julilili42/papers huggingface dataset:
Non-antibiotic drugs break colonization resistance against pathogenicGammaproteobacteria
2023-11-06

Summary Non-antibiotic drugs can alter the composition of the gut microbiome, with largely undefined implications for human health. Here we compared the susceptibility of commensal and pathogenic bacteria to non-antibiotic drugs and found that pathogens show higher drug resistance, which could favor their expansion after treatment. We then developed a model system to screen for drug-microbiome interactions that increase the risk of enteropathogenic infections. Approximately 35% of the &gt;50 drugs we tested increased the abundance of Salmonella Typhimurium in synthetic and human stool-derived microbial communities. This was due to direct effects of non-antibiotics on individual commensals, altered microbial interactions within communities and the potential of Salmonella to exploit different metabolic niches. Non-antibiotic drugs that favored Salmonella expansion in vitro also promoted other enteric pathogens and increased Salmonella loads in gnotobiotic and conventional mice. These findings may inform future strategies to control pathogen proliferation and to assess individual microbiota-drug-pathogen risks for infection.
Rydberg-ion flywheel for quantum work storage
2023-11-06

Trapped ions provide a platform for quantum technologies that offers long coherence times and high degrees of scalability and controllability. Here, we use this platform to develop a realistic model of a thermal device consisting of two laser-driven, strongly coupled Rydberg ions in a harmonic trap. We show that the translational degrees of freedom of this system can be utilized as a flywheel storing the work output that is generated by a cyclic thermodynamic process applied to its electronic degrees of freedom. Mimicking such a process through periodic variations of external control parameters, we use a mean-field approach underpinned by numerical and analytical calculations to identify relevant physical processes and to determine the charging rate of the flywheel. Our work paves the way for the design of microscopic thermal machines based on Rydberg ions that can be equipped with both many-body working media and universal work storages.
Decoding the molecular interplay in the central dogma: An overview of mass spectrometry‐based methods to investigate protein‐metabolite interactions
2023-11-06

Abstract With the emergence of next‐generation nucleotide sequencing and mass spectrometry‐based proteomics and metabolomics tools, we have comprehensive and scalable methods to analyze the genes, transcripts, proteins, and metabolites of a multitude of biological systems. Despite the fascinating new molecular insights at the genome, transcriptome, proteome and metabolome scale, we are still far from fully understanding cellular organization, cell cycles and biology at the molecular level. Significant advances in sensitivity and depth for both sequencing as well as mass spectrometry‐based methods allow the analysis at the single cell and single molecule level. At the same time, new tools are emerging that enable the investigation of molecular interactions throughout the central dogma of molecular biology. In this review, we provide an overview of established and recently developed mass spectrometry‐based tools to probe metabolite‐protein interactions—from individual interaction pairs to interactions at the proteome‐metabolome scale.
Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing l-Thyroxine-Derived Prodrugs
2023-11-06

OATP1C1 (organic anion-transporting polypeptide 1C1) transports thyroid hormones, particularly thyroxine (T<sub>4</sub>), into human astrocytes. In this study, we investigated the potential of utilizing OATP1C1 to improve the delivery of anti-inflammatory drugs into glial cells. We designed and synthesized eight novel prodrugs by incorporating T<sub>4</sub> and 3,5-diiodo-l-tyrosine (DIT) as promoieties to selected anti-inflammatory drugs. The prodrug uptake in OATP1C1-expressing human U-87MG glioma cells demonstrated higher accumulation with T<sub>4</sub> promoiety compared to those with DIT promoiety or the parent drugs themselves. <i>In silico</i> models of OATP1C1 suggested dynamic binding for the prodrugs, wherein the pose changed from vertical to horizontal. The predicted binding energies correlated with the transport profiles, with T<sub>4</sub> derivatives exhibiting higher binding energies when compared to prodrugs with a DIT promoiety. Interestingly, the prodrugs also showed utilization of oatp1a4/1a5/1a6 in mouse primary astrocytes, which was further supported by docking studies and a great potential for improved brain drug delivery.
Metacognition of curiosity: People underestimate the seductive lure of non-instrumental information
2023-11-06

Abstract Curiosity – the desire to seek information – is fundamental for learning and performance. Studies on curiosity have shown that people are intrinsically motivated to seek information even if it does not bring an immediate tangible benefit (i.e., non-instrumental information), but little is known as to whether people have the metacognitive capability to accurately monitor their motivation for seeking information. We examined whether people can accurately predict their own non-instrumental information-seeking behavior. Across six experiments (Experiments 1A–1E and 2, total N = 579), participants predicted that they would engage in information-seeking behavior less frequently than they actually did, suggesting that people tend to underestimate the motivational lure of curiosity. Overall, there was no consistent statistical evidence that this underestimation was altered by contextual factors (e.g., the cost to seek information). These results were consistent with the theoretical account that it is difficult for people to make sense of the internally rewarding value of information in advance.
Endoscopic ultrasound-guided ethanol ablation versus surgical resection of insulinomas
2023-11-06

