bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism
Authors: Baden Pascale , Perez Maria Jose , Raji Hariam , Bertoli Federico , Kalb Stefanie , Illescas María , Spanos Fokion , Giuliano Claudio , Calogero Alessandra Maria , Oldrati Marvin , Hebestreit Hannah , Cappelletti Graziella , Brockmann Kathrin , Gasser Thomas , Schapira Anthony H. V. , Ugalde Cristina , Deleidi Michela 
Published: April 2023

AbstractMutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher’s disease, are the most frequent genetic risk factor for Parkinson’s disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes
Authors: Saha Liton Kumar , Saha Sourav , Yang Xi , Huang Shar-yin Naomi , Sun Yilun , Jo Ukhyun , Pommier Yves 
Published: April 2023

AbstractTopoisomerase IIIα (TOP3A) belongs to the conserved Type IA family of DNA topoisomerases. Here we report that human TOP3A is associated with DNA replication forks and that a “self-trapping” TOP3A mutant (TOP3A-R364W) generates cellular TOP3A DNA cleavage complexes (TOP3Accs). We show that trapped TOP3Accs that interfere with replication, induce DNA damage and genome instability. To elucidate how TOP3Accs are repaired, we explored the role of Spartan (SPRTN), the metalloprotease associated with DNA replication, which digests proteins forming DNA-protein crosslinks (DPCs). We find that SPRTN-deficient cells show elevated TOP3Accs, whereas overexpression of SPRTN lowers cellular TOP3Accs. SPRTN is deubiquitinated and epistatic with TDP2 in response to TOP3Accs. In addition, we found that MRE11 can excise TOP3Accs, and that cell cycle determines the preference for the SPRTN-TDP2 vs. the ATM-MRE11 pathways, in S vs. G2, respectively. Our study highlights the prevalence of TOP3Accs repair mechanisms to ensure normal DNA replication.
Construction of a synthetic metabolic pathway for biosynthesis of 2,4-dihydroxybutyric acid from ethylene glycol
Authors: Frazão Cláudio J. R. , Wagner Nils , Rabe Kenny , Walther Thomas 
Published: April 2023

AbstractEthylene glycol is an attractive two-carbon alcohol substrate for biochemical product synthesis as it can be derived from CO2 or syngas at no sacrifice to human food stocks. Here, we disclose a five-step synthetic metabolic pathway enabling the carbon-conserving biosynthesis of the versatile platform molecule 2,4-dihydroxybutyric acid (DHB) from this compound. The linear pathway chains ethylene glycol dehydrogenase, D-threose aldolase, D-threose dehydrogenase, D-threono-1,4-lactonase, D-threonate dehydratase and 2-oxo-4-hydroxybutyrate reductase enzyme activities in succession. We screen candidate enzymes with D-threose dehydrogenase and D-threonate dehydratase activities on cognate substrates with conserved carbon-centre stereochemistry. Lastly, we show the functionality of the pathway by its expression in an Escherichia coli strain and production of 1 g L−1 and 0.8 g L−1 DHB from, respectively, glycolaldehyde or ethylene glycol.
Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage
Authors: Rosado-Ramos Rita , Poças Gonçalo M. , Marques Daniela , Foito Alexandre , M. Sevillano David , Lopes-da-Silva Mafalda , Gonçalves Luís G. , Menezes Regina , Ottens Marcel , Stewart Derek , Ibáñez de Opakua Alain , Zweckstetter Markus , Seabra Miguel C. , Mendes César S. , Outeiro Tiago Fleming , Domingos Pedro M. , Santos Cláudia N. 
Published: April 2023

AbstractParkinson’s Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.
Associations between mental health, blood pressure and the development of hypertension
Authors: Schaare H. Lina , Blöchl Maria , Kumral Deniz , Uhlig Marie , Lemcke Lorenz , Valk Sofie L. , Villringer Arno 
Published: April 2023

