bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategies of Green Industrial Policy: How States Position Firms in Global Supply Chains
Authors: ALLAN BENTLEY B. , NAHM JONAS
Published: May 2024

The resurgence of industrial policymaking—particularly for emerging low-carbon industries—challenges social science theories that expect such interventions from centralized states or suggest that different kinds of states specialize in various forms of innovation policy. Interventionist forms of industrial policy have made a comeback among liberal economies. Coordinated economies now make use of market-driven strategies. This paper argues that the new generation of industrial strategies is shaped by the industrial development challenges that policymakers face at the sectoral level. It proposes a new theoretical framework that distinguishes between the policy orientation (targeted or open-ended) and the central agents driving financial and technological decision-making (governments or firms). We show that the choice of strategy is shaped by the level of uncertainty and the position of the domestic industry in global supply chains, that is, whether global supply chains are emerging or mature and whether the domestic industry is an entrant or incumbent.
A new morphotype description of Arbacia spatuligera Valenciennes, 1846 (Arbacioida, Echinoidea) and bathymetric range extension from mesophotic reefs of the central coast of Chile
Authors: Moreno-Mendoza Rigoberto , Courville Erwan , Angeles-Gonzalez Luis Enrique , Duarte Julio , Carulla Marc , Malfanti-Bravo Daniel , Mena-Auladell Andrés , Saucède Thomas , Simões Nuno , Poulin Elie
Published: May 2024

The sea urchin Arbacia spatuligera is an echinoid distributed in the Southeastern Pacific Ocean from Peru to Chile. This species was previously reported from the subtidal zone with a bathymetric distribution up to 30 m depth. In this work, 128 individuals were found in four mesophotic reefs along the central coast off Chile using closed-circuit rebreathers in technical diving at higher depths than previously, ranging from 36 to 63 m in depth. A population exhibits unexpected morphological characters, requiring an emended diagnosis and description of a new morphotype for A. spatuligera. These morphological traits are further discussed as potential ecophenotypic adaptations.
Beyond the Politics of Fear: Machiavelli on Hope
Authors: Mitchell Colleen E.
Published: May 2024

Many Machiavelli scholars emphasize his discussion of fear and neglect the important role that hope plays in his thought. I analyze Machiavelli's frequent references to hope throughout his corpus to offer an explanation of what he means by ‘hope,” examine the relation between hope and fear, and identify the benefits, dangers, and limits of these two foundational and complementary passions. Greater attention to the role of hope in Machiavelli's thought can help us understand the significance of this passion for Machiavelli's political project, particularly his view of freedom.
Female bodies and dynastic legitimacy in the Nereid Monument at Xanthos
Authors: Kim Patricia Eunji
Published: May 2024

This article reassesses the so-called Nereid Monument (ca 380 BCE) at Xanthos in Lycia by focusing on the narrative and symbolic role of female figures within its sculptural programme. Constructed as the tomb for the Lycian dynast Erbbina, the monument has been noted for its over-human-size sculpture of Nereids, its historicising city-siege reliefs, as well as its spectacular fusion of visual and architectural styles, motifs and themes from various contexts throughout the Aegean and Anatolia. Building on this scholarship, I turn specifically to the monument’s innovative representations of non-mythological women in prominent areas of its visual programme: Erbbina’s dynastic consort and a distressed woman who is caught in the throes of military violence. By focusing on the role of female bodies in Erbbina’s funerary qua triumphal monument, I argue for the important narrative function of female bodies in articulating dynastic legitimacy and continuity. Finally, this article comments on the importance of femininity in addition to masculinity in dynastic expressions in the fourth century, thus anticipating major art-historical changes in the art of power at the beginning of the Hellenistic period.
Lifecycle HTA: promising applications and a framework for implementation. An HTAi Global Policy Forum Task Force report
Authors: Pichler Franz B. , Boysen Meindert , Mittmann Nicole , Gilardino Ramiro , Bruce Andrew , Bond Kenneth , Vreman Rick A. , Largeron Nathalie , Banhazi Judit , Ollendorf Daniel A. , Jain Mohit , Upadhyaya Sheela , Goettsch Wim G.
Published: May 2024

