bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial co-occurrences on catheters from long-term catheterized patients
Authors: Nye Taylor M. , Zou Zongsen , Obernuefemann Chloe L. P. , Pinkner Jerome S. , Lowry Erin , Kleinschmidt Kent , Bergeron Karla , Klim Aleksandra , Dodson Karen W. , Flores-Mireles Ana L. , Walker Jennifer N. , Wong Daniel Garrett , Desai Alana , Caparon Michael G. , Hultgren Scott J. 
Published: January 2024

AbstractCatheter-associated urinary tract infections (CAUTIs), a common cause of healthcare-associated infections, are caused by a diverse array of pathogens that are increasingly becoming antibiotic resistant. We analyze the microbial occurrences in catheter and urine samples from 55 human long-term catheterized patients collected over one year. Although most of these patients were prescribed antibiotics over several collection periods, their catheter samples remain colonized by one or more bacterial species. Examination of a total of 366 catheter and urine samples identify 13 positive and 13 negative genus co-occurrences over 12 collection periods, representing associations that occur more or less frequently than expected by chance. We find that for many patients, the microbial species composition between collection periods is similar. In a subset of patients, we find that the most frequently sampled bacteria, Escherichia coli and Enterococcus faecalis, co-localize on catheter samples. Further, co-culture of paired isolates recovered from the same patients reveals that E. coli significantly augments E. faecalis growth in an artificial urine medium, where E. faecalis monoculture grows poorly. These findings suggest novel strategies to collapse polymicrobial CAUTI in long-term catheterized patients by targeting mechanisms that promote positive co-associations.
ECOLE: Learning to call copy number variants on whole exome sequencing data
Authors: Mandiracioglu Berk , Ozden Furkan , Kaynar Gun , Yilmaz Mehmet Alper , Alkan Can , Cicek A. Ercument 
Published: January 2024

AbstractCopy number variants (CNV) are shown to contribute to the etiology of several genetic disorders. Accurate detection of CNVs on whole exome sequencing (WES) data has been a long sought-after goal for use in clinics. This was not possible despite recent improvements in performance because algorithms mostly suffer from low precision and even lower recall on expert-curated gold standard call sets. Here, we present a deep learning-based somatic and germline CNV caller for WES data, named ECOLE. Based on a variant of the transformer architecture, the model learns to call CNVs per exon, using high-confidence calls made on matched WGS samples. We further train and fine-tune the model with a small set of expert calls via transfer learning. We show that ECOLE achieves high performance on human expert labelled data for the first time with 68.7% precision and 49.6% recall. This corresponds to precision and recall improvements of 18.7% and 30.8% over the next best-performing methods, respectively. We also show that the same fine-tuning strategy using tumor samples enables ECOLE to detect RT-qPCR-validated variations in bladder cancer samples without the need for a control sample. ECOLE is available at https://github.com/ciceklab/ECOLE.
Histone lactylation couples cellular metabolism with developmental gene regulatory networks
Authors: Merkuri Fjodor , Rothstein Megan , Simoes-Costa Marcos 
Published: January 2024

AbstractEmbryonic cells exhibit diverse metabolic states. Recent studies have demonstrated that metabolic reprogramming drives changes in cell identity by affecting gene expression. However, the connection between cellular metabolism and gene expression remains poorly understood. Here we report that glycolysis-regulated histone lactylation couples the metabolic state of embryonic cells with chromatin organization and gene regulatory network (GRN) activation. We found that lactylation marks genomic regions of glycolytic embryonic tissues, like the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis. This process promotes the accessibility of active enhancers and the deployment of the NC GRN. Reducing the deposition of the mark by targeting LDHA/B leads to the downregulation of NC genes and the impairment of cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism that involves transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism that integrates cellular metabolism with the GRNs that orchestrate embryonic development.
Sequential co-reduction of nitrate and carbon dioxide enables selective urea electrosynthesis
Authors: Li Yang , Zheng Shisheng , Liu Hao , Xiong Qi , Yi Haocong , Yang Haibin , Mei Zongwei , Zhao Qinghe , Yin Zu-Wei , Huang Ming , Lin Yuan , Lai Weihong , Dou Shi-Xue , Pan Feng , Li Shunning 
Published: January 2024

