bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting nerve growth factor-mediated osteosarcoma metastasis: mechanistic insights and therapeutic opportunities using larotrectinib
Authors: Hou Chun-Han , Chen Wei-Li , Lin Chih-Yang
Published: May 2024

Osteosarcoma (OS) therapy presents numerous challenges, due largely to a low survival rate following metastasis onset. Nerve growth factor (NGF) has been implicated in the metastasis and progression of various cancers; however, the mechanism by which NGF promotes metastasis in osteosarcoma has yet to be elucidated. This study investigated the influence of NGF on the migration and metastasis of osteosarcoma patients (88 cases) as well as the underlying molecular mechanisms, based on RNA-sequencing and gene expression data from a public database (TARGET-OS). In osteosarcoma patients, the expression of NGF was significantly higher than that of other growth factors. This observation was confirmed in bone tissue arrays from 91 osteosarcoma patients, in which the expression levels of NGF and matrix metallopeptidase-2 (MMP-2) protein were significantly higher than in normal bone, and strongly correlated with tumor stage. In summary, NGF is positively correlated with MMP-2 in human osteosarcoma tissue and NGF promotes osteosarcoma cell metastasis by upregulating MMP-2 expression. In cellular experiments using human osteosarcoma cells (143B and MG63), NGF upregulated MMP-2 expression and promoted wound healing, cell migration, and cell invasion. Pre-treatment with MEK and ERK inhibitors or siRNA attenuated the effects of NGF on cell migration and invasion. Stimulation with NGF was shown to promote phosphorylation along the MEK/ERK signaling pathway and decrease the expression of microRNA-92a-1-5p (miR-92a-1-5p). In in vivo experiments involving an orthotopic mouse model, the overexpression of NGF enhanced the effects of NGF on lung metastasis. Note that larotrectinib (a tropomyosin kinase receptor) strongly inhibited the effect of NGF on lung metastasis. In conclusion, it appears that NGF promotes MMP-2-dependent cell migration by inhibiting the effects of miR-92a-1-5p via the MEK/ERK signaling cascade. Larotrectinib emerged as a potential drug for the treatment of NGF-mediated metastasis in osteosarcoma.
Targeting CK2 eliminates senescent cells and prolongs lifespan in Zmpste24-deficient mice
Authors: Zhang Jie , Sun Pengfei , Wu Zhuping , Wu Jie , Jia Jiali , Zou Haoman , Mo Yanzhen , Zhou Zhongjun , Liu Baohua , Ao Ying , Wang Zimei
Published: May 2024

Senescent cell clearance is emerging as a promising strategy for treating age-related diseases. Senolytics are small molecules that promote the clearance of senescent cells; however, senolytics are uncommon and their underlying mechanisms remain largely unknown. Here, we investigated whether genomic instability is a potential target for senolytic. We screened small-molecule kinase inhibitors involved in the DNA damage response (DDR) in Zmpste24−/− mouse embryonic fibroblasts, a progeroid model characterized with impaired DDR and DNA repair. 4,5,6,7-tetrabromo-2-azabenzamidazole (TBB), which specifically inhibits casein kinase 2 (CK2), was selected and discovered to preferentially trigger apoptosis in Zmpste24−/− cells. Mechanistically, inhibition of CK2 abolished the phosphorylation of heterochromatin protein 1α (HP1α), which retarded the dynamic HP1α dissociation from repressive histone mark H3K9me3 and its relocalization with γH2AX to DNA damage sites, suggesting that disrupting heterochromatin remodeling in the initiation of DDR accelerates apoptosis in senescent cells. Furthermore, feeding Zmpste24-deficient mice with TBB alleviated progeroid features and extended their lifespan. Our study identified TBB as a new class senolytic compound that can reduce age-related symptoms and prolong lifespan in progeroid mice.
Ferroptosis: A double-edged sword
Authors: Wang Shengmei , Guo Qiuyan , Zhou Lili , Xia Xinhua
Published: May 2024

Ferroptosis represents a form of programmed cell death that is propelled by iron-dependent lipid peroxidation, thereby being distinguished by the prominent features of iron accumulation and lipid peroxidation. Ferroptosis has been implicated in numerous physiological and pathological phenomena, with mounting indications that it holds significant implications for cancer and other medical conditions. On one side, it demonstrates anti-cancer properties by triggering ferroptosis within malignant cells, and on the other hand, it damages normal cells causing other diseases. Therefore, in this paper, we propose to review the paradoxical regulation of ferroptosis in tumors and other diseases. First, we introduce the development history, concept and mechanism of ferroptosis. The second part focuses on the methods of inducing ferroptosis in tumors. The third section emphasizes the utilization of ferroptosis in different medical conditions and strategies to inhibit ferroptosis. The fourth part elucidates the key contradictions in the control of ferroptosis. Finally, potential research avenues in associated domains are suggested.
Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Walker Faye M. , Sobral Lays Martin , Danis Etienne , Sanford Bridget , Donthula Sahiti , Balakrishnan Ilango , Wang Dong , Pierce Angela , Karam Sana D. , Kargar Soudabeh , Serkova Natalie J. , Foreman Nicholas K. , Venkataraman Sujatha , Dowell Robin , Vibhakar Rajeev , Dahl Nathan A.
Published: May 2024

