bluuebunny/crossref_metadata_2025 huggingface dataset:
The MITF/mir-579-3p regulatory axis dictates BRAF-mutated melanoma cell fate in response to MAPK inhibitors
Authors: Liguoro Domenico , Frigerio Rachele , Ortolano Arianna , Sacconi Andrea , Acunzo Mario , Romano Giulia , Nigita Giovanni , Bellei Barbara , Madonna Gabriele , Capone Mariaelena , Ascierto Paolo Antonio , Mancini Rita , Ciliberto Gennaro , Fattore Luigi
Published: March 2024

Therapy of melanoma has improved dramatically over the last years thanks to the development of targeted therapies (MAPKi) and immunotherapies. However, drug resistance continues to limit the efficacy of these therapies. Our research group has provided robust evidence as to the involvement of a set of microRNAs in the development of resistance to target therapy in BRAF-mutated melanomas. Among them, a pivotal role is played by the oncosuppressor miR-579-3p. Here we show that miR-579-3p and the microphthalmia-associated transcription factor (MITF) influence reciprocally their expression through positive feedback regulatory loops. In particular we show that miR-579-3p is specifically deregulated in BRAF-mutant melanomas and that its expression levels mirror those of MITF. Luciferase and ChIP studies show that MITF is a positive regulator of miR-579-3p, which is located in the intron 11 of the human gene ZFR (Zink-finger recombinase) and is co-transcribed with its host gene. Moreover, miR-579-3p, by targeting BRAF, is able to stabilize MITF protein thus inducing its own transcription. From biological points of view, early exposure to MAPKi or, alternatively miR-579-3p transfection, induce block of proliferation and trigger senescence programs in BRAF-mutant melanoma cells. Finally, the long-term development of resistance to MAPKi is able to select cells characterized by the loss of both miR-579-3p and MITF and the same down-regulation is also present in patients relapsing after treatments. Altogether these findings suggest that miR-579-3p/MITF interplay potentially governs the balance between proliferation, senescence and resistance to therapies in BRAF-mutant melanomas.
Hypoxia induced exosomal Circ-ZNF609 promotes pre-metastatic niche formation and cancer progression via miR-150-5p/VEGFA and HuR/ZO-1 axes in esophageal squamous cell carcinoma
Authors: Mao Yu , Wang Jiahao , Wang Yimin , Fu Zhanzhao , Dong Lixin , Liu Jia
Published: March 2024

Exosomes derived from cancer are regarded as significant mediators of cancer-host crosstalk. Hypoxia, on the other hand, is one of the essential characteristics of solid tumors. This research set out to discover how circulating exosomes from hypoxic esophageal squamous cell carcinoma (ESCC) contribute to the formation of metastatic niches and distant metastasis. First, we noticed that human umbilical vein endothelial cells (HUVECs) had their tight connections disrupted and the expression of proteins involved in angiogenesis boosted by ESCC hypoxic exosomes. Hypoxia significantly induced Circ-ZNF609 expression in exosomes from ESCC, which was then internalized by HUVECs, as determined by circular RNA screening. High Circ-ZNF609 expression in HUVECs facilitated angiogenesis and vascular permeability, thereby promoting pre-metastatic niche formation, and enhancing distant metastasis in vitro and in vivo. Exosomal Circ-ZNF609 activated vascular endothelial growth factor A (VEGFA) mechanistically by sponging miR-150-5p. Exosomal Circ-ZNF609 also interacted with HuR and inhibited HuR binding to ZO-1, Claudin-1, and Occludin mRNAs, thereby reducing their translation. Collectively, our findings identified an essential function for exosomal Circ-ZNF609 from ESCC cells, suggesting the potential therapeutic value of exosomes for ESCC patients.
Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells
Authors: Lin Yu-Shan , Sun Zhiwei , Shen Li-Sha , Gong Rui-Hong , Chen Jia-Wen , Xu Yanfeng , Yu Haiyang , Chen Sibao , Chen Guo-Qing
Published: March 2024

Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD’s ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD’s therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.
Controlled formation of three-dimensional cavities during lateral epitaxial growth
Authors: Zhang Yiwen , Wang Baoming , Miao Changxu , Chai Haozhi , Hong Wei , Ross Frances M. , Wen Rui-Tao
Published: March 2024