AbstractDespite the recent achievements in urea electrosynthesis from co-reduction of nitrogen wastes (such as NO3−) and CO2, the product selectivity remains fairly mediocre due to the competing nature of the two parallel reduction reactions. Here we report a catalyst design that affords high selectivity to urea by sequentially reducing NO3− and CO2 at a dynamic catalytic centre, which not only alleviates the competition issue but also facilitates C−N coupling. We exemplify this strategy on a nitrogen-doped carbon catalyst, where a spontaneous switch between NO3− and CO2 reduction paths is enabled by reversible hydrogenation on the nitrogen functional groups. A high urea yield rate of 596.1 µg mg−1 h−1 with a promising Faradaic efficiency of 62% is obtained. These findings, rationalized by in situ spectroscopic techniques and theoretical calculations, are rooted in the proton-involved dynamic catalyst evolution that mitigates overwhelming reduction of reactants and thereby minimizes the formation of side products.
Integrative genotyping of cancer and immune phenotypes by long-read sequencing
Authors: Penter Livius , Borji Mehdi , Nagler Adi , Lyu Haoxiang , Lu Wesley S. , Cieri Nicoletta , Maurer Katie , Oliveira Giacomo , Al’Khafaji Aziz M. , Garimella Kiran V. , Li Shuqiang , Neuberg Donna S. , Ritz Jerome , Soiffer Robert J. , Garcia Jacqueline S. , Livak Kenneth J. , Wu Catherine J. 
Published: January 2024

AbstractSingle-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural ‘barcodes’, we define the optimal targets for nanoranger, namely those loci close to the 5’ end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.
Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication
Authors: Maffei Enea , Woischnig Anne-Kathrin , Burkolter Marco R. , Heyer Yannik , Humolli Dorentina , Thürkauf Nicole , Bock Thomas , Schmidt Alexander , Manfredi Pablo , Egli Adrian , Khanna Nina , Jenal Urs , Harms Alexander 
Published: January 2024

AbstractBacteriophages are ubiquitous viral predators that have primarily been studied using fast-growing laboratory cultures of their bacterial hosts. However, microbial life in nature is mostly in a slow- or non-growing, dormant state. Here, we show that diverse phages can infect deep-dormant bacteria and suspend their replication until the host resuscitates (“hibernation”). However, a newly isolated Pseudomonas aeruginosa phage, named Paride, can directly replicate and induce the lysis of deep-dormant hosts. While non-growing bacteria are notoriously tolerant to antibiotic drugs, the combination with Paride enables the carbapenem meropenem to eradicate deep-dormant cultures in vitro and to reduce a resilient bacterial infection of a tissue cage implant in mice. Our work might inspire new treatments for persistent bacterial infections and, more broadly, highlights two viral strategies to infect dormant bacteria (hibernation and direct replication) that will guide future studies on phage-host interactions.
Field-induced compensation of magnetic exchange as the possible origin of reentrant superconductivity in UTe2
Authors: Helm Toni , Kimata Motoi , Sudo Kenta , Miyata Atsuhiko , Stirnat Julia , Förster Tobias , Hornung Jacob , König Markus , Sheikin Ilya , Pourret Alexandre , Lapertot Gerard , Aoki Dai , Knebel Georg , Wosnitza Joachim , Brison Jean-Pascal 
Published: January 2024

AbstractThe potential spin-triplet heavy-fermion superconductor UTe2exhibits signatures of multiple distinct superconducting phases. For field aligned along thebaxis, a metamagnetic transition occurs atμ0Hm ≈ 35 T. It is associated with magnetic fluctuations that may be beneficial for the field-reinforced superconductivity surviving up toHm. Once the field is tilted away from thebtowards thecaxis, a reentrant superconducting phase emerges just aboveHm. In order to better understand this remarkably field-resistant superconducting phase, we conducted magnetic-torque and magnetotransport measurements in pulsed magnetic fields. We determine the record-breaking upper critical field ofμ0Hc2 ≈ 73 T and its evolution with angle. Furthermore, the normal-state Hall effect experiences a drastic suppression indicative of a reduced band polarization aboveHmin the angular range around 30° caused by a partial compensation between the applied field and an exchange field. This promotes the Jaccarino-Peter effect as a likely mechanism for the reentrant superconductivity aboveHm.
Towards a transferable fermionic neural wavefunction for molecules
Authors: Scherbela Michael , Gerard Leon , Grohs Philipp 
Published: January 2024

