bluuebunny/crossref_metadata_2025 huggingface dataset:
Climate Models Underestimate Dynamic Cloud Feedbacks in the Tropics
Authors: Hill P. G. , Holloway C. E. , Byrne M. P. , Lambert F. H. , Webb M. J.
Published: August 2023

Cloud feedbacks are the leading cause of uncertainty in climate sensitivity. The complex coupling between clouds and the large‐scale circulation in the tropics contributes to this uncertainty. To address this problem, the coupling between clouds and circulation in the latest generation of climate models is compared to observations. Significant biases are identified in the models. The implications of these biases are assessed by combining observations of the present day with future changes predicted by models to calculate observationally constrained feedbacks. For the dynamic cloud feedback (i.e., due to changes in circulation), the observationally constrained values are consistently larger than the model‐only values. This is due to models failing to capture a nonlinear minimum in cloud brightness for weakly descending regimes. Consequently, while the models consistently predict that these regimes increase in frequency in association with a weakening tropical circulation, they underestimate the positive cloud feedback associated with this increase.
Revisiting the Variation of the Ionospheric Irregularities in the Low Latitude Region of China Based on Small Regional Geodetic GNSS Station Network
Authors: Gao H. Y. , Zhang D. H. , Liu Z. Z. , Sun S. J. , Hao Y. Q. , Xiao Z.
Published: August 2023

The rate of total electron content index (ROTI) and loss of lock (LoL) from global navigation satellite system (GNSS) observations are an important data source for ionospheric scintillation study. However, there are certain limitations of these data in ionospheric scintillation study, and clearing these limitations is important to understand the results from these data. In this paper, the variation of the ionospheric scintillation is revisited based on LoL and ROTI from a spatial dense GNSS network in the low latitude region of China. Via a priori knowledge of scintillation morphology, the method to determine the baseline ROTI for discriminating quiet and disturbed conditions is provided, and the abnormal data of ROTI and LoL unrelated to ionosphere are found and eliminated. Results show that the data examination is necessary. Using the qualified ROTI and LoL, the morphological variations of ionospheric irregularities are revisited. The temporal variation of ROTI and LoL are generally consistent, but there are some discrepancies. The maximum LoL occurrence is at about 21:00 LT, it is between 20:00 and 23:00 LT for ROTI. For spatial distribution, both parameters reach maximum occurrence in the southwest direction, but LoL is more concentrated. The azimuth range of maximum occurrence is 180–190° for LoL and 210–220° for ROTI. Statistically, the correlation between LoL occurrence and ROTI value from observation of single GNSS station is relatively good when ROTI <5 TECU/min, but it becomes worse when ROTI >5 TECU/min. However, their correlation can be greatly improved when data are averaged among all the stations.
Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials
Authors: Zhao Zifan , Zhao Qin , Chen Hu , Chen Fanfan , Wang Feifei , Tang Hua , Xia Haibin , Zhou Yongsheng , Sun Yuchun
Published: August 2023

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.
Extracellular matrix remodelling in dental pulp tissue of carious human teeth through the prism of single-cell RNA sequencing
Authors: Balic Anamaria , Perver Dilara , Pagella Pierfrancesco , Rehrauer Hubert , Stadlinger Bernd , Moor Andreas E. , Vogel Viola , Mitsiadis Thimios A.
Published: August 2023

Carious lesions are bacteria-caused destructions of the mineralised dental tissues, marked by the simultaneous activation of immune responses and regenerative events within the soft dental pulp tissue. While major molecular players in tooth decay have been uncovered during the past years, a detailed map of the molecular and cellular landscape of the diseased pulp is still missing. In this study we used single-cell RNA sequencing analysis, supplemented with immunostaining, to generate a comprehensive single-cell atlas of the pulp of carious human teeth. Our data demonstrated modifications in the various cell clusters within the pulp of carious teeth, such as immune cells, mesenchymal stem cells (MSC) and fibroblasts, when compared to the pulp of healthy human teeth. Active immune response in the carious pulp tissue is accompanied by specific changes in the fibroblast and MSC clusters. These changes include the upregulation of genes encoding extracellular matrix (ECM) components, includingCOL1A1andFibronectin (FN1), and the enrichment of the fibroblast cluster with myofibroblasts. The incremental changes in the ECM composition of carious pulp tissues were further confirmed by immunostaining analyses. Assessment of the Fibronectin fibres under mechanical strain conditions showed a significant tension reduction in carious pulp tissues, compared to the healthy ones. The present data demonstrate molecular, cellular and biomechanical alterations in the pulp of human carious teeth, indicative of extensive ECM remodelling, reminiscent of fibrosis observed in other organs. This comprehensive atlas of carious human teeth can facilitate future studies of dental pathologies and enable comparative analyses across diseased organs.
Intravenous ketamine for benzodiazepine deprescription and withdrawal management in treatment-resistant depression: a preliminary report
Authors: Garel Nicolas , Greenway Kyle T. , Dinh-Williams Lê-Anh L. , Thibault-Levesque Julien , Jutras-Aswad Didier , Turecki Gustavo , Rej Soham , Richard-Devantoy Stephane
Published: August 2023