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.
The observation of π-shifts in the Little-Parks effect in 4Hb-TaS2
Authors: Almoalem Avior , Feldman Irena , Mangel Ilay , Shlafman Michael , Yaish Yuval E. , Fischer Mark H. , Moshe Michael , Ruhman Jonathan , Kanigel Amit
Published: May 2024

Finding evidence of non-trivial pairing states is one of the greatest experimental challenges in the field of unconventional superconductivity. Such evidence requires phase-sensitive probes susceptible to the internal structure of the order parameter. We report the measurement of the Little-Parks effect in the unconventional superconductor candidate 4Hb-TaS2. In half of our rings, which are fabricated from single-crystals, we find a π-shift in the transition-temperature oscillations. According to theory, such a π-shift is only possible if the order parameter is non-s-wave. In the absence of crystallographic defects, the shift provides evidence of a multi-component order parameter. Thus, this observation increases the likelihood of the two-component order parameter scenario in 4Hb-TaS2. Furthermore, we show that Tc is enhanced as a function of the out-of-plane field when a constant in-plane field is applied, which we explain using a two-component order-parameter.
Heatwave attribution based on reliable operational weather forecasts
Authors: Leach Nicholas J. , Roberts Christopher D. , Aengenheyster Matthias , Heathcote Daniel , Mitchell Dann M. , Thompson Vikki , Palmer Tim , Weisheimer Antje , Allen Myles R.
Published: May 2024

The 2021 Pacific Northwest heatwave was so extreme as to challenge conventional statistical and climate-model-based approaches to extreme weather attribution. However, state-of-the-art operational weather prediction systems are demonstrably able to simulate the detailed physics of the heatwave. Here, we leverage these systems to show that human influence on the climate made this event at least 8 [2–50] times more likely. At the current rate of global warming, the likelihood of such an event is doubling every 20 [10–50] years. Given the multi-decade lower-bound return-time implied by the length of the historical record, this rate of change in likelihood is highly relevant for decision makers. Further, forecast-based attribution can synthesise the conditional event-specific storyline and unconditional event-class probabilistic approaches to attribution. If developed as a routine service in forecasting centres, it could provide reliable estimates of human influence on extreme weather risk, which is critical to supporting effective adaptation planning.
FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity
Authors: Chen Enni , Wu Jiawei , Huang Jiajia , Zhu Wancui , Sun Haohui , Wang Xiaonan , Lin Dagui , Li Xiaodi , Shi Dingbo , Liu Zhiqiao , Huang Jinsheng , Chen Miao , Xie Fangyun , Deng Wuguo
Published: May 2024

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
Elastic strain-induced amorphization in high-entropy alloys
Authors: Bu Yeqiang , Wu Yuan , Lei Zhifeng , Yuan Xiaoyuan , Liu Leqing , Wang Peng , Liu Xiongjun , Wu Honghui , Liu Jiabin , Wang Hongtao , Ritchie R. O. , Lu Zhaoping , Yang Wei
Published: May 2024

Elastic stability is the basis for understanding structural responses to external stimuli in crystalline solids, including melting, incipient plasticity and fracture. In this work, elastic stability is investigated in a series of high-entropy alloys (HEAs) using in situ mechanical tests and atomic-resolution characterization in transmission electron microscopy. Under tensile loading, the HEA lattices are observed to undergo a sudden loss of ordering as the elastic strain reached ∽ 10%. Such elastic strain-induced amorphization stands in intrinsic contrast to previously reported dislocation-mediated elastic instability and defect accumulation-mediated amorphization, introducing a form of elastic instability. Together with the first principle calculations and atomic-resolution chemical mapping, we identify that the elastic strain-induced amorphization is closely related to the depressed dislocation nucleation due to the local atomic environment inhomogeneity of HEAs. Our findings provide insights for the understanding of the fundamental nature of physical mechanical phenomena like elastic instability and incipient plasticity.
The debranching enzyme Dbr1 regulates lariat turnover and intron splicing
Authors: Buerer Luke , Clark Nathaniel E. , Welch Anastasia , Duan Chaorui , Taggart Allison J. , Townley Brittany A. , Wang Jing , Soemedi Rachel , Rong Stephen , Lin Chien-Ling , Zeng Yi , Katolik Adam , Staley Jonathan P. , Damha Masad J. , Mosammaparast Nima , Fairbrother William G.
Published: May 2024

