bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clr4SUV39H1 ubiquitination and non-coding RNA mediate transcriptional silencing of heterochromatin via Swi6 phase separation
Authors: Kim Hyun-Soo , Roche Benjamin , Bhattacharjee Sonali , Todeschini Leila , Chang An-Yun , Hammell Christopher , Verdel André , Martienssen Robert A. 
Published: October 2024

AbstractTranscriptional silencing by RNAi paradoxically relies on transcription, but how the transition from transcription to silencing is achieved has remained unclear. The Cryptic Loci Regulator complex (CLRC) in Schizosaccharomyces pombe is a cullin-ring E3 ligase required for silencing that is recruited by RNAi. We found that the E2 ubiquitin conjugating enzyme Ubc4 interacts with CLRC and mono-ubiquitinates the histone H3K9 methyltransferase Clr4SUV39H1, promoting the transition from co-transcriptional gene silencing (H3K9me2) to transcriptional gene silencing (H3K9me3). Ubiquitination of Clr4 occurs in an intrinsically disordered region (Clr4IDR), which undergoes liquid droplet formation in vitro, along with Swi6HP1 the effector of transcriptional gene silencing. Our data suggests that phase separation is exquisitely sensitive to non-coding RNA (ncRNA) which promotes self-association of Clr4, chromatin association, and di-, but not tri- methylation instead. Ubc4-CLRC also targets the transcriptional co-activator Bdf2BRD4, down-regulating centromeric transcription and small RNA (sRNA) production. The deubiquitinase Ubp3 counteracts both activities.
Cryo-EM reveals structural basis for human AIM/CD5L recognition of polymeric immunoglobulin M
Authors: Chen Qu , Ishii Kazuhiro , Mori Haruka , Nishijima Akemi , Arai Satoko , Miyazaki Toru , Rosenthal Peter B. 
Published: October 2024

AbstractCell surface scavenger receptors contribute to homoeostasis and the response to pathogens and products associated with damage by binding to common molecular features on a wide range of targets. Apoptosis inhibitor of macrophage (AIM/CD5L) is a soluble protein belonging to the scavenger receptor cysteine-rich (SRCR) superfamily that contributes to prevention of a wide range of diseases associated with infection, inflammation, and cancer. AIM forms complexes with IgM pentamers which helps maintain high-levels of circulating AIM in serum for subsequent activation on release from the complex. The structural basis for AIM recognition of IgM as well as other binding targets is unknown. Here we apply cryogenic electron microscopy imaging (cryo-EM) to show how interfaces on both of AIM’s C-terminal SRCR domains interact with the Fcμ constant region and J chain components of the IgM core. Both SRCR interfaces are also shown to contribute interactions important for AIM binding to damage-associated molecular patterns (DAMPs).
TamGen: drug design with target-aware molecule generation through a chemical language model
Authors: Wu Kehan , Xia Yingce , Deng Pan , Liu Renhe , Zhang Yuan , Guo Han , Cui Yumeng , Pei Qizhi , Wu Lijun , Xie Shufang , Chen Si , Lu Xi , Hu Song , Wu Jinzhi , Chan Chi-Kin , Chen Shawn , Zhou Liangliang , Yu Nenghai , Chen Enhong , Liu Haiguang , Guo Jinjiang , Qin Tao , Liu Tie-Yan 
Published: October 2024

AbstractGenerative drug design facilitates the creation of compounds effective against pathogenic target proteins. This opens up the potential to discover novel compounds within the vast chemical space and fosters the development of innovative therapeutic strategies. However, the practicality of generated molecules is often limited, as many designs focus on a narrow set of drug-related properties, failing to improve the success rate of subsequent drug discovery process. To overcome these challenges, we develop TamGen, a method that employs a GPT-like chemical language model and enables target-aware molecule generation and compound refinement. We demonstrate that the compounds generated by TamGen have improved molecular quality and viability. Additionally, we have integrated TamGen into a drug discovery pipeline and identified 14 compounds showing compelling inhibitory activity against the Tuberculosis ClpP protease, with the most effective compound exhibiting a half maximal inhibitory concentration (IC50) of 1.9 μM. Our findings underscore the practical potential and real-world applicability of generative drug design approaches, paving the way for future advancements in the field.
Atmospheric health burden across the century and the accelerating impact of temperature compared to pollution
Authors: Pozzer Andrea , Steffens Brendan , Proestos Yiannis , Sciare Jean , Akritidis Dimitris , Chowdhury Sourangsu , Burkart Katrin , Bacer Sara 
Published: October 2024

