bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxyfluorfen use in combination with clomazone or quinclorac
Authors: Norsworthy Jason K. , Arnold Casey H. , Butts Thomas R. , Shelton Chad W.
Published: October 2024

Oxyfluorfen is a herbicide that inhibits protoporphyrinogen IX oxidase and has shown significant potential in its ability to control barnyardgrass. Oxyfluorfen is categorized as a Group 14 herbicide by the Herbicide Resistance Action Committee (HRAC)/Weed Science Society of America (WSSA). Despite its current lack of labeling for use on rice in the mid-southern United States due to its potential to cause crop injury, the introduction of a trait in rice that confers resistance to oxyfluorfen could provide producers with an effective alternative site of action for weed control. Field experiments were conducted during the 2021 and 2022 growing seasons near Stuttgart, AR, and near Lonoke, AR, to determine the optimum rates of clomazone (280 or 336 g ha−1) and oxyfluorfen (673 or 840 g ha−1) to use in sequential preemergence (PRE) and postemergence (POST) applications on a silt loam soil and to assess the efficacy of oxyfluorfen when combined with clomazone and quinclorac applied PRE, followed by oxyfluorfen applied POST. No differences in barnyardgrass control were observed among treatments 14 d after emergence in 3 site years, as all control was ≥90%. By 35 d after the POST application, barnyardgrass control was ≥94% for all herbicide treatments in all site years. All herbicide treatments resulted in lower barnyardgrass seed production than a nontreated control in 2021. Contrasts revealed that oxyfluorfen applied PRE on a silt loam soil resulted in barnyardgrass control that was similar to that of clomazone or quinclorac applied alone at 14 d after emergence. Although oxyfluorfen combined with clomazone or quinclorac did not increase barnyardgrass control, an additional site of action for control of this weed could help reduce the evolution of resistance. Mixing oxyfluorfen with clomazone in a dry-seeded rice production system in the mid-southern United States would effectively control barnyardgrass and reduce the risk for resistance to both herbicides, further highlighting the potential of oxyfluorfen in rice production.
Baseline survey reveals glyphosate and dicamba resistance in broadleaf weeds before sugar beet trait introduction
Authors: Simões Araujo André Lucas , Westra Eric P. , Shergill Lovreet , Gaines Todd A.
Published: October 2024

A prelaunch survey of broadleaf weeds was conducted to predict the weed management efficacy of a novel genetically engineered sugar beet with resistance traits for glyphosate, dicamba, and glufosinate. We targeted problematic broadleaf weed species prevalent in sugar beet fields, including kochia, common lambsquarters, Palmer amaranth, and redroot pigweed in Colorado, Nebraska, and Wyoming. The results revealed that a significant percentage of kochia populations in Colorado, Nebraska, and Wyoming exhibited resistance to glyphosate (94%, 98%, and 75%, respectively) and dicamba (30%, 42%, and 17%, respectively). Palmer amaranth populations had resistance frequencies for glyphosate and dicamba of 80% and 20% in Colorado and 20% and 3% in Nebraska, respectively. No resistance to the tested herbicides was identified in common lambsquarters or redroot pigweed. Glufosinate resistance was not identified for any species. Kochia and Palmer amaranth populations from Colorado and Nebraska exhibited glyphosate resistance primarily through 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene amplification. However, one glyphosate-resistant kochia population from Wyoming lacked EPSPS gene amplification, indicating the presence of an alternative resistance mechanism. We identified the previously characterized IAA16 G73N substitution in a dicamba-resistant kochia population from Nebraska. However, dicamba-resistant kochia populations from Colorado did not possess this substitution, suggesting an alternative, yet-to-be-determined resistance mechanism. The widespread prevalence of glyphosate and dicamba resistance, coupled with the emergence of novel resistance mechanisms, poses a significant challenge to the long-term efficacy of this novel genetically engineered sugar beet technology. These findings underscore the urgent need for integrated weed management strategies that diversify effective herbicide sites-of-action and incorporate alternative weed management practices within cropping systems.
Dynamics, Monitoring, and Forecasting of Tephra in the Atmosphere
Authors: Pardini F. , Barsotti S. , Bonadonna C. , de’ Michieli Vitturi M. , Folch A. , Mastin L. , Osores S. , Prata A. T.
Published: October 2024