The 2022 Health Technology Assessment International (HTAi) Global Policy Forum (GPF) established the goal of developing a position statement and framework for lifecycle HTA (LC-HTA), through a Task Force leveraging multi-stakeholder monthly discussions and GPF member input. The Task Force developed a working definition: LC-HTA is a systematic process utilizing sequential HTA activities to inform decision making where the evidence base, the health technology itself, or the context in which it is applied, has a potential to meaningfully change at different points in its LC. Four key scenarios were identified where it was considered that an LC-HTA approach would add sufficient value to HTA bodies and their key stakeholders to justify the additional resource burden. Based on the four scenarios, a high-level LC-HTA framework was developed consisting of (i) defining the decision problem, (ii) sequencing of HTA activities, and (iii) developing optimization criteria. Subsequently, the Task Force developed operationalization guidance for LC-HTA in a companion paper.
Chemically induced cone degeneration in the 13-lined ground squirrel
Authors: Follett Hannah M. , Warr Emma , Grieshop Jenna , Yu Ching Tzu , Gaffney Mina , Bowie Owen R. , Lee Jong Won , Tarima Sergey , Merriman Dana K. , Carroll Joseph
Published: May 2024

Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.
The typical and atypical developing mind: a common model
Authors: Demetriou Andreas , Spanoudis George , Papadopoulos Timothy C.
Published: May 2024

We present a theory of atypical development based on a developmental theory of the typical mind integrating developmental, cognitive, and psychometric theory and research. The paper comprises three parts. First, it outlines the theory of typical development. The theory postulates central cognitive mechanisms, such as relational integration, executive and inferential processes, and domain-specific processes underlying different environmental relations, such as visuospatial or quantitative relations. Cognitive development advances in cycles satisfying developmental priorities in mastering these systems, such as executive control from 2–6 years, inferential control from 7–11 years, and truth control from 12–18 years. Second, we discuss atypical development, showing how each neurodevelopmental disorder emerges from deficiencies in one or more of the processes comprising the architecture of the mind. Deficiencies in relational integration mechanisms, together with deficiencies in social understanding, yield autism spectrum disorder. Deficiencies in executive processes yield attention-deficit and hyperactivity disorder. Deficiencies in symbolic representation yield specialized learning difficulties, such as dyslexia and dyscalculia. Finally, we discuss clinical and educational implications, suggesting the importance of early diagnosis of malfunctioning in each of these dimensions and specific programs for their remediation.
Regulating surrogacy intermediaries: a comparative analysis of regulatory approaches and implications in the Chinese context
Authors: Luo Yingyi
Published: May 2024

This article addresses the significant research gap concerning the regulation of surrogacy intermediaries in China’s rapidly growing surrogacy market. Employing a ‘law in context’ perspective, it explores the question of how to effectively regulate surrogacy intermediaries in the Chinese context. Situated within China’s unique socio-cultural landscape, where procreation carries profound significance, the study navigates the complexities of surrogacy regulation, including ethical dilemmas, rights infringements and regulatory ambiguities. The article advocates for the regulation of surrogacy in China to prevent possible exploitation, referencing three international models: prohibiting commercial surrogacy, governing non-profit surrogacy organisations and imposing duties on for-profit surrogacy agents. The aim is to construct a robust, context-sensitive regulatory framework for surrogacy in China, focusing on identifying suitable intermediaries and defining the scope of effective regulatory oversight.
Onset of Plate Motion in the Presence of Chemical Heterogeneities in the Mantle and the Effect of Mantle Temperature
Authors: Stein Claudia , Hansen Ulrich
Published: May 2024

Chemical heterogeneities of various origins have been observed in the Earth's mantle. Their assumed higher density acts on the style of mantle convection and therefore, as tectonic plates form the highly viscous upper boundary layer of mantle convection, the onset of surface motion is also affected by chemical heterogeneities. We perform 2D basally heated thermochemical mantle convection models which initially include layers of dense material at different mantle depths. In comparison to purely thermal convection models, the onset of first plate motion is delayed. This delay is even more pronounced, the deeper the location of dense material, the larger its volume and the higher its density. Additionally, we varied the starting temperature of our models. In an initially hot mantle, a strong temperature‐dependent viscosity contrast between the mantle and cold surface leads to a cold, highly viscous plate (stagnant lid). For an initially cold mantle, rising plumes first need to transport basal heat upwards to create a sufficient viscosity contrast. Consequently, the formation and subsequent breaking of the stagnant lid is delayed. Considering a hotter mantle after Earth's magma ocean phase, we find that plate motion can occur within approximately the first 0.5 Gyr of solid‐state convection if no chemical structures are present or for dense material situated at the surface. Deep chemical heterogeneities delay the onset by at least one order of magnitude. Furthermore, the early surface motion will have been more erratic than todays stable plate motion, probably with a few single subduction events.
On the Relative Importance of Buoyancy and Thickening of Aging Lithosphere in Mantle Upwelling and Crustal Production Beneath Global Mid‐Ocean Ridge System
Authors: Zha Caicai , Zhang Fan , Lin Jian , Zhang Tao , Tian Jinyu
Published: May 2024

