bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incorporation of Sub‐Resolution Porosity Into Two‐Phase Flow Models With a Multiscale Pore Network for Complex Microporous Rocks
Authors: Foroughi Sajjad , Bijeljic Branko , Gao Ying , Blunt Martin J. 
Published: April 2024

AbstractPorous materials, such as carbonate rocks, frequently have pore sizes which span many orders of magnitude. This is a challenge for models that rely on an image of the pore space, since much of the pore space may be unresolved. In this work, sub‐resolution porosity in X‐ray images is characterized using differential imaging which quantifies the difference between a dry scan and 30 wt% potassium iodide brine saturated images. Once characterized, we develop a robust workflow to incorporate the sub‐resolution pore space into a network model using Darcy‐type elements called microlinks. Each grain voxel with sub‐resolution porosity is assigned to the two nearest resolved pores using an automatic dilation algorithm. By including these microlinks with empirical models in flow modeling, we simulate single‐phase and multiphase flow. By fine‐tuning the microlink empirical models, we match permeability, formation factor (the ratio of the resistivity of a rock filled with brine to the resistivity of that brine), and drainage capillary pressure to experimental results. We then show that our model can successfully predict steady‐state relative permeability measurements on a water‐wet Estaillades carbonate sample within the uncertainty of the experiments and modeling. Our approach of incorporating sub‐resolution porosity in two‐phase flow modeling using image‐based multiscale pore network techniques can capture complex pore structures and accurately predict flow behavior in porous materials with a wide range of pore size.
High frequency deep brain stimulation of the dorsal raphe nucleus prevents methamphetamine priming-induced reinstatement of drug seeking in rats
Authors: Zhang Libo , Meng Shiqiu , Huang Enze , Di Tianqi , Ding Zengbo , Huang Shihao , Chen Wenjun , Zhang Jiayi , Zhao Shenghong , Yuwen Ting , Chen Yang , Xue Yanxue , Wang Feng , Shi Jie , Shi Yu 
Published: April 2024

AbstractDrug addiction represents a multifaceted and recurrent brain disorder that possesses the capability to create persistent and ineradicable pathological memory. Deep brain stimulation (DBS) has shown a therapeutic potential for neuropsychological disorders, while the precise stimulation targets and therapeutic parameters for addiction remain deficient. Among the crucial brain regions implicated in drug addiction, the dorsal raphe nucleus (DRN) has been found to exert an essential role in the manifestation of addiction memory. Thus, we investigated the effects of DRN DBS in the treatment of addiction and whether it might produce side effects by a series of behavioral assessments, including methamphetamine priming-induced reinstatement of drug seeking behaviors, food-induced conditioned place preference (CPP), open field test and elevated plus-maze test, and examined brain activity and connectivity after DBS of DRN. We found that high-frequency DBS of the DRN significantly lowered the CPP scores and the number of active-nosepokes in the methamphetamine-primed CPP test and the self-administration model. Moreover, both high-frequency and sham DBS group rats were able to establish significant food-induced place preference, and no significant difference was observed in the open field test and in the elevated plus-maze test between the two groups. Immunofluorescence staining and functional magnetic resonance imaging revealed that high-frequency DBS of the DRN could alter the activity and functional connectivity of brain regions related to addiction. These results indicate that high-frequency DBS of the DRN effectively inhibits methamphetamine priming-induced relapse and seeking behaviors in rats and provides a new target for the treatment of drug addiction.
Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression
Authors: Cui Zhao , Li Caifeng , Liu Wei , Sun Mo , Deng Shiwen , Cao Junxian , Yang Hongjun , Chen Peng 
Published: April 2024

AbstractIsochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1–α-KG–HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.
Glacial isostatic adjustment reduces past and future Arctic subsea permafrost
Authors: Creel Roger C. , Miesner Frederieke , Wilkenskjeld Stiig , Austermann Jacqueline , Overduin Pier Paul 
Published: April 2024

