julilili42/papers huggingface dataset:
Investigation of the anti-cancer potential of epoxyazadiradione in neuroblastoma: experimental assays and molecular analysis
2023-09-27

Neuroblastoma, the most common childhood solid tumor, originates from primitive sympathetic nervous system cells. Epoxyazadiradione (EAD) is a limonoid derived from <i>Azadirachta indica</i>, belonging to the family Meliaceae. In this study, we isolated the EAD from <i>Azadirachta indica</i> seed and studied the anti-cancer potential against neuroblastoma. Herein, EAD demonstrated significant efficacy against neuroblastoma by suppressing cell proliferation, enhancing the rate of apoptosis and cycle arrest at the SubG<sub>0</sub> and G<sub>2</sub>/M phases. EAD enhanced the pro-apoptotic Caspase 3 and Caspase 9 and inhibited the NF-kβ translocation in a dose-dependent manner. In order to identify the specific EAD target, a gel-free quantitative proteomics study on SH-SY5Y cells using Liquid Chromatography with tandem mass spectrometry was done in a dose-dependent manner, followed by detailed bioinformatics analysis to identify effects on protein. Proteomics data identified that Enolase1 and HSP90 were up-regulated in neuroblastoma. EAD inhibited the expression of Enolase1 and HSP90, validated by mRNA expression, immunoblotting, Enolase1 and HSP90 kit and flow-cytometry based bioassay. Molecular docking study, Molecular dynamic simulation, and along with molecular mechanics/Poisson-Boltzmann surface area analysis also suggested that EAD binds at the active site of the proteins and were stable throughout the 100 ns Molecular dynamic simulation study. Overall, this study suggested EAD exhibited anti-cancer activity against neuroblastoma by targeting Enolase1 and HSP90 pathways. Communicated by Ramaswamy H. Sarma
Design Strategies for Perovskite-Type High-Entropy Oxides with Applications in Optics
2023-09-28

It is essential and challenging to develop advanced ceramic materials with thermal stability and high reflectivity for optical fields. Encouragingly, recent breakthroughs and significant advances in high-entropy ceramics have made high-entropy oxides a potential candidate material for optical applications. Therefore, in this study, we analyzed the effect of lattice distortion on the design of high-reflectivity, high-entropy oxides using first-principles calculations and aberration-corrected microscopy. In order to optimize the optical properties of the materials, a series of novel perovskite-type high-entropy oxides, (La<sub><i>x</i></sub>K<sub>0.4-<i>x</i></sub>Ca<sub>0.2</sub>Sr<sub>0.2</sub>Ba<sub>0.2</sub>)TiO<sub>3+δ</sub> (<i>x</i> = 0.1, 0.15, 0.2, 0.25, 0.3), were designed and synthesized using solid-state sintering based on the charge conservation principle and bond energy principle. When the content of La in the A-site element was 30%, the optical reflectivity reached 94% by suppressing the oxygen vacancy. Furthermore, we have successfully prepared a series of coatings by air spraying based on the regulation of the mass ratio of resin and powder. Compared to the uncoated substrate, the backside temperature can be reduced by 41%. This work provides a feasible design route with the first clear guidelines for highly reflective high-entropy ceramic materials and enables highly stable material design in multielement spaces.
Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies
2023-09-28

Abstract Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the &amp;gt;20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.
On the reproducibility of extrusion-based bioprinting: round robin study on standardization in the field
2023-09-28

Abstract The outcome of three-dimensional (3D) bioprinting heavily depends, amongst others, on the interaction between the developed bioink, the printing process, and the printing equipment. However, if this interplay is ensured, bioprinting promises unmatched possibilities in the health care area. To pave the way for comparing newly developed biomaterials, clinical studies, and medical applications (i.e. printed organs, patient-specific tissues), there is a great need for standardization of manufacturing methods in order to enable technology transfers. Despite the importance of such standardization, there is currently a tremendous lack of empirical data that examines the reproducibility and robustness of production in more than one location at a time. In this work, we present data derived from a round robin test for extrusion-based 3D printing performance comprising 12 different academic laboratories throughout Germany and analyze the respective prints using automated image analysis (IA) in three independent academic groups. The fabrication of objects from polymer solutions was standardized as much as currently possible to allow studying the comparability of results from different laboratories. This study has led to the conclusion that current standardization conditions still leave room for the intervention of operators due to missing automation of the equipment. This affects significantly the reproducibility and comparability of bioprinting experiments in multiple laboratories. Nevertheless, automated IA proved to be a suitable methodology for quality assurance as three independently developed workflows achieved similar results. Moreover, the extracted data describing geometric features showed how the function of printers affects the quality of the printed object. A significant step toward standardization of the process was made as an infrastructure for distribution of material and methods, as well as for data transfer and storage was successfully established.
The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics
2023-09-28