Beneath mid‐ocean ridges, mantle upwelling and decompression melting are fundamental processes contributing to the formation of oceanic crust. Previous geodynamic models have suggested that mantle upwelling driven by separating plates can be intensified by thermochemical buoyancy and the thickening of aging lithosphere, resulting in thicker crust. However, the relative contributions of these factors to crustal accretion remain uncertain. We conducted numerical modeling in three scenarios to investigate this: (a) buoyant flow models incorporating age‐dependent lithospheric thickening as a reference; (b) passive flow models incorporating age‐dependent lithospheric thickening to isolate the effect of buoyancy; and (c) passive flow models that neglect age‐dependent lithospheric thickening to isolate its effect. Models are performed under varying potential mantle temperatures (Tp), viscosity structures, and spreading rates. The model‐predicted crustal thickness suggests that both buoyancy and thickening of aging lithosphere increasingly contribute to crustal production as spreading rate decreases. However, given the range of reference mantle viscosities examined here (1019–1020 Pa s), except in ultraslow spreading rates with lower reference viscosity and warmer Tp, the impact of the thickening of aging lithosphere predominates over buoyancy. Furthermore, the relative importance of buoyancy‐induced crustal production increases as spreading rates decrease. Variations in Tp further amplify the variability in crustal thickness compared to that at fast‐spreading ridges where passive upwelling dominates, when combined with 3‐D effects of buoyant flow on altering axial crustal production at ultraslow‐spreading ridge segments. This 4‐D effects of buoyant flow on melt production may explain the observed more variable crustal thickness at ultraslow‐spreading ridges.
Magnitude of and Hydroclimatic Controls on CO2 and CH4 Emissions in the Subtropical Monsoon Pearl River Basin
Authors: Chen Shuai , Ran Lishan , Zhong Jun , Liu Boyi , Yang Xiankun , Yang Ping , Tian Mingyang , Yang Qianqian , Li Si‐Liang , Yan Zhifeng , Fang Nufang
Published: May 2024

Rivers are important ecosystems for carbon emissions and play a crucial role in the global carbon cycle. However, CO2 and CH4 emissions from subtropical rivers are substantially under‐represented in global‐scale estimates. Here, we explored the regional patterns of riverine CO2 and CH4 dynamics in the Pearl River basin with a subtropical monsoon climate. We found that its CO2 and diffusive CH4 emissions showed a decreasing trend with increasing stream order. Seasonality in CO2 and diffusive CH4 emissions was primarily driven by variations in partial pressure of CO2 (pCO2) and CH4 (pCH4) and gas transfer velocities, which were strongly regulated by hydrology and climate. We further estimated the basin‐wide CO2 and diffusive CH4 fluxes at 17.8 ± 7.4 Tg C yr−1 and 191.5 ± 139.9 Gg C yr−1, respectively. When normalized to the water surface, the mean diffusive fluxes were 790.1 and 8.5 mmol m−2 d−1 for CO2 and CH4, respectively, which were 1.3 and 2.5 times higher than the global mean riverine CO2 and CH4 fluxes, respectively. This suggests that the global significance of subtropical rivers is probably underestimated because their substantially higher CH4 fluxes are unaccounted for. Furthermore, compared with measured pCO2, the alkalinity‐based pCO2 could introduce significant errors by 20% at ∼30% of the sampling sites, underscoring the necessity of direct measurements to reduce uncertainty. This study provides the first estimate of basin‐wide CO2 and diffusive CH4 emissions in the PRB through direct pCO2 and pCH4 measurements, and highlights the role of hydrologic and climatic factors in governing riverine carbon emissions.
On the Formation of Trapped Electron Radiation Belts at Ganymede
Authors: Liuzzo Lucas , Nénon Quentin , Poppe Andrew R. , Stahl Aaron , Simon Sven , Fatemi Shahab
Published: May 2024