Epitaxial growth is a fundamental step required to create devices for the semiconductor industry, enabling different materials to be combined in layers with precise control of strain and defect structure. Patterning the growth substrate with a mask before performing epitaxial growth offers additional degrees of freedom to engineer the structure and hence function of the semiconductor device. Here, we demonstrate that conditions exist where such epitaxial lateral overgrowth can produce complex, three-dimensional structures that incorporate cavities of deterministic size. We grow germanium on silicon substrates patterned with a dielectric mask and show that fully-enclosed cavities can be created through an unexpected self-assembly process that is controlled by surface diffusion and surface energy minimization. The result is confined cavities enclosed by single crystalline Ge, with size and position tunable through the initial mask pattern. We present a model to account for the observed cavity symmetry, pinch-off and subsequent evolution, reflecting the dominant role of surface energy. Since dielectric mask patterning and epitaxial growth are compatible with conventional device processing steps, we suggest that this mechanism provides a strategy for developing electronic and photonic functionalities.
Reconfigurable spin current transmission and magnon–magnon coupling in hybrid ferrimagnetic insulators
Authors: Li Yan , Zhang Zhitao , Liu Chen , Zheng Dongxing , Fang Bin , Zhang Chenhui , Chen Aitian , Ma Yinchang , Wang Chunmei , Liu Haoliang , Shen Ka , Manchon Aurélien , Xiao John Q. , Qiu Ziqiang , Hu Can-Ming , Zhang Xixiang
Published: March 2024

Coherent spin waves possess immense potential in wave-based information computation, storage, and transmission with high fidelity and ultra-low energy consumption. However, despite their seminal importance for magnonic devices, there is a paucity of both structural prototypes and theoretical frameworks that regulate the spin current transmission and magnon hybridization mediated by coherent spin waves. Here, we demonstrate reconfigurable coherent spin current transmission, as well as magnon–magnon coupling, in a hybrid ferrimagnetic heterostructure comprising epitaxial Gd3Fe5O12 and Y3Fe5O12 insulators. By adjusting the compensated moment in Gd3Fe5O12, magnon–magnon coupling was achieved and engineered with pronounced anticrossings between two Kittel modes, accompanied by divergent dissipative coupling approaching the magnetic compensation temperature of Gd3Fe5O12 (TM,GdIG), which were modeled by coherent spin pumping. Remarkably, we further identified, both experimentally and theoretically, a drastic variation in the coherent spin wave-mediated spin current across TM,GdIG, which manifested as a strong dependence on the relative alignment of magnetic moments. Our findings provide significant fundamental insight into the reconfiguration of coherent spin waves and offer a new route towards constructing artificial magnonic architectures.
Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Authors: Chelban Viorica , Aksnes Henriette , Maroofian Reza , LaMonica Lauren C. , Seabra Luis , Siggervåg Anette , Devic Perrine , Shamseldin Hanan E. , Vandrovcova Jana , Murphy David , Richard Anne-Claire , Quenez Olivier , Bonnevalle Antoine , Zanetti M. Natalia , Kaiyrzhanov Rauan , Salpietro Vincenzo , Efthymiou Stephanie , Schottlaender Lucia V. , Morsy Heba , Scardamaglia Annarita , Tariq Ambreen , Pagnamenta Alistair T. , Pennavaria Ajia , Krogstad Liv S. , Bekkelund Åse K. , Caiella Alessia , Glomnes Nina , Brønstad Kirsten M. , Tury Sandrine , Moreno De Luca Andrés , Boland-Auge Anne , Olaso Robert , Deleuze Jean-François , Anheim Mathieu , Cretin Benjamin , Vona Barbara , Alajlan Fahad , Abdulwahab Firdous , Battini Jean-Luc , İpek Rojan , Bauer Peter , Zifarelli Giovanni , Gungor Serdal , Kurul Semra Hiz , Lochmuller Hanns , Da’as Sahar I. , Fakhro Khalid A. , Gómez-Pascual Alicia , Botía Juan A. , Wood Nicholas W. , Horvath Rita , Ernst Andreas M. , Rothman James E. , McEntagart Meriel , Crow Yanick J. , Alkuraya Fowzan S. , Nicolas Gaël ,   SYNaPS Study Group, Houlden Henry , Alkuraya Fowzan S. , Arnesen Thomas , Houlden Henry
Published: March 2024

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.
Precise atom-to-atom mapping for organic reactions via human-in-the-loop machine learning
Authors: Chen Shuan , An Sunggi , Babazade Ramil , Jung Yousung
Published: March 2024

Atom-to-atom mapping (AAM) is a task of identifying the position of each atom in the molecules before and after a chemical reaction, which is important for understanding the reaction mechanism. As more machine learning (ML) models were developed for retrosynthesis and reaction outcome prediction recently, the quality of these models is highly dependent on the quality of the AAM in reaction datasets. Although there are algorithms using graph theory or unsupervised learning to label the AAM for reaction datasets, existing methods map the atoms based on substructure alignments instead of chemistry knowledge. Here, we present LocalMapper, an ML model that learns correct AAM from chemist-labeled reactions via human-in-the-loop machine learning. We show that LocalMapper can predict the AAM for 50 K reactions with 98.5% calibrated accuracy by learning from only 2% of the human-labeled reactions from the entire dataset. More importantly, the confident predictions given by LocalMapper, which cover 97% of 50 K reactions, show 100% accuracy for 3,000 randomly sampled reactions. In an out-of-distribution experiment, LocalMapper shows favorable performance over other existing methods. We expect LocalMapper can be used to generate more precise reaction AAM and improve the quality of future ML-based reaction prediction models.
High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design
Authors: Cushing Victoria I. , Koh Adrian F. , Feng Junjie , Jurgaityte Kaste , Bondke Alexander , Kroll Sebastian H. B. , Barbazanges Marion , Scheiper Bodo , Bahl Ash K. , Barrett Anthony G. M. , Ali Simak , Kotecha Abhay , Greber Basil J.
Published: March 2024

Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin-dependent kinase 7 and provide insights into the mechanisms contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. These results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.
Thunder-DDA-PASEF enables high-coverage immunopeptidomics and is boosted by MS2Rescore with MS2PIP timsTOF fragmentation prediction model
Authors: Gomez-Zepeda David , Arnold-Schild Danielle , Beyrle Julian , Declercq Arthur , Gabriels Ralf , Kumm Elena , Preikschat Annica , Łącki Mateusz Krzysztof , Hirschler Aurélie , Rijal Jeewan Babu , Carapito Christine , Martens Lennart , Distler Ute , Schild Hansjörg , Tenzer Stefan
Published: March 2024

Human leukocyte antigen (HLA) class I peptide ligands (HLAIps) are key targets for developing vaccines and immunotherapies against infectious pathogens or cancer cells. Identifying HLAIps is challenging due to their high diversity, low abundance, and patient individuality. Here, we develop a highly sensitive method for identifying HLAIps using liquid chromatography-ion mobility-tandem mass spectrometry (LC-IMS-MS/MS). In addition, we train a timsTOF-specific peak intensity MS2PIP model for tryptic and non-tryptic peptides and implement it in MS2Rescore (v3) together with the CCS predictor from ionmob. The optimized method, Thunder-DDA-PASEF, semi-selectively fragments singly and multiply charged HLAIps based on their IMS and m/z. Moreover, the method employs the high sensitivity mode and extended IMS resolution with fewer MS/MS frames (300 ms TIMS ramp, 3 MS/MS frames), doubling the coverage of immunopeptidomics analyses, compared to the proteomics-tailored DDA-PASEF (100 ms TIMS ramp, 10 MS/MS frames). Additionally, rescoring boosts the HLAIps identification by 41.7% to 33%, resulting in 5738 HLAIps from as little as one million JY cell equivalents, and 14,516 HLAIps from 20 million. This enables in-depth profiling of HLAIps from diverse human cell lines and human plasma. Finally, profiling JY and Raji cells transfected to express the SARS-CoV-2 spike protein results in 16 spike HLAIps, thirteen of which have been reported to elicit immune responses in human patients.
Understanding of complex spin up-conversion processes in charge-transfer-type organic molecules
Authors: Kim Hyung Suk , Lee Sang Hoon , Yoo Seunghyup , Adachi Chihaya
Published: March 2024

Despite significant progress made over the past decade in thermally activated delayed fluorescence (TADF) molecules as a material paradigm for enhancing the performance of organic light-emitting diodes, the underlying spin-flip mechanism in these charge-transfer (CT)-type molecular systems remains an enigma, even since its initial report in 2012. While the initial and final electronic states involved in spin-flip between the lowest singlet and lowest triplet excited states are well understood, the exact dynamic processes and the role of intermediate high-lying triplet (T) states are still not fully comprehended. In this context, we propose a comprehensive model to describe the spin-flip processes applicable for a typical CT-type molecule, revealing the origin of the high-lying T state in a partial molecular framework in CT-type molecules. This work provides experimental and theoretical insights into the understanding of intersystem crossing for CT-type molecules, facilitating more precise control over spin-flip rates and thus advancing toward developing the next-generation platform for purely organic luminescent candidates.
A transposon insertion in the promoter of OsUBC12 enhances cold tolerance during japonica rice germination
Authors: Zhang Chuanzhong , Wang Hongru , Tian Xiaojie , Lin Xinyan , Han Yunfei , Han Zhongmin , Sha Hanjing , Liu Jia , Liu Jianfeng , Zhang Jian , Bu Qingyun , Fang Jun
Published: March 2024