AbstractAnthropogenic emissions alter atmospheric composition and therefore the climate, with implications for air pollution- and climate-related human health. Mortality attributable to air pollution and non-optimal temperature is a major concern, expected to shift under future climate change and socioeconomic scenarios. In this work, results from numerical simulations are used to assess future changes in mortality attributable to long-term exposure to both non-optimal temperature and air pollution simultaneously. Here we show that under a realistic scenario, end-of-century mortality could quadruple from present-day values to around 30 (95% confidence level:12-53) million people/year. While pollution-related mortality is projected to increase five-fold, temperature-related mortality will experience a seven-fold rise, making it a more important health risk factor than air pollution for at least 20% of the world’s population. These findings highlight the urgent need to implement stronger climate policies to prevent future loss of life, outweighing the benefits of air quality improvements alone.
Seed coat-derived brassinosteroid signaling regulates endosperm development
Authors: Lima Rita B. , Pankaj Rishabh , Ehlert Sinah T. , Finger Pascal , Fröhlich Anja , Bayle Vincent , Landrein Benoit , Sampathkumar Arun , Figueiredo Duarte D. 
Published: October 2024

AbstractAn angiosperm seed is formed by the embryo and endosperm, which are direct products of fertilization, and by the maternal seed coat. These tissues communicate with each other to ensure synchronized seed development. After fertilization, auxin produced in the endosperm is exported to the integuments where it drives seed coat formation. Here, we show that the seed coat signals back to the endosperm to promote its proliferation via the steroid hormones brassinosteroids (BR). We show that BR regulate cell wall-related processes in the seed coat and that the biophysical properties of this maternal organ determine the proliferation rate of the endosperm in a manner independent of the timing of its cellularization. We thus propose that maternal BR signaling tunes endosperm proliferation to seed coat expansion.
A history-dependent integrase recorder of plant gene expression with single-cell resolution
Authors: Maranas Cassandra J. , George Wesley , Scallon Sarah K. , VanGilder Sydney , Nemhauser Jennifer L. , Guiziou Sarah 
Published: October 2024

AbstractDuring development, most cells experience a progressive restriction of fate that ultimately results in a fully differentiated mature state. Understanding more about the gene expression patterns that underlie developmental programs can inform engineering efforts for new or optimized forms. Here, we present a four-state integrase-based recorder of gene expression history and demonstrate its use in tracking gene expression events in Arabidopsis thaliana in two developmental contexts: lateral root initiation and stomatal differentiation. The recorder uses two serine integrases to mediate sequential DNA recombination events, resulting in step-wise, history-dependent switching between expression of fluorescent reporters. By using promoters that express at different times along each of the two differentiation pathways to drive integrase expression, we tie fluorescent status to an ordered progression of gene expression along the developmental trajectory. In one snapshot of a mature tissue, our recorder is able to reveal past gene expression with single cell resolution. In this way, we are able to capture heterogeneity in stomatal development, confirming the existence of two alternate paths of differentiation.
Selective monodeuteration enabled by bisphosphonium catalyzed ring opening processes
Authors: Xu Yuanli , Chen Wenlong , Pu Ruihua , Ding Jia , An Qing , Yang Yi , Liu Weimin , Zuo Zhiwei 
Published: October 2024