AbstractSea-level rise submerges terrestrial permafrost in the Arctic, turning it into subsea permafrost. Subsea permafrost underlies ~ 1.8 million km2 of Arctic continental shelf, with thicknesses in places exceeding 700 m. Sea-level variations over glacial-interglacial cycles control subsea permafrost distribution and thickness, yet no permafrost model has accounted for glacial isostatic adjustment (GIA), which deviates local sea level from the global mean due to changes in ice and ocean loading. Here we incorporate GIA into a pan-Arctic model of subsea permafrost over the last 400,000 years. Including GIA significantly reduces present-day subsea permafrost thickness, chiefly because of hydro-isostatic effects as well as deformation related to Northern Hemisphere ice sheets. Additionally, we extend the simulation 1000 years into the future for emissions scenarios outlined in the Intergovernmental Panel on Climate Change’s sixth assessment report. We find that subsea permafrost is preserved under a low emissions scenario but mostly disappears under a high emissions scenario.
Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
Authors: Blomgren Linnea K. M. , Huber Melanie , Mackinnon Sabrina R. , Bürer Céline , Baslé Arnaud , Yue Wyatt W. , Froese D. Sean , McCorvie Thomas J. 
Published: April 2024

Abstract5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor s-adenosyl-l-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. Here we determine the cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product s-adenosyl-l-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.
Trace gas oxidation sustains energy needs of a thermophilic archaeon at suboptimal temperatures
Authors: Leung Pok Man , Grinter Rhys , Tudor-Matthew Eve , Lingford James P. , Jimenez Luis , Lee Han-Chung , Milton Michael , Hanchapola Iresha , Tanuwidjaya Erwin , Kropp Ashleigh , Peach Hanna A. , Carere Carlo R. , Stott Matthew B. , Schittenhelm Ralf B. , Greening Chris 
Published: April 2024

AbstractDiverse aerobic bacteria use atmospheric hydrogen (H2) and carbon monoxide (CO) as energy sources to support growth and survival. Such trace gas oxidation is recognised as a globally significant process that serves as the main sink in the biogeochemical H2cycle and sustains microbial biodiversity in oligotrophic ecosystems. However, it is unclear whether archaea can also use atmospheric H2. Here we show that a thermoacidophilic archaeon,Acidianus brierleyi(Thermoproteota), constitutively consumes H2and CO to sub-atmospheric levels. Oxidation occurs across a wide range of temperatures (10 to 70 °C) and enhances ATP production during starvation-induced persistence under temperate conditions. The genome ofA. brierleyiencodes a canonical CO dehydrogenase and four distinct [NiFe]-hydrogenases, which are differentially produced in response to electron donor and acceptor availability. Another archaeon,Metallosphaera sedula, can also oxidize atmospheric H2. Our results suggest that trace gas oxidation is a common trait of Sulfolobales archaea and may play a role in their survival and niche expansion, including during dispersal through temperate environments.
An experimental framework to assess biomolecular condensates in bacteria
Authors: Hoang Y , Azaldegui Christopher A. , Dow Rachel E. , Ghalmi Maria , Biteen Julie S. , Vecchiarelli Anthony G. 
Published: April 2024

AbstractHigh-resolution imaging of biomolecular condensates in living cells is essential for correlating their properties to those observed through in vitro assays. However, such experiments are limited in bacteria due to resolution limitations. Here we present an experimental framework that probes the formation, reversibility, and dynamics of condensate-forming proteins in Escherichia coli as a means to determine the nature of biomolecular condensates in bacteria. We demonstrate that condensates form after passing a threshold concentration, maintain a soluble fraction, dissolve upon shifts in temperature and concentration, and exhibit dynamics consistent with internal rearrangement and exchange between condensed and soluble fractions. We also discover that an established marker for insoluble protein aggregates, IbpA, has different colocalization patterns with bacterial condensates and aggregates, demonstrating its potential applicability as a reporter to differentiate the two in vivo. Overall, this framework provides a generalizable, accessible, and rigorous set of experiments to probe the nature of biomolecular condensates on the sub-micron scale in bacterial cells.
An ensemble penalized regression method for multi-ancestry polygenic risk prediction
Authors: Zhang Jingning , Zhan Jianan , Jin Jin , Ma Cheng , Zhao Ruzhang , O’Connell Jared , Jiang Yunxuan ,   23andMe Research Team, Koelsch Bertram L. , Zhang Haoyu , Chatterjee Nilanjan 
Published: April 2024

