bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin resistance compromises midbrain organoid neural activity and metabolic efficiency predisposing to Parkinson’s disease pathology
Authors: Zagare Alise , Kurlovics Janis , Almeida Catarina , Ferrante Daniele , Frangenberg Daniela , Neises Laura , Vitali Armelle , Gomez-Giro Gemma , Jäger Christian , Antony Paul , Halder Rashi , Krüger Rejko , Glaab Enrico , Meiser Johannes , Stalidzans Egils , Arena Giuseppe , Schwamborn Jens C
Published: May 2024

Growing evidence indicates that Type 2 Diabetes (T2D) is associated with an increased risk of developing Parkinson’s disease through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism, and survival. To investigate insulin resistance caused pathological changes in the human midbrain, which could predispose a healthy midbrain to PD development, we exposed iPSC-derived human midbrain organoids from healthy individuals to either high insulin concentrations, promoting insulin resistance, or to more physiological insulin concentrations restoring insulin signalling function. We combined experimental methods with metabolic modelling to identify the most insulin resistance-dependent pathogenic processes. We demonstrate that insulin resistance compromises organoid metabolic efficiency, leading to increased levels of oxidative stress. Additionally, insulin-resistant midbrain organoids showed decreased neural activity and reduced amount of dopaminergic neurons, highlighting insulin resistance as a significant target in PD prevention.
Optimizing ex vivo CAR-T cell-mediated cytotoxicity assay through multimodality imaging
Authors: Foulke John G. , Chen Luping , Chang Hyeyoun , McManus Catherine E. , Tian Fang , Gu Zhizhan
Published: May 2024

CAR-T cell-based therapies have demonstrated remarkable efficacy in treating malignant cancers, especially liquid tumors, and are increasingly being evaluated in clinical trials for solid tumors. With the FDA’s initiative for advancing alternative methods for drug discovery and development, full human ex vivo assays are increasingly essential for precision CAR-T development. However, prevailing ex vivo CAR-T cell-mediated cytotoxicity assays are limited by their use of radioactive materials, lack of real-time measurement, low throughput, and inability to automate, among others. To address these limitations, we optimized the assay using multimodality imaging methods, including bioluminescence, impedance tracking, phase contrast, and fluorescence, to track CAR-T cells co-cultured with CD19, CD20, and HER2 luciferase reporter cancer cells in real-time. Additionally, we varied the ratio of CAR-T cells to cancer cells to determine optimal cytotoxicity readouts. Our findings demonstrated that the CAR-T cell group effectively attacked cancer cells, and the optimized assay provided superior temporal and spatial precision measurements of ex vivo CAR-T killing of cancer cells, confirming the reliability, consistency, and high throughput of the optimized assay.
Locityper: targeted genotyping of complex polymorphic genes
Authors: Prodanov Timofey , Plender Elizabeth G. , Seebohm Guiscard , Meuth Sven G. , Eichler Evan E. , Marschall Tobias
Published: May 2024

The human genome contains numerous structurally-variable polymorphic loci, including several hundred disease-associated genes, almost inaccessible for accurate variant calling. Here we present Locityper, a tool capable of genotyping such challenging genes using short and long-read whole genome sequencing. For each target, Locityper recruits and aligns reads to locus haplotypes, for instance extracted from a pangenome, and finds the likeliest haplotype pair by optimizing read alignment, insert size and read depth profiles. Locityper accurately genotypes up to 194 of 256 challenging medically relevant loci (95% haplotypes at QV33), an 8.8-fold gain compared to 22 genes achieved with standard variant calling pipelines. Furthermore, Locityper provides access to hyperpolymorphic HLA genes and other gene families, including KIR, MUC and FCGR. With its low running time of 1h10m per sample at 8 threads, Locityper is scalable to biobank-sized cohorts, enabling association studies for previously intractable disease-relevant genes.
Ancestral role of Pax6 in chordate brain regionalization
Authors: Kozmik Zbynek , Kozmikova Iryna
Published: May 2024

ThePax6gene is essential for eye and brain development across various animal species. Here, we investigate the function ofPax6in the development of the anterior central nervous system (CNS) of the invertebrate chordate amphioxus using CRISPR/Cas9-induced genome editing. Specifically, we examined Pax6 mutants featuring a 6bp deletion encompassing two invariant amino acids in the conserved paired domain, hypothesized to impair Pax6 DNA-binding capacity and gene regulatory functions. Although this mutation did not result in gross morphological changes in amphioxus larvae, it demonstrated a reduced ability to activate Pax6-responsive reporter gene, suggesting a hypomorphic effect. Expression analysis in mutant larvae revealed changes in gene expression within the anterior CNS, supporting the conserved role ofPax6gene in brain regionalization across chordates. Additionally, our findings lend support to the hypothesis of a zona limitans intrathalamica (ZLI)-like region in amphioxus, suggesting evolutionary continuity in brain patterning mechanisms.
Tuning of Chitosan with Lignin derived Bioactive Properties to develop a Lignin Reinforced and Sustainable Food Packaging Biomaterial
Authors: Garg Sumona , Avanthi Althuri
Published: May 2024