The majority of genic transcription is intronic. Introns are removed by splicing as branched lariat RNAs which require rapid recycling. The branch site is recognized during splicing catalysis and later debranched by Dbr1 in the rate-limiting step of lariat turnover. Through generation of a viable DBR1 knockout cell line, we find the predominantly nuclear Dbr1 enzyme to encode the sole debranching activity in human cells. Dbr1 preferentially debranches substrates that contain canonical U2 binding motifs, suggesting that branchsites discovered through sequencing do not necessarily represent those favored by the spliceosome. We find that Dbr1 also exhibits specificity for particular 5’ splice site sequences. We identify Dbr1 interactors through co-immunoprecipitation mass spectrometry. We present a mechanistic model for Dbr1 recruitment to the branchpoint through the intron-binding protein AQR. In addition to a 20-fold increase in lariats, Dbr1 depletion increases exon skipping. Using ADAR fusions to timestamp lariats, we demonstrate a defect in spliceosome recycling. In the absence of Dbr1, spliceosomal components remain associated with the lariat for a longer period of time. As splicing is co-transcriptional, slower recycling increases the likelihood that downstream exons will be available for exon skipping.
Discovering two general characteristic times of transient responses in solid oxide cells
Authors: Liang Zhaojian , Wang Jingyi , Ren Keda , Jiao Zhenjun , Ni Meng , An Liang , Wang Yang , Yang Jinbin , Li Mengying
Published: May 2024

A comprehensive understanding of the transient characteristics in solid oxide cells (SOCs) is crucial for advancing SOC technology in renewable energy storage and conversion. However, general formulas describing the relationship between SOC transients and multiple parameters remain elusive. Through comprehensive numerical analysis, we find that the thermal and gaseous response times of SOCs upon rapid electrical variations are on the order of two characteristic times (τh and τm), respectively. The gaseous response time is approximately 1τm, and the thermal response time aligns with roughly 2τh. These characteristic times represent the overall heat and mass transfer rates within the cell, and their mathematical relationships with various SOC design and operating parameters are revealed. Validation of τh and τm is achieved through comparison with an in-house experiment and existing literature data, achieving the same order of magnitude for a wide range of electrochemical cells, showcasing their potential use for characterizing transient behaviors in a wide range of electrochemical cells. Moreover, two examples are presented to demonstrate how these characteristic times can streamline SOC design and control without the need for complex numerical simulations, thus offering valuable insights and tools for enhancing the efficiency and durability of electrochemical cells.
Hydrogen peroxide serves as pivotal fountainhead for aerosol aqueous sulfate formation from a global perspective
Authors: Gao Jie , Wang Haoqi , Liu Wenqi , Xu Han , Wei Yuting , Tian Xiao , Feng Yinchang , Song Shaojie , Shi Guoliang
Published: May 2024

Traditional atmospheric chemistry posits that sulfur dioxide (SO2) can be oxidized to sulfate (SO42–) through aqueous-phase reactions in clouds and gas-phase oxidation. Despite adequate knowledge of traditional mechanisms, several studies have highlighted the potential for SO2 oxidation within aerosol water. Given the widespread presence of tropospheric aerosols, SO42− production through aqueous-phase oxidation in aerosol water could have a pervasive global impact. Here, we quantify the potential contributions of aerosol aqueous pathways to global sulfate formation based on the GEOS-Chem simulations and subsequent theoretical calculations. Hydrogen peroxide (H2O2) oxidation significantly influences continental regions both horizontally and vertically. Over the past two decades, shifts in the formation pathways within typical cities reveal an intriguing trend: despite reductions in SO2 emissions, the increased atmospheric oxidation capacities, like rising H2O2 levels, prevent a steady decline in SO42− concentrations. Abating oxidants would facilitate the benefit of SO2 reduction and the positive feedback in sulfate mitigation.
The quantum geometric origin of capacitance in insulators
Authors: Komissarov Ilia , Holder Tobias , Queiroz Raquel
Published: May 2024

In band insulators, without a Fermi surface, adiabatic transport can exist due to the geometry of the ground state wavefunction. Here we show that for systems driven at a small but finite frequency ω, transport likewise depends sensitively on quantum geometry. We make this statement precise by expressing the Kubo formula for conductivity as the variation of the time-dependent polarization with respect to the applied field. We find that at linear order in frequency, the longitudinal conductivity results from an intrinsic capacitance determined by the ratio of the quantum metric and the spectral gap, establishing a fundamental link between the dielectric response and the quantum metric of insulators. We demonstrate that quantum geometry is responsible for the electronic contribution to the dielectric constant in a wide range of insulators, including the free electron gas in a quantizing magnetic field, for which we show the capacitance is quantized. We also study gapped bands of hBN-aligned twisted bilayer graphene and obstructed atomic insulators such as diamond. In the latter, we find its abnormally large refractive index to have a topological origin.
Atroposelective synthesis of biaxial bridged eight-membered terphenyls via a Co/SPDO-catalyzed aerobic oxidative coupling/desymmetrization of phenols
Authors: Wang Shuang-Hu , Wei Shi-Qiang , Zhang Ye , Zhang Xiao-Ming , Zhang Shu-Yu , Dai Kun-Long , Tu Yong-Qiang , Lu Ka , Ding Tong-Mei
Published: May 2024

Bridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).
Targeted suppression of siRNA biogenesis in Arabidopsis pollen promotes triploid seed viability
Authors: Pachamuthu Kannan , Simon Matthieu , Borges Filipe
Published: May 2024