A global genome database of all of Earth's species diversity could be a treasure trove of scientific discoveries. However, regardless of the major advances in genome sequencing technologies, only a tiny fraction of species have genomic information available. To contribute to a more complete planetary genomic database, scientists and institutions across the world have united under the Earth BioGenome Project (EBP), which plans to sequence and assemble high-quality reference genomes for all ~1.5 million recognized eukaryotic species through a stepwise phased approach. As the initiative transitions into Phase II, where 150,000 species are to be sequenced in just four years, worldwide participation in the project will be fundamental to success. As the European node of the EBP, the European Reference Genome Atlas (ERGA) seeks to implement a new decentralised, accessible, equitable and inclusive model for producing high-quality reference genomes, which will inform EBP as it scales. To embark on this mission, ERGA launched a Pilot Project to establish a network across Europe to develop and test the first infrastructure of its kind for the coordinated and distributed reference genome production on 98 European eukaryotic species from sample providers across 34 European countries. Here we outline the process and challenges faced during the development of a pilot infrastructure for the production of reference genome resources, and explore the effectiveness of this approach in terms of high-quality reference genome production, considering also equity and inclusion. The outcomes and lessons learned during this pilot provide a solid foundation for ERGA while offering key learnings to other transnational and national genomic resource projects.
The Development and Validation of Radiopharmaceuticals Targeting Bacterial Infection
2023-09-28

The International Atomic Energy Agency organized a technical meeting at its headquarters in Vienna, Austria, in 2022 that included 17 experts representing 12 countries, whose research spanned the development and use of radiolabeled agents for imaging infection. The meeting focused largely on bacterial pathogens. The group discussed and evaluated the advantages and disadvantages of several radiopharmaceuticals, as well as the science driving various imaging approaches. The main objective was to understand why few infection-targeted radiotracers are used in clinical practice despite the urgent need to better characterize bacterial infections. This article summarizes the resulting consensus, at least among the included scientists and countries, on the current status of radiopharmaceutical development for infection imaging. Also included are opinions and recommendations regarding current research standards in this area. This and future International Atomic Energy Agency-sponsored collaborations will advance the goal of providing the medical community with innovative, practical tools for the specific image-based diagnosis of infection.
Retinal metabolism displays evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle
2023-09-28

The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilised 1 H-NMR spectroscopy-based metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: (1) the mini-Krebs-cycle, fuelled by glutamine and branched chain amino acids, generating N -acetylaspartate; (2) the alanine-generating Cahill-cycle; (3) the lactate-releasing Cori-cycle. Moreover, the metabolomics data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.
Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD Gene
2023-09-28

Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding DMD gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (FKTN) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the DMD gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing.
Dynamical scalarization during neutron star mergers in scalar-Gauss-Bonnet theory
2023-09-28

In certain classes of the scalar-Gauss-Bonnet theory strong spacetime curvature in the vicinity of neutron stars and black holes can spontaneously trigger scalarization in the compact object if the coupling strength of the scalar field to the Gauss-Bonnet invariant exceeds a critical value. Specifying on neutron stars, this threshold depends on the mass and equation of state. The presence of a companion will further influence the required coupling strength for scalarization, and thus, a stable hair can be installed at a lower magnitude of coupling for those neutron stars as members of binaries. Focusing on binary neutron star mergers, we investigate this latter dynamically driven scalarization, and find that the reduction in the threshold coupling strength seems to be more profound for symmetric binaries, while the threshold is only marginally reduced for rather asymmetric binaries. The associated scalar radiation is also discussed. We discover in addition a universal relation between the critical coupling strength and the stellar compactness for isolated neutron stars and perform a detailed comparison with the dynamical scalarization threshold. In synergy with such relations, one can, at least in principle, constrain the theory parameters regardless of the uncertainty in the equation of state.
Translating pharmacogenomic sequencing data into drug response predictions—How to interpret variants of unknown significance
2023-09-28