AbstractMultiple studies have reported a link between mental health and high blood pressure with mixed or even contradictory findings. Here, we resolve those contradictions and further dissect the cross-sectional and longitudinal relationship between mental health, systolic blood pressure, and hypertension using extensive psychological, medical and neuroimaging data from the UK Biobank. We show that higher systolic blood pressure is associated with fewer depressive symptoms, greater well-being, and lower emotion-related brain activity. Interestingly, impending hypertension is associated with poorer mental health years before HTN is diagnosed. In addition, a stronger baseline association between systolic blood pressure and better mental health was observed in individuals who develop hypertension until follow-up. Overall, our findings offer insights on the complex relationship between mental health, blood pressure, and hypertension, suggesting that—via baroreceptor mechanisms and reinforcement learning—the association of higher blood pressure with better mental health may ultimately contribute to the development of hypertension.
Evaluating the evidence for exponential quantum advantage in ground-state quantum chemistry
Authors: Lee Seunghoon , Lee Joonho , Zhai Huanchen , Tong Yu , Dalzell Alexander M. , Kumar Ashutosh , Helms Phillip , Gray Johnnie , Cui Zhi-Hao , Liu Wenyuan , Kastoryano Michael , Babbush Ryan , Preskill John , Reichman David R. , Campbell Earl T. , Valeev Edward F. , Lin Lin , Chan Garnet Kin-Lic 
Published: April 2023

AbstractDue to intense interest in the potential applications of quantum computing, it is critical to understand the basis for potential exponential quantum advantage in quantum chemistry. Here we gather the evidence for this case in the most common task in quantum chemistry, namely, ground-state energy estimation, for generic chemical problems where heuristic quantum state preparation might be assumed to be efficient. The availability of exponential quantum advantage then centers on whether features of the physical problem that enable efficient heuristic quantum state preparation also enable efficient solution by classical heuristics. Through numerical studies of quantum state preparation and empirical complexity analysis (including the error scaling) of classical heuristics, in both ab initio and model Hamiltonian settings, we conclude that evidence for such an exponential advantage across chemical space has yet to be found. While quantum computers may still prove useful for ground-state quantum chemistry through polynomial speedups, it may be prudent to assume exponential speedups are not generically available for this problem.
Mapping the landscape of genetic dependencies in chordoma
Authors: Sharifnia Tanaz , Wawer Mathias J. , Goodale Amy , Lee Yenarae , Kazachkova Mariya , Dempster Joshua M. , Muller Sandrine , Levy Joan , Freed Daniel M. , Sommer Josh , Kalfon Jérémie , Vazquez Francisca , Hahn William C. , Root David E. , Clemons Paul A. , Schreiber Stuart L. 
Published: April 2023

AbstractIdentifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency,TBXT(T; brachyury), and identifies a range of additional dependencies, includingPTPN11, ADAR, PRKRA, LUC7L2, SRRM2,SLC2A1, SLC7A5, FANCM, andTHAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates withADARdependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded byPTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.
New constraints on Cenozoic subduction between India and Tibet
Authors: Liu Liang , Liu Lijun , Morgan Jason. P. , Xu Yi-Gang , Chen Ling 
Published: April 2023

AbstractThe type of lithosphere subducted between India and Tibet since the Paleocene remains controversial; it has been suggested to be either entirely continental, oceanic, or a mixture of the two. As the subduction history of this lost lithosphere strongly shaped Tibetan intraplate tectonism, we attempt to further constrain its nature and density structure with numerical models that aim to reproduce the observed history of magmatism and crustal thickening in addition to present-day plateau properties between 83°E and 88°E. By matching time-evolving geological patterns, here we show that Tibetan tectonism away from the Himalayan syntaxis is consistent with the initial indentation of a craton-like terrane at 55 ± 5 Ma, followed by a buoyant tectonic plate with a thin crust, e.g., a broad continental margin (Himalandia). This new geodynamic scenario can explain the seemingly contradictory observations that had led to competing hypotheses like the subduction of Greater India versus largely oceanic subduction prior to Indian indentation.
Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy
Authors: Hu Ningyan , Kim Eunjoo , Antoury Layal , Wheeler Thurman M. 
Published: April 2023