Abstract Purpose Insulinoma is a rare tumor of the pancreas that can lead to hypoglycemia. To date, the standard therapy is surgical resection. After the first case report of successful endoscopic ultrasound-guided (EUS) ethanol injection 16 years ago, the need for establishing an alternative treatment method remains unchanged given the high morbidity rates of surgery and its unsuitability in some patients. Materials and Methods Here, we provide retrospective data from 33 insulinoma patients that were treated at our center between 2010 and 2021. Of these, 9 patients were treated with EUS-guided ethanol injection and 24 underwent pancreatic surgery. Results The ethanol group was older (ethanol: mean ± SE 67.8±11.2 years vs. surgery: 52.3±15.7, p=0.014) with a higher Charlson Comorbidity Index (3.0 (1.0;4.0) vs. 1.0 (0.0;2.0), p=0.008). The lowest glucose values were similar between groups before (ethanol: 2.09±0.17 mmol/l vs. surgery: 1.81±0.08, p=0.158) and after (4.95±0.74 vs. 5.41±0.28, p=0.581) the respective treatments. Complications occurred more frequently in the surgery group (11 % vs. 54 %, p=0.026). One patient after prior partial pancreatectomy died postoperatively. The hospitalization time was significantly shorter in the ethanol group (4.78±0.78 days vs. 19.88±4.07, p&lt;0.001). Conclusion EUS-guided ethanol injection can be similarly effective for the treatment of hyperinsulinemic hypoglycemia compared with pancreatic surgery but seems to be associated with less severe complications. This implies the need for prospective randomized trials in insulinoma patients with a low risk for malignancy.
Direct Spectroscopic Identification of BN‐Arynes and Subtle Steric Effects on Nitrogen Fixation**
2023-11-06

Abstract 1,2‐Azaborinines are the BN analogues of arynes through exchange of the formal CC triple bond by an isoelectronic BN bond. The BN‐arynes are an underexplored class of reactive intermediates. Dibenzo[c,e][1,2]azaborinine (10,9‐BN‐phenanthryne) 1 was inferred as reactive intermediate by trapping reactions. Here it is shown that 1 can be generated in the gas phase by thermolysis from the pyridine adduct of 9‐azido‐9‐borafluorene by cleavage of the dative bond with pyridine and dinitrogen extrusion. The ionization potential of 1 is 8.2 eV with ionization resulting from the π HOMO. Under cryogenic matrix isolation conditions, 9‐azido‐9‐borafluorene photolysis results in isomerization to the dinitrogen adduct of 1 without involvement of a triplet borylnitrene intermediate. Photochemical nitrogen extrusion from 1 ⋅ N 2 is not possible and nitrogen fixation is irreversible under cryogenic conditions. In contrast, 2,4,7,9‐tetra‐ tert ‐butyldibenzo[c,e][1,2]azaborinine can be photogenerated from the corresponding azidoborole precursor under cryogenic matrix isolation conditions, and nitrogen fixation is precluded due to steric hindrance. The BN stretching vibration at about 1750 cm −1 is much weaker than in typical linear diaryl iminoboranes.
Exploratory Study of Gastrointestinal Redox Biomarkers in the Presymptomatic and Symptomatic Tg2576 Mouse Model of Familial Alzheimer’s Disease: Phenotypic Correlates and Effects of Chronic Oral d-Galactose
2023-11-06

The gut might play an important role in the etiopathogenesis of Alzheimer's disease (AD) as gastrointestinal alterations often precede the development of neuropathological changes in the brain and correlate with disease progression in animal models. The gut has an immense capacity to generate free radicals whose role in the etiopathogenesis of AD is well-known; however, it remains to be clarified whether gastrointestinal redox homeostasis is associated with the development of AD. The aim was to (i) examine gastrointestinal redox homeostasis in the presymptomatic and symptomatic Tg2576 mouse model of AD; (ii) investigate the effects of oral d-galactose previously shown to alleviate cognitive deficits and metabolic changes in animal models of AD and reduce gastrointestinal oxidative stress; and (iii) investigate the association between gastrointestinal redox biomarkers and behavioral alterations in Tg2576 mice. In the presymptomatic stage, Tg2576 mice displayed an increased gastrointestinal electrophilic tone, characterized by higher lipid peroxidation and elevated Mn/Fe-SOD activity. In the symptomatic stage, these alterations are rectified, but the total antioxidant capacity is decreased. Chronic oral d-galactose increased the antioxidant capacity and reduced lipid peroxidation in the Tg2576 but had the opposite effects in the wild-type animals. The total antioxidant capacity of the gastrointestinal tract was associated with greater spatial memory. Gut redox homeostasis might be involved in the development and progression of AD pathophysiology and should be further explored in this context.
A microphysiological system for parallelized morphological and electrophysiological read-out of 3D neuronal cell culture
2023-11-06