In plants, small-interfering RNAs (siRNAs) mediate epigenetic silencing via the RNA-directed DNA methylation (RdDM) pathway, which is particularly prominent during reproduction and seed development. However, there is limited understanding of the origins and dynamics of reproductive siRNAs acting in different cellular and developmental contexts. Here, we used the RNaseIII-like protein RTL1 to suppress siRNA biogenesis in Arabidopsis pollen, and found distinct siRNA subsets produced during pollen development. We demonstrate that RTL1 expression in the late microspore and vegetative cell strongly impairs epigenetic silencing, and resembles RdDM mutants in their ability to bypass interploidy hybridization barriers in the seed. However, germline-specific RTL1 expression did not impact transgenerational inheritance of triploid seed lethality. These results reveal the existence of multiple siRNA subsets accumulated in mature pollen, and suggest that mobile siRNAs involved in the triploid block are produced in germline precursor cells after meiosis, or in the vegetative cell during pollen mitosis.
Structures of co-transcriptional RNA capping enzymes on paused transcription complex
Authors: Li Yan , Wang Qianmin , Xu Yanhui , Li Ze
Published: May 2024

The 5′-end capping of nascent pre-mRNA represents the initial step in RNA processing, with evidence demonstrating that guanosine addition and 2′-O-ribose methylation occur in tandem with early steps of transcription by RNA polymerase II, especially at the pausing stage. Here, we determine the cryo-EM structures of the paused elongation complex in complex with RNGTT, as well as the paused elongation complex in complex with RNGTT and CMTR1. Our findings show the simultaneous presence of RNGTT and the NELF complex bound to RNA polymerase II. The NELF complex exhibits two conformations, one of which shows a notable rearrangement of NELF-A/D compared to that of the paused elongation complex. Moreover, CMTR1 aligns adjacent to RNGTT on the RNA polymerase II stalk. Our structures indicate that RNGTT and CMTR1 directly bind the paused elongation complex, illuminating the mechanism by which 5’-end capping of pre-mRNA during transcriptional pausing.
High-speed optical imaging with sCMOS pixel reassignment
Authors: Mandracchia Biagio , Zheng Corey , Rajendran Suraj , Liu Wenhao , Forghani Parvin , Xu Chunhui , Jia Shu
Published: May 2024

Fluorescence microscopy has undergone rapid advancements, offering unprecedented visualization of biological events and shedding light on the intricate mechanisms governing living organisms. However, the exploration of rapid biological dynamics still poses a significant challenge due to the limitations of current digital camera architectures and the inherent compromise between imaging speed and other capabilities. Here, we introduce sHAPR, a high-speed acquisition technique that leverages the operating principles of sCMOS cameras to capture fast cellular and subcellular processes. sHAPR harnesses custom fiber optics to convert microscopy images into one-dimensional recordings, enabling acquisition at the maximum camera readout rate, typically between 25 and 250 kHz. We have demonstrated the utility of sHAPR with a variety of phantom and dynamic systems, including high-throughput flow cytometry, cardiomyocyte contraction, and neuronal calcium waves, using a standard epi-fluorescence microscope. sHAPR is highly adaptable and can be integrated into existing microscopy systems without requiring extensive platform modifications. This method pushes the boundaries of current fluorescence imaging capabilities, opening up new avenues for investigating high-speed biological phenomena.
TCAF1 promotes TRPV2-mediated Ca2+ release in response to cytosolic DNA to protect stressed replication forks
Authors: Kong Lingzhen , Cheng Chen , Cheruiyot Abigael , Yuan Jiayi , Yang Yichan , Hwang Sydney , Foust Daniel , Tsao Ning , Wilkerson Emily , Mosammaparast Nima , Major Michael B. , Piston David W. , Li Shan , You Zhongsheng
Published: May 2024

The protection of the replication fork structure under stress conditions is essential for genome maintenance and cancer prevention. A key signaling pathway for fork protection involves TRPV2-mediated Ca2+ release from the ER, which is triggered after the generation of cytosolic DNA and the activation of cGAS/STING. This results in CaMKK2/AMPK activation and subsequent Exo1 phosphorylation, which prevent aberrant fork processing, thereby ensuring genome stability. However, it remains poorly understood how the TRPV2 channel is activated by the presence of cytosolic DNA. Here, through a genome-wide CRISPR-based screen, we identify TRPM8 channel-associated factor 1 (TCAF1) as a key factor promoting TRPV2-mediated Ca2+ release under replication stress or other conditions that activate cGAS/STING. Mechanistically, TCAF1 assists Ca2+ release by facilitating the dissociation of STING from TRPV2, thereby relieving TRPV2 repression. Consistent with this function, TCAF1 is required for fork protection, chromosomal stability, and cell survival after replication stress.
Functional and structural dissection of glycosyltransferases underlying the glycodiversity of wolfberry-derived bioactive ingredients lycibarbarspermidines
Authors: Li Shao-Yang , Wang Gao-Qian , Long Liang , Gao Jia-Ling , Zhou Zheng-Qun , Wang Yong-Heng , Lv Jian-Ming , Chen Guo-Dong , Hu Dan , Abe Ikuro , Gao Hao
Published: May 2024