AbstractGreat efforts are being made to develop advanced polygenic risk scores (PRS) to improve the prediction of complex traits and diseases. However, most existing PRS are primarily trained on European ancestry populations, limiting their transferability to non-European populations. In this article, we propose a novel method for generating multi-ancestry Polygenic Risk scOres based on enSemble of PEnalized Regression models (PROSPER). PROSPER integrates genome-wide association studies (GWAS) summary statistics from diverse populations to develop ancestry-specific PRS with improved predictive power for minority populations. The method uses a combination of $${{{{{{\mathscr{L}}}}}}}_{1}$$

L

1

(lasso) and $${{{{{{\mathscr{L}}}}}}}_{2}$$

L

2

(ridge) penalty functions, a parsimonious specification of the penalty parameters across populations, and an ensemble step to combine PRS generated across different penalty parameters. We evaluate the performance of PROSPER and other existing methods on large-scale simulated and real datasets, including those from 23andMe Inc., the Global Lipids Genetics Consortium, and All of Us. Results show that PROSPER can substantially improve multi-ancestry polygenic prediction compared to alternative methods across a wide variety of genetic architectures. In real data analyses, for example, PROSPER increased out-of-sample prediction R2 for continuous traits by an average of 70% compared to a state-of-the-art Bayesian method (PRS-CSx) in the African ancestry population. Further, PROSPER is computationally highly scalable for the analysis of large SNP contents and many diverse populations.
Sm-like protein Rof inhibits transcription termination factor ρ by binding site obstruction and conformational insulation
Authors: Said Nelly , Finazzo Mark , Hilal Tarek , Wang Bing , Selinger Tim Luca , Gjorgjevikj Daniela , Artsimovitch Irina , Wahl Markus C. 
Published: April 2024

AbstractTranscription termination factor ρ is a hexameric, RNA-dependent NTPase that can adopt active closed-ring and inactive open-ring conformations. The Sm-like protein Rof, a homolog of the RNA chaperone Hfq, inhibits ρ-dependent termination in vivo but recapitulation of this activity in vitro has proven difficult and the precise mode of Rof action is presently unknown. Here, our cryo-EM structures of ρ-Rof and ρ-RNA complexes show that Rof undergoes pronounced conformational changes to bind ρ at the protomer interfaces, undercutting ρ conformational dynamics associated with ring closure and occluding extended primary RNA-binding sites that are also part of interfaces between ρ and RNA polymerase. Consistently, Rof impedes ρ ring closure, ρ-RNA interactions and ρ association with transcription elongation complexes. Structure-guided mutagenesis coupled with functional assays confirms that the observed ρ-Rof interface is required for Rof-mediated inhibition of cell growth and ρ-termination in vitro. Bioinformatic analyses reveal that Rof is restricted to Pseudomonadota and that the ρ-Rof interface is conserved. Genomic contexts of rof differ between Enterobacteriaceae and Vibrionaceae, suggesting distinct modes of Rof regulation. We hypothesize that Rof and other cellular anti-terminators silence ρ under diverse, but yet to be identified, stress conditions when unrestrained transcription termination by ρ may be detrimental.
Hybridizing carbonate and ether at molecular scales for high-energy and high-safety lithium metal batteries
Authors: Chen Jiawei , Zhang Daoming , Zhu Lei , Liu Mingzhu , Zheng Tianle , Xu Jie , Li Jun , Wang Fei , Wang Yonggang , Dong Xiaoli , Xia Yongyao 
Published: April 2024