This study presents evidence of stably trapped electrons at Jupiter's moon Ganymede. We model energetic electron pitch angle distributions and compare them to observations from the Galileo Energetic Particle Detector to identify signatures of trapped particles during the G28 encounter. We trace electron trajectories to show that they enter Ganymede's mini‐magnetospheric environment, become trapped, and drift around the moon for up to 30 min, in some cases stably orbiting the moon multiple times. Conservation of the first adiabatic invariant partially contributes to energy changes throughout the electrons' orbits, with additional acceleration driven by local electric fields, before they return to Jupiter's magnetosphere or impact the surface. These trapped particles manifest as an electron population with an enhanced flux compared to elsewhere within the mini‐magnetosphere that are detectable by future spacecraft.
Fundamentals for predicting transcriptional regulations from DNA sequence patterns
Authors: Koido Masaru , Tomizuka Kohei , Terao Chikashi
Published: May 2024

Cell-type-specific regulatory elements, cataloged through extensive experiments and bioinformatics in large-scale consortiums, have enabled enrichment analyses of genetic associations that primarily utilize positional information of the regulatory elements. These analyses have identified cell types and pathways genetically associated with human complex traits. However, our understanding of detailed allelic effects on these elements’ activities and on-off states remains incomplete, hampering the interpretation of human genetic study results. This review introduces machine learning methods to learn sequence-dependent transcriptional regulation mechanisms from DNA sequences for predicting such allelic effects (not associations). We provide a concise history of machine-learning-based approaches, the requirements, and the key computational processes, focusing on primers in machine learning. Convolution and self-attention, pivotal in modern deep-learning models, are explained through geometrical interpretations using dot products. This facilitates understanding of the concept and why these have been used for machine learning for DNA sequences. These will inspire further research in this genetics and genomics field.
m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling
Authors: Li Shujin , Feng Tian , Liu Yuantong , Yang Qichao , Song An , Wang Shuo , Xie Jun , Zhang Junjie , Yuan Bifeng , Sun Zhijun
Published: May 2024

N1-methyladenosine (m1A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels. Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.
Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks
Authors: Wohlfromm Fabian , Ivanisenko Nikita V. , Pietkiewicz Sabine , König Corinna , Seyrek Kamil , Kähne Thilo , Lavrik Inna N.
Published: May 2024

Procaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by the PRMT5/RIOK1/WD45 methylosome complex. Furthermore, two potential methylation sites of PRMT5 on procaspase-8, R233 and R435, were identified in silico. R233 and R435 are highly conserved in mammals and their point mutations are among the most common mutations of caspase-8 in cancer. The introduction of mutations at these positions resulted in inhibitory effects on CD95L-induced caspase-8 activity, effector caspase activation and apoptosis. In addition, we show that procaspase-8 can undergo symmetric di-methylation. Finally, the pharmacological inhibition of PRMT5 resulted in the inhibitory effects on caspase activity and apoptotic cell death. Taken together, we have unraveled the additional control checkpoint in procaspase-8 activation and the arginine methylation network in the extrinsic apoptosis pathway.
New evidence calls into question NICE's endocarditis prevention guidance
Authors: Thornhill Martin , Prendergast Bernard , Dayer Mark , Frisby Ash , Lockhart Peter , Baddour Larry M.
Published: May 2024

In 2008, National Institute for Health and Care Excellence (NICE) guidelines recommended against the use of antibiotic prophylaxis (AP) before invasive dental procedures (IDPs) to prevent infective endocarditis (IE). They did so because of lack of AP efficacy evidence and adverse reaction concerns. Consequently, NICE concluded AP was not cost-effective and should not be recommended. In 2015, NICE reviewed its guidance and continued to recommend against AP. However, it subsequently changed its wording to ‘antibiotic prophylaxis against infective endocarditis is not routinely recommended'. The lack of explanation of what constituted routinely (and not routinely), or how to manage non-routine patients, caused enormous confusion and NICE remained out of step with all major international guideline committees who continued to recommend AP for those at high risk.

Since the 2015 guideline review, new data have confirmed an association between IDPs and subsequent IE and demonstrated AP efficacy in reducing IE risk following IDPs in high-risk patients. New evidence also shows that in high-risk patients, the IE risk following IDPs substantially exceeds any adverse reaction risk, and that AP is therefore highly cost-effective. Given the new evidence, a NICE guideline review would seem appropriate so that UK high-risk patients can receive the same protection afforded high-risk patients in the rest of the world.
Integrating spatial and single-cell transcriptomics reveals tumor heterogeneity and intercellular networks in colorectal cancer
Authors: Xiao Jing , Yu Xinyang , Meng Fanlin , Zhang Yuncong , Zhou Wenbin , Ren Yonghong , Li Jingxia , Sun Yimin , Sun Hongwei , Chen Guokai , He Ke , Lu Ligong
Published: May 2024