Lycibarbarspermidines are unusual phenolamide glycosides characterized by a dicaffeoylspermidine core with multiple glycosyl substitutions, and serve as a major class of bioactive ingredients in the wolfberry. So far, little is known about the enzymatic basis of the glycosylation of phenolamides including dicaffeoylspermidine. Here, we identify five lycibarbarspermidine glycosyltransferases, LbUGT1-5, which are the first phenolamide-type glycosyltransferases and catalyze regioselective glycosylation of dicaffeoylspermidines to form structurally diverse lycibarbarspermidines in wolfberry. Notably, LbUGT3 acts as a distinctive enzyme that catalyzes a tandem sugar transfer to the ortho-dihydroxy group on the caffeoyl moiety to form the unusual ortho-diglucosylated product, while LbUGT1 accurately discriminates caffeoyl and dihydrocaffeoyl groups to catalyze a site-selective sugar transfer. Crystal structure analysis of the complexes of LbUGT1 and LbUGT3 with UDP, combined with molecular dynamics simulations, revealed the structural basis of the difference in glycosylation selectivity between LbUGT1 and LbUGT3. Site-directed mutagenesis illuminates a conserved tyrosine residue (Y389 in LbUGT1 and Y390 in LbUGT3) in PSPG box that plays a crucial role in regulating the regioselectivity of LbUGT1 and LbUGT3. Our study thus sheds light on the enzymatic underpinnings of the chemical diversity of lycibarbarspermidines in wolfberry, and expands the repertoire of glycosyltransferases in nature.
The link between ancient microbial fluoride resistance mechanisms and bioengineering organofluorine degradation or synthesis
Authors: Stockbridge Randy B. , Wackett Lawrence P.
Published: May 2024

Fluorinated organic chemicals, such as per- and polyfluorinated alkyl substances (PFAS) and fluorinated pesticides, are both broadly useful and unusually long-lived. To combat problems related to the accumulation of these compounds, microbial PFAS and organofluorine degradation and biosynthesis of less-fluorinated replacement chemicals are under intense study. Both efforts are undermined by the substantial toxicity of fluoride, an anion that powerfully inhibits metabolism. Microorganisms have contended with environmental mineral fluoride over evolutionary time, evolving a suite of detoxification mechanisms. In this perspective, we synthesize emerging ideas on microbial defluorination/fluorination and fluoride resistance mechanisms and identify best approaches for bioengineering new approaches for degrading and making organofluorine compounds.
Environment-induced heritable variations are common in Arabidopsis thaliana
Authors: Lin Xiaohe , Yin Junjie , Wang Yifan , Yao Jing , Li Qingshun Q. , Latzel Vit , Bossdorf Oliver , Zhang Yuan-Ye
Published: May 2024

Parental or ancestral environments can induce heritable phenotypic changes, but whether such environment-induced heritable changes are a common phenomenon remains unexplored. Here, we subject 14 genotypes of Arabidopsis thaliana to 10 different environmental treatments and observe phenotypic and genome-wide gene expression changes over four successive generations. We find that all treatments caused heritable phenotypic and gene expression changes, with a substantial proportion stably transmitted over all observed generations. Intriguingly, the susceptibility of a genotype to environmental inductions could be predicted based on the transposon abundance in the genome. Our study thus challenges the classic view that the environment only participates in the selection of heritable variation and suggests that the environment can play a significant role in generating of heritable variations.
Loop-extruders alter bacterial chromosome topology to direct entropic forces for segregation
Authors: Harju Janni , van Teeseling Muriel C. F. , Broedersz Chase P.
Published: May 2024

Entropic forces have been argued to drive bacterial chromosome segregation during replication. In many bacterial species, however, specifically evolved mechanisms, such as loop-extruding SMC complexes and the ParABS origin segregation system, contribute to or are even required for chromosome segregation, suggesting that entropic forces alone may be insufficient. The interplay between and the relative contributions of these segregation mechanisms remain unclear. Here, we develop a biophysical model showing that purely entropic forces actually inhibit bacterial chromosome segregation until late replication stages. By contrast, our model reveals that loop-extruders loaded at the origins of replication, as observed in many bacterial species, alter the effective topology of the chromosome, thereby redirecting and enhancing entropic forces to enable accurate chromosome segregation during replication. We confirm our model predictions with polymer simulations: purely entropic forces do not allow for concurrent replication and segregation, whereas entropic forces steered by specifically loaded loop-extruders lead to robust, global chromosome segregation during replication. Finally, we show how loop-extruders can complement locally acting origin separation mechanisms, such as the ParABS system. Together, our results illustrate how changes in the geometry and topology of the polymer, induced by DNA-replication and loop-extrusion, impact the organization and segregation of bacterial chromosomes.
Complete telomere-to-telomere genomes uncover virulence evolution conferred by chromosome fusion in oomycete plant pathogens
Authors: Zhang Zhichao , Zhang Xiaoyi , Tian Yuan , Wang Liyuan , Cao Jingting , Feng Hui , Li Kainan , Wang Yan , Dong Suomeng , Ye Wenwu , Wang Yuanchao
Published: May 2024