AbstractIn myotonic dystrophy type 1 (DM1), deregulated alternative splicing of the muscle chloride channel Clcn1 causes myotonia, a delayed relaxation of muscles due to repetitive action potentials. The degree of weakness in adult DM1 is associated with increased frequency of oxidative muscle fibers. However, the mechanism for glycolytic-to-oxidative fiber type transition in DM1 and its relationship to myotonia are uncertain. Here we cross two mouse models of DM1 to create a double homozygous model that features progressive functional impairment, severe myotonia, and near absence of type 2B glycolytic fibers. Intramuscular injection of an antisense oligonucleotide for targeted skipping of Clcn1 exon 7a corrects Clcn1 alternative splicing, increases glycolytic 2B levels to ≥ 40% frequency, reduces muscle injury, and improves fiber hypertrophy relative to treatment with a control oligo. Our results demonstrate that fiber type transitions in DM1 result from myotonia and are reversible, and support the development of Clcn1-targeting therapies for DM1.
All-optical closed-loop voltage clamp for precise control of muscles and neurons in live animals
Authors: Bergs Amelie C. F. , Liewald Jana F. , Rodriguez-Rozada Silvia , Liu Qiang , Wirt Christin , Bessel Artur , Zeitzschel Nadja , Durmaz Hilal , Nozownik Adrianna , Dill Holger , Jospin Maëlle , Vierock Johannes , Bargmann Cornelia I. , Hegemann Peter , Wiegert J. Simon , Gottschalk Alexander 
Published: April 2023

AbstractExcitable cells can be stimulated or inhibited by optogenetics. Since optogenetic actuation regimes are often static, neurons and circuits can quickly adapt, allowing perturbation, but not true control. Hence, we established an optogenetic voltage-clamp (OVC). The voltage-indicator QuasAr2 provides information for fast, closed-loop optical feedback to the bidirectional optogenetic actuator BiPOLES. Voltage-dependent fluorescence is held within tight margins, thus clamping the cell to distinct potentials. We established the OVC in muscles and neurons of Caenorhabditis elegans, and transferred it to rat hippocampal neurons in slice culture. Fluorescence signals were calibrated to electrically measured potentials, and wavelengths to currents, enabling to determine optical I/V-relationships. The OVC reports on homeostatically altered cellular physiology in mutants and on Ca2+-channel properties, and can dynamically clamp spiking in C. elegans. Combining non-invasive imaging with control capabilities of electrophysiology, the OVC facilitates high-throughput, contact-less electrophysiology in individual cells and paves the way for true optogenetic control in behaving animals.
A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast
Authors: Naseri Gita 
Published: April 2023

AbstractSecondary natural products (NPs) are a rich source for drug discovery. However, the low abundance of NPs makes their extraction from nature inefficient, while chemical synthesis is challenging and unsustainable.Saccharomyces cerevisiaeandPichia pastorisare excellent manufacturing systems for the production of NPs. This Perspective discusses a comprehensive platform for sustainable production of NPs in the two yeasts through system-associated optimization at four levels: genetics, temporal controllers, productivity screening, and scalability. Additionally, it is pointed out critical metabolic building blocks in NP bioengineering can be identified through connecting multilevel data of the optimized system using deep learning.
Intracytoplasmic membranes develop in Geobacter sulfurreducens under thermodynamically limiting conditions
Authors: Howley Ethan , Mangus Anna , Williams Dewight , Torres César I. 
Published: April 2023