The crucial component of food storage, preservation, and transportation is food packaging. Biodegradable biopolymers are a major area of focus for the future development of food packaging materials due to their ability to mitigate adverse environmental impact by reducing plastic pollution and promoting sustainable waste management practices. Exploring renewable resources is crucial for facilitating the transition from non-renewable practices to sustainability. Chitosan is known for its superior film-forming abilities but has limited antibacterial activity. The inherent properties of lignin, including its high tensile strength, antioxidant, antimicrobial, and UV barrier ability, can contribute to enhance chitosan film performance when added as a co-polymer, making it an active material for food packaging applications. The present work explores the acid-alkali treatment to extract lignin from sugarcane tops, an abundant agricultural waste, and the application of extracted lignin in biopolymer-based hydrogel synthesis for food packaging. The goal is to enhance the hydrogel formulation by incorporation and optimisation of lignin that holds high antioxidant, antimicrobial, UV barrier, and mechanical properties along with significantly low water transmissibility. This study introduces a novel approach by utilizing lignin extracted from sugarcane tops (SCT) rather than commercially derived lignin, thereby expanding the raw material scope of lignin applications. The incorporation of higher proportions of lignin in the hydrogel formulations represents an advancement over reported studies, aimed at improving the bioactivity of the hydrogel by leveraging its advantageous characteristics emanating from lignin. This approach can also reduce the dependency on chitosan which is relatively expensive. Further, the modified synthesis of hydrogels expedited through heating method contributes to shorten the time duration needed for hydrogel film casting and drying.

Graphical Abstract

Highlights

Enhanced lignin extraction from sugarcane tops using Plackett Burman Design

Formulating green packaging hydrogels through valorisation of sugarcane tops

Heating-based short time casting method for Lignin/Chitosan hydrogel synthesis

Optimization of lignin content in the hydrogels for balanced mechanical and bioactive properties
Discovery of cyclic peptide natural product inhibitors ofBalamuthia mandrillaris
Authors: Lu Chenyang , Nelson Samantha , Coy Gabriela , Neumann Christopher , Parkinson Elizabeth I. , Rice Christopher A.
Published: May 2024

Balamuthia mandrillarisis a pathogenic free-living amoeba that causes infection of central nervous system, calledBalamuthiaamoebic encephalitis (BAE), as well as cutaneous and systemic diseases. Patients infected withB. mandrillarishave a high mortality rate due to the lack of effective treatments. A combination of non-optimized antimicrobial drug regimen is typically recommended; however, they have poor parasite activity and can cause various severe side effects. Cyclic peptides exhibit a broad spectrum of antimicrobial activities and lower cytotoxicity. In this study, we evaluated the anti-B. mandrillariseffect of cyclic peptides. The predicted natural product-43 (pNP-43), identified from the SNaPP (Synthetic Natural Product Inspired Cyclic Peptides) library, and its derivates displayed a significant inhibition forB. mandrillaristrophozoites. Eight pNPs had IC50s <5 μM. Furthermore, all hit pNPs demonstrated minimal hemolytic and cytotoxic effects on human cells. Our study first indicates the anti-B. mandrillariseffect of cyclic peptides, which provides a new direction for drug development. Further studies of the mechanism of action andin vivoeffects will be elucidated to confirm the potency as a treatment forB. mandrillarisinfection in the future.
Hijacked Immune Cells Traverse Microenvironmental Barriers by Positioning and Pushing their Intracellular Parasite Cargo
Authors: Ruiz-Fernandez Mauricio J.A. , Jiang Jianfei , Mortazavi Armina , Wang Bingzhi , Kuznetcov Artur , Merrin Jack , Meissner Markus , Periz Javier , Sabass Benedikt , Renkawitz Jörg
Published: May 2024

Intracellular pathogens hijack the cytoskeletal networks of their host cells to facilitate their uptake, drive their intracellular motility, or prevent their degradation. While many underlying principles have been explored during host cell infections by intracellular bacteria likeListeria, Chlamydia, orShigella, it remains less well understood how large eukaryotic intracellular parasites likeToxoplasma gondiiexploit the host cytoskeleton. In particular, howToxoplasmaachieves its transport within highly motile immune cells remains largely unknown despite its large intracellular size. Here, we discover thatToxoplasma gondiihijacks host myosin forces for translocation through microenvironmental barriers along immune cell migration paths. Using highly defined micro-engineered migration paths and dendritic cells as a highly motile immune cell model, we reveal that large parasitic cargos acquire a surprising intracellular position frontward of the host nucleus and microtubule-organizing center. This frontward localization of parasitic cargos depends on microenvironmental confinement and host myosin activity. We identify that the parasite cargos cause high contractility within their motile host cells mediated by host myosin-II, thereby facilitating their squeezing and deformation to enable transversal through confining microenvironments. Our findings establish parasitic hijacking of myosin forces as a novel principle of how parasites exploit host cytoskeletal networks.
Lcn2 protects from cisplatin induced AKI by regulating DNA damage response via EGFR activation
Authors: Zablocki Aniela , Marques Eloise , Yammine Lucie , Nguyen Clément , Terzi Fabiola , Gallazzini Morgan
Published: May 2024