We present the first evidence that sub-anesthetic ketamine infusions for treatment resistant depression (TRD) may facilitate deprescription of long-term benzodiazepine/z-drugs (BZDRs). Long-term BZDR prescriptions are potentially harmful yet common, partly because of challenging withdrawal symptoms. Few pharmacological interventions have evidence for facilitating BZDR discontinuation, and none in patients actively suffering from TRD. In this ambi-directional cohort study, discontinuation of long-term (>6 month) BZDRs was attempted in 22 patients with severe unipolar or bipolar TRD receiving a course of six subanesthetic ketamine infusions over four weeks. We investigated the rates of successful BZDRs deprescription, trajectories of acute psychological withdrawal symptoms, and subsequent BZDRs abstinence during a mean follow-up of 1 year (primary outcome). Clinically significant deteriorations in depression, anxiety, sleep, and/or suicidality during the acute BZDR discontinuation phase were measured by repeated standardized scales and analyzed by latent growth curve models and percent correct classification analysis. Of the 22 eligible patients, all enrolled in this study and 91% (20/22) successfully discontinued all BZDRs by the end of the 4-week intervention, confirmed by urinary analyses. Less than 25% of discontinuers experienced any significant worsening of anxiety, depression, sleep difficulties, or suicidality during treatment. During follow-up (mean [range] duration, 12 [3–24] months), 64% (14/22) of patients remained abstinent from any BZDRs. These preliminary results suggest that ketamine infusions for TRD may facilitate the deprescription of BZDRs, even in patients with active depressive symptoms and significant comorbidity. Further investigation is warranted into this potential novel application of ketamine.
A multiplexed bacterial two-hybrid for rapid characterization of protein–protein interactions and iterative protein design
Authors: Boldridge W. Clifford , Ljubetič Ajasja , Kim Hwangbeom , Lubock Nathan , Szilágyi Dániel , Lee Jonathan , Brodnik Andrej , Jerala Roman , Kosuri Sriram
Published: August 2023

Protein-protein interactions (PPIs) are crucial for biological functions and have applications ranging from drug design to synthetic cell circuits. Coiled-coils have been used as a model to study the sequence determinants of specificity. However, building well-behaved sets of orthogonal pairs of coiled-coils remains challenging due to inaccurate predictions of orthogonality and difficulties in testing at scale. To address this, we develop the next-generation bacterial two-hybrid (NGB2H) method, which allows for the rapid exploration of interactions of programmed protein libraries in a quantitative and scalable way using next-generation sequencing readout. We design, build, and test large sets of orthogonal synthetic coiled-coils, assayed over 8,000 PPIs, and used the dataset to train a more accurate coiled-coil scoring algorithm (iCipa). After characterizing nearly 18,000 new PPIs, we identify to the best of our knowledge the largest set of orthogonal coiled-coils to date, with fifteen on-target interactions. Our approach provides a powerful tool for the design of orthogonal PPIs.
Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification
Authors: Tretter Celina , de Andrade Krätzig Niklas , Pecoraro Matteo , Lange Sebastian , Seifert Philipp , von Frankenberg Clara , Untch Johannes , Zuleger Gabriela , Wilhelm Mathias , Zolg Daniel P. , Dreyer Florian S. , Bräunlein Eva , Engleitner Thomas , Uhrig Sebastian , Boxberg Melanie , Steiger Katja , Slotta-Huspenina Julia , Ochsenreither Sebastian , von Bubnoff Nikolas , Bauer Sebastian , Boerries Melanie , Jost Philipp J. , Schenck Kristina , Dresing Iska , Bassermann Florian , Friess Helmut , Reim Daniel , Grützmann Konrad , Pfütze Katrin , Klink Barbara , Schröck Evelin , Haller Bernhard , Kuster Bernhard , Mann Matthias , Weichert Wilko , Fröhling Stefan , Rad Roland , Hiltensperger Michael , Krackhardt Angela M.
Published: August 2023

Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.
The sharp structural switch of covalent cages mediated by subtle variation of directing groups
Authors: Chen Qiong , Li Zhaoyong , Lei Ye , Chen Yixin , Tang Hua , Wu Guangcheng , Sun Bin , Wei Yuxi , Jiao Tianyu , Zhang Songna , Huang Feihe , Wang Linjun , Li Hao
Published: August 2023

It is considered a more formidable task to precisely control the self-assembled products containing purely covalent components, due to a lack of intrinsic templates such as transition metals to suppress entropy loss during self-assembly. Here, we attempt to tackle this challenge by using directing groups. That is, the self-assembly products of condensing a 1:2 mixture of a tetraformyl and a biamine can be precisely controlled by slightly changing the substituent groups in the aldehyde precursor. This is because different directing groups provide hydrogen bonds with different modes to the adjacent imine units, so that the building blocks are endowed with totally different conformations. Each conformation favors the formation of a specific product that is thus produced selectively, including chiral and achiral cages. These results of using a specific directing group to favor a target product pave the way for accomplishing atom economy in synthesizing purely covalent molecules without relying on toxic transition metal templates.
Photothermia at the nanoscale induces ferroptosis via nanoparticle degradation
Authors: Fromain Alexandre , Perez Jose Efrain , Van de Walle Aurore , Lalatonne Yoann , Wilhelm Claire
Published: August 2023