AbstractThe selective incorporation of a deuterium atom into small molecules with high selectivity is highly valuable for medical and chemical research. Unfortunately, this remains challenging due to the complete deuteration caused by commonly used hydrogen isotope exchange strategies. We report the development of a photocatalytic selective monodeuteration protocol utilizing C–C bond as the unconventional functional handle. The synergistic combination of radical-mediated C–C bond scission and deuterium atom transfer processes enables the effective constructions of benzylic CDH moieties with high selectivity for monodeuteration. The combinational use of a bisphosphonium photocatalyst, thiol catalyst, and CH3OD deuteration agent provides operationally simple conditions for photocatalytic monodeuteration. Moreover, the photoinduced electron transfer process of the bisphosphonium photocatalyst is elucidated through a series of spectroscopy experiments, identifying a peculiar back electron transfer process that can be regulated by subsequent nucleophilic additions.
Assessing the validity of a self-reported clinical diagnosis of schizophrenia
Authors: Woolway Grace E. , Legge Sophie E. , Lynham Amy J. , Smart Sophie E. , Hubbard Leon , Daniel Ellie R. , Pardiñas Antonio F. , Escott-Price Valentina , O’Donovan Michael C. , Owen Michael J. , Jones Ian R. , Walters James T. R. 
Published: October 2024

AbstractThe increasing availability of biobanks is changing the way individuals are identified for genomic research. This study assesses the validity of a self-reported clinical diagnosis of schizophrenia. The study included 1744 clinically-ascertained participants with schizophrenia or schizoaffective disorder depressed-type (SA-D) diagnosed by self-report and/or research interview and 1453 UK Biobank participants with self-reported and/or medical record diagnosis of schizophrenia or SA-D. Unaffected controls included a total of 501,837 participants. We assessed the positive predictive values (PPV) of self-reported clinical diagnoses against research interview and medical record diagnoses. Polygenic risk scores (PRS) and phenotypes relating to demographics, education and employment were compared across diagnostic groups. The variance explained (r2) in schizophrenia PRS for each diagnostic group was compared to samples in the Psychiatric Genomics Consortium (PGC). In the clinically-ascertained participants, the PPV of self-reported schizophrenia for a research diagnosis of schizophrenia was 0.70, which increased to 0.81 after expanding the research diagnosis to schizophrenia or SA-D. In UK Biobank, the PPV of self-reported schizophrenia for a medical record diagnosis was 0.74. Compared to participants who self-reported, participants with a clinically-ascertained research diagnosis were younger and more likely to have a high school qualification. Participants with a medical record diagnosis in UK Biobank were less likely to be employed or have a high school qualification than those who self-reported. Schizophrenia PRS did not differ between participants that had a diagnosis from self-report, research diagnosis or medical records. Polygenic liability r2, for all diagnosis definitions, fell within the distribution of PGC schizophrenia cohorts. Self-reported measures of schizophrenia are justified in genomic research to maximise sample size and reduce the burden of in-depth interviews on participants, although within sample validation of diagnoses is recommended.
Cryptic degassing and protracted greenhouse climates after flood basalt events
Authors: Black Benjamin A. , Karlstrom Leif , Mills Benjamin J. W. , Mather Tamsin A. , Rudolph Maxwell L. , Longman Jack , Merdith Andrew 
Published: October 2024

AbstractLarge igneous provinces erupt highly reactive, predominantly basaltic lavas onto Earth’s surface, which should boost the weathering flux leading to long-term CO2 drawdown and cooling following cessation of volcanism. However, throughout Earth’s geological history, the aftermaths of multiple Phanerozoic large igneous provinces are marked by unexpectedly protracted climatic warming and delayed biotic recovery lasting millions of years beyond the most voluminous phases of extrusive volcanism. Here we conduct geodynamic modelling of mantle melting and thermomechanical modelling of magma transport to show that rheologic feedbacks in the crust can throttle eruption rates despite continued melt generation and CO2 supply. Our results demonstrate how the mantle-derived flux of CO2 to the atmosphere during large igneous provinces can decouple from rates of surface volcanism, representing an important flux driving long-term climate. Climate–biogeochemical modelling spanning intervals with temporally calibrated palaeoclimate data further shows how accounting for this non-eruptive cryptic CO2 can help reconcile the life cycle of large igneous provinces with climate disruption and recovery during the Permian–Triassic, Mid-Miocene and other critical moments in Earth’s climate history. These findings underscore the key role that outgassing from intrusive magmas plays in modulating our planet’s surface environment.
Inferring allele-specific copy number aberrations and tumor phylogeography from spatially resolved transcriptomics
Authors: Ma Cong , Balaban Metin , Liu Jingxian , Chen Siqi , Wilson Michael J. , Sun Christopher H. , Ding Li , Raphael Benjamin J. 
Published: October 2024