Explosive volcanic eruptions inject hot mixtures of solid particles (tephra) and gasses into the atmosphere. Entraining ambient air, these mixtures can form plumes rising tens of kilometers until they spread laterally, forming umbrella clouds. While the largest clasts tend to settle in proximity to the volcano, the smallest fragments, commonly referred to as ash (≤2 mm in diameter), can be transported over long distances, forming volcanic clouds. Tephra plumes and clouds pose significant hazards to human society, affecting infrastructure, and human health through deposition on the ground or airborne suspension at low altitudes. Additionally, volcanic clouds are a threat to aviation, during both high‐risk actions such as take‐off and landing and at standard cruising altitudes. The ability to monitor and forecast tephra plumes and clouds is fundamental to mitigate the hazard associated with explosive eruptions. To that end, various monitoring techniques, ranging from ground‐based instruments to sensors on‐board satellites, and forecasting strategies, based on running numerical models to track the position of volcanic clouds, are efficiently employed. However, some limitations still exist, mainly due to the high unpredictability and variability of explosive eruptions, as well as the multiphase and complex nature of volcanic plumes. In the next decades, advances in monitoring and computational capabilities are expected to address these limitations and significantly improve the mitigation of the risk associated with tephra plumes and clouds.
Radiative Feedback From Dry Environmental Air Accelerates Tropical Cyclogenesis
Authors: Wu S.‐N. , Soden B. J.
Published: October 2024

A number of recent studies have highlighted how radiative feedback from clouds accelerates tropical cyclone (TC) development by amplifying spatial gradients in radiative heating. This study extends this work by examining how spatial gradients in free tropospheric moisture influence TC development through their impact on environmental radiative heating. We conduct a series of idealized model experiments in which only the longwave radiative heating due to water vapor is modified in the environmental region outside of the TC area. These experiments demonstrate that a vortex in a drier environmental free troposphere experiences faster development. Moreover, weaker vortices actually require a dry environmental free troposphere to develop. The accelerated genesis mainly results from a stronger spatial gradient in moisture‐induced radiative heating, which enhances energy convergence through a stronger transverse circulation. These results highlight a potentially important and overlooked role of dry air in facilitating TC genesis.
Midlatitude Plasma Blob‐like Structures Along With Super Equatorial Plasma Bubbles During the May 2024 Great Geomagnetic Storm
Authors: Sun Wenjie , Li Guozhu , Zhao Biqiang , Zhang Shun‐Rong , Otsuka Yuichi , Hu Lianhuan , Dai Guofeng , Zhao Xiukuan , Xie Haiyong , Li Yi , Liu Jianfei , Li Yu , Ning Baiqi , Liu Libo , Shinbori Atsuki , Nishioka Michi , Perwitasari Septi
Published: October 2024

Plasma blob is generally a low‐latitude phenomenon occurring at the poleward edge of equatorial plasma bubble (EPB) during post‐sunset periods. Here we report a case of midlatitude ionospheric plasma blob‐like structures occurring along with super EPBs over East Asia around sunrise during the May 2024 great geomagnetic storm. Interestingly, the blob‐like structures appeared at both the poleward and westward edges of EPBs, reached up to 40°N magnetic latitudes, and migrated westward several thousand kilometers together with the bubble. The total electron content (TEC) inside the blob‐like structures was enhanced by ∼50 TEC units relative to the ambient ionosphere. The blob‐like structure at the EPB poleward edge could be partly linked with field‐aligned plasma accumulation due to poleward development of bubble. For the blob‐like structure at the EPB west side, one possible mechanism is that it was formed and enhanced accompanying the bubble evolution and westward drift.
Modeling the Post‐Midnight Equatorial Plasma Bubbles With SAMI3/SD‐WACCM‐X: Large‐Scale Wave Structure
Authors: Chou Min‐Yang , Yue Jia , McDonald Sarah , Sassi Fabrizio , Tate Jennifer , Pedatella Nicholas , Harvey V. Lynn
Published: October 2024

This study investigates the relative significance of gravity wave and gravity dynamo effects in large‐scale wave structure (LSWS) development using the coupled Sami3 is Also a Model of the Ionosphere (SAMI3) and Specified Dynamics Whole Atmosphere Community Climate Model with thermosphere‐ionosphere eXtension (SD‐WACCM‐X). Simulations show significant vertical E × B drift perturbations associated with gravity waves in the F region after ∼1700 LT, leading to LSWS near midnight. Notably, LSWS can occur independently of gravity‐driven dynamo current, emphasizing the significance of the gravity wave wind dynamo mechanism. However, LSWS exhibits more pronounced vertical E × B drift perturbations, indicating the involvement of background wind fields. Both gravity wave and background wind dynamo effects cause LSWS to grow vertically by ∼20 km and extend to ±10° in latitude. Gravity‐driven Pedersen current, therefore, plays a role in amplifying the upwelling growth and equatorial plasma bubble development. Furthermore, simulations demonstrate the emergence of predawn ionospheric irregularities in the bottomside F layer, even without gravity‐driven currents, attributed to concentric gravity waves over the magnetic equator. A comparison between FORMOSAT‐7/COSMIC2 and SAMI3 ion density is also conducted. These findings emphasize the significant influence of gravity waves and background wind fields on the formation of LSWS and irregularities.
On the Inverse Correlation Between the Thermosphere Winter Helium Bulge and Solar Activity: Impact of Gravity Wave Drag From the Mesosphere
Authors: Ren Dexin , Lei Jiuhou , Liu Han‐Li , Wang Wenbin , Yue Jia , Liu Huixin , Liu Yu
Published: October 2024

