bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node
Authors: Melo-Silva Carolina R. , Sigal Luis J. 
Published: June 2024

AbstractThe interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8+ T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+ T-cells following secondary infection or CD8+ T-cell vaccination.
Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation
Authors: Niu Yunhui , Heddes Marjolein , Altaha Baraa , Birkner Michael , Kleigrewe Karin , Meng Chen , Haller Dirk , Kiessling Silke 
Published: June 2024

AbstractThe expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The peripheral circadian clock in intestinal epithelial cells (IECs) was previously shown to balance gastrointestinal homeostasis by regulating the microbiome. Here, we demonstrated that the intestinal clock is disrupted in an IBD-relevant mouse model (IL-10−/−). A lack of the intestinal clock gene (Bmal1) in intestinal epithelial cells (IECs) in a chemically and a novel genetically induced colitis model (DSS, Bmal1IEC−/−xIL-10−/−) promoted colitis and dramatically reduced survival rates. Germ-free Bmal1IEC−/− mice colonized with disease-associated microbiota from IL-10−/− mice exhibited increased inflammatory responses, highlighting the importance of the local intestinal clock for microbiota-induced IBD development. Targeting the intestinal clock directly by timed restricted feeding (RF) in IL-10−/− mice restored intestinal clock functions, including immune cell recruitment and microbial rhythmicity; improved inflammatory responses; dramatically enhanced survival rates and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC−/−xIL-10−/− mice, demonstrating the significance of the intestinal clock in determining the beneficial effect of RF. Overall, we provide evidence that intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate symptoms in IBD patients.
Landscape features support natural pest control and farm income when pesticide application is reduced
Authors: Klinnert Ana , Barbosa Ana Luisa , Catarino Rui , Fellmann Thomas , Baldoni Edoardo , Beber Caetano , Hristov Jordan , Paracchini Maria Luisa , Rega Carlo , Weiss Franz , Witzke Peter , Rodriguez-Cerezo Emilio 
Published: June 2024

AbstractFuture trajectories of agricultural productivity need to incorporate environmental targets, including the reduction of pesticides use. Landscape features supporting natural pest control (LF-NPC) offer a nature-based solution that can serve as a partial substitute for synthetic pesticides, thereby supporting future productivity levels. Here, we introduce a novel approach to quantify the contribution of LF-NPC to agricultural yields and its associated economic value to crop production in a broad-scale context. Using the European Union as case study, we combine granular farm-level data, a spatially explicit map of LF-NPC potential, and a regional agro-economic supply and market model. The results reveal that farms located in areas characterized by higher LF-NPC potential experience lower productivity losses in a context of reduced synthetic pesticides use. Our analysis suggests that LF-NPC reduces yield gaps on average by four percentage points, and increases income by a similar magnitude. These results highlight the significance of LF-NPC for agricultural production and income, and provide a valuable reference point for farmers and policymakers aiming to successfully invest in landscape features to achieve pesticides reduction targets.
Ferroelectric freestanding hafnia membranes with metastable rhombohedral structure down to 1-nm-thick
Authors: Shen Yufan , Ooe Kousuke , Yuan Xueyou , Yamada Tomoaki , Kobayashi Shunsuke , Haruta Mitsutaka , Kan Daisuke , Shimakawa Yuichi 
Published: June 2024

AbstractTwo-dimensional freestanding membranes of materials, which can be transferred onto and make interfaces with any material, have attracted attention in the search for functional properties that can be utilized for next-generation nanoscale devices. We fabricated stable 1-nm-thick hafnia membranes exhibiting the metastable rhombohedral structure and out-of-plane ferroelectric polarizations as large as 13 μC/cm2. We also found that the rhombohedral phase transforms into another metastable orthorhombic phase without the ferroelectricity deteriorating as the thickness increases. Our results reveal the key role of the rhombohedral phase in the scale-free ferroelectricity in hafnia and also provide critical insights into the formation mechanism and phase stability of the metastable hafnia. Moreover, ultrathin hafnia membranes enable heterointerfaces and devices to be fabricated from structurally dissimilar materials beyond structural constrictions in conventional film-growth techniques.
A trans-oceanic flight of over 4,200 km by painted lady butterflies
Authors: Suchan Tomasz , Bataille Clément P. , Reich Megan S. , Toro-Delgado Eric , Vila Roger , Pierce Naomi E. , Talavera Gerard 
Published: June 2024