AbstractCommonly-used ether and carbonate electrolytes show distinct advantages in active lithium-metal anode and high-voltage cathode, respectively. While these complementary characteristics hold promise for energy-dense lithium metal batteries, such synergy cannot be realized solely through physical blending. Herein, a linear functionalized solvent, bis(2-methoxyethyl) carbonate (BMC), is conceived by intramolecularly hybridizing ethers and carbonates. The integration of the electron-donating ether group with the electron-withdrawing carbonate group can rationalizes the charge distribution, imparting BMC with notable oxidative/reductive stability and relatively weak solvation ability. Furthermore, BMC also offers advantages including the ability to slightly dissolve LiNO3, excellent thermostability and nonflammability. Consequently, the optimized BMC-based electrolyte, even with typical concentrations in the single solvent, demonstrates high-voltage tolerance (4.4 V) and impressive Li plating/stripping Coulombic efficiency (99.4%). Moreover, it fulfills practical lithium metal batteries with satisfactory cycling performance and exceptional tolerance towards thermal/mechanical abuse, showcasing its suitability for safe high-energy lithium metal batteries.
KdpD is a tandem serine histidine kinase that controls K+ pump KdpFABC transcriptionally and post-translationally
Authors: Silberberg Jakob M. , Ketter Sophie , Böhm Paul J. N. , Jordan Kristin , Wittenberg Marcel , Grass Julia , Hänelt Inga 
Published: April 2024

AbstractTwo-component systems, consisting of a histidine kinase and a response regulator, serve signal transduction in bacteria, often regulating transcription in response to environmental stimuli. Here, we identify a tandem serine histidine kinase function for KdpD, previously described as a histidine kinase of the KdpDE two-component system, which controls production of the potassium pump KdpFABC. We show that KdpD additionally mediates an inhibitory serine phosphorylation of KdpFABC at high potassium levels, using not its C-terminal histidine kinase domain but an N-terminal atypical serine kinase domain. Sequence analysis of KdpDs from different species highlights that some KdpDs are much shorter than others. We show that, while Escherichia coli KdpD’s atypical serine kinase domain responds directly to potassium levels, a shorter version from Deinococcus geothermalis is controlled by second messenger cyclic di-AMP. Our findings add to the growing functional diversity of sensor kinases while simultaneously expanding the framework for regulatory mechanisms in bacterial potassium homeostasis.
Alkyne-tagged SERS nanoprobe for understanding Cu+ and Cu2+ conversion in cuproptosis processes
Authors: Zhang Sihan , Mei Yuxiao , Liu Jiaqi , Liu Zhichao , Tian Yang 
Published: April 2024

AbstractSimultaneously quantifying mitochondrial Cu+ and Cu2+ levels is crucial for evaluating the molecular mechanisms of copper accumulation-involved pathological processes. Here, a series of molecules containing various diacetylene derivatives as Raman reporters are designed and synthesized, and the alkyne-tagged SERS probe is created for determination Cu+ and Cu2+ with high selectivity and sensitivity. The developed SERS probe generates well-separated distinguishable Raman fingerprint peaks with built-in corrections in the cellular silent region, resulting in accurate quantification of Cu+ and Cu2+. The present probe demonstrates high tempo-spatial resolution for real-time imaging and simultaneously quantifying mitochondrial Cu+ and Cu2+ with long-term stability benefiting from the probe assembly with designed Au-C≡C groups. Using this powerful tool, it is found that mitochondrial Cu+ and Cu2+ increase during ischemia are associated with breakdown of proteins containing copper as well as conversion of Cu+ and Cu2+. Meanwhile, we observe that parts of Cu+ and Cu2+ are transported out of neurons by ATPase. More importantly, cuproptosis in neurons is found including the oxidative stress process caused by the conversion of Cu+ to Cu2+, which dominates at the early stage (<9 h), and subsequent proteotoxic stress. Both oxidative and proteotoxic stresses contribute to neuronal death.
X-ray-activated polymerization expanding the frontiers of deep-tissue hydrogel formation
Authors: Zhang Hailei , Tang Boyan , Zhang Bo , Huang Kai , Li Shanshan , Zhang Yuangong , Zhang Haisong , Bai Libin , Wu Yonggang , Cheng Yongqiang , Yang Yanmin , Han Gang 
Published: April 2024