AbstractGeobacter sulfurreducensis an electroactive bacterium capable of reducing metal oxides in the environment and electrodes in engineered systems1,2.Geobacter sp. are the keystone organisms in electrogenic biofilms, as their respiration consumes fermentation products produced by other organisms and reduces a terminal electron acceptor e.g. iron oxide or an electrode. To respire extracellular electron acceptors with a wide range of redox potentials,G. sulfurreducenshas a complex network of respiratory proteins, many of which are membrane-bound3–5. We have identified intracytoplasmic membrane (ICM) structures inG. sulfurreducens. This ICM is an invagination of the inner membrane that has folded and organized by an unknown mechanism, often but not always located near the tip of a cell. Using confocal microscopy, we can identify that at least half of the cells contain an ICM when grown on low potential anode surfaces, whereas cells grown at higher potential anode surfaces or using fumarate as electron acceptor had significantly lower ICM frequency. 3D models developed from cryo-electron tomograms show the ICM to be a continuous extension of the inner membrane in contact with the cytoplasmic and periplasmic space. The differential abundance of ICM in cells grown under different thermodynamic conditions supports the hypothesis that it is an adaptation to limited energy availability, as an increase in membrane-bound respiratory proteins could increase electron flux. Thus, the ICM provides extra inner-membrane surface to increase the abundance of these proteins.G. sulfurreducensis the first Thermodesulfobacterium or metal-oxide reducer found to produce ICMs.
Glycosylated nanoparticle-based PfCSP vaccine confers long-lasting antibody responses and sterile protection in mouse malaria model
Authors: Ludwig Julia , Scally Stephen W. , Costa Giulia , Hoffmann Sandro , Murugan Rajagopal , Lossin Jana , Prieto Katherine , Obraztsova Anna , Lobeto Nina , Franke-Fayard Blandine , Janse Chris J. , Lebas Celia , Collin Nicolas , Binter Spela , Kellam Paul , Levashina Elena A. , Wardemann Hedda , Julien Jean-Philippe 
Published: April 2023

AbstractThe development of an effective and durable vaccine remains a central goal in the fight against malaria. Circumsporozoite protein (CSP) is the major surface protein of sporozoites and the target of the only licensed Plasmodium falciparum (Pf) malaria vaccine, RTS,S/AS01. However, vaccine efficacy is low and short-lived, highlighting the need for a second-generation vaccine with superior efficacy and durability. Here, we report a Helicobacter pylori apoferritin-based nanoparticle immunogen that elicits strong B cell responses against PfCSP epitopes that are targeted by the most potent human monoclonal antibodies. Glycan engineering of the scaffold and fusion of an exogenous T cell epitope enhanced the anti-PfCSP B cell response eliciting strong, long-lived and protective humoral immunity in mice. Our study highlights the power of rational vaccine design to generate a highly efficacious second-generation anti-infective malaria vaccine candidate and provides the basis for its further development.
Rapid single-cell physical phenotyping of mechanically dissociated tissue biopsies
Authors: Soteriou Despina , Kubánková Markéta , Schweitzer Christine , López-Posadas Rocío , Pradhan Rashmita , Thoma Oana-Maria , Györfi Andrea-Hermina , Matei Alexandru-Emil , Waldner Maximilian , Distler Jörg H. W. , Scheuermann Stefan , Langejürgen Jens , Eckstein Markus , Schneider-Stock Regine , Atreya Raja , Neurath Markus F. , Hartmann Arndt , Guck Jochen 
Published: April 2023