AbstractThe extent of aerial flows of insects circulating around the planet and their impact on ecosystems and biogeography remain enigmatic because of methodological challenges. Here we report a transatlantic crossing by Vanessa cardui butterflies spanning at least 4200 km, from West Africa to South America (French Guiana) and lasting between 5 and 8 days. Even more, we infer a likely natal origin for these individuals in Western Europe, and the journey Europe-Africa-South America could expand to 7000 km or more. This discovery was possible through an integrative approach, including coastal field surveys, wind trajectory modelling, genomics, pollen metabarcoding, ecological niche modelling, and multi-isotope geolocation of natal origins. The overall journey, which was energetically feasible only if assisted by winds, is among the longest documented for individual insects, and potentially the first verified transatlantic crossing. Our findings suggest that we may be underestimating transoceanic dispersal in insects and highlight the importance of aerial highways connecting continents by trade winds.
Production of constrained L-cyclo-tetrapeptides by epimerization-resistant direct aminolysis
Authors: Chen Huan , Zhang Yuchen , Wen Yuming , Fan Xinhao , Sciolino Nicholas , Lin Yanyun , Breindel Leonard , Dai Yuanwei , Shekhtman Alexander , Xue Xiao-Song , Zhang Qiang 
Published: June 2024

AbstractThe synthesis of constrained 12-membered rings is notably difficult. The main challenges result from constraints during the linear peptide cyclization. Attempts to overcome constraints through excessive activation frequently cause peptidyl epimerization, while insufficient activation of the C-terminus hampers cyclization and promotes intermolecular oligomer formation. We present a β-thiolactone framework that enables the synthesis of cyclo-tetrapeptides via direct aminolysis. This tactic utilizes a mechanism that restricts C-terminal carbonyl rotation while maintaining high reactivity, thereby enabling efficient head-to-tail amidation, reducing oligomerization, and preventing epimerization. A broad range of challenging cyclo-tetrapeptides ( > 20 examples) are synthesized in buffer and exhibits excellent tolerance toward nearly all proteinogenic amino acids. Previously unattainable macrocycles, such as cyclo-L-(Pro-Tyr-Pro-Val), have been produced and identified as μ-opioid receptor (MOR) agonists, with an EC50 value of 2.5 nM. Non-epimerizable direct aminolysis offers a practical solution for constrained peptide cyclization, and the discovery of MOR agonist activity highlights the importance of overcoming synthetic challenges for therapeutic development.
Tandem dehydrogenation-olefination-decarboxylation of cycloalkyl carboxylic acids via multifold C–H activation
Authors: Pal Tanay , Ghosh Premananda , Islam Minhajul , Guin Srimanta , Maji Suman , Dutta Suparna , Das Jayabrata , Ge Haibo , Maiti Debabrata 
Published: June 2024

AbstractDehydrogenation chemistry has long been established as a fundamental aspect of organic synthesis, commonly encountered in carbonyl compounds. Transition metal catalysis revolutionized it, with strategies like transfer-dehydrogenation, single electron transfer and C–H activation. These approaches, extended to multiple dehydrogenations, can lead to aromatization. Dehydrogenative transformations of aliphatic carboxylic acids pose challenges, yet engineered ligands and metal catalysis can initiate dehydrogenation via C–H activation, though outcomes vary based on substrate structures. Herein, we have developed a catalytic system enabling cyclohexane carboxylic acids to undergo multifold C–H activation to furnish olefinated arenes, bypassing lactone formation. This showcases unique reactivity in aliphatic carboxylic acids, involving tandem dehydrogenation-olefination-decarboxylation-aromatization sequences, validated by control experiments and key intermediate isolation. For cyclopentane carboxylic acids, reluctant to aromatization, the catalytic system facilitates controlled dehydrogenation, providing difunctionalized cyclopentenes through tandem dehydrogenation-olefination-decarboxylation-allylic acyloxylation sequences. This transformation expands carboxylic acids into diverse molecular entities with wide applications, underscoring its importance.
Battery electronification: intracell actuation and thermal management
Authors: Longchamps Ryan S. , Ge Shanhai , Trdinich Zachary J. , Liao Jie , Wang Chao-Yang 
Published: June 2024