AbstractPhoto-crosslinking polymerization stands as a fundamental pillar in the domains of chemistry, biology, and medicine. Yet, prevailing strategies heavily rely on ultraviolet/visible (UV/Vis) light to elicit in situ crosslinking. The inherent perils associated with UV radiation, namely the potential for DNA damage, coupled with the limited depth of tissue penetration exhibited by UV/Vis light, severely restrict the scope of photo-crosslinking within living organisms. Although near-infrared light has been explored as an external excitation source, enabling partial mitigation of these constraints, its penetration depth remains insufficient, particularly within bone tissues. In this study, we introduce an approach employing X-ray activation for deep-tissue hydrogel formation, surpassing all previous boundaries. Our approach harnesses a low-dose X-ray-activated persistent luminescent phosphor, triggering on demand in situ photo-crosslinking reactions and enabling the formation of hydrogels in male rats. A breakthrough of our method lies in its capability to penetrate deep even within thick bovine bone, demonstrating unmatched potential for bone penetration. By extending the reach of hydrogel formation within such formidable depths, our study represents an advancement in the field. This application of X-ray-activated polymerization enables precise and safe deep-tissue photo-crosslinking hydrogel formation, with profound implications for a multitude of disciplines.
Remote loop evolution reveals a complex biological function for chitinase enzymes beyond the active site
Authors: Kozome Dan , Sljoka Adnan , Laurino Paola 
Published: April 2024

AbstractLoops are small secondary structural elements that play a crucial role in the emergence of new enzyme functions. However, the evolutionary molecular mechanisms how proteins acquire these loop elements and obtain new function is poorly understood. To address this question, we study glycoside hydrolase family 19 (GH19) chitinase—an essential enzyme family for pathogen degradation in plants. By revealing the evolutionary history and loops appearance of GH19 chitinase, we discover that one loop which is remote from the catalytic site, is necessary to acquire the new antifungal activity. We demonstrate that this remote loop directly accesses the fungal cell wall, and surprisingly, it needs to adopt a defined structure supported by long-range intramolecular interactions to perform its function. Our findings prove that nature applies this strategy at the molecular level to achieve a complex biological function while maintaining the original activity in the catalytic pocket, suggesting an alternative way to design new enzyme function.
Diversity and potential host-interactions of viruses inhabiting deep-sea seamount sediments
Authors: Yu Meishun , Zhang Menghui , Zeng Runying , Cheng Ruolin , Zhang Rui , Hou Yanping , Kuang Fangfang , Feng Xuejin , Dong Xiyang , Li Yinfang , Shao Zongze , Jin Min 
Published: April 2024

AbstractSeamounts are globally distributed across the oceans and form one of the major oceanic biomes. Here, we utilized combined analyses of bulk metagenome and virome to study viral communities in seamount sediments in the western Pacific Ocean. Phylogenetic analyses and the protein-sharing network demonstrate extensive diversity and previously unknown viral clades. Inference of virus-host linkages uncovers extensive interactions between viruses and dominant prokaryote lineages, and suggests that viruses play significant roles in carbon, sulfur, and nitrogen cycling by compensating or augmenting host metabolisms. Moreover, temperate viruses are predicted to be prevalent in seamount sediments, which tend to carry auxiliary metabolic genes for host survivability. Intriguingly, the geographical features of seamounts likely compromise the connectivity of viral communities and thus contribute to the high divergence of viral genetic spaces and populations across seamounts. Altogether, these findings provides knowledge essential for understanding the biogeography and ecological roles of viruses in globally widespread seamounts.