AbstractAnalyzing somatic evolution within a tumor over time and across space is a key challenge in cancer research. Spatially resolved transcriptomics (SRT) measures gene expression at thousands of spatial locations in a tumor, but does not directly reveal genomic aberrations. We introduce CalicoST, an algorithm to simultaneously infer allele-specific copy number aberrations (CNAs) and reconstruct spatial tumor evolution, or phylogeography, from SRT data. CalicoST identifies important classes of CNAs—including copy-neutral loss of heterozygosity and mirrored subclonal CNAs—that are invisible to total copy number analysis. Using nine patients’ data from the Human Tumor Atlas Network, CalicoST achieves an average accuracy of 86%, approximately 21% higher than existing methods. CalicoST reconstructs a tumor phylogeography in three-dimensional space for two patients with multiple adjacent slices. CalicoST analysis of multiple SRT slices from a cancerous prostate organ reveals mirrored subclonal CNAs on the two sides of the prostate, forming a bifurcating phylogeography in both genetic and physical space.
NPKGRIDS: a global georeferenced dataset of N, P2O5, and K2O fertilizer application rates for 173 crops
Authors: Nguyen Thu Ha , Tang Fiona H. M. , Conchedda Giulia , Casse Leon , Obli-Laryea Griffiths , Tubiello Francesco N. , Maggi Federico 
Published: October 2024

AbstractWe introduce NPKGRIDS, a new geospatial dataset, providing for the first time data on application rates for all three main plant nutrients, nitrogen (N), phosphorus (P, in terms of phosphorus pentoxide, P2O5) and potassium (K, in terms of potassium oxide, K2O) across 173 crops as of 2020, with a geospatial resolution of 0.05° (approximately 5.6 km at the equator). Development of NPKGRIDS adopted a data fusion approach to integrate crop mask information with eight published datasets of fertilizer application rates, compiled from either georeferenced data or national and subnational statistics. Furthermore, the total applied mass of N, P2O5, and K2O were benchmarked against the country level information from FAO and the International Fertilizers Association (IFA) and validated against data available from National Statistical Offices (NSOs). NPKGRIDS can be used in global modelling, and decision and policy making to help maximize crop yields while reducing environmental impacts.
Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine
Authors: Künzel Stephan R. , Klapproth Erik , Zimmermann Nick , Kämmerer Susanne , Schubert Mario , Künzel Karolina , Hoffmann Maximilian , Drukewitz Stephan , Vehlow Anne , Eitler Jiri , Arriens Marieke , Thiel Jessica , Kronstein-Wiedemann Romy , Tietze Maximiliane , Beissert Stefan , Renner Bertold , El-Armouche Ali , Günther Claudia 
Published: October 2024

AbstractRadiation-induced morphea (RIM) is a rare complication of radiotherapy presenting as inflammatory fibrosis, most commonly reported in breast cancer patients. As underlying disease mechanisms are not well understood, targeted therapies are lacking. Since fibroblasts are the key mediators of all fibroproliferative diseases, this study aimed to characterize patient-derived fibroblasts to identify therapeutic targets. We studied primary human control and RIM-fibroblasts on a functional and molecular basis, analyzed peripheral blood and tissue samples and conducted, based on our findings, a treatment attempt in one patient. In RIM, we identified a distinct myofibroblast phenotype reflected by increased alpha-smooth-muscle-actin (αSMA) expression, reduced proliferation and migration rates, and overexpression of osteopontin (OPN). Our RNA sequencing identified aberrant Myc activation as a potential disease driver in RIM fibroblasts, similar to previous findings in systemic sclerosis. Treatment with the anti-inflammatory drug mesalazine reversed the myofibroblast phenotype by targeting Myc. Based on these findings, a patient with RIM was successfully treated with mesalazine, resulting in reduced inflammation and pain and tissue softening, while serum OPN was halved. The present study provides a comprehensive characterization of RIM fibroblasts, suggests a disease-driving role for Myc, demonstrates promising antifibrotic effects of mesalazine and proposes OPN as a biomarker for RIM.
The impact of physiological state and environmental stress on bacterial load estimation methodologies for Mycobacterium tuberculosis
Authors: Maitra Arundhati , Wijk Marie , Margaryan Hasmik , Denti Paolo , McHugh Timothy D. , Kloprogge Frank 
Published: October 2024