Low-temperature germination (LTG) is an important agronomic trait for rice (Oryza sativa). Japonica rice generally has greater capacity for germination at low temperatures than the indica subpopulation. However, the genetic basis and molecular mechanisms underlying this complex trait are poorly understood. Here, we report that OsUBC12, encoding an E2 ubiquitin-conjugating enzyme, increases low-temperature germinability in japonica, owing to a transposon insertion in its promoter enhancing its expression. Natural variation analysis reveals that transposon insertion in the OsUBC12 promoter mainly occurs in the japonica lineage. The variation detected in eight representative two-line male sterile lines suggests the existence of this allele introgression by indica-japonica hybridization breeding, and varieties carrying the japonica OsUBC12 locus (transposon insertion) have higher low-temperature germinability than varieties without the locus. Further molecular analysis shows that OsUBC12 negatively regulate ABA signaling. OsUBC12-regulated seed germination and ABA signaling mainly depend on a conserved active site required for ubiquitin-conjugating enzyme activity. Furthermore, OsUBC12 directly associates with rice SUCROSE NON-FERMENTING 1-RELATED PROTEIN KINASE 1.1 (OsSnRK1.1), promoting its degradation. OsSnRK1.1 inhibits LTG by enhancing ABA signaling and acts downstream of OsUBC12. These findings shed light on the underlying mechanisms of UBC12 regulating LTG and provide genetic reference points for improving LTG in indica rice.
A solid-state lithium-ion battery with micron-sized silicon anode operating free from external pressure
Authors: Pan Hui , Wang Lei , Shi Yu , Sheng Chuanchao , Yang Sixie , He Ping , Zhou Haoshen
Published: March 2024

Applying high stack pressure (often up to tens of megapascals) to solid-state Li-ion batteries is primarily done to address the issues of internal voids formation and subsequent Li-ion transport blockage within the solid electrode due to volume changes. Whereas, redundant pressurizing devices lower the energy density of batteries and raise the cost. Herein, a mechanical optimization strategy involving elastic electrolyte is proposed for SSBs operating without external pressurizing, but relying solely on the built-in pressure of cells. We combine soft-rigid dual monomer copolymer with deep eutectic mixture to design an elastic solid electrolyte, which exhibits not only high stretchability and deformation recovery capability but also high room-temperature Li-ion conductivity of 2×10−3 S cm−1 and nonflammability. The micron-sized Si anode without additional stack pressure, paired with the elastic electrolyte, exhibits exceptional stability for 300 cycles with 90.8% capacity retention. Furthermore, the solid Li/elastic electrolyte/LiFePO4 battery delivers 143.3 mAh g−1 after 400 cycles. Finally, the micron-sized Si/elastic electrolyte/LiFePO4 full cell operates stably for 100 cycles in the absence of any additional pressure, maintaining a capacity retention rate of 98.3%. This significantly advances the practical applications of solid-state batteries.
Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion
Authors: Planas Delphine , Staropoli Isabelle , Michel Vincent , Lemoine Frederic , Donati Flora , Prot Matthieu , Porrot Francoise , Guivel-Benhassine Florence , Jeyarajah Banujaa , Brisebarre Angela , Dehan Océane , Avon Léa , Bolland William Henry , Hubert Mathieu , Buchrieser Julian , Vanhoucke Thibault , Rosenbaum Pierre , Veyer David , Péré Hélène , Lina Bruno , Trouillet-Assant Sophie , Hocqueloux Laurent , Prazuck Thierry , Simon-Loriere Etienne , Schwartz Olivier
Published: March 2024

The unceasing circulation of SARS-CoV-2 leads to the continuous emergence of novel viral sublineages. Here, we isolate and characterize XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 and JN.1 variants, representing >80% of circulating variants in January 2024. The XBB subvariants carry few but recurrent mutations in the spike, whereas BA.2.86.1 and JN.1 harbor >30 additional changes. These variants replicate in IGROV-1 but no longer in Vero E6 and are not markedly fusogenic. They potently infect nasal epithelial cells, with EG.5.1.3 exhibiting the highest fitness. Antivirals remain active. Neutralizing antibody (NAb) responses from vaccinees and BA.1/BA.2-infected individuals are markedly lower compared to BA.1, without major differences between variants. An XBB breakthrough infection enhances NAb responses against both XBB and BA.2.86 variants. JN.1 displays lower affinity to ACE2 and higher immune evasion properties compared to BA.2.86.1. Thus, while distinct, the evolutionary trajectory of these variants combines increased fitness and antibody evasion.
Intranational synergies and trade-offs reveal common and differentiated priorities of sustainable development goals in China
Authors: Xing Qiang , Wu Chaoyang , Chen Fang , Liu Jianguo , Pradhan Prajal , Bryan Brett A. , Schaubroeck Thomas , Carrasco L. Roman , Gonsamo Alemu , Li Yunkai , Chen Xiuzhi , Deng Xiangzheng , Albanese Andrea , Li Yingjie , Xu Zhenci
Published: March 2024

Accelerating efforts for the Sustainable Development Goals requires understanding their synergies and trade-offs at the national and sub-national levels, which will help identify the key hurdles and opportunities to prioritize them in an indivisible manner for a country. Here, we present the importance of the 17 goals through synergy and trade-off networks. Our results reveal that 19 provinces show the highest trade-offs in SDG13 (Combating Climate Change) or SDG5 (Gender Equality) consistent with the national level, with other 12 provinces varying. 24 provinces show the highest synergies in SDG1 (No Poverty) or SDG6 (Clean Water and Sanitation) consistent with the national level, with the remaining 7 provinces varying. These common but differentiated SDG priorities reflect that to ensure a coordinated national response, China should pay more attention to the provincial situation, so that provincial governments can formulate more targeted policies in line with their own priorities towards accelerating sustainable development.
Toll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity
Authors: Wang Xufeng , Yu Dongli , Yu Jiancheng , Hu Hao , Hang Runlai , Amador Zachary , Chen Qi , Chai Jijie , Chen Xuemei
Published: March 2024