Single cell RNA sequencing (scRNA-seq), a powerful tool for studying the tumor microenvironment (TME), does not preserve/provide spatial information on tissue morphology and cellular interactions. To understand the crosstalk between diverse cellular components in proximity in the TME, we performed scRNA-seq coupled with spatial transcriptomic (ST) assay to profile 41,700 cells from three colorectal cancer (CRC) tumor-normal-blood pairs. Standalone scRNA-seq analyses revealed eight major cell populations, including B cells, T cells, Monocytes, NK cells, Epithelial cells, Fibroblasts, Mast cells, Endothelial cells. After the identification of malignant cells from epithelial cells, we observed seven subtypes of malignant cells that reflect heterogeneous status in tumor, including tumor_CAV1, tumor_ATF3_JUN | FOS, tumor_ZEB2, tumor_VIM, tumor_WSB1, tumor_LXN, and tumor_PGM1. By transferring the cellular annotations obtained by scRNA-seq to ST spots, we annotated four regions in a cryosection from CRC patients, including tumor, stroma, immune infiltration, and colon epithelium regions. Furthermore, we observed intensive intercellular interactions between stroma and tumor regions which were extremely proximal in the cryosection. In particular, one pair of ligands and receptors (C5AR1 and RPS19) was inferred to play key roles in the crosstalk of stroma and tumor regions. For the tumor region, a typical feature of TMSB4X-high expression was identified, which could be a potential marker of CRC. The stroma region was found to be characterized by VIM-high expression, suggesting it fostered a stromal niche in the TME. Collectively, single cell and spatial analysis in our study reveal the tumor heterogeneity and molecular interactions in CRC TME, which provides insights into the mechanisms underlying CRC progression and may contribute to the development of anticancer therapies targeting on non-tumor components, such as the extracellular matrix (ECM) in CRC. The typical genes we identified may facilitate to new molecular subtypes of CRC.
Confidence of Emergency Department doctors in managing ophthalmic emergencies: a systematic review
Authors: Mendall Jessica , Tolley Abraham , Parisi Veronica , Hornby Stella , Brown Ruth , Nowak Victoria
Published: May 2024

Background

Eye emergencies constitute a significant portion of attendances to general Emergency Departments (EDs) in the UK, therefore it is important to assess the confidence of doctors who work in this setting in managing these potentially sight- and life-threatening presentations. This systematic review aims to assess the confidence of UK doctors working in general EDs in managing ophthalmic emergencies.

Methods

MEDLINE (Ovid), EMBASE (Ovid), ProQuest Central and Web of Science databases and grey literature were searched from inception to 1 October 2022 for publications that (1) featured doctors working in UK general EDs, (2) assessed doctors’ confidence in managing ophthalmic emergencies, (3) contained original data, (4) were full-text, and (5) written in English. Methodological quality was assessed using the AXIS tool.

Results

462 articles were screened, and 7 papers included for data extraction, which collectively assessed the confidence of 956 doctors working in EDs in managing ophthalmic emergencies. There was a widespread lack of confidence amongst foundation doctors, which has worsened over time. Most doctors lacked confidence in performing funduscopy and using the slit-lamp, and considered formal ophthalmology training received in EDs to be inadequate.

Conclusions

Evidence suggests a lack of confidence amongst foundation doctors in managing ophthalmic emergencies. High-quality evidence investigating the confidence amongst more experienced Emergency Medicine (EM) physicians was lacking. It is important to assess why foundation doctors feel so ill-prepared to manage eye emergencies and develop further ophthalmic training for doctors working in EDs. Further investigation exploring the confidence of EM trainees and consultants is required.
Single-photon detection using large-scale high-temperature MgB2 sensors at 20 K
Authors: Charaev Ilya , Batson Emma K. , Cherednichenko Sergey , Reidy Kate , Drakinskiy Vladimir , Yu Yang , Lara-Avila Samuel , Thomsen Joachim D. , Colangelo Marco , Incalza Francesca , Ilin Konstantin , Schilling Andreas , Berggren Karl K.
Published: May 2024

