 soft tissue metastases from 55 patients with stage IV melanoma. Three radiologists from two institutions performed both AI-assisted and manual segmentation, and the results were statistically analyzed and compared to a manual segmentation reference standard. Results AI-assisted segmentation reduced user interaction time significantly by 33% (222 s vs. 336 s), achieved similar Dice scores (0.80–0.84 vs. 0.81–0.82) and decreased inter-reader variability (median Dice 0.85–1.0 vs. 0.80–0.82; ICC 0.84 vs. 0.80), compared to manual segmentation. Conclusion The findings of this study support the use of AI-assisted registration and volumetric segmentation for lymph node and soft tissue metastases in follow-up CT scans. The AI-assisted workflow achieved significant time savings, similar segmentation quality, and reduced inter-reader variability compared to manual segmentation.
Advancing Parkinson’s Disease Diagnostics: The Potential of Arylpyrazolethiazole Derivatives for Imaging α-Synuclein Aggregates
2024-05-30

The development of positron emission tomography (PET) tracers capable of detecting α-synuclein (α-syn) aggregates in vivo would represent a breakthrough for advancing the understanding and enabling the early diagnosis of Parkinson's disease and related disorders. It also holds the potential to assess the efficacy of therapeutic interventions. However, this remains challenging due to different structures of α-syn aggregates, the need for selectivity over other structurally similar amyloid proteins, like amyloid-β (Aβ), which frequently coexist with α-syn pathology, and the low abundance of the target in the brain that requires the development of a high-affinity ligand. To develop a successful PET tracer for the central nervous system (CNS), stringent criteria in terms of polarity and molecular size must also be considered, as the tracer must penetrate the blood-brain barrier and have low nonspecific binding to brain tissue. Here, we report a series of arylpyrazolethiazole (APT) derivatives, rationally designed from a structure-activity relationship study centered on existing ligands for α-syn fibrils, with a particular focus on the selectivity toward α-syn fibrils and control of physicochemical properties suitable for a CNS PET tracer. In vitro competition binding assays performed against [<sup>3</sup>H]MODAG-001 using recombinant α-syn and Aβ<sub>1-42</sub> fibrils revealed <b>APT-13</b> with an inhibition constant of 27.8 ± 9.7 nM and a selectivity of more than 3.3 fold over Aβ. Radiolabeled [<sup>11</sup>C]<b>APT-13</b> demonstrated excellent brain penetration in healthy mice with a peak standardized uptake value of 1.94 ± 0.29 and fast washout from the brain (<i>t</i> <sub>1/2</sub> = 9 ± 1 min). This study highlights the potential of <b>APT-13</b> as a lead compound for developing PET tracers to detect α-syn aggregates in vivo.
Negation mitigates rather than inverts the neural representations of adjectives
2024-05-30

Combinatoric linguistic operations underpin human language processes, but how meaning is composed and refined in the mind of the reader is not well understood. We address this puzzle by exploiting the ubiquitous function of negation. We track the online effects of negation (“not”) and intensifiers (“really”) on the representation of scalar adjectives (e.g., “good”) in parametrically designed behavioral and neurophysiological (MEG) experiments. The behavioral data show that participants first interpret negated adjectives as affirmative and later modify their interpretation towards, but never exactly as, the opposite meaning. Decoding analyses of neural activity further reveal significant above chance decoding accuracy for negated adjectives within 600 ms from adjective onset, suggesting that negation does not invert the representation of adjectives (i.e., “not bad” represented as “good”); furthermore, decoding accuracy for negated adjectives is found to be significantly lower than that for affirmative adjectives. Overall, these results suggest that negation mitigates rather than inverts the neural representations of adjectives. This putative suppression mechanism of negation is supported by increased synchronization of beta-band neural activity in sensorimotor areas. The analysis of negation provides a steppingstone to understand how the human brain represents changes of meaning over time.
Chlorite chemical refinement during giant quartz vein formation
2024-05-30