The occurrence of NAD+ as a non-canonical RNA cap has been demonstrated in diverse organisms. TIR domain-containing proteins present in all kingdoms of life act in defense responses and can have NADase activity that hydrolyzes NAD+. Here, we show that TIR domain-containing proteins from several bacterial and one archaeal species can remove the NAM moiety from NAD-capped RNAs (NAD-RNAs). We demonstrate that the deNAMing activity of AbTir (from Acinetobacter baumannii) on NAD-RNA specifically produces a cyclic ADPR-RNA, which can be further decapped in vitro by known decapping enzymes. Heterologous expression of the wild-type but not a catalytic mutant AbTir in E. coli suppressed cell propagation and reduced the levels of NAD-RNAs from a subset of genes before cellular NAD+ levels are impacted. Collectively, the in vitro and in vivo analyses demonstrate that TIR domain-containing proteins can function as a deNAMing enzyme of NAD-RNAs, raising the possibility of TIR domain proteins acting in gene expression regulation.
Time-of-flight detection of terahertz phonon-polariton
Authors: Luo Tianchuang , Ilyas Batyr , Hoegen A. von , Lee Youjin , Park Jaena , Park Je-Geun , Gedik Nuh
Published: March 2024

A polariton is a fundamental quasiparticle that arises from strong light-matter interaction and as such has attracted wide scientific and practical interest. When light is strongly coupled to the crystal lattice, it gives rise to phonon-polaritons (PPs), which have been proven useful in the dynamical manipulation of quantum materials and the advancement of terahertz technologies. Yet, current detection and characterization methods of polaritons are still limited. Traditional techniques such as Raman or transient grating either rely on fine-tuning of external parameters or complex phase extraction techniques. To overcome these inherent limitations, we propose and demonstrate a technique based on a time-of-flight measurement of PPs. We resonantly launch broadband PPs with intense terahertz fields and measure the time-of-flight of each spectral component with time-resolved second harmonic generation. The time-of-flight information, combined with the PP attenuation, enables us to resolve the real and imaginary parts of the PP dispersion relation. We demonstrate this technique in the van der Waals magnets NiI2 and MnPS3 and reveal a hidden magnon-phonon interaction. We believe that this approach will unlock new opportunities for studying polaritons across diverse material systems and enhance our understanding of strong light-matter interaction.
Characterization of elusive rhamnosyl dioxanium ions and their application in complex oligosaccharide synthesis
Authors: Moons Peter H. , ter Braak Floor , de Kleijne Frank F. J. , Bijleveld Bart , Corver Sybren J. R. , Houthuijs Kas J. , Almizori Hero R. , Berden Giel , Martens Jonathan , Oomens Jos , White Paul B. , Boltje Thomas J.
Published: March 2024

Attaining complete anomeric control is still one of the biggest challenges in carbohydrate chemistry. Glycosyl cations such as oxocarbenium and dioxanium ions are key intermediates of glycosylation reactions. Characterizing these highly-reactive intermediates and understanding their glycosylation mechanisms are essential to the stereoselective synthesis of complex carbohydrates. Although C-2 acyl neighbouring-group participation has been well-studied, the reactive intermediates in more remote participation remain elusive and are challenging to study. Herein, we report a workflow that is utilized to characterize rhamnosyl 1,3-bridged dioxanium ions derived from C-3 p-anisoyl esterified donors. First, we use a combination of quantum-chemical calculations and infrared ion spectroscopy to determine the structure of the cationic glycosylation intermediate in the gas-phase. In addition, we establish the structure and exchange kinetics of highly-reactive, low-abundance species in the solution-phase using chemical exchange saturation transfer, exchange spectroscopy, correlation spectroscopy, heteronuclear single-quantum correlation, and heteronuclear multiple-bond correlation nuclear magnetic resonance spectroscopy. Finally, we apply C-3 acyl neighbouring-group participation to the synthesis of complex bacterial oligosaccharides. This combined approach of finding answers to fundamental physical-chemical questions and their application in organic synthesis provides a robust basis for elucidating highly-reactive intermediates in glycosylation reactions.
Spatial engineering of single-atom Fe adjacent to Cu-assisted nanozymes for biomimetic O2 activation
Authors: Wang Ying , Paidi Vinod K. , Wang Weizhen , Wang Yong , Jia Guangri , Yan Tingyu , Cui Xiaoqiang , Cai Songhua , Zhao Jingxiang , Lee Kug-Seung , Lee Lawrence Yoon Suk , Wong Kwok-Yin
Published: March 2024