Abstract Three-dimensional in vitro models in microfluidic systems are promising tools for studying cell biology, with complex models using multiple cell types combined with high resolution imaging. Neuronal models demand electrical readout of the activity of networks of single neurons, yet classical planar microelectrode arrays struggle to capture extracellular action potentials when neural soma are suspended distant from the microelectrodes. This study introduces sophisticated microfluidic microelectrode arrays, specifically tailored for electrophysiology of 3D neuronal cultures. Using multilayer photolithography of permanent epoxy photoresists, we developed devices having 12 independent culture modules in a convenient format. Each module has two adjacent compartments for hydrogel-based 3D cell culture, with tunnels allowing projection of neurites between compartments. Microelectrodes integrated in the tunnels record action potentials as they pass between the compartments. Mesh ceilings separate the compartments from overlying wells, allowing for simple cell seeding and later nutrient, gas and waste exchange and application of test substances. Using these devices, we have demonstrated 3D neuronal culture, including electrophysiological recording and live imaging. This microphysiological platform will enable high-throughput investigation of neuronal networks for investigation of neurological disorders, neural pharmacology and basic neuroscience. Further models could include cocultures representing multiple brain regions or innervation models of other organs.
Genomic insights into the evolution of secondary metabolism ofEscovopsisand its allies, specialized fungal symbionts of fungus-farming ants
2023-11-06

Abstract The metabolic intimacy of symbiosis often demands the work of specialists. Natural products and defensive secondary metabolites can drive specificity by ensuring infection and propagation across host generations. But in contrast to bacteria, little is known about the diversity and distribution of natural product biosynthetic pathways among fungi and how they evolve to facilitate symbiosis and adaptation to their host environment. In this study, we define the secondary metabolism of Escovopsis and closely related genera, members of which are specialized, diverse ascomycete fungi best known as mycoparasites of the fungal cultivars grown by fungus-growing ants. We ask how the gain and loss of various biosynthetic pathways corresponds to divergent lifestyles. Long-read sequencing allowed us to define the chromosomal features of representative Escovopsis strains, revealing highly reduced genomes (21.4-38.3 Mb) composed of 7-8 chromosomes. Escovopsis genomes are highly co-linear, with genes localizing not only in the same chromosome, but also in the same order. Macrosynteny is high within Escovopsis clades, and decreases with increasing phylogenetic distance, while maintaining a high degree of mesosynteny. To explore the evolutionary history of biosynthetic pathways in this group of symbionts relative to their encoding lineages, we performed an ancestral state reconstruction analysis, which revealed that, while many secondary metabolites are shared with non-ant associated sordariomycetes, 56 pathways are unique to the symbiotic genera. Reflecting adaptation to diverging ant agricultural systems, we observe that the stepwise acquisition of these pathways mirrors the ecological radiations of attine ants and the dynamic recruitment and replacement of their fungal cultivars. As different clades encode characteristic combinations of biosynthetic gene clusters, these delineating profiles provide important insights into the possible mechanisms underlying specificity between these symbionts and their hosts. Collectively, our findings shed light on the evolutionary dynamic nature of secondary metabolism in Escovopsis and its allies, reflecting adaptation of the symbionts to an ancient agricultural system.
Discovering causal relations and equations from data
2023-11-07

Physics is a field of science that has traditionally used the scientific method to answer questions about why natural phenomena occur and to make testable models that explain the phenomena. Discovering equations, laws, and principles that are invariant, robust, and causal has been fundamental in physical sciences throughout the centuries. Discoveries emerge from observing the world and, when possible, performing interventions on the system under study. With the advent of big data and data-driven methods, the fields of causal and equation discovery have developed and accelerated progress in computer science, physics, statistics, philosophy, and many applied fields. This paper reviews the concepts, methods, and relevant works on causal and equation discovery in the broad field of physics and outlines the most important challenges and promising future lines of research. We also provide a taxonomy for data-driven causal and equation discovery, point out connections, and showcase comprehensive case studies in Earth and climate sciences, fluid dynamics and mechanics, and the neurosciences. This review demonstrates that discovering fundamental laws and causal relations by observing natural phenomena is revolutionised with the efficient exploitation of observational data and simulations, modern machine learning algorithms and the combination with domain knowledge. Exciting times are ahead with many challenges and opportunities to improve our understanding of complex systems.
What do brain endocasts tell us? A comparative analysis of the accuracy of sulcal identification by experts and perspectives in palaeoanthropology
2023-11-07