The Fe(II)-induced ferroptotic cell death pathway is an asset in cancer therapy, yet it calls into question the biocompatibility of magnetic nanoparticles. In the latter, Fe(II) is sequestered within the crystal structure and is released only upon nanoparticle degradation, a transition that is not well understood. Here, we dissect the chemical environment necessary for nanoparticle degradation and subsequent Fe(II) release. Importantly, temperature acts as an accelerator of the process and can be triggered remotely by laser-mediated photothermal conversion, as evidenced by the loss of the nanoparticles’ magnetic fingerprint. Remarkably, the local hot-spot temperature generated at the nanoscale can be measured in operando, in the vicinity of each nanoparticle, by comparing the photothermal-induced nanoparticle degradation patterns with those of global heating. Further, remote photothermal irradiation accelerates degradation inside cancer cells in a tumor spheroid model, with efficiency correlating with the endocytosis progression state of the nanoparticles. High-throughput imaging quantification of Fe2+ release, ROS generation, lipid peroxidation and cell death at the spheroid level confirm the synergistic thermo-ferroptotic therapy due to the photothermal degradation at the nanoparticle level.
Site-selective superassembly of biomimetic nanorobots enabling deep penetration into tumor with stiff stroma
Authors: Yan Miao , Chen Qing , Liu Tianyi , Li Xiaofeng , Pei Peng , Zhou Lei , Zhou Shan , Zhang Runhao , Liang Kang , Dong Jian , Wei Xunbin , Wang Jinqiang , Terasaki Osamu , Chen Pu , Gu Zhen , Jiang Libo , Kong Biao
Published: August 2023

Chemotherapy remains as the first-choice treatment option for triple-negative breast cancer (TNBC). However, the limited tumor penetration and low cellular internalization efficiency of current nanocarrier-based systems impede the access of anticancer drugs to TNBC with dense stroma and thereby greatly restricts clinical therapeutic efficacy, especially for TNBC bone metastasis. In this work, biomimetic head/hollow tail nanorobots were designed through a site-selective superassembly strategy. We show that nanorobots enable efficient remodeling of the dense tumor stromal microenvironments (TSM) for deep tumor penetration. Furthermore, the self-movement ability and spiky head markedly promote interfacial cellular uptake efficacy, transvascular extravasation, and intratumoral penetration. These nanorobots, which integrate deep tumor penetration, active cellular internalization, near-infrared (NIR) light-responsive release, and photothermal therapy capacities into a single nanodevice efficiently suppress tumor growth in a bone metastasis female mouse model of TNBC and also demonstrate potent antitumor efficacy in three different subcutaneous tumor models.
A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses
Authors: Huang Ying , Qin Geng , Cui TingTing , Zhao Chuanqi , Ren Jinsong , Qu Xiaogang
Published: August 2023

Lack of sufficient cytotoxic T lymphocytes (CD8+ T cells) infiltration and dysfunctional state of CD8+ T cells are considered enormous obstacles to antitumor immunity. Herein, we construct a synergistic nanoplatform to promote CD8+ T cell infiltration in tumors while restoring T cell function by regulating methionine metabolism and activating the STING innate immune pathway. The CRISPR/Cas9 system down-regulates the methionine transporter SLC43A2 and restricts the methionine uptake by tumor cells, thereby relieving the methionine competition pressure of T cells; simultaneously, the released nutrition metal ions activate the cGAS/STING pathway. In this work, the described nanoplatform can enhance the effect of immunotherapy in preclinical cancer models in female mice, enhancing STING pathway mediated immunity and facilitating the development of amino acid metabolic intervention-based cancer therapy.
Grasping through dynamic weaving with entangled closed loops
Authors: Kang Gyeongji , Kim Young-Joo , Lee Sung-Jin , Kim Se Kwon , Lee Dae-Young , Song Kahye
Published: August 2023

Pick-and-place is essential in diverse robotic applications for industries including manufacturing, and assembly. Soft grippers offer a cost-effective, and low-maintenance alternative for secure object grasping without complex sensing and control systems. However, their inherent softness normally limits payload capabilities and robustness to external disturbances, constraining their applications and hindering reliable performance. In this study, we propose a weaving-inspired grasping mechanism that substantially increases payload capacity while maintaining the use of soft and flexible materials. Drawing from weaving principles, we designed a flexible continuum structure featuring multiple closed-loop strips and employing a kirigami-inspired approach to enable the instantaneous and reversible creation of a woven configuration. The mechanical stability of the woven configuration offers exceptional loading capacity, while the softness of the gripper material ensures safe and adaptive interactions with objects. Experimental results show that the 130 g·f gripper can support up to 100 kg·f. Outperforming competitors in similar weight and softness domains, this breakthrough, enabled by the weaving principle, will broaden the scope of gripper applications to previously inaccessible or barely accessible fields, such as agriculture and logistics.
Unraveling surface structures of gallium promoted transition metal catalysts in CO2 hydrogenation
Authors: Lee Si Woo , Luna Mauricio Lopez , Berdunov Nikolay , Wan Weiming , Kunze Sebastian , Shaikhutdinov Shamil , Cuenya Beatriz Roldan
Published: August 2023