Background

Lipocalin 2 (Lcn2), a small-secreted protein, is an established sensitive biomarker of kidney injury. In Cisplatin (CDDP) induced acute kidney injury (AKI), Lcn2 expression is swiftly and strongly increased in suffering renal medullary tubules. While recent reports correlates Lcn2 expression in cancer cells with CDDP resistance, the role of Lcn2 in kidney tubule damaged by CDDP remains unknown.

Methods

To better understand the role of Lcn2 in CDDP-induced AKI, experiments onLcn2+/+orLcn2−/−mice as well as immortalized kidney cells knock-down (KD) for Lcn2 were conducted. Kidney function and injury were assessed using standard techniques. Cellular and molecular mechanisms were studied in WT and Lcn2 KD cells in combination with pathways inhibitors in order to gain insight Lcn2 driven mechanisms.

Results

In animal injected with CDDP, Lcn2 was upregulated mostly in kidney inner medulla collecting duct while it was reabsorbed in the proximal tubules.Lcn2−/−in mice significantly decreased kidney function compare to WT mice, while it increased parenchymal damage due to increased cell death and cast formation. Interestingly, while little to no damage were present in the medulla of CDDP injected WT animal, a clear increase of medulla tubular lesions was observed inLcn2−/−mice. Using Inner Medullary Collecting Duct cells (mIMDC-3), we showed that Lcn2 KD induces a p53-dependent apoptosis upon Cisplatin exposure while no effect on necrosis was observed. Finally, we demonstrated that Lcn2 drives CDDP resistance to apoptosis through the activation of the pro-survival EGFR pathway.

Conclusions

We established that Lcn2 is a renoprotective protein in CDDP-induced AKI via the activation of EGFR pathway. This new mechanism might represent a new approach for the treatment of AKI.
Directed evolution for cell separation in budding yeast
Authors: Galeota-Sprung Benjamin , Pritchard Erik , Huang Crystal , Fernandez Amy , Sniegowski Paul
Published: May 2024

Haploid and diploid natural isolates of the yeastSaccharomyces cerevisiaewere evolved under a daily transfer protocol that selected against clumpy growth and for cell separation. For the haploid populations, whole genome sequencing revealed strong selection to deactivateAMN1, a known regulator of cell separation, recapitulating evolution that likely occurred during the domestication of common lab strains. We also observed multiple mutational hits to the Rim101 pathway, which was not expected. Mutations to bothAMN1and the Rim101 pathway were strongly associated with cell separation. In the diploid populations, we observed the parallel emergence of a large partial deletion of chrIII, the so-called Hawthorn’s deletion. We show that this deletion is associated with reduced clumpy growth. The mechanism by which Hawthorne’s deletion affects cell separation is unknown but may be related to an effect on budding pattern.
CodY controls the SaeR/S two-component system by modulating branched-chain fatty acid synthesis inStaphylococcus aureus
Authors: Alqahtani Shahad , DiMaggio Dennis A. , Brinsmade Shaun R
Published: May 2024

Staphylococcus aureusis a Gram-positive, opportunistic human pathogen that is a leading cause of skin and soft tissue infections and invasive disease worldwide. Virulence in this bacterium is tightly controlled by a network of regulatory factors. One such factor is the global regulatory protein CodY. CodY links branched-chain amino acid sufficiency to the production of surface-associated and secreted factors that facilitate immune evasion and subversion. Our previous work revealed that CodY regulates virulence factor gene expression indirectly in part by controlling the activity of the SaeRS two-component system. While this is correlated with an increase in membrane anteiso-15:0 and −17:0 branched-chain fatty acids (BCFAs) derived from isoleucine, the true mechanism of control has remained elusive. Herein, we report that CodY-dependent regulation of SaeS sensor kinase activity requires BCFA synthesis. During periods of nutrient sufficiency, BCFA synthesis and Sae TCS activity is heavily suppressed by CodY-dependent repression of theilv-leuoperon and the isoleucine-specific permease genebrnQ2.In acodYnull mutant, which simulates extreme nutrient limitation, de-repression ofilv-leuandbrnQ2directs the synthesis of enzymes in redundant de novo and import pathways to catalyze the production of BCFA precursors. Overexpression ofbrnQ2independent of CodY is sufficient to increase membrane anteiso BCFAs, Sae-dependent promoter activity, and SaeR∼P levels. Our results further clarify the molecular mechanism by which CodY controls virulence inS. aureus.