Variations in chromosome number are occasionally observed among oomycetes, a group that includes many plant pathogens, but the emergence of such variations and their effects on genome and virulence evolution remain ambiguous. We generated complete telomere-to-telomere genome assemblies for Phytophthora sojae, Globisporangium ultimum, Pythium oligandrum, and G. spinosum. Reconstructing the karyotype of the most recent common ancestor in Peronosporales revealed that frequent chromosome fusion and fission drove changes in chromosome number. Centromeres enriched with Copia-like transposons may contribute to chromosome fusion and fission events. Chromosome fusion facilitated the emergence of pathogenicity genes and their adaptive evolution. Effectors tended to duplicate in the sub-telomere regions of fused chromosomes, which exhibited evolutionary features distinct to the non-fused chromosomes. By integrating ancestral genomic dynamics and structural predictions, we have identified secreted Ankyrin repeat-containing proteins (ANKs) as a novel class of effectors in P. sojae. Phylogenetic analysis and experiments further revealed that ANK is a specifically expanded effector family in oomycetes. These results revealed chromosome dynamics in oomycete plant pathogens, and provided novel insights into karyotype and effector evolution.
Plasmodium falciparum infection in humans and mosquitoes influence natural Anopheline biting behavior and transmission
Authors: Markwalter Christine F. , Lapp Zena , Abel Lucy , Kimachas Emmah , Omollo Evans , Freedman Elizabeth , Chepkwony Tabitha , Amunga Mark , McCormick Tyler , Bérubé Sophie , Mangeni Judith N. , Wesolowski Amy , Obala Andrew A. , Taylor Steve M. , Prudhomme O’Meara Wendy
Published: May 2024

The human infectious reservoir ofPlasmodium falciparumis governed by transmission efficiency during vector-human contact and mosquito biting preferences. Understanding biting bias in a natural setting can help target interventions to interrupt transmission. In a 15-month cohort in western Kenya, we detectedP. falciparumin indoor-restingAnophelesand human blood samples by qPCR and matched mosquito bloodmeals to cohort participants using short-tandem repeat genotyping. Using risk factor analyses and discrete choice models, we assessed mosquito biting behavior with respect to parasite transmission. Biting was highly unequal; 20% of people received 86% of bites. Biting rates were higher on males (biting rate ratio (BRR): 1.68; CI: 1.28–2.19), children 5–15 years (BRR: 1.49; CI: 1.13–1.98), andP. falciparum-infected individuals (BRR: 1.25; CI: 1.01–1.55). In aggregate,P. falciparum-infected school-age (5–15 years) boys accounted for 50% of bites potentially leading to onward transmission and had an entomological inoculation rate 6.4x higher than any other group. Additionally, infectious mosquitoes were nearly 3x more likely than non-infectious mosquitoes to biteP. falciparum-infected individuals (relative risk ratio 2.76, 95% CI 1.65–4.61). Thus, persistentP. falciparumtransmission was characterized by disproportionate onward transmission from school-age boys and by the preference of infected mosquitoes to feed upon infected people.
CO electrolysis to multicarbon products over grain boundary-rich Cu nanoparticles in membrane electrode assembly electrolyzers
Authors: Li Hefei , Wei Pengfei , Liu Tianfu , Li Mingrun , Wang Chao , Li Rongtan , Ye Jinyu , Zhou Zhi-You , Sun Shi-Gang , Fu Qiang , Gao Dunfeng , Wang Guoxiong , Bao Xinhe
Published: May 2024

Producing valuable chemicals like ethylene via catalytic carbon monoxide conversion is an important nonpetroleum route. Here we demonstrate an electrochemical route for highly efficient synthesis of multicarbon (C2+) chemicals from CO. We achieve a C2+ partial current density as high as 4.35 ± 0.07 A cm−2 at a low cell voltage of 2.78 ± 0.01 V over a grain boundary-rich Cu nanoparticle catalyst in an alkaline membrane electrode assembly (MEA) electrolyzer, with a C2+ Faradaic efficiency of 87 ± 1% and a CO conversion of 85 ± 3%. Operando Raman spectroscopy and density functional theory calculations reveal that the grain boundaries of Cu nanoparticles facilitate CO adsorption and C − C coupling, thus rationalizing a qualitative trend between C2+ production and grain boundary density. A scale-up demonstration using an electrolyzer stack with five 100 cm2 MEAs achieves high C2+ and ethylene formation rates of 118.9 mmol min−1 and 1.2 L min−1, respectively, at a total current of 400 A (4 A cm−2) with a C2+ Faradaic efficiency of 64%.
The cage effect of electron beam irradiation damage in cryo-electron microscopy
Authors: Li Yi , Kang Dong-Dong , Dai Jia-Yu , Wang Lin-Wang
Published: May 2024