AbstractDuring surgery, rapid and accurate histopathological diagnosis is essential for clinical decision making. Yet the prevalent method of intra-operative consultation pathology is intensive in time, labour and costs, and requires the expertise of trained pathologists. Here we show that biopsy samples can be analysed within 30 min by sequentially assessing the physical phenotypes of singularized suspended cells dissociated from the tissues. The diagnostic method combines the enzyme-free mechanical dissociation of tissues, real-time deformability cytometry at rates of 100–1,000 cells s−1 and data analysis by unsupervised dimensionality reduction and logistic regression. Physical phenotype parameters extracted from brightfield images of single cells distinguished cell subpopulations in various tissues, enhancing or even substituting measurements of molecular markers. We used the method to quantify the degree of colon inflammation and to accurately discriminate healthy and tumorous tissue in biopsy samples of mouse and human colons. This fast and label-free approach may aid the intra-operative detection of pathological changes in solid biopsies.
Viruses interact with hosts that span distantly related microbial domains in dense hydrothermal mats
Authors: Hwang Yunha , Roux Simon , Coclet Clément , Krause Sebastian J. E. , Girguis Peter R. 
Published: April 2023

AbstractMany microbes in nature reside in dense, metabolically interdependent communities. We investigated the nature and extent of microbe-virus interactions in relation to microbial density and syntrophy by examining microbe-virus interactions in a biomass dense, deep-sea hydrothermal mat. Using metagenomic sequencing, we find numerous instances where phylogenetically distant (up to domain level) microbes encode CRISPR-based immunity against the same viruses in the mat. Evidence of viral interactions with hosts cross-cutting microbial domains is particularly striking between known syntrophic partners, for example those engaged in anaerobic methanotrophy. These patterns are corroborated by proximity-ligation-based (Hi-C) inference. Surveys of public datasets reveal additional viruses interacting with hosts across domains in diverse ecosystems known to harbour syntrophic biofilms. We propose that the entry of viral particles and/or DNA to non-primary host cells may be a common phenomenon in densely populated ecosystems, with eco-evolutionary implications for syntrophic microbes and CRISPR-mediated inter-population augmentation of resilience against viruses.
Very-large-scale integrated quantum graph photonics
Authors: Bao Jueming , Fu Zhaorong , Pramanik Tanumoy , Mao Jun , Chi Yulin , Cao Yingkang , Zhai Chonghao , Mao Yifei , Dai Tianxiang , Chen Xiaojiong , Jia Xinyu , Zhao Leshi , Zheng Yun , Tang Bo , Li Zhihua , Luo Jun , Wang Wenwu , Yang Yan , Peng Yingying , Liu Dajian , Dai Daoxin , He Qiongyi , Muthali Alif Laila , Oxenløwe Leif K. , Vigliar Caterina , Paesani Stefano , Hou Huili , Santagati Raffaele , Silverstone Joshua W. , Laing Anthony , Thompson Mark G. , O’Brien Jeremy L. , Ding Yunhong , Gong Qihuang , Wang Jianwei 
Published: April 2023

AbstractGraphs have provided an expressive mathematical tool to model quantum-mechanical devices and systems. In particular, it has been recently discovered that graph theory can be used to describe and design quantum components, devices, setups and systems, based on the two-dimensional lattice of parametric nonlinear optical crystals and linear optical circuits, different to the standard quantum photonic framework. Realizing such graph-theoretical quantum photonic hardware, however, remains extremely challenging experimentally using conventional technologies. Here we demonstrate a graph-theoretical programmable quantum photonic device in very-large-scale integrated nanophotonic circuits. The device monolithically integrates about 2,500 components, constructing a synthetic lattice of nonlinear photon-pair waveguide sources and linear optical waveguide circuits, and it is fabricated on an eight-inch silicon-on-insulator wafer by complementary metal–oxide–semiconductor processes. We reconfigure the quantum device to realize and process complex-weighted graphs with different topologies and to implement different tasks associated with the perfect matching property of graphs. As two non-trivial examples, we show the generation of genuine multipartite multidimensional quantum entanglement with different entanglement structures, and the measurement of probability distributions proportional to the modulus-squared hafnian (permanent) of the graph’s adjacency matrices. This work realizes a prototype of graph-theoretical quantum photonic devices manufactured by very-large-scale integration technologies, featuring arbitrary programmability, high architectural modularity and massive manufacturing scalability.