IMPORTANCE

Expression of bacterial virulence genes often correlates with the exhaustion of nutrients, but how the signaling of nutrient availability and the resulting physiological responses are coordinated is unclear. InS. aureus,CodY controls the activity of two major regulators of virulence – the Agr and Sae two-component systems – by unknown mechanisms. This work identifies a mechanism by which CodY controls the activity of the sensor kinase SaeS by modulating the flux of anteiso branched-chain amino acids to the membrane. Understanding the mechanism adds to our understanding of how bacterial physiology and metabolism are linked to virulence and underscores the homeostatic nature of virulence. Understanding the mechanism also opens potential avenues for targeted therapeutic strategies againstS. aureusinfections.
Mycelium as a scaffold for biomineralized engineered living materials
Authors: Viles Ethan , Heyneman Ethan , Lin Shuyi , Montague Virginia , Darabi Amir , Cox Lewis M. , Phillips Adrienne , Gerlach Robin , Espinosa-Ortiz Erika , Heveran Chelsea
Published: May 2024

Engineered living materials (ELMs) are garnering considerable attention as a promising alternative to traditional building materials because of their potentially lower carbon footprint and additional functionalities conferred by living cells. However, biomineralized ELMs designed for load-bearing purposes are limited in their current design and usage for several reasons, including (1) low microbial viability and (2) limited control of specimen internal microarchitecture. We created ‘third generation’ biomineralized ELMs from fungal mycelium scaffolds that were mineralized either by the fungus itself or by ureolytic bacteria. Both self-mineralized (i.e. fungally-mineralized) and bacterially-mineralized scaffolds retained high microbial viability for at least four weeks in room temperature or accelerated dehydration storage conditions, without the addition of protectants against desiccation. The microscale modulus of calcium carbonate varied with the different biomineralized scaffold conditions, and moduli were largest and stiffest for bacterial biomineralization of fungal mycelium. As an example of how mycelium scaffolds can enable the design of complex internal geometries of biomineralized materials, osteonal-bone mimetic architectures were patterned from mycelium and mineralized using ureolytic bacteria. These results demonstrate the potential for mycelium scaffolds to enable new frontiers in the design of biomineralized ELMs with improved viability and structural complexity.

Progress and Potential

Biomineralized engineered living materials (ELMs) offer new approaches for increasing the sustainability of building materials and processes. However, the design and usage of biomineralized ELMs is constrained by several important limitations, including low microbial viability and limited ability to control internal microarchitecture. Fungal mycelium scaffolds, biomineralized by either fungi or bacteria, achieve much higher viability of ureolytic microorganisms than what has been reported for biomineralized ELMs. Further, mycelium scaffolds permit the manufacturing of complex architectures, such as inspired by the structure of osteonal bone. Mycelium scaffolds have the potential to enable new frontiers in the design and use of biomineralized ELMs.

Graphical Abstract
Bisphenol A affects the development and the onset of photosymbiosis in the acoelSymsagittifera roscoffensis
Authors: Pennati R. , Cartelli N. , Castelletti C. , Ficetola F. , Bailly X. , Mercurio S.
Published: May 2024

Photosymbiosis indicates a long-term association between animals and photosynthetic organisms. It has been mainly investigated in photosymbiotic cnidarians, while other photosymbiotic associations have been largely neglected. The acoelSymsagittifera roscoffensislives in obligatory symbiosis with the microalgalTetraselmis convolutaeand has recently emerged as alternative model to study photosymbiosis. Here, we investigated the effects of Bisphenol A, a common plastic additive, on two pivotal stages of its lifecycle: aposymbiotic juvenile development and photosymbiogenesis. Based on our results, this pollutant altered the development of the worms and their capacity to engulf algae from the environment at concentrations higher than the levels detected in seawater, yet aligning with those documented in sediments of populated areas. Data provide novel information about the effects of pollutants on photosymbiotic associations and prompt the necessity to monitor their concentrations in marine environmental matrices.
Optimal antimicrobial dosing combinations when drug-resistance mutation rates differ
Authors: Delaney Oscar , Letten Andrew D. , Engelstädter Jan
Published: May 2024

Given the ongoing antimicrobial resistance crisis, it is imperative to develop dosing regimens optimised for avoiding the evolution of resistance. The rate at which bacteria acquire resistance-conferring mutations to different antimicrobial drugs spans multiple orders of magnitude. By using a mathematical model and computer simulations, we show that knowledge of relative mutation rates can meaningfully inform the optimal combination of two drugs in a treatment regimen. We demonstrate that under plausible assumptions there is a linear relationship in log-log space between the drugA:drugBdose ratio that maximises the chance of treatment success and the ratio of their mutation rates. This power law relationship holds for bacteriostatic and bactericidal drugs. If borne out empirically, these findings suggest there might be significant room to further optimise antimicrobial dosing strategies.
The CcpNmr Analysis Simulated Metabolomics Database (CASMDB): An Open-Source Collection of Metabolite Annotation Data for 1D1H NMR-Based Metabolomics
Authors: Hayward Morgan W. , Mureddu Luca G. , Thompson Gary , Phelan Marie , Brooksbank Edward J. , Vuister Geerten W.
Published: May 2024