Ultra-fast single-photon detectors with high current density and operating temperature can benefit space and ground applications, including quantum optical communication systems, lightweight cryogenics for space crafts, and medical use. Here we demonstrate magnesium diboride (MgB2) thin-film superconducting microwires capable of single-photon detection at 1.55  μm optical wavelength. We used helium ions to alter the properties of MgB2, resulting in microwire-based detectors exhibiting single-photon sensitivity across a broad temperature range of up to 20 K, and detection efficiency saturation for 1  μm wide microwires at 3.7 K. Linearity of detection rate vs incident power was preserved up to at least 100 Mcps. Despite the large active area of up to 400 × 400 μm2, the reset time was found to be as low as ~ 1 ns. Our research provides possibilities for breaking the operating temperature limit and maximum single-pixel count rate, expanding the detector area, and raises inquiries about the fundamental mechanisms of single-photon detection in high-critical-temperature superconductors.
Genetic and functional diversity of β-N-acetylgalactosamine-targeting glycosidases expanded by deep-sea metagenome analysis
Authors: Sumida Tomomi , Hiraoka Satoshi , Usui Keiko , Ishiwata Akihiro , Sengoku Toru , Stubbs Keith A. , Tanaka Katsunori , Deguchi Shigeru , Fushinobu Shinya , Nunoura Takuro
Published: May 2024

β-N-Acetylgalactosamine-containing glycans play essential roles in several biological processes, including cell adhesion, signal transduction, and immune responses. β-N-Acetylgalactosaminidases hydrolyze β-N-acetylgalactosamine linkages of various glycoconjugates. However, their biological significance remains ambiguous, primarily because only one type of enzyme, exo-β-N-acetylgalactosaminidases that specifically act on β-N-acetylgalactosamine residues, has been documented to date. In this study, we identify four groups distributed among all three domains of life and characterize eight β-N-acetylgalactosaminidases and β-N-acetylhexosaminidase through sequence-based screening of deep-sea metagenomes and subsequent searching of public protein databases. Despite low sequence similarity, the crystal structures of these enzymes demonstrate that all enzymes share a prototype structure and have diversified their substrate specificities (oligosaccharide-releasing, oligosaccharide/monosaccharide-releasing, and monosaccharide-releasing) through the accumulation of mutations and insertional amino acid sequences. The diverse β-N-acetylgalactosaminidases reported in this study could facilitate the comprehension of their structures and functions and present evolutionary pathways for expanding their substrate specificity.
The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis
Authors: Cooreman Michael P. , Butler Javed , Giugliano Robert P. , Zannad Faiez , Dzen Lucile , Huot-Marchand Philippe , Baudin Martine , Beard Daniel R. , Junien Jean-Louis , Broqua Pierre , Abdelmalek Manal F. , Francque Sven M.
Published: May 2024

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.
Rapid expansion and international spread of M1UK in the post-pandemic UK upsurge of Streptococcus pyogenes
Authors: Vieira Ana , Wan Yu , Ryan Yan , Li Ho Kwong , Guy Rebecca L. , Papangeli Maria , Huse Kristin K. , Reeves Lucy C. , Soo Valerie W. C. , Daniel Roger , Harley Alessandra , Broughton Karen , Dhami Chenchal , Ganner Mark , Ganner Marjorie A. , Mumin Zaynab , Razaei Maryam , Rundberg Emma , Mammadov Rufat , Mills Ewurabena A. , Sgro Vincenzo , Mok Kai Yi , Didelot Xavier , Croucher Nicholas J. , Jauneikaite Elita , Lamagni Theresa , Brown Colin S. , Coelho Juliana , Sriskandan Shiranee
Published: May 2024

The UK observed a marked increase in scarlet fever and invasive group A streptococcal infection in 2022 with severe outcomes in children and similar trends worldwide. Here we report lineage M1UK to be the dominant source of invasive infections in this upsurge. Compared with ancestral M1global strains, invasive M1UK strains exhibit reduced genomic diversity and fewer mutations in two-component regulator genes covRS. The emergence of M1UK is dated to 2008. Following a bottleneck coinciding with the COVID-19 pandemic, three emergent M1UK clades underwent rapid nationwide expansion, despite lack of detection in previous years. All M1UK isolates thus-far sequenced globally have a phylogenetic origin in the UK, with dispersal of the new clades in Europe. While waning immunity may promote streptococcal epidemics, the genetic features of M1UK point to a fitness advantage in pathogenicity, and a striking ability to persist through population bottlenecks.
Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus
Authors: Benjamin Kynon J. M. , Arora Ria , Feltrin Arthur S. , Pertea Geo , Giles Hunter H. , Stolz Joshua M. , D’Ignazio Laura , Collado-Torres Leonardo , Shin Joo Heon , Ulrich William S. , Hyde Thomas M. , Kleinman Joel E. , Weinberger Daniel R. , Paquola Apuã C. M. , Erwin Jennifer A.
Published: May 2024