Understanding the temporal and spatial variations in the ideal inert tracer helium can provide insight into the dynamic evolution of the thermosphere. The magnitude of the thermospheric winter helium bulge was inversely correlated with the level of solar activity. However, this feature has been found to be not reproduced by the Thermosphere‐Ionosphere Electrodynamic General Circulation Model (TIEGCM), and the associated physical mechanisms remain unknown. Using the Thermosphere‐Ionosphere‐Mesosphere Electrodynamic General Circulation Model (TIME‐GCM), we found that mesospheric gravity wave drag (GWD) is a factor contributing to this inverse correlation. Specifically, the summer‐to‐winter circulation in thermosphere becomes the main cause of the helium bulge, as mesospheric GWD can play a role in strengthening this circulation. The GWD contributions to temperature change below the lower thermosphere do not depend prominently on solar activity. However, because the temperature impacts on the pressure gradient force are height‐integrated according to the background temperature of the neutral gas, the higher background temperature in the thermosphere at the solar maximum corresponds to a relatively weaker response in pressure gradient force in the thermosphere. Therefore, the response of the thermospheric circulation that might be expected to accompany increasing solar activity is suppressed due to the influence of mesospheric GWD, which results in a decrease in the magnitude of the winter helium bulge with increasing solar activity. Thus, our results demonstrated that lower atmosphere forcing can play a significant role in the response of thermospheric helium to solar activity.
Magnetosheath Plasma Flow and Its Response to IMF and Geodipole Tilt as Obtained From the Data‐Based Modeling
Authors: Tsyganenko N. A. , Semenov V. S. , Erkaev N. V. , Gubaidulin N. T.
Published: October 2024

Large‐scale patterns of the steady‐state magnetosheath plasma flow and their dependence on the interplanetary magnetic field (IMF) have been reconstructed for the first time on the basis of large multi‐year multi‐mission pool of spacecraft observations, concurrent interplanetary data, and an empirical high‐resolution model. The flow model architecture builds upon a recently developed magnetosheath magnetic field representation by flexible expansions of its toroidal and poloidal components in a coordinate system, naturally conformed with the magnetopause and bow shock shapes. The model includes two physics‐based flow symmetry modes: the first one treats the magnetosphere as an axisymmetric unmagnetized obstacle, whereas the second mode takes into account the geodipole tilt, an important factor in the reconnection effects. The spacecraft data pool includes 1‐min average data by Themis (2007–2024), Cluster (2001–2022), and MMS‐1 (2015–2024) missions, as well as OMNI interplanetary data. The model drivers include the solar wind particle flux, IMF components, and the geodipole tilt angle. The model calculations faithfully reproduce the average plasma flow geometry and substantial effects have been found of the IMF orientation and magnitude, a principal factor that defines electromagnetic forces inside the magnetosheath. A strong dependence of the magnetosheath flow patterns on the Earth's dipole tilt indicates an important contribution of reconnection effects at the magnetopause to the solar wind particle transport around the dayside magnetosphere.
Advanced Hybrid Optimization Algorithms for Energy Efficient Cloud Resource Allocation
Authors: Kumar M. Suresh , Hussain D. Mansoor , Rohini M. , Manoj S. Oswalt
Published: October 2024

Cloud computing is highly sought after for its dynamic resource allocation capabilities and pay‐per‐use model. However, previous research has identified several challenges, such as lower coverage, high integration rates, longer computation times, and complex operators, all of which are associated with NP‐hard problems. These issues negatively impact the efficiency of resource allocation and scheduling, leading to slower processes, inefficiencies in multi‐objective optimization, lower throughput, and higher power consumption. To address these challenges, we propose a unique Hybridized Optimization Algorithm that integrates Crow Swarm Optimization (CSO), Cuckoo Search Optimization (CSO), and Cat Hunting Optimization (CHO). Initially, Particle Swarm Optimization (PSO) and the Crow Search Algorithm (CSA) handle the exploitation and exploration phases to balance task loads. Subsequently, Cuckoo Search Optimization (CSO) enhances resource utilization and addresses NP‐hard issues, while Cat Hunting Optimization (CHO) refines the search from global to local optimal spaces to achieve the best values. The results demonstrate that the proposed hybrid technique effectively reduces user request waiting times, lowers energy consumption, and decreases execution times on cloud servers compared to baseline approaches, thereby significantly improving overall system performance.
Enhancing Streamflow Prediction in Ungauged Basins Using a Nonlinear Knowledge‐Based Framework and Deep Learning
Authors: Ghaneei Parnian , Foroumandi Ehsan , Moradkhani Hamid
Published: October 2024