Gallium-containing alloys have recently been reported to hydrogenate CO2 to methanol at ambient pressures. However, a full understanding of the Ga-promoted catalysts is still missing due to the lack of information about the surface structures formed under reaction conditions. Here, we employed near ambient pressure scanning tunneling microscopy and x-ray photoelectron spectroscopy to monitor the evolution of well-defined Cu-Ga surfaces during CO2 hydrogenation. We show the formation of two-dimensional Ga(III) oxide islands embedded into the Cu surface in the reaction atmosphere. The islands are a few atomic layers in thickness and considerably differ from bulk Ga2O3 polymorphs. Such a complex structure, which could not be determined with conventional characterization methods on powder catalysts, should be used for elucidating the reaction mechanism on the Ga-promoted metal catalysts.
BIK1 protein homeostasis is maintained by the interplay of different ubiquitin ligases in immune signaling
Authors: Bai Jiaojiao , Zhou Yuanyuan , Sun Jianhang , Chen Kexin , Han Yufang , Wang Ranran , Zou Yanmin , Du Mingshuo , Lu Dongping
Published: August 2023

Pathogen-associated molecular patterns (PAMPs) trigger plant innate immunity that acts as the first line of inducible defense against pathogen infection. A receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) functions as a signaling hub immediately downstream of multiple pattern recognition receptors (PRRs). It is known that PLANT U-BOX PROTEIN 25 (PUB25) and PUB26 ubiquitinate BIK1 and mediate BIK1 degradation. However, how BIK1 homeostasis is maintained is not fully understood. Here, we show that two closely related ubiquitin ligases, RING DOMAIN LIGASE 1 (RGLG1) and RGLG2, preferentially associate with the hypo-phosphorylated BIK1 and promote the association of BIK1 with the co-receptor for several PRRs, BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1). PUB25 interacts with RGLG2 and mediates its degradation. In turn, RGLG2 represses the ubiquitin ligase activity of PUB25. RGLG1/2 suppress PUB25-mediated BIK1 degradation, promote BIK1 protein accumulation, and positively regulate immune signaling in a ubiquitin ligase activity-dependent manner. Our work reveals how BIK1 homeostasis is maintained by the interplay of different ubiquitin ligases.
Reaction-passivation mechanism driven materials separation for recycling of spent lithium-ion batteries
Authors: Chen Zihe , Feng Ruikang , Wang Wenyu , Tu Shuibin , Hu Yang , Wang Xiancheng , Zhan Renming , Wang Jiao , Zhao Jianzhi , Liu Shuyuan , Fu Lin , Sun Yongming
Published: August 2023

Development of effective recycling strategies for cathode materials in spent lithium-ion batteries are highly desirable but remain significant challenges, among which facile separation of Al foil and active material layer of cathode makes up the first important step. Here, we propose a reaction-passivation driven mechanism for facile separation of Al foil and active material layer. Experimentally, >99.9% separation efficiency for Al foil and LiNi0.55Co0.15Mn0.3O2 layer is realized for a 102 Ah spent cell within 5 mins, and ultrathin, dense aluminum-phytic acid complex layer is in-situ formed on Al foil immediately after its contact with phytic acid, which suppresses continuous Al corrosion. Besides, the dissolution of transitional metal from LiNi0.55Co0.15Mn0.3O2 is negligible and good structural integrity of LiNi0.55Co0.15Mn0.3O2 is well-maintained during the processing. This work demonstrates a feasible approach for Al foil-active material layer separation of cathode and can promote the green and energy-saving battery recycling towards practical applications.
Long-term organic carbon preservation enhanced by iron and manganese
Authors: Moore Oliver W. , Curti Lisa , Woulds Clare , Bradley James A. , Babakhani Peyman , Mills Benjamin J. W. , Homoky William B. , Xiao Ke-Qing , Bray Andrew W. , Fisher Ben J. , Kazemian Majid , Kaulich Burkhard , Dale Andrew W. , Peacock Caroline L.
Published: August 2023

The balance between degradation and preservation of sedimentary organic carbon (OC) is important for global carbon and oxygen cycles1. The relative importance of different mechanisms and environmental conditions contributing to marine sedimentary OC preservation, however, remains unclear2–8. Simple organic molecules can be geopolymerized into recalcitrant forms by means of the Maillard reaction5, although reaction kinetics at marine sedimentary temperatures are thought to be slow9,10. More recent work in terrestrial systems suggests that the reaction can be catalysed by manganese minerals11–13, but the potential for the promotion of geopolymerized OC formation at marine sedimentary temperatures is uncertain. Here we present incubation experiments and find that iron and manganese ions and minerals abiotically catalyse the Maillard reaction by up to two orders of magnitude at temperatures relevant to continental margins where most preservation occurs4. Furthermore, the chemical signature of the reaction products closely resembles dissolved and total OC found in continental margin sediments globally. With the aid of a pore-water model14, we estimate that iron- and manganese-catalysed transformation of simple organic molecules into complex macromolecules might generate on the order of approximately 4.1 Tg C yr−1 for preservation in marine sediments. In the context of perhaps only about 63 Tg C yr−1 variation in sedimentary organic preservation over the past 300 million years6, we propose that variable iron and manganese inputs to the ocean could exert a substantial but hitherto unexplored impact on global OC preservation over geological time.
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer
Authors: Cassier Philippe A. , Navaridas Raul , Bellina Melanie , Rama Nicolas , Ducarouge Benjamin , Hernandez-Vargas Hector , Delord Jean-Pierre , Lengrand Justine , Paradisi Andrea , Fattet Laurent , Garin Gwenaële , Gheit Hanane , Dalban Cecile , Pastushenko Ievgenia , Neves David , Jelin Remy , Gadot Nicolas , Braissand Nicolas , Léon Sophie , Degletagne Cyril , Matias-Guiu Xavier , Devouassoux-Shisheboran Mojgan , Mery-Lamarche Eliane , Allard Justine , Zindy Egor , Decaestecker Christine , Salmon Isabelle , Perol David , Dolcet Xavi , Ray-Coquard Isabelle , Blanpain Cédric , Bernet Agnès , Mehlen Patrick
Published: August 2023