The precise design of single-atom nanozymes (SAzymes) and understanding of their biocatalytic mechanisms hold great promise for developing ideal bio-enzyme substitutes. While considerable efforts have been directed towards mimicking partial bio-inspired structures, the integration of heterogeneous SAzymes configurations and homogeneous enzyme-like mechanism remains an enormous challenge. Here, we show a spatial engineering strategy to fabricate dual-sites SAzymes with atomic Fe active center and adjacent Cu sites. Compared to planar Fe–Cu dual-atomic sites, vertically stacked Fe–Cu geometry in FePc@2D-Cu–N–C possesses highly optimized scaffolds, favorable substrate affinity, and fast electron transfer. These characteristics of FePc@2D-Cu–N–C SAzyme induces biomimetic O2 activation through homogenous enzymatic pathway, resembling functional and mechanistic similarity to natural cytochrome c oxidase. Furthermore, it presents an appealing alternative of cytochrome P450 3A4 for drug metabolism and drug–drug interaction. These findings are expected to deepen the fundamental understanding of atomic-level design in next-generation bio-inspired nanozymes.
Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis
Authors: Xie Ouli , Morris Jacqueline M. , Hayes Andrew J. , Towers Rebecca J. , Jespersen Magnus G. , Lees John A. , Ben Zakour Nouri L. , Berking Olga , Baines Sarah L. , Carter Glen P. , Tonkin-Hill Gerry , Schrieber Layla , McIntyre Liam , Lacey Jake A. , James Taylah B. , Sriprakash Kadaba S. , Beatson Scott A. , Hasegawa Tadao , Giffard Phil , Steer Andrew C. , Batzloff Michael R. , Beall Bernard W. , Pinho Marcos D. , Ramirez Mario , Bessen Debra E. , Dougan Gordon , Bentley Stephen D. , Walker Mark J. , Currie Bart J. , Tong Steven Y. C. , McMillan David J. , Davies Mark R.
Published: March 2024

Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.
Complete separation of benzene-cyclohexene-cyclohexane mixtures via temperature-dependent molecular sieving by a flexible chain-like coordination polymer
Authors: Xie Feng , Chen Lihang , Cedeño Morales Eder Moisés , Ullah Saif , Fu Yiwen , Thonhauser Timo , Tan Kui , Bao Zongbi , Li Jing
Published: March 2024

The separation and purification of C6 cyclic hydrocarbons (benzene, cyclohexene, cyclohexane) represent a critically important but energy intensive process. Developing adsorptive separation technique to replace thermally driven distillation processes holds great promise to significantly reduce energy consumption. Here we report a flexible one-dimensional coordination polymer as an efficient adsorbent to discriminate ternary C6 cyclic hydrocarbons via an ideal molecular sieving mechanism. The compound undergoes fully reversible structural transformation associated with removal/re-coordination of water molecules and between activated and hydrocarbon-loaded forms. It exhibits distinct temperature- and adsorbate-dependent adsorption behavior which facilitates the complete separation of benzene, cyclohexene and cyclohexane from their binary and ternary mixtures, with the record-high uptake ratios for C6H6/C6H12 and C6H10/C6H12 in vapor phase and highest binary and ternary selectivities in liquid phase. In situ infrared spectroscopic analysis and ab initio calculations provide insight into the host-guest interactions and their effect on the preferential adsorption and structural transformation.
HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice
Authors: Long Jianting , Chen Xihe , He Mian , Ou Shudan , Zhao Yunhe , Yan Qingjia , Ma Minjun , Chen Jingyu , Qin Xuping , Zhou Xiangjun , Chu Junjun , Han Yanyan
Published: March 2024

T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E784-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4+ and CD8+ T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment.
Double charge flips of polyamide membrane by ionic liquid-decoupled bulk and interfacial diffusion for on-demand nanofiltration
Authors: Guo Bian-Bian , Liu Chang , Zhu Cheng-Ye , Xin Jia-Hui , Zhang Chao , Yang Hao-Cheng , Xu Zhi-Kang
Published: March 2024