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.
Unconventional superconductivity without doping in infinite-layer nickelates under pressure
Authors: Di Cataldo Simone , Worm Paul , Tomczak Jan M. , Si Liang , Held Karsten
Published: May 2024

High-temperature unconventional superconductivity quite generically emerges from doping a strongly correlated parent compound, often (close to) an antiferromagnetic insulator. The recently developed dynamical vertex approximation is a state-of-the-art technique that has quantitatively predicted the superconducting dome of nickelates. Here, we apply it to study the effect of pressure in the infinite-layer nickelate SrxPr1−xNiO2. We reproduce the increase of the critical temperature (Tc) under pressure found in experiment up to 12 GPa. According to our results, Tc can be further increased with higher pressures. Even without Sr-doping the parent compound, PrNiO2, will become a high-temperature superconductor thanks to a strongly enhanced self-doping of the Ni $${d}_{{x}^{2}-{y}^{2}}$$

d

x

2

−

y

2

orbital under pressure. With a maximal Tc of 100 K around 100 GPa, nickelate superconductors can reach that of the best cuprates.
High carbon dioxide emissions from Australian estuaries driven by geomorphology and climate
Authors: Yeo Jacob Z.-Q. , Rosentreter Judith A. , Oakes Joanne M. , Schulz Kai G. , Eyre Bradley D.
Published: May 2024

Estuaries play an important role in connecting the global carbon cycle across the land-to-ocean continuum, but little is known about Australia’s contribution to global CO2 emissions. Here we present an Australia-wide assessment, based on CO2 concentrations for 47 estuaries upscaled to 971 assessed Australian estuaries. We estimate total mean (±SE) estuary CO2 emissions of 8.67 ± 0.54 Tg CO2-C yr−1, with tidal systems, lagoons, and small deltas contributing 94.4%, 3.1%, and 2.5%, respectively. Although higher disturbance increased water-air CO2 fluxes, its effect on total Australian estuarine CO2 emissions was small due to the large surface areas of low and moderately disturbed tidal systems. Mean water-air CO2 fluxes from Australian small deltas and tidal systems were higher than from global estuaries because of the dominance of macrotidal subtropical and tropical systems in Australia, which have higher emissions due to lateral inputs. We suggest that global estuarine CO2 emissions should be upscaled based on geomorphology, but should also consider land-use disturbance, and climate.
The translocation of a chloride channel from the Golgi to the plasma membrane helps plants adapt to salt stress
Authors: Rajappa Sivamathini , Krishnamurthy Pannaga , Huang Hua , Yu Dejie , Friml Jiří , Xu Jian , Kumar Prakash P.
Published: May 2024

A key mechanism employed by plants to adapt to salinity stress involves maintaining ion homeostasis via the actions of ion transporters. While the function of cation transporters in maintaining ion homeostasis in plants has been extensively studied, little is known about the roles of their anion counterparts in this process. Here, we describe a mechanism of salt adaptation in plants. We characterized the chloride channel (CLC) gene AtCLCf, whose expression is regulated by WRKY transcription factor under salt stress in Arabidopsis thaliana. Loss-of-function atclcf seedlings show increased sensitivity to salt, whereas AtCLCf overexpression confers enhanced resistance to salt stress. Salt stress induces the translocation of GFP-AtCLCf fusion protein to the plasma membrane (PM). Blocking AtCLCf translocation using the exocytosis inhibitor brefeldin-A or mutating the small GTPase gene AtRABA1b/BEX5 (RAS GENES FROM RAT BRAINA1b homolog) increases salt sensitivity in plants. Electrophysiology and liposome-based assays confirm the Cl−/H+ antiport function of AtCLCf. Therefore, we have uncovered a mechanism of plant adaptation to salt stress involving the NaCl-induced translocation of AtCLCf to the PM, thus facilitating Cl− removal at the roots, and increasing the plant’s salinity tolerance.
A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues
Authors: Yan Ze , Yang Ji , Wei Wen-Tian , Zhou Ming-Liang , Mo Dong-Xin , Wan Xing , Ma Rui , Wu Mei-Ming , Huang Jia-Hui , Liu Ya-Jing , Lv Feng-Hua , Li Meng-Hua
Published: May 2024