Netrin-1 is upregulated in cancers as a protumoural mechanism1. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care2, we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments.
Einkorn genomics sheds light on history of the oldest domesticated wheat
Authors: Ahmed Hanin Ibrahim , Heuberger Matthias , Schoen Adam , Koo Dal-Hoe , Quiroz-Chavez Jesus , Adhikari Laxman , Raupp John , Cauet Stéphane , Rodde Nathalie , Cravero Charlotte , Callot Caroline , Lazo Gerard R. , Kathiresan Nagarajan , Sharma Parva K. , Moot Ian , Yadav Inderjit Singh , Singh Lovepreet , Saripalli Gautam , Rawat Nidhi , Datla Raju , Athiyannan Naveenkumar , Ramirez-Gonzalez Ricardo H. , Uauy Cristobal , Wicker Thomas , Tiwari Vijay K. , Abrouk Michael , Poland Jesse , Krattinger Simon G.
Published: August 2023

Einkorn (Triticum monococcum) was the first domesticated wheat species, and was central to the birth of agriculture and the Neolithic Revolution in the Fertile Crescent around 10,000 years ago1,2. Here we generate and analyse 5.2-Gb genome assemblies for wild and domesticated einkorn, including completely assembled centromeres. Einkorn centromeres are highly dynamic, showing evidence of ancient and recent centromere shifts caused by structural rearrangements. Whole-genome sequencing analysis of a diversity panel uncovered the population structure and evolutionary history of einkorn, revealing complex patterns of hybridizations and introgressions after the dispersal of domesticated einkorn from the Fertile Crescent. We also show that around 1% of the modern bread wheat (Triticum aestivum) A subgenome originates from einkorn. These resources and findings highlight the history of einkorn evolution and provide a basis to accelerate the genomics-assisted improvement of einkorn and bread wheat.
Development and validation of a 21-gene prognostic signature in neuroblastoma
Authors: Gupta Mehul , Kannappan Sunand , Jain Mohit , Douglass David , Shah Ravi , Bose Pinaki , Narendran Aru
Published: August 2023

Survival outcomes for patients with neuroblastoma vary markedly and reliable prognostic markers and risk stratification tools are lacking. We sought to identify and validate a transcriptomic signature capable of predicting risk of mortality in patients with neuroblastoma. The TARGET NBL dataset (n = 243) was used to develop the model and two independent cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 240) were used as validation sets. EFS was the primary outcome and OS was the secondary outcome of interest for all analysis. We identified a 21-gene signature capable of stratifying neuroblastoma patients into high and low risk groups in the E-MTAB-179 (HR 5.87 [3.83–9.01], p < 0.0001, 5 year AUC 0.827) and GSE85047 (HR 3.74 [2.36–5.92], p < 0.0001, 5 year AUC 0.815) validation cohorts. Moreover, the signature remained independent of known clinicopathological variables, and remained prognostic within clinically important subgroups. Further, the signature was effectively incorporated into a risk model with clinicopathological variables to improve prognostic performance across validation cohorts (Pooled Validation HR 6.93 [4.89–9.83], p < 0.0001, 5 year AUC 0.839). Similar prognostic utility was also demonstrated with OS. The identified signature is a robust independent predictor of EFS and OS outcomes in neuroblastoma patients and can be combined with clinically utilized clinicopathological variables to improve prognostic performance.
Lithium concentration in tap water, bottled mineral water, and Danube River water in Hungary
Authors: Dobosy Péter , Illés Ádám , Endrédi Anett , Záray Gyula
Published: August 2023