Fine design of surface charge properties of polyamide membranes is crucial for selective ionic and molecular sieving. Traditional membranes face limitations due to their inherent negative charge and limited charge modification range. Herein, we report a facile ionic liquid-decoupled bulk/interfacial diffusion strategy to elaborate the double charge flips of polyamide membranes, enabling on-demand transformation from inherently negative to highly positive and near-neutral charges. The key to these flips lies in the meticulous utilization of ionic liquid that decouples intertwined bulk/interfacial diffusion, enhancing interfacial while inhibiting bulk diffusion. These charge-tunable polyamide membranes can be customized for impressive separation performance, for example, profound Cl−/SO42− selectivity above 470 in sulfate recovery, ultrahigh Li+/Mg2+ selectivity up to 68 in lithium extraction, and effective divalent ion removal in pharmaceutical purification, surpassing many reported polyamide nanofiltration membranes. This advancement adds a new dimension to in the design of advanced polymer membranes via interfacial polymerization.
An exposome atlas of serum reveals the risk of chronic diseases in the Chinese population
Authors: You Lei , Kou Jing , Wang Mengdie , Ji Guoqin , Li Xiang , Su Chang , Zheng Fujian , Zhang Mingye , Wang Yuting , Chen Tiantian , Li Ting , Zhou Lina , Shi Xianzhe , Zhao Chunxia , Liu Xinyu , Mei Surong , Xu Guowang
Published: March 2024

Although adverse environmental exposures are considered a major cause of chronic diseases, current studies provide limited information on real-world chemical exposures and related risks. For this study, we collected serum samples from 5696 healthy people and patients, including those with 12 chronic diseases, in China and completed serum biomonitoring including 267 chemicals via gas and liquid chromatography-tandem mass spectrometry. Seventy-four highly frequently detected exposures were used for exposure characterization and risk analysis. The results show that region is the most critical factor influencing human exposure levels, followed by age. Organochlorine pesticides and perfluoroalkyl substances are associated with multiple chronic diseases, and some of them exceed safe ranges. Multi-exposure models reveal significant risk effects of exposure on hyperlipidemia, metabolic syndrome and hyperuricemia. Overall, this study provides a comprehensive human serum exposome atlas and disease risk information, which can guide subsequent in-depth cause-and-effect studies between environmental exposures and human health.
A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
Authors: Tsartsalis Stergios , Sleven Hannah , Fancy Nurun , Wessely Frank , Smith Amy M. , Willumsen Nanet , Cheung To Ka Dorcas , Rokicki Michal J. , Chau Vicky , Ifie Eseoghene , Khozoie Combiz , Ansorge Olaf , Yang Xin , Jenkyns Marion H. , Davey Karen , McGarry Aisling , Muirhead Robert C. J. , Debette Stephanie , Jackson Johanna S. , Montagne Axel , Owen David R. , Miners J. Scott , Love Seth , Webber Caleb , Cader M. Zameel , Matthews Paul M.
Published: March 2024

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.
Vortex-based soft magnetic composite with ultrastable permeability up to gigahertz frequencies
Authors: Bai Guohua , Sun Jiayi , Zhang Zhenhua , Liu Xiaolian , Bandaru Sateesh , Liu Weiwei , Li Zhong , Li Hongxia , Wang Ningning , Zhang Xuefeng
Published: March 2024

Soft magnetic materials with stable permeability up to hundreds of megahertz (MHz) are urgently needed for integrated transformers and inductors, which are crucial in the more-than-Moore era. However, traditional frequency-stable soft magnetic ferrites suffer from low saturation magnetization and temperature instability, making them unsuitable for integrated circuits. Herein, we fabricate a frequency-stable soft magnetic composite featuring a magnetic vortex structure via cold-sintering, where ultrafine FeSiAl particles are magnetically isolated and covalently bonded by Al2SiO5/SiO2/Fe2(MoO4)3multilayered heterostructure. This construction results in an ultrastable permeability of 13 up to 1 gigahertz (GHz), relatively large saturation magnetization of 105 Am2/kg and low coercivity of 48 A/m, which we ascribe to the elimination of domain walls associated with almost uniform single-vortex structures, as observed by Lorentz transmission electron microscopy and reconstructed by micromagnetic simulation. Moreover, the ultimate compressive strength has been simultaneously increased up to 337.1 MPa attributed to the epitaxially grown interfaces between particles. This study deepens our understanding on the characteristics of magnetic vortices and provides alternative concept for designing integrated magnetic devices.
Electronic structure modulation of iron sites with fluorine coordination enables ultra-effective H2O2 activation
Authors: Yu Deyou , Xu Licong , Fu Kaixing , Liu Xia , Wang Shanli , Wu Minghua , Lu Wangyang , Lv Chunyu , Luo Jinming
Published: March 2024

Electronic structure modulation of active sites is critical important in Fenton catalysis as it offers a promising strategy for boosting H2O2 activation. However, efficient generation of hydroxyl radicals (•OH) is often limited to the unoptimized coordination environment of active sites. Herein, we report the rational design and synthesis of iron oxyfluoride (FeOF), whose iron sites strongly coordinate with the most electronegative fluorine atoms in a characteristic moiety of F-(Fe(III)O3)-F, for effective H2O2 activation with potent •OH generation. Results demonstrate that the fluorine coordination plays a pivotal role in lowering the local electron density and optimizing the electronic structures of iron sites, thus facilitating the rate-limiting H2O2 adsorption and subsequent peroxyl bond cleavage reactions. Consequently, FeOF exhibits a significant and pH-adaptive •OH yield (~450 µM) with high selectivity, which is 1 ~ 3 orders of magnitude higher than the state-of-the-art iron-based catalysts, leading to excellent degradation activities against various organic pollutants at neutral condition. This work provides fundamental insights into the function of fluorine coordination in boosting Fenton catalysis at atomic level, which may inspire the design of efficient active sites for sustainable environmental remediation.
Daily artificial gravity partially mitigates vestibular processing changes associated with head-down tilt bedrest
Authors: Tays G. D. , Hupfeld K. E. , McGregor H. R. , Beltran N. E. , De Dios Y. E. , Mulder E. , Bloomberg J. J. , Mulavara A. P. , Wood S. J. , Seidler R. D.
Published: March 2024