In hydrology, a fundamental task involves enhancing the predictive power of a model in ungagged basins by transferring information on physical attributes and hydroclimate dynamics from gauged basins. Introducing an integrated nonlinear clustering framework, this study aims to develop a comprehensive framework that augments predictive performance in basins where direct measurements are sparse or absent. In this framework, uniform manifold approximation and projection (UMAP) is used as a nonlinear method to extract the essential features embedded in hydro‐climatological attributes and physical properties. Then, the Growing Neural Gas (GNG) clustering model is used to find the basins that potentially share similar hydro‐climatological behaviors. Besides UMAP‐GNG, the integration of Principal Component Analysis (PCA) as a linear method to reduce dimensionality with common clustering methods are also assessed to serve as benchmarks. The results reveal that the combination of clustering algorithms with the PCA method may lead to loss of information while the nonlinear method (UMAP) can extract more informative features. The efficacy of the proposed framework is assessed across the Contiguous United States (CONUS) by training a single Base Model using long short‐term memory (LSTM) for the centroids of all clusters and then, fine‐tuning the model on the centroids of each cluster separately to create a regional model. The results indicate that using the information extracted by the UMAP‐GNG method to guide a Base Model can significantly improve the accuracy in most of the clusters and enhance the median prediction accuracy within different clusters from 0.04 to 0.37 of KGE in ungauged basins.
Assessing Nitrate Leaching During Drought and Extreme Precipitation: Exploring Deep Vadose‐Zone Monitoring, Groundwater Observations, and Field Mass Balance
Authors: Raij‐Hoffman Iael , Dahan Ofer , Dahlke Helen E. , Harter Thomas , Kisekka Isaya
Published: October 2024

The increasing concern over agricultural practices' impact on groundwater quality necessitates comprehensive studies to evaluate and compare monitoring strategies for nitrate leaching. This work addresses this imperative by examining three methodologies: deep vadose‐zone monitoring, shallow groundwater intensive monitoring, and field‐level mass balance. The primary objective of the study was to assess nitrate leaching from an intensively cropped processing tomato rotation field using three different methods. Additionally, this study focuses on contrasting conditions between the growing season (characterized by drought in some years) and the winter/rainy season (characterized by extreme precipitation in some years). Results indicate varying degrees of nitrate leaching across methods, with all approaches detecting leaching events during the growing season and off‐season precipitation. Despite uncertainties inherent in field‐level mass balance estimates, they align reasonably with intensive in‐situ monitoring results using the deep Vadose Monitoring System (VMS). Throughout two growing seasons and corresponding fall‐winter rainy periods, the VMS effectively tracked seasonal nitrogen leaching below the root zone, correlating with observed groundwater nitrate concentrations increases following extreme precipitation events. Nitrate leaching increased during heavy rainfall in the winter following dry summer periods observed across the deep vadose zone using two VMS systems. This underscores the importance of continuous monitoring and assessment in understanding nitrate dynamics and groundwater contamination risks. In conclusion, this study contributes to knowledge and ongoing research by providing insights into effective monitoring strategies for nitrate leaching into groundwater from intensive cropping systems.
Bridging piezoelectric and electrostatic effects: a novel piezo-MEMS pitch/roll gyroscope with sub 10°/h bias instability
Authors: Qi Zhenxiang , Wang Bowen , Zhai Zhaoyang , Wang Zheng , Xiong Xingyin , Yang Wuhao , Bie Xiaorui , Wang Yao , Zou Xudong
Published: October 2024