Due to increased manufacture and recycling of lithium batteries across the world, we may anticipate a rise in lithium pollution in the aquatic environment and drinking water reservoirs. In order to investigate the current status regarding the lithium content in Hungarian tap waters, samples were collected from the public drinking water supply systems of 19 county seats in Hungary during seasonally selected times. Depending on the water sources, such as bank-filtrated river water, surface water from open reservoirs, and groundwater, the lithium concentrations varied between 0.90–4.23, 2.12–11.7 and 1.11–31.4 µg/L, respectively, while the median values were 3.52, 5.02 and 8.55 µg/L, respectively. The lithium concentration in the bottled Hungarian mineral waters was also determined since the daily intake of lithium can be influenced by the consumption of mineral waters. The concentrations ranged from 4.2 to 209 µg/L, while the median value was only 17.8 µg/L. Additionally, a correlation was only found between lithium and potassium concentrations. The lithium concentration was also assessed at ten sampling locations in the Hungarian segment of the Danube River since the Danube water is also a water source for additional drinking water utilities using bank filtration technology. The mean and median lithium concentrations were 2.78 and 2.64 µg/L, respectively.
Pediatric T-cell acute lymphoblastic leukemia blast signature and MRD associated immune environment changes defined by single cell transcriptomics analysis
Authors: Bhasin Swati S. , Thomas Beena E. , Summers Ryan J. , Sarkar Debasree , Mumme Hope , Pilcher William , Emam Mohamed , Raikar Sunil S. , Park Sunita I. , Castellino Sharon M. , Graham Douglas K. , Bhasin Manoj K. , DeRyckere Deborah
Published: August 2023

Different driver mutations and/or chromosomal aberrations and dysregulated signaling interactions between leukemia cells and the immune microenvironment have been implicated in the development of T-cell acute lymphoblastic leukemia (T-ALL). To better understand changes in the bone marrow microenvironment and signaling pathways in pediatric T-ALL, bone marrows collected at diagnosis (Dx) and end of induction therapy (EOI) from 11 patients at a single center were profiled by single cell transcriptomics (10 Dx, 5 paired EOI, 1 relapse). T-ALL blasts were identified by comparison with healthy bone marrow cells. T-ALL blast-associated gene signature included SOX4, STMN1, JUN, HES4, CDK6, ARMH1 among the most significantly overexpressed genes, some of which are associated with poor prognosis in children with T-ALL. Transcriptome profiles of the blast cells exhibited significant inter-patient heterogeneity. Post induction therapy expression profiles of the immune cells revealed significant changes. Residual blast cells in MRD+ EOI samples exhibited significant upregulation (P < 0.01) of PD-1 and RhoGDI signaling pathways. Differences in cellular communication were noted in the presence of residual disease in T cell and hematopoietic stem cell compartments in the bone marrow. Together, these studies generate new insights and expand our understanding of the bone marrow landscape in pediatric T-ALL.
Synergistic performance evaluation of MoS2–hBN hybrid nanoparticles as a tribological additive in diesel-based engine oil
Authors: Nagarajan Thachnatharen , Sridewi Nanthini , Wong Weng Pin , Walvekar Rashmi , Khanna Virat , Khalid Mohammad
Published: August 2023

In this study, MoS2–hBN hybrid nanoparticles were synthesized using an advanced microwave platform for new nanolubricant formulations. The synthesized nanoparticles were characterized by field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and Raman spectroscopy. The hybrid nanoparticles were then introduced into a 20W40 diesel-based engine oil to produce a nanolubricant. The physical and chemical properties of the nanolubricant were investigated, including the viscosity index, stability, volatility, tribological properties, oxidation properties, and thermal conductivity. The results showed that the inclusion of 0.05 wt% MoS2–hBN hybrid nanoparticles in the oil significantly reduced the coefficient of friction and wear scar diameter by 68.48% and 35.54%, respectively. Moreover, it exhibited substantial oxidation and thermal conductivity improvement of 38.76% and 28.30%, respectively, at 100 °C. These findings demonstrate the potential of MoS2-hBN hybrid nanoparticles as an effective additive to enhance the properties of nanolubricant significantly. Furthermore, this study offers valuable insights into the underlying mechanisms responsible for the observed enhancements. The promising outcomes of this investigation contribute to the advancement of nanotechnology-based lubricants, showcasing their potential for improving engine efficiency and prolonging the lifespan of machinery.
Effectiveness and safety of normoxic allogenic umbilical cord mesenchymal stem cells administered as adjunctive treatment in patients with severe COVID-19
Authors: Soetjahjo Bintang , Malueka Rusdy Ghazali , Nurudhin Arief , Purwoko  , Sumardi  , Wisaksana Rudi , Adhiputri Artrien , Sudadi  , Soeroto Arto Yuwono , Sidharta Brigitte Rina Aninda , Thobari Jarir At , Murni Tri Wahyu , Soewondo Widiastuti , Herningtyas Elizabeth Henny , Sudjud Reza Widianto , Trisnawati Ika , Ananda Nur Rahmi , Faried Ahmad
Published: August 2023