Abstract The rapid development of sequencing technologies during the past 20 years has provided a variety of methods and tools to interrogate human genomic variations at the population level. Pharmacogenes are well known to be highly polymorphic and a plethora of pharmacogenomic variants has been identified in population sequencing data. However, so far only a small number of these variants have been functionally characterized regarding their impact on drug efficacy and toxicity and the significance of the vast majority remains unknown. It is therefore of high importance to develop tools and frameworks to accurately infer the effects of pharmacogenomic variants and, eventually, aggregate the effect of individual variations into personalized drug response predictions. To address this challenge, we here first describe the technological advances, including sequencing methods and accompanying bioinformatic processing pipelines that have enabled reliable variant identification. Subsequently, we highlight advances in computational algorithms for pharmacogenomic variant interpretation and discuss the added value of emerging strategies, such as machine learning and the integrative use of omics techniques that have the potential to further contribute to the refinement of personalized pharmacological response predictions. Lastly, we provide an overview of experimental and clinical approaches to validate in silico predictions. We conclude that the iterative feedback between computational predictions and experimental validations is likely to rapidly improve the accuracy of pharmacogenomic prediction models, which might soon allow for an incorporation of the entire pharmacogenetic profile into personalized response predictions.
Traditional Chinese medicine Dingkun pill to increase fertility in women with a thin endometrium—a prospective randomized study
2023-09-28

Objective The aim of this study is to optimize the treatment methods of infertility, which is suggested to be mainly caused by thin endometrium, using a special form of traditional Chinese medicine, the Dingkun pill (DKP), to increase the beneficial endometrial effect of conventional hormone/progestogen therapy. Methods A total of 307 patients visiting our specialized gynecological endocrinology department because of infertility, which we suggested to be caused by thin endometrium [endometrial thickness (EMT) &amp;lt; 7 mm], were randomly assigned to the experimental group and the control group. The experimental group was treated with estradiol + sequential dydrogesterone + DKP (every day); the control group received hormonal treatment without the Chinese medicine. All patients were monitored in terms of follicle diameter, EMT, and endometrial type every 2 days from the 8th to the 10th day of the menstrual cycle until ovulation day during three menstrual cycles. Serum progesterone levels on 7–8 days after ovulation were measured, and the cumulative pregnancy rate during three menstrual cycles between the two groups was compared. Results EMT on ovulation day in the experimental group was significantly higher than that in the control group (7.88 vs. 7.15 mm; p &amp;lt; 0.001). The proportion of type A and type B endometrium in total was significantly higher in the experimental group than that in the control group (83.2% vs. 77.7%; p &amp;lt; 0.05). Progesterone levels were significantly higher in the experimental group than those in the control group (10.874 vs. 10.074 ng/mL; p &amp;lt; 0.001). The cumulative pregnancy rate, the main outcome of the study, was significantly higher in the experimental group than that in the control group (29.2% vs. 15.7%; p &amp;lt; 0.05). Conclusion DKP added to conventional estrogen/progestogen therapy can significantly improve EMT and luteal function in patients attending due to infertility. Because this regimen increased the cumulative pregnancy rate in our study, we conclude that DKP can be used to increase the so-called “thin endometrium infertility”.
Immunosuppressive CD29+Treg accumulation in the liver in mice on checkpoint inhibitor therapy
2023-09-28

Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown. Design Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy. Results We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29 + ( Itgb1 , integrin β1) Tregs, that were highly proliferative at baseline, doubled its size in response to αPD-1. Partial and full depletion of Tregs identified CD29 + Tregs as the prominent niche-filling subpopulation in the liver, and CD29 + Tregs demonstrated enhanced suppression in vitro when derived from the liver but not the spleen. We identified IL2 as a critical modulator of both CD29 + and CD29 − hepatic Tregs, but expansion of the liver Treg population with αPD-1 driven by CD29 + Tregs was in part IL2-independent. Conclusion We propose that CD29 + Tregs constitute a unique subpopulation of hepatic Tregs that are primed to respond to ICI agents and mediate resistance.
The retina uncouples glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle
2023-09-28

Abstract The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilized 1H-NMR spectroscopy-based metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were highly dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors were able to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: 1) the mini-Krebs-cycle, fueled by glutamine and branched-chain amino acids, generating N-acetylaspartate; 2) the alanine-generating Cahill-cycle; 3) the lactate-releasing Cori-cycle. Moreover, the metabolomic data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.
Insight into heterogeneous dynamics of growing islands using coherent x-ray scattering
2023-09-28

Abstract Understanding the non-equilibrium structure formation of thin films is a fundamental challenge with important implications also for technical applications. The interplay between adsorption, desorption, and surface diffusion may result in the formation of nontrivial surface morphologies. X-ray photon correlation spectroscopy opens up new possibilities for understanding these processes. In this work, we perform in situ x-ray experiments in grazing incidence geometry to follow the growth of diindenoperylene thin films in real time, revealing details of the dynamics during molecular island formation. Comparison with simulations allows to extract dynamic and kinetic time scales. We observe time scales in the range of a few hundred seconds which occur mainly due to kinetics, i.e. island growth. Importantly, we can relate the observed heterogeneous behavior in dynamics to the number of open layers, revealing information about the change in the roughness, and the growth speed of each layer.