Abstract Palaeoneurology is a complex field as the object of study, the brain, does not fossilize. Studies rely therefore on the (brain) endocranial cast (often named endocast), the only available and reliable proxy for brain shape, size and details of surface. However, researchers debate whether or not specific marks found on endocasts correspond reliably to particular sulci and/or gyri of the brain that were imprinted in the braincase. The aim of this study is to measure the accuracy of sulcal identification through an experiment that reproduces the conditions that palaeoneurologists face when working with hominin endocasts. We asked 14 experts to manually identify well‐known foldings in a proxy endocast that was obtained from an MRI of an actual in vivo Homo sapiens head. We observe clear differences in the results when comparing the non‐corrected labels (the original labels proposed by each expert) with the corrected labels. This result illustrates that trying to reconstruct a sulcus following the very general known shape/position in the literature or from a mean specimen may induce a bias when looking at an endocast and trying to follow the marks observed there. We also observe that the identification of sulci appears to be better in the lower part of the endocast compared to the upper part. The results concerning specific anatomical traits have implications for highly debated topics in palaeoanthropology. Endocranial description of fossil specimens should in the future consider the variation in position and shape of sulci in addition to using models of mean brain shape. Moreover, it is clear from this study that researchers can perceive sulcal imprints with reasonably high accuracy, but their correct identification and labelling remains a challenge, particularly when dealing with extinct species for which we lack direct knowledge of the brain.
The Edicts of the Praetors: Law, Time, and Revolution in Ancient Rome
2023-11-07

Abstract This paper revises current understandings of judicial edicts in ancient Rome—the annually published texts in which Roman magistrates set out the formulae according to which they would institute trials during their year in office. While standard accounts see these edicts as the work of legal specialists, heretofore neglected sources for how contemporaries talked about these texts suggest that they were indeed the work of the magistrates that issued them. At times these magistrates formulated new provisions; for the most part they selectively drew on past edicts, not least to accommodate the demands of their friends and clients. These patterns in compositional practice can only be understood within the framework of Roman political culture. More importantly, in their annually changing published form judicial edicts emerge as crucial objects in the construction of time in ancient Rome. Arguably, they constituted a legal practice that could encompass revolution—at least for a year.
Inhibition of glutaminase-1 in DLBCL potentiates venetoclax-induced antitumor activity by promoting oxidative stress
2023-11-07

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, but first-line immunochemotherapy fails to produce a durable response in about one-third of the patients. Because tumor cells often reprogram their metabolism, we investigated the importance of glutaminolysis, a pathway converting glutamine to generate energy and various metabolites, for the growth of DLBCL cells. Glutaminase-1 (GLS1) expression was robustly detected in DLBCL biopsy samples and cell lines. Both pharmacological inhibition and genetic knockdown of GLS1 induced cell death in DLBCL cells regardless of their subtype classification, whereas primary B cells remained unaffected. Interestingly, GLS1 inhibition resulted not only in reduced levels of intermediates of the tricarboxylic acid cycle but also in a strong mitochondrial accumulation of reactive oxygen species. Supplementation of DLBCL cells with α-ketoglutarate or with the antioxidant α-tocopherol mitigated oxidative stress and abrogated cell death upon GLS1 inhibition, indicating an essential role of glutaminolysis in the protection from oxidative stress. Furthermore, the combination of the GLS1 inhibitor CB-839 with the therapeutic BCL2 inhibitor ABT-199 not only induced massive reactive oxygen species (ROS) production but also exhibited highly synergistic cytotoxicity, suggesting that simultaneous targeting of GLS1 and BCL2 could represent a novel therapeutic strategy for patients with DLBCL.
Simulating higher-order fabric structure in a coupled, anisotropic ice-flow model: application to Dome C
2023-11-07

Abstract Ice-crystal fabric can induce mechanical anisotropy that significantly affects flow, but ice-flow models generally do not include fabric development or its effect upon flow. Here, we incorporate a new spectral expansion of fabric, and more complete description of its evolution, into the ice-flow model Elmer/Ice. This approach allows us to model the effect of both lattice rotation and migration recrystallization on large-scale ice flow. The fabric evolution is coupled to flow using an unapproximated non-linear orthotropic rheology that better describes deformation when the stress and fabric states are misaligned. These improvements are most relevant for simulating dynamically interesting areas, where recrystallization can be important, tuning data are scarce and rapid flow can lead to misalignment between stress and fabric. We validate the model by comparing simulated fabric to ice-core and phase-sensitive radar measurements on a transect across Dome C, East Antarctica. With appropriately tuned rates for recrystallization, the model is able to reproduce observations of fabric. However, these tuned rates differ from those previously derived from laboratory experiments, suggesting a need to better understand how recrystallization acts differently in the laboratory compared to natural settings.