Databases are invaluable for the identification of individual metabolites in untargeted metabolomics analyses, providing annotated pure metabolite references that allow for comparisons with experimentally collected mixture samples. Despite the value of an extensive reference database, publicly available databases for NMR-based metabolomics are often incomplete with respect to experimental conditions and derived NMR annotation parameters, such as peak positions. Hence, they are not designed for visualising the reference spectra alongside an experimental sample spectrum of interest, thus limiting the usefulness of the database. As a consequence, researchers have resorted to their own user- or application based database implementations.

In this paper we describe the collection, remediation and integration of annotation data from the publicly available HMDB, BRMB and GISMO NMR metabolomics databases to build the CcpNmr Analysis Simulated Metabolomics Database (CASMDB) that contains 1932 unique metabolite entries. This database, in concert with the AnalysisMetabolomics programme, also allows or accurate simulation of spectra at arbitrary field strengths. Together, these tools underpin the visualising of experimental and simulated metabolite references and their usage in 1D1H NMR-based metabolomics studies.
Serotonin attenuates tumor-necrosis-factor-alpha-induced intestinal inflammation by interacting with human mucosal tissue
Authors: Bosáková Veronika , Papatheodorou Ioanna , Kafka Filip , Tomášiková Zuzana , Hortová Kohoutková Marcela , Frič Jan
Published: May 2024

The intestine houses the largest reservoir of immune cells and is serviced by the largest and most complex peripheral nervous system in the human body. The gut-brain axis orchestrates bidirectional communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Using a human 3Din vitromodel, we investigated the effect of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Our findings revealed that serotonin attenuates the tumor-necrosis-factor-alpha-induced pro-inflammatory response, mostly by affecting the expression of chemokines. Serotonin was found to impact tissue-migrating monocytes’ phenotype and distribution, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, using fully human 3D model of intestine, our results show for the first time that serotonin has a crucial role in communication among gut-brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of intestinal inflammation.In vivostudies focused on role of neuromodulators in gut homeostasis and inflammation have shown controversial results, highlighting importance of development of human experimental models. Moreover, our results emphasize importance of human health research in human-cell-based models and suggests serotonin signaling pathway as new potential therapeutic target for inflammatory bowel disease patients.
Alcohol-induced sleep dysregulation in Drosophila is dependent on the neuropeptide PDF
Authors: Ramirez-Roman Maria E. , Fuenzalida-Uribe Nicolás L. , Ayala-Santiago Genesis , Agosto Jose L. , Ghezzi Alfredo
Published: May 2024

Alcohol exposure is known to trigger homeostatic adaptations in the brain that lead to the development of tolerance and dependence. These adaptations are also believed to be the root of a series of disturbances in sleep patterns that often manifest during the development of alcoholism and can have significant clinical and economic consequences. Unfortunately, the neuronal and genetic pathways that control the effects of alcohol on sleep are currently unknown, thus limiting our efforts to find effective treatment. In this study, we conduct a mechanistic exploration of the relationships between alcohol and sleep alterations using aDrosophilamodel system. We show that the genetic manipulation of the ventral lateral neurons (LNv) —a set of neurons known to control sleep inDrosophila— disrupts alcohol sensitivity and tolerance. Moreover, we show that alcohol exposure induces a series of alterations in sleep patterns that last for several days. Our results demonstrate that a single alcohol exposure promotes daytime sleep, alters the structure of sleep during the night, and reduces morning anticipatory behavior. In addition, we show that some of these alterations partially depend on the activity of the neuropeptide PDF, a key element in regulating sleep architecture. We propose that alcohol-induced sleep disruption stems from alterations in the activity of the PDF-releasing LNv neurons and that these alterations are similar to those that produce alcohol tolerance.
Clearing method adapted to FFPE tissues for 3D imaging of nerve fibers, B cells, and tertiary lymphoid structures
Authors: Azar Safa , Letaïef Laïla , Malkinson Guy , Martin Sabrina , Validire Pierre , Teillaud Jean-Luc , Dieu-Nosjean Marie-Caroline , Brunet Isabelle
Published: May 2024