Inflammatory response in COVID-19 contributes greatly to disease severity. Mesenchymal Stem Cells (MSCs) have the potential to alleviate inflammation and reduce mortality and length of stay in COVID-19 patients. We investigated the safety and effectiveness of normoxic-allogenic umbilical cord (NA-UC)-MSCs as an adjunctive treatment in severe COVID-19 patients. A double-blind, multicentric, randomized, placebo-controlled trial involving severe COVID-19 patients was performed from January to June 2021 in three major hospitals across Java, Indonesia. Eligible participants (n = 42) were randomly assigned to two groups (1:1), namely the intervention (n = 21) and control (n = 21) groups. UC-MSCs dose was 1 × 106 /kg body weight on day D0, D3, and D6. The primary outcome was the duration of hospitalization. Meanwhile, the secondary outcomes were radiographical progression (Brixia score), respiratory and oxygenation parameters, and inflammatory markers, in addition to the safety profile of NA-UC-MSCs. NA-UC-MSCs administration did not affect the length of hospital stay of severe COVID-19 patients, nor did it improve the Brixia score or mMRC dyspnoea scale better than placebo. Nevertheless, NA-UC-MSCs led to a better recuperation in oxygenation index (120.80 ± 72.70 baseline vs. 309.63 ± 319.30 D + 22, p = 0.038) and oxygen saturation (97.24 ± 4.10% vs. 96.19 ± 3.75% in placebo, p = 0.028). Additionally, compared to the placebo group, the treatment group had a significantly smaller increase in PCT level at D + 22 (1.43 vs. 12.76, p = 0.011). No adverse effects, including serious ones, were recorded until D + 91. NA-UC-MSCs therapy is a very safe adjunct for COVID-19 patients. It improves the oxygenation profile and carries potential to suppress inflammation.
Mathematical expertise: the role of domain-specific knowledge for memory and creativity
Authors: Meier Michaela A. , Gross Franz , Vogel Stephan E. , Grabner Roland H.
Published: August 2023

In contrast to traditional expertise domains like chess and music, very little is known about the cognitive mechanisms in broader, more education-oriented domains like mathematics. This is particularly true for the role of mathematical experts’ knowledge for domain-specific information processing in memory as well as for domain-specific and domain-general creativity. In the present work, we compared 115 experts in mathematics with 109 gender, age, and educational level matched novices in their performance in (a) a newly developed mathematical memory task requiring encoding and recall of structured and unstructured information and (b) tasks drawing either on mathematical or on domain-general creativity. Consistent with other expertise domains, experts in mathematics (compared to novices) showed superior short-term memory capacity for complex domain-specific material when presented in a structured, meaningful way. Further, experts exhibited higher mathematical creativity than novices, but did not differ from them in their domain-general creativity. Both lines of findings demonstrate the importance of experts’ knowledge base in processing domain-specific material and provide new insights into the characteristics of mathematical expertise.
Evaluating anti-thymocyte globulin induction doses for better allograft and patient survival in Asian kidney transplant recipients
Authors: Shim Ye Eun , Ko Youngmin , Lee Jung Pyo , Jeon Jin Seok , Jun Heungman , Yang Jaeseok , Kim Myoung Soo , Lim Seong Jun , Kwon Hye Eun , Jung Joo Hee , Kwon Hyunwook , Kim Young Hoon , Lee Jungbok , Shin Sung ,   the Korean Organ Transplantation Registry (KOTRY) study group, Kong Jin Min , Kwon Oh Jung , Kim Deok Gie , Jung Cheol Woong , Kim Yeong Hoon , Kim Joong Kyung , Kim Chan-Duck , Min Ji Won , Lee Sik , Park Yeon Ho , Park Jae Berm , Park Jung Hwan , Park Jong-Won , Ban Tae Hyun , Song Sang Heon , Song Seung Hwan , Shin Ho Sik , Yang Chul Woo , Yoon Hye Eun , Lee Kang Wook , Lee Dong Ryeol , Lee Dong Won , Oh Jieun , Lee Sang-Ho , Lee Su Hyung , Lee Yu Ho , Lee Jeong-Hoon , Jeong Kyung Hwan , Chung Ku Yong , Lee Jong Soo , Ki Ju Man , Chae Dong-Wan , Choi Soo Jin Na , Han Seungyeup , Huh Kyu Ha
Published: August 2023

Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the optimal dose of ATG induction regimen in Asian kidney recipients is unclear. Using the Korean Organ Transplantation Registry, we performed a retrospective cohort study of 4579 adult patients who received renal transplantation in South Korea and divided them into three groups according to the induction regimen: basiliximab group (n = 3655), low-dose ATG group (≤ 4.5 mg/kg; n = 467), and high-dose ATG group (> 4.5 mg/kg; n = 457). We applied the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) package to generate high-quality propensity score weights for intergroup comparisons. During four-year follow-ups, the high-dose ATG group had the highest biopsy-proven acute rejection rate (basiliximab 20.8% vs. low-dose ATG 22.4% vs. high-dose ATG 25.6%; P < 0.001). However, the rates of overall graft failure (4.0% vs. 5.0% vs. 2.6%; P < 0.001) and mortality (1.7% vs. 2.8% vs. 1.0%; P < 0.001) were the lowest in the high-dose ATG group. Our results show that high-dose ATG induction (> 4.5 mg/kg) was superior to basiliximab and low-dose ATG induction in terms of graft and patient survival in Asian patients undergoing kidney transplant.
Application of multi-echo Dixon and MRS in quantifying hepatic fat content and staging liver fibrosis
Authors: Jiang Yanli , Zou Jie , Fan Fengxian , Yang Pin , Ma Laiyang , Gan Tiejun , Wang Shaoyu , Zhang Jing
Published: August 2023