Abstract The major elemental composition of chlorite is widely used for petrogenetic investigations on low-temperature geological processes. However, compositional variations of chlorite within a given tectonic environment are common and, when overlooked, can lead to erroneous petrological interpretations. We thoroughly investigate chlorites occurring within giant quartz veins (GQVs) in the basement rocks of the Pyrenees. These structures have widths of up to tens of meters and lengths of kilometers and form in both mid-crustal ductile and upper-crustal seismogenic domains. Texturally constrained chlorite analyses and spatially resolved whole-rock elemental analyses reveal a progressive chemical evolution of chlorite coupled to GQV formation. Six chlorite generations that were distinguished according to their texture show consistent chemical variations at the microscale. Host rock– and quartz vein–related chlorites are the textural and compositional endmembers. Between them, a progressive chemical refinement occurred in transitional chlorite compositions linked to host rock, vein quartz, and pressure-solution microstructures, in accordance with significant fluid-rock interactions leading to GQV formation. This rock alteration process is further confirmed at the macroscale by the progressive depletion of all major and trace elements but silica, with decreasing distance toward GQVs. We demonstrate that (1) inferring the temperature conditions of chlorite crystallization is not as straightforward as generally assumed and that (2) GQVs can be formed under rock-buffered conditions, at lower temperatures than previously thought. These results have implications for the practice commonly used in chlorite-based geothermometry, as well as for the modes of fluid, heat, and mass transport within Earth’s crust.
Nanobodies as novel tools to monitor the mitochondrial fission factor Drp1
2024-05-30

In cells, mitochondria undergo constant fusion and fission. An essential factor for fission is the mammalian dynamin-related protein 1 (Drp1). Dysregulation of Drp1 is associated with neurodegenerative diseases including Parkinson’s, cardiovascular diseases and cancer, making Drp1 a pivotal biomarker for monitoring mitochondrial status and potential pathophysiological conditions. Here, we developed nanobodies (Nbs) as versatile binding molecules for proteomics, advanced microscopy and live cell imaging of Drp1. To specifically enrich endogenous Drp1 with interacting proteins for proteomics, we functionalized high-affinity Nbs into advanced capture matrices. Furthermore, we detected Drp1 by bivalent Nbs combined with site-directed fluorophore labelling in super-resolution STORM microscopy. For real-time imaging of Drp1, we intracellularly expressed fluorescently labelled Nbs, so-called chromobodies (Cbs). To improve the signal-to-noise ratio, we further converted Cbs into a “turnover-accelerated” format. With these imaging probes, we visualized the dynamics of endogenous Drp1 upon compound-induced mitochondrial fission in living cells. Considering the wide range of research applications, the presented Nb toolset will open up new possibilities for advanced functional studies of Drp1 in disease-relevant models.
An agent-based model of the role of resource dynamics and the environment in human female life cycles
2024-05-30

A recommendation of: Pablo J. Varas Enríquez, Daniel Redhead, Monique Borgerhoff Mulder, Heidi Colleran, Dieter Lukas The role of resource dynamics in the distribution of life cycles within a female human population https://osf.io/nzeq9
Comment on egusphere-2024-820
2024-05-30

<strong class="journal-contentHeaderColor">Abstract.</strong> Western disturbances (WDs) are synoptic-scale weather systems embedded within the subtropical westerly jet. Manifesting as upper-level troughs often associated with a lower-tropospheric low over Western India, they share some dynamical features with extratropical cyclones. WDs are most common during the boreal winter (December to March), during which they bring the majority of precipitation &ndash; both rain and snow &ndash; to the Western Himalaya, as well as to surrounding areas of north India, Pakistan and the Tibetan Plateau. WDs are also associated with weather hazards such as heavy snowfall, hailstorms, fog, cloudbursts, avalanches, frost, and coldwaves. In this paper, we review the recent understanding and development on WDs. Recent studies have collectively made use of novel data, novel analysis techniques, and the increasing availability of high-resolution weather and climate models. This review is separated into six main sections &ndash; structure and thermodynamics, precipitation and impacts, teleconnections, modelling experiments, forecasting at a range of scales, and paleoclimate and climate change &ndash; each motivated with a brief discussion of the accomplishments and limitations of previous research. A number of step changes in understanding are synthesised. Use of new modelling frameworks and tracking algorithms has significantly improved knowledge of WD structure and variability, and a more frequentist approach can now be taken. Improved observation systems have helped quantification of water security over the Western Himalaya. Convection-permitting models have improved our understanding of how WDs interact with the Himalayas to trigger natural hazards. Improvements in paleoclimate and future climate modelling experiments have helped to explain how WDs and their impacts over the Himalaya respond to large-scale natural and anthropogenic forcings. We end by summarising unresolved questions and outlining key future WD research topics.
Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes
2024-05-31

Abstract Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value.