Electron beam irradiation can cause damage to biological and organic samples, as determined via transmission electron microscopy (TEM). Cryo-electron microscopy (cryo-EM) significantly reduces such damage by quickly freezing the environmental water around organic molecules. However, there are multiple hypotheses about the mechanism of cryo-protection in cryo-EM. A lower temperature can cause less molecular dissociation in the first stage, or frozen water can have a “cage” effect by preventing the dissociated fragments from flying away. In this work, we use real-time time-dependent density functional theory molecular dynamics(rt-TDDFT-MD) simulations to study the related dynamics. We use our recently developed natural orbital branching (NOB) algorithm to describe the molecular dissociation process after the molecule is ionized. We find that despite the difference in surrounding water molecules at different temperatures, the initial dissociation process is similar. On the other hand, the dissociated fragments fly away at room temperature, while they remain in the same cage when frozen water is used. Our results provide direct support for the cage effect mechanism.
A brief tablet-based intervention benefits linguistic and communicative abilities in toddlers and preschoolers
Authors: Peña Marcela , Vásquez-Venegas Constanza , Cortés Patricia , Pittaluga Enrica , Herrera Mitzy , Pino Esteban J. , Escobar Raul G. , Dehaene-Lambertz Ghislaine , Guevara Pamela
Published: May 2024

Young children’s linguistic and communicative abilities are foundational for their academic achievement and overall well-being. We present the positive outcomes of a brief tablet-based intervention aimed at teaching toddlers and preschoolers new word-object and letter-sound associations. We conducted two experiments, one involving toddlers ( ~ 24 months old, n = 101) and the other with preschoolers ( ~ 42 months old, n = 152). Using a pre-post equivalent group design, we measured the children’s improvements in language and communication skills resulting from the intervention. Our results showed that the intervention benefited toddlers’ verbal communication and preschoolers’ speech comprehension. Additionally, it encouraged vocalizations in preschoolers and enhanced long-term memory for the associations taught in the study for all participants. In summary, our study demonstrates that the use of a ludic tablet-based intervention for teaching new vocabulary and pre-reading skills can improve young children’s linguistic and communicative abilities, which are essential for future development.
Global high-resolution growth projections dataset for rooftop area consistent with the shared socioeconomic pathways, 2020–2050
Authors: Joshi Siddharth , Zakeri Behnam , Mittal Shivika , Mastrucci Alessio , Holloway Paul , Krey Volker , Shukla Priyadarshi Ramprasad , O’Gallachoir Brian , Glynn James
Published: May 2024

Assessment of current and future growth in the global rooftop area is important for understanding and planning for a robust and sustainable decentralised energy system. These estimates are also important for urban planning studies and designing sustainable cities thereby forwarding the ethos of the Sustainable Development Goals 7 (clean energy), 11 (sustainable cities), 13 (climate action) and 15 (life on land). Here, we develop a machine learning framework that trains on big data containing ~700 million open-source building footprints, global land cover, road, and population datasets to generate globally harmonised estimates of growth in rooftop area for five different future growth narratives covered by Shared Socioeconomic Pathways. The dataset provides estimates for ~3.5 million fishnet tiles of 1/8 degree spatial resolution with data on gross rooftop area for five growth narratives covering years 2020–2050 in decadal time steps. This single harmonised global dataset can be used for climate change, energy transition, biodiversity, urban planning, and disaster risk management studies covering continental to conurbation geospatial levels.
A large-scale multivariate soccer athlete health, performance, and position monitoring dataset
Authors: Midoglu Cise , Kjæreng Winther Andreas , Boeker Matthias , Dahl Pettersen Susann , Pedersen Sigurd , Ragab Nourhan , Kupka Tomas , Hicks Steven A. , Bredsgaard Randers Morten , Jain Ramesh , Dagenborg Håvard J. , Pettersen Svein Arne , Johansen Dag , Riegler Michael A. , Halvorsen Pål
Published: May 2024

Data analysis for athletic performance optimization and injury prevention is of tremendous interest to sports teams and the scientific community. However, sports data are often sparse and hard to obtain due to legal restrictions, unwillingness to share, and lack of personnel resources to be assigned to the tedious process of data curation. These constraints make it difficult to develop automated systems for analysis, which require large datasets for learning. We therefore present SoccerMon, the largest soccer athlete dataset available today containing both subjective and objective metrics, collected from two different elite women’s soccer teams over two years. Our dataset contains 33,849 subjective reports and 10,075 objective reports, the latter including over six billion GPS position measurements. SoccerMon can not only play a valuable role in developing better analysis and prediction systems for soccer, but also inspire similar data collection activities in other domains which can benefit from subjective athlete reports, GPS position information, and/or time-series data in general.
Time-of-Flight MRA of Intracranial Aneurysms with Interval Surveillance, Clinical Segmentation and Annotations
Authors: de Nys Chloe M. , Liang Ee Shern , Prior Marita , Woodruff Maria A. , Novak James I. , Murphy Ashley R. , Li Zhiyong , Winter Craig D. , Allenby Mark C.
Published: May 2024