AbstractWhen processed in solid or liquid medium, tuberculosis patient samples yield different proportions of a heterogenous bacterial community over the duration of treatment. We aimed to derive a relationship between methodologies for bacterial load determination and assess the effect of the growth phase of the parent culture and its exposure to stress on the results. Mycobacterium tuberculosis H37Rv was grown with and without antibiotic (isoniazid or rifampicin) and sampled on day 0, 3, 11 and 21 of growth in broth culture. The bacterial load was estimated by colony counts and the BD BACTEC MGIT system. Linear and nonlinear mixed-effects models were used to describe the relationship between time-to-positivity (TTP) and time-to-growth (TTG) versus colony forming units (CFU), and growth units (GU) versus incubation time in MGIT. For samples with the same CFU, antibiotic-treated and stationary phase cells had a shorter TTP than antibiotic-free controls and early-logarithmic phase cells, respectively. Similarly, stationary phase samples reached higher GUs and had shorter TTG than early-log phase ones. This suggests that there is a population of bacterial cells that can be differentially recovered in liquid medium, giving us insight into the physiological states of the original culture, aiding the interpretation of clinical trial outputs.
Perceptions of building-integrated nature-based solutions by suppliers versus consumers in Egypt
Authors: Marzouk Mai A. , Salheen Mohamed A. , Fischer Leonie K. 
Published: October 2024

AbstractCan Building-Integrated Nature-based Solutions (BI-NbS) reach their full potential in the Global South? In the Egyptian context, BI-NbS are relatively new with an identified gap between the high potential in theory and low implementation rates in practice. To bridge this gap, the study conducts an in-depth investigation of BI-NbS market conditions to reveal the current trends in the residential buildings market in Egypt. It also identifies the gaps and overlaps in the perceptions of the suppliers and consumers of BI-NbS. Results reveal that the residential sector sales mainly target high-income groups yet very limited and dominated by rooftop systems. Suppliers advocate for high-tech systems over low-tech systems, whereas consumers prefer the latter. The perceptions of suppliers and consumers mostly align regarding the basic aspects such as the production and operation preferences as well as the anxieties and concerns about the relatively new BI-NbS in this regional context. However, they diverge in key aspects affecting market penetration such as implementation conditions, aims, and barriers. Accordingly, the study identified the gap between suppliers and consumers, and outlined recommendations, directed to suppliers and policymakers, for improved market development and local implementation of BI-NbS in emerging markets of the Global South, such as Egypt.
Native multi-qubit gates in transmon qubits via synchronous driving
Authors: Pratapsi Sagar Silva , Cruz Diogo , André Paulo 
Published: October 2024

AbstractQuantum computation holds the promise of solving computational problems which are believed to be classically intractable. However, in practice, quantum devices are still limited by their relatively short coherence times and imperfect circuit-hardware mapping. In this work, we present the parallelization of pre-calibrated pulses at the hardware level as an easy-to-implement strategy to optimize quantum gates. Focusing on $$R_{ZX}$$

R

ZX

gates, we demonstrate that such parallelization leads to improved fidelity and gate time reduction, when compared to serial concatenation. As measured by Cycle Benchmarking and Process Tomography, we reduce gate errors by half. We show that this strategy can be applied to other gates like the CNOT and CZ, and it may benefit tasks such as Hamiltonian simulation problems, amplitude amplification, and error-correction codes.