AbstractElectrochemical batteries – essential to vehicle electrification and renewable energy storage – have ever-present reaction interfaces that require compromise among power, energy, lifetime, and safety. Here we report a chip-in-cell battery by integrating an ultrathin foil heater and a microswitch into the layer-by-layer architecture of a battery cell to harness intracell actuation and mutual thermal management between the heat-generating switch and heat-absorbing battery materials. The result is a two-terminal, drop-in ready battery with no bulky heat sinks or heavy wiring needed for an external high-power switch. We demonstrate rapid self-heating (∼ 60 °C min−1), low energy consumption (0.138% °C−1 of battery energy), and excellent durability (> 2000 cycles) of the greatly simplified chip-in-cell structure. The battery electronification platform unveiled here opens doors to include integrated-circuit chips inside energy storage cells for sensing, control, actuating, and wireless communications such that performance, lifetime, and safety of electrochemical energy storage devices can be internally regulated.
3D architecture and complex behavior along the simple central San Andreas fault
Authors: Cheng Yifang , Bürgmann Roland , Allen Richard M. 
Published: June 2024

AbstractThe central San Andreas Fault (CSAF) exhibits a simple linear large-scale fault geometry, yet seismic and aseismic deformation features vary in a complex way along the fault. Here we investigate fault zone behaviors using geodetic observation, seismicity and microearthquake focal mechanisms. We employ an improved focal-mechanism characterization method using relative earthquake radiation patterns on 75,164 Ml ≥ 1 earthquakes along a 2-km-wide, 190-km-long segment of the CSAF, from 1984 to 2015. The data reveal the 3D fine-scale structure and interseismic kinematics of the CSAF. Our findings indicate that the first-order spatial variations in interseismic fault creep rate, creep direction, and the fault zone stress field can be explained by a simple fault coupling model. The inferred 3D mechanical properties of a mechanically weak and poorly coupled fault zone provide a unified understanding of the complex fine-scale kinematics, indicating distributed slip deficits facilitating small-to-moderate earthquakes, localized stress heterogeneities, and complex multi-scale ruptures along the fault. Through this detailed mapping, we aim to relate the fine-scale fault architecture to potential future faulting behavior along the CSAF.
Automated neuronal reconstruction with super-multicolour Tetbow labelling and threshold-based clustering of colour hues
Authors: Leiwe Marcus N. , Fujimoto Satoshi , Baba Toshikazu , Moriyasu Daichi , Saha Biswanath , Sakaguchi Richi , Inagaki Shigenori , Imai Takeshi 
Published: June 2024

AbstractFluorescence imaging is widely used for the mesoscopic mapping of neuronal connectivity. However, neurite reconstruction is challenging, especially when neurons are densely labelled. Here, we report a strategy for the fully automated reconstruction of densely labelled neuronal circuits. Firstly, we establish stochastic super-multicolour labelling with up to seven different fluorescent proteins using the Tetbow method. With this method, each neuron is labelled with a unique combination of fluorescent proteins, which are then imaged and separated by linear unmixing. We also establish an automated neurite reconstruction pipeline based on the quantitative analysis of multiple dyes (QDyeFinder), which identifies neurite fragments with similar colour combinations. To classify colour combinations, we develop unsupervised clustering algorithm, dCrawler, in which data points in multi-dimensional space are clustered based on a given threshold distance. Our strategy allows the reconstruction of neurites for up to hundreds of neurons at the millimetre scale without using their physical continuity.
N-terminal cysteine acetylation and oxidation patterns may define protein stability
Authors: Heathcote Karen C. , Keeley Thomas P. , Myllykoski Matti , Lundekvam Malin , McTiernan Nina , Akter Salma , Masson Norma , Ratcliffe Peter J. , Arnesen Thomas , Flashman Emily 
Published: June 2024

AbstractOxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.
Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode
Authors: Shenol Aslihan , Tenente Ricardo , Lückmann Michael , Frimurer Thomas M. , Schwartz Thue W. 
Published: June 2024

AbstractA surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.
Discovering type I cis-AT polyketides through computational mass spectrometry and genome mining with Seq2PKS
Authors: Yan Donghui , Zhou Muqing , Adduri Abhinav , Zhuang Yihao , Guler Mustafa , Liu Sitong , Shin Hyonyoung , Kovach Torin , Oh Gloria , Liu Xiao , Deng Yuting , Wang Xiaofeng , Cao Liu , Sherman David H. , Schultz Pamela J. , Kersten Roland D. , Clement Jason A. , Tripathi Ashootosh , Behsaz Bahar , Mohimani Hosein 
Published: June 2024

AbstractType 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown. Characterizing polyketides relies on bioactivity-guided purification, which is expensive and time-consuming. To address this, we present Seq2PKS, a machine learning algorithm that predicts chemical structures derived from Type 1 polyketide synthases. Seq2PKS predicts numerous putative structures for each gene cluster to enhance accuracy. The correct structure is identified using a variable mass spectral database search. Benchmarks show that Seq2PKS outperforms existing methods. Applying Seq2PKS to Actinobacteria datasets, we discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamide-actiphenol.
Deep representation learning of chemical-induced transcriptional profile for phenotype-based drug discovery
Authors: Tong Xiaochu , Qu Ning , Kong Xiangtai , Ni Shengkun , Zhou Jingyi , Wang Kun , Zhang Lehan , Wen Yiming , Shi Jiangshan , Zhang Sulin , Li Xutong , Zheng Mingyue 
Published: June 2024

AbstractArtificial intelligence transforms drug discovery, with phenotype-based approaches emerging as a promising alternative to target-based methods, overcoming limitations like lack of well-defined targets. While chemical-induced transcriptional profiles offer a comprehensive view of drug mechanisms, inherent noise often obscures the true signal, hindering their potential for meaningful insights. Here, we highlight the development of TranSiGen, a deep generative model employing self-supervised representation learning. TranSiGen analyzes basal cell gene expression and molecular structures to reconstruct chemical-induced transcriptional profiles with high accuracy. By capturing both cellular and compound information, TranSiGen-derived representations demonstrate efficacy in diverse downstream tasks like ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. Notably, in vitro validation of TranSiGen’s application in pancreatic cancer drug discovery highlights its potential for identifying effective compounds. We envisage that integrating TranSiGen into the drug discovery and mechanism research holds significant promise for advancing biomedicine.
Beta-lactamase dependent and independent evolutionary paths to high-level ampicillin resistance
Authors: Gross Rotem , Yelin Idan , Lázár Viktória , Datta Manoshi Sen , Kishony Roy 
Published: June 2024

AbstractThe incidence of beta-lactam resistance among clinical isolates is a major health concern. A key method to study the emergence of antibiotic resistance is adaptive laboratory evolution. However, in the case of the beta-lactam ampicillin, bacteria evolved in laboratory settings do not recapitulate clinical-like resistance levels, hindering efforts to identify major evolutionary paths and their dependency on genetic background. Here, we used the Microbial Evolution and Growth Arena (MEGA) plate to select ampicillin-resistant Escherichia coli mutants with varying degrees of resistance. Whole-genome sequencing of resistant isolates revealed that ampicillin resistance was acquired via a combination of single-point mutations and amplification of the gene encoding beta-lactamase AmpC. However, blocking AmpC-mediated resistance revealed latent adaptive pathways: strains deleted for ampC were able to adapt through combinations of changes in genes involved in multidrug resistance encoding efflux pumps, transcriptional regulators, and porins. Our results reveal that combinations of distinct genetic mutations, accessible at large population sizes, can drive high-level resistance to ampicillin even independently of beta-lactamases.