AbstractDeep neural networks have become a highly accurate and powerful wavefunction ansatz in combination with variational Monte Carlo methods for solving the electronic Schrödinger equation. However, despite their success and favorable scaling, these methods are still computationally too costly for wide adoption. A significant obstacle is the requirement to optimize the wavefunction from scratch for each new system, thus requiring long optimization. In this work, we propose a neural network ansatz, which effectively maps uncorrelated, computationally cheap Hartree-Fock orbitals, to correlated, high-accuracy neural network orbitals. This ansatz is inherently capable of learning a single wavefunction across multiple compounds and geometries, as we demonstrate by successfully transferring a wavefunction model pre-trained on smaller fragments to larger compounds. Furthermore, we provide ample experimental evidence to support the idea that extensive pre-training of such a generalized wavefunction model across different compounds and geometries could lead to a foundation wavefunction model. Such a model could yield high-accuracy ab-initio energies using only minimal computational effort for fine-tuning and evaluation of observables.
Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response
Authors: Zhao Mei , Wang Tianxiao , Gleber-Netto Frederico O. , Chen Zhen , McGrail Daniel J. , Gomez Javier A. , Ju Wutong , Gadhikar Mayur A. , Ma Wencai , Shen Li , Wang Qi , Tang Ximing , Pathak Sen , Raso Maria Gabriela , Burks Jared K. , Lin Shiaw-Yih , Wang Jing , Multani Asha S. , Pickering Curtis R. , Chen Junjie , Myers Jeffrey N. , Zhou Ge 
Published: January 2024

AbstractInactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.
Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
Authors: Wang Sheng , Klein Sebastian O. , Urban Sylvia , Staudt Maximilian , Barthes Nicolas P. F. , Willmann Dominica , Bacher Johannes , Sum Manuela , Bauer Helena , Peng Ling , Rennar Georg A. , Gratzke Christian , Schüle Katrin M. , Zhang Lin , Einsle Oliver , Greschik Holger , MacLeod Calum , Thomson Christopher G. , Jung Manfred , Metzger Eric , Schüle Roland 
Published: January 2024

AbstractInhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 as a potential therapeutic target. Here, we report the development of a potent and selective KMT9 inhibitor (compound 4, KMI169) with cellular activity through structure-based drug design. KMI169 functions as a bi-substrate inhibitor targeting the SAM and substrate binding pockets of KMT9 and exhibits high potency, selectivity, and cellular target engagement. KMT9 inhibition selectively downregulates target genes involved in cell cycle regulation and impairs proliferation of tumours cells including castration- and enzalutamide-resistant prostate cancer cells. KMI169 represents a valuable tool to probe cellular KMT9 functions and paves the way for the development of clinical candidate inhibitors as therapeutic options to treat malignancies such as therapy-resistant prostate cancer.
BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination
Authors: van Meijgaarden Krista E. , Li Wenchao , Moorlag Simone J. C. F. M. , Koeken Valerie A. C. M. , Koenen Hans J. P. M. , Joosten Leo A. B. , Vyakarnam Annapurna , Ahmed Asma , Rakshit Srabanti , Adiga Vasista , Ottenhoff Tom H. M. , Li Yang , Netea Mihai G. , Joosten Simone A. 
Published: January 2024

AbstractBacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against non-tuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.
DomiRank Centrality reveals structural fragility of complex networks via node dominance
Authors: Engsig Marcus , Tejedor Alejandro , Moreno Yamir , Foufoula-Georgiou Efi , Kasmi Chaouki 
Published: January 2024

AbstractDetermining the key elements of interconnected infrastructure and complex systems is paramount to ensure system functionality and integrity. This work quantifies the dominance of the networks’ nodes in their respective neighborhoods, introducing a centrality metric, DomiRank, that integrates local and global topological information via a tunable parameter. We present an analytical formula and an efficient parallelizable algorithm for DomiRank centrality, making it applicable to massive networks. From the networks’ structure and function perspective, nodes with high values of DomiRank highlight fragile neighborhoods whose integrity and functionality are highly dependent on those dominant nodes. Underscoring this relation between dominance and fragility, we show that DomiRank systematically outperforms other centrality metrics in generating targeted attacks that effectively compromise network structure and disrupt its functionality for synthetic and real-world topologies. Moreover, we show that DomiRank-based attacks inflict more enduring damage in the network, hindering its ability to rebound and, thus, impairing system resilience. DomiRank centrality capitalizes on the competition mechanism embedded in its definition to expose the fragility of networks, paving the way to design strategies to mitigate vulnerability and enhance the resilience of critical infrastructures.
Dynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad
Authors: Cho Hyunju , Liu Yumeng , Chung SangYoon , Chandrasekar Sowmya , Weiss Shimon , Shan Shu-ou 
Published: January 2024