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.
Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries
Authors: Kakaraskoska Boceska Biljana , Vilken Tuba , Xavier Basil Britto , Kostyanev Tomislav , Lin Qiang , Lammens Christine , Ellis Sally , O’Brien Seamus , da Costa Renata Maria Augusto , Cook Aislinn , Russell Neal , Bielicki Julia , Riddell Amy , Stohr Wolfgang , Walker Ann Sarah , Berezin Eitan Naaman , Roilides Emmanuel , De Luca Maia , Romani Lorenza , Ballot Daynia , Dramowski Angela , Wadula Jeannette , Lochindarat Sorasak , Boonkasidecha Suppawat , Namiiro Flavia , Ngoc Hoang Thi Bich , Tran Minh Dien , Cressey Tim R. , Preedisripipat Kanchana , Berkley James A. , Musyimi Robert , Zarras Charalampos , Nana Trusha , Whitelaw Andrew , da Silva Cely Barreto , Jaglal Prenika , Ssengooba Willy , Saha Samir K. , Islam Mohammad Shahidul , Mussi-Pinhata Marisa Marcia , Carvalheiro Cristina Gardonyi , Piddock Laura J. V. , Heath Paul T. , Malhotra-Kumar Surbhi , Sharland Michael , Glupczynski Youri , Goossens Herman
Published: May 2024

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.
Overlooked shelf sediment reductive sinks of dissolved rhenium and uranium in the modern ocean
Authors: Hong Qingquan , Cheng Yilin , Qu Yang , Wei Lin , Liu Yumeng , Gao Jianfeng , Cai Pinghe , Chen Tianyu
Published: May 2024

Rhenium (Re) and uranium (U) are essential proxies in reconstructing past oceanic oxygenation evolution. However, their removal in continental shelf sediments, hotspots of early diagenesis, were previously treated as quantitatively unimportant sinks in the ocean. Here we examine the sedimentary reductive removal of Re and U and their coupling with organic carbon decomposition, utilizing the 224Ra/228Th disequilibria within the East China Sea shelf. We identified positive correlations between their removal fluxes and the rates of sediment oxygen consumption or organic carbon decomposition. These correlations enable an evaluation of global shelf reductive sinks that are comparable to (for Re) or higher than (~4-fold for U) previously established suboxic/anoxic sinks. These findings suggest potential imbalances in the modern budgets of Re and U, or perhaps a substantial underestimation of their sources. Our study thus highlights shelf sedimentary reductive removal as critical yet overlooked sinks for Re and U in the modern ocean.
TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia
Authors: Ma Jun-Kai , Su Li-Da , Feng Lin-Lin , Li Jing-Lin , Pan Li , Danzeng Qupei , Li Yanwei , Shang Tongyao , Zhan Xiao-Lin , Chen Si-Ying , Ying Shibo , Hu Jian-Rao , Chen Xue Qun , Zhang Qi , Liang Tingbo , Lu Xin-Jiang
Published: May 2024

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.
Unveiling the A-to-I mRNA editing machinery and its regulation and evolution in fungi
Authors: Feng Chanjing , Xin Kaiyun , Du Yanfei , Zou Jingwen , Xing Xiaoxing , Xiu Qi , Zhang Yijie , Zhang Rui , Huang Weiwei , Wang Qinhu , Jiang Cong , Wang Xiaojie , Kang Zhensheng , Xu Jin-Rong , Liu Huiquan
Published: May 2024

A-to-I mRNA editing in animals is mediated by ADARs, but the mechanism underlying sexual stage-specific A-to-I mRNA editing in fungi remains unknown. Here, we show that the eukaryotic tRNA-specific heterodimeric deaminase FgTad2-FgTad3 is responsible for A-to-I mRNA editing in Fusarium graminearum. This editing capacity relies on the interaction between FgTad3 and a sexual stage-specific protein called Ame1. Although Ame1 orthologs are widely distributed in fungi, the interaction originates in Sordariomycetes. We have identified key residues responsible for the FgTad3-Ame1 interaction. The expression and activity of FgTad2-FgTad3 are regulated through alternative promoters, alternative translation initiation, and post-translational modifications. Our study demonstrates that the FgTad2-FgTad3-Ame1 complex can efficiently edit mRNA in yeasts, bacteria, and human cells, with important implications for the development of base editors in therapy and agriculture. Overall, this study uncovers mechanisms, regulation, and evolution of RNA editing in fungi, highlighting the role of protein-protein interactions in modulating deaminase function.