Intracranial aneurysms (IAs) are present in 2–6% of the global population and can be catastrophic upon rupture with a mortality rate of 30–50%. IAs are commonly detected through time-of-flight magnetic resonance angiography (TOF-MRA), however, this data is rarely available for research and training purposes. The provision of imaging resources such as TOF-MRA images is imperative to develop new strategies for IA detection, rupture prediction, and surgical training. To support efforts in addressing data availability bottlenecks, we provide an open-access TOF-MRA dataset comprising 63 patients, of which 24 underwent interval surveillance imaging by TOF-MRA. Patient scans were evaluated by a neuroradiologist, providing aneurysm and vessel segmentations, clinical annotations, 3D models, in addition to 3D Slicer software environments containing all this data for each patient. This dataset is the first to provide interval surveillance imaging for supporting the understanding of IA growth and stability. This dataset will support computational and experimental research into IA dynamics and assist surgical and radiology training in IA treatment.
Direct comparison of mass cytometry and single-cell RNA sequencing of human peripheral blood mononuclear cells
Authors: Su Emily Y. , Fread Kristen , Goggin Sarah , Zunder Eli R. , Cahan Patrick
Published: May 2024

Single-cell methods offer a high-resolution approach for characterizing cell populations. Many studies rely on single-cell transcriptomics to draw conclusions regarding cell state and behavior, with the underlying assumption that transcriptomic readouts largely parallel their protein counterparts and subsequent activity. However, the relationship between transcriptomic and proteomic measurements is imprecise, and thus datasets that probe the extent of their concordance will be useful to refine such conclusions. Additionally, novel single-cell analysis tools often lack appropriate gold standard datasets for the purposes of assessment. Integrative (combining the two data modalities) and predictive (using one modality to improve results from the other) approaches in particular, would benefit from transcriptomic and proteomic data from the same sample of cells. For these reasons, we performed single-cell RNA sequencing, mass cytometry, and flow cytometry on a split-sample of human peripheral blood mononuclear cells. We directly compare the proportions of specific cell types resolved by each technique, and further describe the extent to which protein and mRNA measurements correlate within distinct cell types.
Chromosome-level genome assembly and annotation of the cold-water species Ophiura sarsii
Authors: Han Chen , Zhang Qian , Li Yixuan , Sun Yuyao , Dong Yue , Ge Meiling , Li Zhong , Hu Xuying , Liu Bing , Zhang Xuelei , Wang Zongling , Xu Qinzeng
Published: May 2024

The cold-water species Ophiura sarsii, a brittle star, is a key echinoderm in the Arctic continental shelf region, highly sensitive to climate change. However, the absence of a high-quality genome has hindered a thorough understanding of its adaptive evolution. In this study, we reported the first chromosome-level genome assembly of O. sarsii. The genome assembly totalled 1.57 Gb, encompassing 19 chromosomes with a GC content of 37.11% and a scaffold N50 length of 78.03 Mb. The Benchmarking Universal Single-Copy Orthologs (BUSCO) assessment yielded a completeness estimate of 93.5% for this assembly. We predicted a total of 27,099 protein-coding genes, with 25,079 functionally annotated. The genome was comprised of 58.09% transposable elements. This chromosome-level genome of O. sarsii contributes to our understanding of the origin and evolution of marine organisms.
Structural, radiation shielding, thermal and dynamic mechanical analysis for waste rubber/EPDM rubber composite loaded with Fe2O3 for green environment
Authors: AbdelKader M. M. , Abou-Laila M. T. , El-Deeb M. S. S. , Taha Eman O. , El-Deeb A. S.
Published: May 2024

Increasing waste rubber recycling produces a specious range of products for many valuable applications. Waste Rubber/EPDM composite with different concentrations was prepared. Infrared spectroscopy (FTIR) is used to identify the chemical composition. A water absorption test, Dynamic mechanical analysis (DMA), and Thermal Gravimetric Analysis (TGA) were performed. The (75/25) WR/EPDM rubber composite exhibited the best behavior with the highest mechanical performance. Fe2O3 was added to (75/25) WR/EPDM rubber composite. Water absorption, FTIR, TGA, and DMA were investigated. The composite performance was improved with increasing Fe2O3 content. The linear attenuation coefficients (μ) were also measured as a function of the concentrations of Fe2O3 for γ-ray energy 662 keV by using 137Cs point source; the radiation shielding can be denoted by numbers of parameters like mass attenuation coefficient (μm), half value layer (HVL), Tenth value layer TVL and radiation protection efficiency (RPE%), radiation protection efficiency increased as Fe2O3 increased.
Salvianolic acid A inhibits ferroptosis and protects against intracerebral hemorrhage
Authors: Shi Yunpeng , Yan Dongdong , Nan Chengrui , Sun Zhimin , Zhuo Yayu , Huo Haoran , Jin Qianxu , Yan Hongshan , Zhao Zongmao
Published: May 2024

Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein–protein interactions (PPIs). Find the specific mechanism of SAA acting on ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 μM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that AKT (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3β/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the AKT inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting ferroptosis was activating the Akt/GSK-3β/Nrf2 signaling pathway.