Biomedical samples are commonly used for histological examination after their inclusion in paraffin (Formalin-Fixed Paraffin-Embedded (FFPE) biopsy). However, they provide minimal information about the interactions between different tissue components such as blood vessels, nerves, and cellular aggregates. Here we present a modified iDISCO tissue-clearing method that we term miDISCO+. miDISCO+can be used for analyzing FFPE samples, requires the use of only one single FFPE sample, and allows to acquire a detailed image of the 3D tissue/organ architecture and the relevant cellular interactions. The addition of an antigen retrieval step to the protocol enables to use antibodies whose binding is sensitive to formalin fixation due to antigen masking. This method enabled us to detect CD20+B cell follicles and to show that they are in close contact with TH+sympathetic nerve fibers in FFPE biopsies of human palatine tonsils, and to detect CD20+B cells in lung tumors and observe their 3D organization within tertiary lymphoid structures. Thus, miDISCO+could be a potent tool for clinicians to refine diagnosis and to select optimal personalized treatment by giving an integrated 3D view of the tissue structures and cellular interactions in single FFPE samples.
WITHDRAWN: Molecular Insights into Zea mays Active Phytochemicals for Diabetes and Inflammation Treatment: A Web App-Based Machine Learning and Network Pharmacology Approach
Authors: Manaithiya Ajay , Bhowmik Ratul , Elhenawy Ahmed A. , Sharma Sameer , Dinesh Susha , Parkkila Seppo , Aspatwar Ashok
Published: May 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Combinatorial microRNA activity is essential for the transition of pluripotent cells from proliferation into dormancy
Authors: Iyer Dhanur P. , Moyon Lambert , Wittler Lars , Cheng Chieh-Yu , Ringeling Francisca R. , Canzar Stefan , Marsico Annalisa , Bulut-Karslioğlu Aydan
Published: May 2024

Dormancy is a key feature of stem cell function in adult tissues as well as in embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring. How these processes are coordinated to successfully transition cells to the resting dormant state remains unclear. Here we show that microRNA activity, which is otherwise dispensable for preimplantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in the loss of pluripotent cells. Through the integration of high-sensitivity small RNA expression profiling of individual embryos and protein expression of miRNA targets with public data of protein–protein interactions, we constructed the miRNA-mediated regulatory network of mouse early embryos specific to diapause. We find that individual miRNAs contribute to the combinatorial regulation by the network, and the perturbation of the network compromises embryo survival in diapause. We further identified the nutrient-sensitive transcription factor TFE3 as an upstream regulator of diapause-specific miRNAs, linking cytoplasmic MTOR activity to nuclear miRNA biogenesis. Our results place miRNAs as a critical regulatory layer for the molecular rewiring of early embryos to establish dormancy.
Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions
Authors: Joosten Stacey E.P. , Gregoricchio Sebastian , Stelloo Suzan , Yapıcı Elif , Huang Chia-Chi Flora , Yavuz Kerim , Donaldson Collier Maria , Morova Tunç , Altintaş Umut Berkay , Kim Yongsoo , Canisius Sander , Moelans Cathy B. , van Diest Paul J. , Korkmaz Gozde , Lack Nathan A. , Vermeulen Michiel , Linn Sabine C. , Zwart Wilbert
Published: May 2024

Estrogen Receptor 1 (ESR1; also known as ERα, encoded byESR1gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1–chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription
Authors: Keenan Christine R. , Coughlan Hannah D. , Iannarella Nadia , Tapia del Fierro Andres , Keniry Andrew , Johanson Timothy M. , Chan Wing Fuk , Garnham Alexandra L. , Whitehead Lachlan W. , Blewitt Marnie E. , Smyth Gordon K. , Allan Rhys S.
Published: May 2024

H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both SUV39H1 and SUV39H2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (Tn5-accessible, H3K4me3- and H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) or polycomb (H3K27me3-marked) regions. Examination of the three-dimensional (3D) nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3D space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3D genome organization in Suv39DKO cells. Together, our results suggest that the nuclear lamina-tethering of Suv39-dependent H3K9me3 domains provides an essential scaffold to support euchromatic genome organization and the maintenance of gene transcription for healthy cellular function.
Controllable odd-frequency Cooper pairs in multisuperconductor Josephson junctions
Authors: Cayao Jorge , Burset Pablo , Tanaka Yukio
Published: May 2024

We consider Josephson junctions formed by multiple superconductors with distinct phases and explore the formation of nonlocal or intersuperconductor pair correlations. We find that the multiple superconductor nature offers an additional degree of freedom that broadens the classification of pair symmetries, enabling nonlocal even- and odd-frequency pairings that can be highly controlled by the superconducting phases and the energy of the superconductors. Specially, when the phase difference between two superconductors is π, their associated nonlocal odd-frequency pairing is the only type of intersuperconductor pair correlations. Finally, we show that these nonlocal odd-frequency Cooper pairs dominate the nonlocal conductance via crossed Andreev reflections, which constitutes a direct evidence of odd-frequency pairing.