This study associated the liver proton density fat fraction (PDFF), measured by multi-echo Dixon (ME-Dixon) and breath-hold single-voxel high-speed T2-corrected multi-echo 1H magnetic resonance spectroscopy (HISTO) at 1.5 T, with serum biomarkers and liver fibrosis stages. This prospective study enrolled 75 patients suspected of liver fibrosis and scheduled for liver biopsy and 23 healthy participants with normal liver function. The participant underwent ME-Dixon and HISTO scanning. The agreement of PDFF measured by ME-Dixon (PDFF-D) and HISTO (PDFF-H) were compared. Correlations between PDFF and serum fat biomarkers (total cholesterol, triglyceride, and high- and low-density lipoproteins) and the liver fibrosis stages were assessed. PDFF were compared among the liver fibrosis stages (F0–F4) based on clinical liver biopsies. The Bland–Altman plot showed agreement between PDFF-D and PDFF-H(LoA, − 4.44 to 6.75), which have high consistency (ICC 0.752, P < 0.001). The correlations with the blood serum markers were mild to moderate (PDFF-H: r = 0.261–0.410, P < 0.01; PDFF-D: r = 0.265–0.367, P < 0.01). PDFF-D, PDFF-H, and steatosis were distributed similarly among the liver fibrosis stages. PDFF-H showed a slight negative correlation with the liver fibrosis stages (r = − 0.220, P = 0.04). Both ME-Dixon and HISTO sequences measured liver fat content noninvasively. Liver fat content was not directly associated with liver fibrosis stages.
Spiritual practices predict migration behavior
Authors: Auer Daniel , Gereke Johanna , Schaub Max
Published: August 2023

Each year, several thousand migrants from sub-Saharan Africa lose their lives attempting to reach Europe’s southern shores. Social scientists and policymakers have puzzled over the question of why so many people are willing to take this extremely high risk of dying. Drawing on panel data from over 10,000 individuals collected over the course of 1 year in The Gambia—a country with one of the highest emigration rates in the world—we show that consulting a local healer for spiritual protection predicts migration outcomes. Furthermore, we find that spiritual practices are strongly associated with a decreased perception of one's own risk of dying on the migration journey. Our findings demonstrate the relevance of ideational factors in explaining risky migration choices, and point to spiritual leaders as important interlocutors for migration policy makers.
Monitoring within-farm transmission dynamics of antimicrobial-resistant Campylobacter in dairy cattle using broth microdilution and long-read whole genome sequencing
Authors: Ocejo Medelin , Oporto Beatriz , Lavín José Luis , Hurtado Ana
Published: August 2023

Campylobacter jejuni and Campylobacter coli are important foodborne zoonotic pathogens and cause for concern due to the increasing trend in antimicrobial resistance. A long-run surveillance study was conducted in animals from different age groups in five dairy cattle farms to investigate the within-farm diversity and transmission dynamics of resistant Campylobacter throughout time. The resistance phenotype of the circulating isolates (170 C. jejuni and 37 C. coli) was determined by broth microdilution and a selection of 56 isolates were whole genome sequenced using the Oxford-Nanopore long-fragment sequencing technology resulting in completely resolved and circularized genomes (both chromosomes and plasmids). C. jejuni was isolated from all farms while C. coli was isolated from only two farms, but resistance rates were higher in C. coli than in C. jejuni and in calves than in adult animals. Some genotypes (e.g. ST-48, gyrA_T86I/tet(O)/blaOXA-61 in farm F1; ST-12000, aadE-Cc/tet(O)/blaOXA-489 in F4) persisted throughout the study while others were only sporadically detected. Acquisition of extracellular genes from other isolates and intracellular mutational events were identified as the processes that led to the emergence of the resistant genotypes that spread within the herds. Monitoring with Oxford Nanopore Technologies sequencing helped to decipher the complex molecular epidemiology underlying the within-farm dissemination of resistant Campylobacter.
Quantum violation of LGI under an energy constraint for different scenarios systems
Authors: Zhang Yuxia , Tan Xiangguan , Qiu Tianhui
Published: August 2023

In this paper, we consider a qubit in four scenarios: with drive, without drive, and in the presence of dissipation and dephasing, to investigate the quantum violation of the Leggett–Garg inequality (LGI) in an energy constraint. In the case of the energy constraint, we find that under the coarsening measurement in reference and final resolution, the quantum violation of the LGI for the pure qubit is the most robust; on the other hand, the quantum violation of the LGI for the dephasing qubit is the most vulnerable, and the quantum violation of the LGI for driven qubit lies between that of pure qubit and dissipation qubit. Under the coarsening of measurement temporal reference, the quantum violation of the LGI for the pure qubit is more robust than that of the qubit with driven. Moreover, in the case of a qubit that is subjected to driving and is in the presence of dissipation and dephasing, the robustness of quantum violations of the LGI for these scenario systems will become vulnerable, with the driven intensity and the rate of spontaneous emission increasing, respectively, for coarsening measurement both in reference and in final resolution. In addition, in the energy constraint and the projective measurement, the LGI can attain its maximum violation value, 1.5, for the coherent dynamics; while for drive, dissipative and dephasing qubits, the LGI cannot attain the value of 1.5. For systems in the presence of dissipation and dephasing, we find that in the energy constraint, the robustness of the coarsening measurement in final resolution exhibits more vulnerable than that of the coarsening measurement in reference. And for systems with drive and without drive, the robustness of the coarsening measurement in temporal reference is the most robust, and the robustness of the coarsening of measurement final measurement resolution is the most vulnerable.