Microgravity alters vestibular signaling and reduces body loading, driving sensory reweighting. The unloading effects can be modelled using head-down tilt bedrest (HDT). Artificial gravity (AG) has been hypothesized to serve as an integrated countermeasure for the declines associated with HDT and spaceflight. Here, we examined the efficacy of 30 min of daily AG to counteract brain and behavior changes from 60 days of HDT. Two groups received 30 min of AG delivered via short-arm centrifuge daily (n = 8 per condition), either in one continuous bout, or in 6 bouts of 5 min. To improve statistical power, we combined these groups (AG; n = 16). Another group served as controls in HDT with no AG (CTRL; n = 8). We examined how HDT and AG affect vestibular processing by collecting fMRI scans during vestibular stimulation. We collected these data prior to, during, and post-HDT. We assessed brain activation initially in 12 regions of interest (ROIs) and then conducted an exploratory whole brain analysis. The AG group showed no changes in activation during vestibular stimulation in a cerebellar ROI, whereas the CTRL group showed decreased activation specific to HDT. Those that received AG and showed little pre- to post-HDT changes in left vestibular cortex activation had better post-HDT balance performance. Whole brain analyses identified increased pre- to during-HDT activation in CTRLs in the right precentral gyrus and right inferior frontal gyrus, whereas AG maintained pre-HDT activation levels. These results indicate that AG could mitigate activation changes in vestibular processing that is associated with better balance performance.
The effects of long-term exposure to microgravity and body orientation relative to gravity on perceived traveled distance
Authors: Jörges Björn , Bury Nils , McManus Meaghan , Bansal Ambika , Allison Robert S. , Jenkin Michael , Harris Laurence R.
Published: March 2024

Self-motion perception is a multi-sensory process that involves visual, vestibular, and other cues. When perception of self-motion is induced using only visual motion, vestibular cues indicate that the body remains stationary, which may bias an observer’s perception. When lowering the precision of the vestibular cue by for example, lying down or by adapting to microgravity, these biases may decrease, accompanied by a decrease in precision. To test this hypothesis, we used a move-to-target task in virtual reality. Astronauts and Earth-based controls were shown a target at a range of simulated distances. After the target disappeared, forward self-motion was induced by optic flow. Participants indicated when they thought they had arrived at the target’s previously seen location. Astronauts completed the task on Earth (supine and sitting upright) prior to space travel, early and late in space, and early and late after landing. Controls completed the experiment on Earth using a similar regime with a supine posture used to simulate being in space. While variability was similar across all conditions, the supine posture led to significantly higher gains (target distance/perceived travel distance) than the sitting posture for the astronauts pre-flight and early post-flight but not late post-flight. No difference was detected between the astronauts’ performance on Earth and onboard the ISS, indicating that judgments of traveled distance were largely unaffected by long-term exposure to microgravity. Overall, this constitutes mixed evidence as to whether non-visual cues to travel distance are integrated with relevant visual cues when self-motion is simulated using optic flow alone.
Intergranular corrosion of Ni-30Cr in high-temperature hydrogenated water after removing surface passivating film
Authors: Kruska K. , Olszta M. J. , Wang J. , Schreiber D. K.
Published: March 2024

High-resolution transmission electron microscopy and atom probe tomography are used to characterize the initial passivation and subsequent intergranular corrosion of degraded grain boundaries in a model Ni-30Cr alloy exposed to 360 °C hydrogenated water. Upon initial exposure for 1000 h, the alloy surface directly above the grain boundary forms a thin passivating film of Cr2O3, protecting the underlying grain boundary from intergranular corrosion. However, the metal grain boundary experiences severe Cr depletion and grain boundary migration during this initial exposure. To understand how Cr depletion affects further corrosion, the local protective film was sputtered away using a glancing angle focused ion beam. Upon further exposure, the surface fails to repassivate, and intergranular corrosion is observed through the Cr-depleted region. Through this combination of high-resolution microscopy and localized passive film removal, we show that, although high-Cr alloys are resistant to intergranular attack and stress corrosion cracking, degradation-induced changes in the underlying metal at grain boundaries make the material more susceptible once the initial passive film is breached.