Published by the American Physical Society
2024
Detection prospects of long-lived quirk pairs at the LHC far detectors
Authors: Li Jinmian , Liao Xufei , Ni Jian , Pei Junle
Published: May 2024

We examine the sensitivity reaches of several LHC far detectors, such as FASER2, MATHUSLA, ANUBIS, SND@LHC, and FACET, to five simplified quirk scenarios. We include the next-to-leading order QCD corrections in our simulation of quirk events, which enhance the total production rate and increase the fraction of events in the forward direction for most cases. We calculate the timescales for the quirk pair to lose energy through radiations and for the quirk pair annihilation. Our results show that these far detectors can offer promising probes to the quirk scenario, complementing the searches at the main detectors. Especially, FACET and FASER2 detectors can surpass the majority of searches conducted at the LHC main detector, with the exception of the HSCP search, for the color-neutral quirk E.

Published by the American Physical Society
2024
Sum rule for the pseudo-Rényi entropy
Authors: Guo Wu-zhong , Zhang Jiaju
Published: May 2024

By generalizing the density matrix to a transition matrix between two states, represented as |ϕ⟩ and |ψ⟩, one can define the pseudoentropy analogous to the entanglement entropy. In this paper, we establish an operator sum rule that pertains to the reduced transition matrix and reduced density matrices corresponding to the superposition states of |ϕ⟩ and |ψ⟩. It is demonstrated that the off-diagonal elements of operators can be correlated with the expectation value in the superposition state. Furthermore, we illustrate the connection between the pseudo-Rényi entropy and the Rényi entropy of the superposition states. We provide proof of the operator sum rule and verify its validity in both finite-dimensional systems and quantum field theory. We additionally demonstrate the significance of these sum rules in gaining insights into the physical implications of transition matrices, pseudoentropy, and their gravity dual.

Published by the American Physical Society
2024
Four-gluon vertex from the Curci-Ferrari model at one-loop order
Authors: Barrios Nahuel , De Fabritiis Philipe , Peláez Marcela
Published: May 2024

We compute the four-gluon vertex from the Curci-Ferrari model at one-loop order for a collinear configuration. Our results display a good agreement with the first lattice data for this vertex, released very recently []. A noteworthy novelty of our work is that we can provide analytical expressions for the four-gluon vertex in collinear configurations, together with a renormalization scheme that allows us to perform reliable perturbative computations even in the infrared regime. We observe an infrared suppression in the form factor associated with the tree-level four-gluon tensor with a possible zero crossing in the deep infrared which demands new lattice investigations to be confirmed. Moreover, we report an infrared divergence in the completely symmetric tensor form factor due to the ghost-loop contributions. These results come as predictions, since previous two-point correlations fix all the available parameters of the model, up to an overall constant factor.

Published by the American Physical Society
2024
Entanglement of purification in random tensor networks
Authors: Akers Chris , Faulkner Thomas , Lin Simon , Rath Pratik
Published: May 2024

The entanglement of purification EP(A∶B) is a powerful correlation measure, but it is notoriously difficult to compute because it involves an optimization over all possible purifications. In this paper, we prove a new inequality: EP(A∶B)≥12SR(2)(A∶B), where SR(n)(A∶B) is the Renyi reflected entropy. Using this, we compute EP(A∶B) for a large class of random tensor networks at large bond dimension and show that it is equal to the entanglement wedge cross section EW(A∶B), proving a previous conjecture motivated from AdS/CFT.

Published by the American Physical Society
2024
Network science: Ising states of matter
Authors: Sun Hanlin , Panda Rajat Kumar , Verdel Roberto , Rodriguez Alex , Dalmonte Marcello , Bianconi Ginestra
Published: May 2024

Network science provides very powerful tools for extracting information from interacting data. Although recently the unsupervised detection of phases of matter using machine learning has raised significant interest, the full prediction power of network science has not yet been systematically explored in this context. Here we fill this gap by providing an in-depth statistical, combinatorial, geometrical, and topological characterization of 2D Ising snapshot networks (IsingNets) extracted from Monte Carlo simulations of the 2D Ising model at different temperatures, going across the phase transition. Our analysis reveals the complex organization properties of IsingNets in both the ferromagnetic and paramagnetic phases and demonstrates the significant deviations of the IsingNets with respect to randomized null models. In particular percolation properties of the IsingNets reflect the existence of the symmetry between configurations with opposite magnetization below the critical temperature and the very compact nature of the two emerging giant clusters revealed by our persistent homology analysis of the IsingNets. Moreover, the IsingNets display a very broad degree distribution and significant degree-degree correlations and weight-degree correlations demonstrating that they encode relevant information present in the configuration space of the 2D Ising model. The geometrical organization of the critical IsingNets is reflected in their spectral properties deviating from the one of the null model. This work reveals the important insights that network science can bring to the characterization of phases of matter. The set of tools described hereby can be applied as well to numerical and experimental data.