AbstractMembrane protein biogenesis poses acute challenges to protein homeostasis, and how they are selectively escorted to the target membrane is not well understood. Here we address this question in the guided-entry-of-tail-anchored protein (GET) pathway, in which tail-anchored membrane proteins (TAs) are relayed through an Hsp70-Sgt2-Get3 chaperone triad for targeting to the endoplasmic reticulum. We show that the Hsp70 ATPase cycle and TA substrate drive dimeric Sgt2 from a wide-open conformation to a closed state, in which TAs are protected by both substrate binding domains of Sgt2. Get3 is privileged to receive TA from closed Sgt2, whereas off-pathway chaperones remove TAs from open Sgt2. Sgt2 closing is less favorable with suboptimal GET substrates, which are rejected during or after the Hsp70-to-Sgt2 handover. Our results demonstrate how fine-tuned conformational dynamics in Sgt2 enable hydrophobic TAs to be effectively funneled onto their dedicated targeting factor while also providing a mechanism for substrate selection.
Exact inversion of partially coherent dynamical electron scattering for picometric structure retrieval
Authors: Diederichs Benedikt , Herdegen Ziria , Strauch Achim , Filbir Frank , Müller-Caspary Knut 
Published: January 2024

AbstractThe greatly nonlinear diffraction of high-energy electron probes focused to subatomic diameters frustrates the direct inversion of ptychographic data sets to decipher the atomic structure. Several iterative algorithms have been proposed to yield atomically-resolved phase distributions within slices of a 3D specimen, corresponding to the scattering centers of the electron wave. By pixelwise phase retrieval, current approaches do not only involve orders of magnitude more free parameters than necessary, but also neglect essential details of scattering physics such as the atomistic nature of the specimen and thermal effects. Here, we introduce a parametrized, fully differentiable scheme employing neural network concepts which allows the inversion of ptychographic data by means of entirely physical quantities. Omnipresent thermal diffuse scattering in thick specimens is treated accurately using frozen phonons, and atom types, positions and partial coherence are accounted for in the inverse model as relativistic scattering theory demands. Our approach exploits 4D experimental data collected in an aberration-corrected momentum-resolved scanning transmission electron microscopy setup. Atom positions in a 20 nm thick PbZr0.2Ti0.8O3 ferroelectric are measured with picometer precision, including the discrimination of different atom types and positions in mixed columns.
Dipeptide coacervates as artificial membraneless organelles for bioorthogonal catalysis
Authors: Cao Shoupeng , Ivanov Tsvetomir , Heuer Julian , Ferguson Calum T. J. , Landfester Katharina , Caire da Silva Lucas 
Published: January 2024

AbstractArtificial organelles can manipulate cellular functions and introduce non-biological processes into cells. Coacervate droplets have emerged as a close analog of membraneless cellular organelles. Their biomimetic properties, such as molecular crowding and selective partitioning, make them promising components for designing cell-like materials. However, their use as artificial organelles has been limited by their complex molecular structure, limited control over internal microenvironment properties, and inherent colloidal instability. Here we report the design of dipeptide coacervates that exhibit enhanced stability, biocompatibility, and a hydrophobic microenvironment. The hydrophobic character facilitates the encapsulation of hydrophobic species, including transition metal-based catalysts, enhancing their efficiency in aqueous environments. Dipeptide coacervates carrying a metal-based catalyst are incorporated as active artificial organelles in cells and trigger an internal non-biological chemical reaction. The development of coacervates with a hydrophobic microenvironment opens an alternative avenue in the field of biomimetic materials with applications in catalysis and synthetic biology.
AI-driven projection tomography with multicore fibre-optic cell rotation
Authors: Sun Jiawei , Yang Bin , Koukourakis Nektarios , Guck Jochen , Czarske Juergen W. 
Published: January 2024

AbstractOptical tomography has emerged as a non-invasive imaging method, providing three-dimensional insights into subcellular structures and thereby enabling a deeper understanding of cellular functions, interactions, and processes. Conventional optical tomography methods are constrained by a limited illumination scanning range, leading to anisotropic resolution and incomplete imaging of cellular structures. To overcome this problem, we employ a compact multi-core fibre-optic cell rotator system that facilitates precise optical manipulation of cells within a microfluidic chip, achieving full-angle projection tomography with isotropic resolution. Moreover, we demonstrate an AI-driven tomographic reconstruction workflow, which can be a paradigm shift from conventional computational methods, often demanding manual processing, to a fully autonomous process. The performance of the proposed cell rotation tomography approach is validated through the three-dimensional reconstruction of cell phantoms and HL60 human cancer cells. The versatility of this learning-based tomographic reconstruction workflow paves the way for its broad application across diverse tomographic imaging modalities, including but not limited to flow cytometry tomography and acoustic rotation tomography. Therefore, this AI-driven approach can propel advancements in cell biology, aiding in the inception of pioneering therapeutics, and augmenting early-stage cancer diagnostics.