Published by the American Physical Society
2024
Theory of electron spin resonance in scanning tunneling microscopy
Authors: Ast Christian R. , Kot Piotr , Ismail Maneesha , de-la-Peña Sebastián , Fernández-Domínguez Antonio I. , Cuevas Juan Carlos
Published: May 2024

Electron spin resonance (ESR) spectroscopy in scanning tunneling microscopy (STM) has enabled probing the electronic structure of single magnetic atoms and molecules on surfaces with unprecedented energy resolution, as well as demonstrating coherent manipulation of single spins. Despite this remarkable success, the field could still be greatly advanced by a more quantitative understanding of the ESR-STM physical mechanisms. Here, we present a theory of ESR-STM that quantitatively models not only the ESR signal itself, but also the full background tunneling current, from which the ESR signal is derived. Our theory is based on a combination of Green's function techniques to describe the electron tunneling and a quantum master equation for the dynamics of the spin system along with microwave radiation interacting with both the tunneling current and the magnetic system. We show that this theory is able to quantitatively reproduce the experimental results for a spin-1/2 system (TiH molecules on MgO) across many orders of magnitude in tunneling current, providing access to the relaxation and decoherence rates that govern the spin dynamics due to intrinsic mechanisms and to the applied bias voltage. More importantly, our work establishes that (i) sizable ESR signals, which are a measure of microwave-induced changes in the junction magnetoresistance, require surprisingly high tip spin polarizations, and (ii) the coupling of the magnetization dynamics to the microwave field gives rise to the asymmetric ESR spectra often observed in this spectroscopy. Additionally, our theory provides very specific predictions for the dependence of the relaxation and decoherence times on the bias voltage and the tip-sample distance. Finally, with the help of electromagnetic simulations, we find that the transitions in our ESR-STM experiments, in which the tunnel junction is irradiated by a nearby microwave antenna, can be driven by the ac magnetic field at the junction.

Published by the American Physical Society
2024
Topology-dependent coalescence controls scaling exponents in finite networks
Authors: Zeraati Roxana , Buendía Victor , Engel Tatiana A. , Levina Anna
Published: May 2024

Studies of neural avalanches across different data modalities led to the prominent hypothesis that the brain operates near a critical point. The observed exponents often indicate the mean-field directed-percolation universality class, leading to the fully connected or random network models to study the avalanche dynamics. However, cortical networks have distinct nonrandom features and spatial organization that is known to affect critical exponents. Here we show that distinct empirical exponents arise in networks with different topology and depend on the network size. In particular, we find apparent scale-free behavior with mean-field exponents appearing as quasicritical dynamics in structured networks. This quasicritical dynamics cannot be easily discriminated from an actual critical point in small networks. We find that the local coalescence in activity dynamics can explain the distinct exponents. Therefore, both topology and system size should be considered when assessing criticality from empirical observables.

Published by the American Physical Society
2024
Prospects for thermalization of microwave-shielded ultracold molecules
Authors: Wang Reuben R. W. , Bohn John L.
Published: May 2024

Toward more efficient schemes for achieving deeply degenerate molecular Fermi gases, we study anisotropic thermalization in dilute gases of microwave shielded polar molecular fermions. For collision energies above the threshold regime, we find that thermalization is suppressed due to a strong preference for forward scattering and a reduction in total cross section with energy, significantly reducing the efficiency of evaporative cooling. We perform close-coupling calculations on the effective potential energy surface derived by Deng [] to obtain accurate two-body elastic differential cross sections across a range of collision energies. We use Gaussian process regression to obtain a global representation of the differential cross section over a wide range of collision angles and energies. The route to equilibrium is then analyzed with cross-dimensional rethermalization experiments, quantified by a measure of collisional efficiency toward achieving thermalization.

Published by the American Physical Society
2024
The effect of NaCl concentration on impact-sliding fretting corrosion behavior of Inconel 690TT heat transfer tubes
Authors: Li Yinghong , Tan Wei , Pei Wenjie , Zhu Guorui
Published: May 2024

Purpose

The purpose of this paper is to investigate the effect of NaCl solution with different concentrations on impact-sliding fretting corrosion behavior of Inconel 690TT steam generator heat transfer tubes.

Design/methodology/approach

The optical 3D profiler was used to measure the wear profile and calculated the wear volume. Corrosion behavior was studied using open circuit potential monitoring and potentiodynamic polarization testing. The morphologies and elemental distributions of wear scars were analyzed using scanning electron microscopy and energy-dispersive spectroscopy. The synergism of wear and corrosion was analyzed according to the ASTM G119 standard.

Findings

The corrosion tendency reflected by OCP and the corrosion current calculated by Tafel both increased with the increase of NaCl concentration. The total volume loss of the material increased with concentration, and it was known from the synergism that the volume loss caused by corrosion-enhanced wear accounted for the largest proportion, while the wear-enhanced corrosion also made a greater contribution to volume loss than tangential fretting corrosion. Through the analysis of the material morphologies and synergism of wear and corrosion, the damage mechanism was elucidated.

Originality/value

The research findings can provide reference for impact-sliding fretting corrosion behavior of Inconel 690TT heat transfer tubes in NaCl solution with different concentrations.