This paper proposes a novel piezo-MEMS pitch/roll gyroscope that co-integrates piezoelectric and electrostatic effects, for the first time achieves electrostatic mode-matching operation for piezoelectric gyroscopes. Movement of operated out-of-plane (OOP) mode (n = 3) and in-plane (IP) mode (n = 2) are orthogonal, ensuring that the OOP amplitude is not significantly limited by parallel plates set at nodes of IP mode. Therefore, a large OOP driving amplitude actuated by piezoelectric and frequency tuning in the IP sense mode trimmed by electrostatic can be achieved together with a low risk of pull-in, hence releases the trade-off between the tuning range and the linear actuation range. At a tuning voltage of 66 V, the frequency split decreased from 171 Hz to 0.1 Hz, resulting in a 167x times improvement in sensitivity. The mode-matched gyroscope exhibits an angle random walk (ARW) of 0.41°/√h and a bias instability (BI) of 8.85°/h on a test board within a customized vacuum chamber, marking enhancements of 68x and 301x, respectively, compared to its performance under mode-mismatch conditions. The BI performance of the presented pitch/roll gyroscope is comparable to that of the highest-performing mechanically trimmed piezo-MEMS yaw gyroscopes known to date, while offering the unique advantage of lower cost, better mode-matching resolution, and the flexibility of real-time frequency control.
Sequential activation of ERα-AMPKα signaling by the flavonoid baicalin down-regulates viral HNF-dependent HBV replication
Authors: Niu Yi-jun , Xia Cheng-jie , Ai Xin , Xu Wei-ming , Lin Xiao-tong , Zhu Ying-qi , Zhu Hai-yan , Zeng Xian , Cao Zhong-lian , Zhou Wei , Huang Hai , Shi Xun-long
Published: October 2024

Baicalin (BA), a natural component found in many traditional Chinese medicines, exerts protective effects against several viruses. Although our previous studies have revealed that the anti-hepatitis B virus (anti-HBV) activity of BA depends on hepatocyte nuclear factor (HNF) signaling, the specific mechanisms remain unclear. The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression. Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor (ER) and AMPK signaling pathways in HepG2 cells. The ER alpha (ERα) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ERα affinity detection experiments, ERα luciferase reporter gene assays, and qRT-PCR. ERα knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses.
Shuttle HAT for mild alkene transfer hydrofunctionalization
Authors: Jankins Tanner C. , Blank Philip M. , Brugnetti Andrea , Boehm Philip , Aouane Françoise A. , Morandi Bill
Published: October 2024

Hydrogen atom transfer (HAT) from a metal-hydride is a reliable and powerful method for functionalizing unsaturated C–C bonds in organic synthesis. Cobalt hydrides (Co–H) have garnered significant attention in this field, where the weak Co–H bonds are most commonly generated in a catalytic fashion through a mixture of stoichiometric amounts of peroxide oxidant and silane reductant. Here we show that the reverse process of HAT to an alkene, i.e. hydrogen atom abstraction of a C–H adjacent to a radical, can be leveraged to generate catalytically active Co–H species in an application of shuttle catalysis coined shuttle HAT. This method obviates the need for stoichiometric reductant/oxidant mixtures thereby greatly simplifying the generation of Co–H. To demonstrate the generality of this shuttle HAT platform, five different reaction manifolds are shown, and the reaction can easily be scaled up to 100 mmol.
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

Transcriptional 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

Cell 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

Generative 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

Anthropogenic 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

An 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

During 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

The 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

The 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

Large 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

Analyzing 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

We 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

Radiation-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

When 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

Can 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

Quantum 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.
Crystal structure of the HMGA AT-hook 1 domain bound to the minor groove of AT-rich DNA and inhibition by antikinetoplastid drugs
Authors: Nué-Martinez J. Jonathan , Maturana Marta , Lagartera Laura , Rodríguez-Gutiérrez Juan-Antonio , Boer Roeland , Campos J. Lourdes , Saperas Núria , Dardonville Christophe
Published: October 2024

High mobility group (HMG) proteins are intrinsically disordered nuclear non-histone chromosomal proteins that play an essential role in many biological processes by regulating the expression of numerous genes in eukaryote cells. HMGA proteins contain three DNA binding motifs, the “AT-hooks”, that bind preferentially to AT-rich sequences in the minor groove of B-form DNA. Understanding the interactions of AT-hook domains with DNA is very relevant from a medical point of view because HMGA proteins are involved in different conditions including cancer and parasitic diseases. We present here the first crystal structure (1.40 Å resolution) of the HMGA AT-hook 1 domain, bound to the minor groove of AT-rich DNA. In contrast to AT-hook 3 which bends DNA and shows a larger minor groove widening, AT-hook 1 binds neighbouring DNA molecules and displays moderate widening of DNA upon binding. The binding affinity and thermodynamics of binding were studied in solution with surface plasmon resonance (SPR)-biosensor and isothermal titration calorimetry (ITC) experiments. AT-hook 1 forms an entropy-driven 2:1 complex with (TTAA)2-containing DNA with relatively slow kinetics of association/dissociation. We show that N-phenylbenzamide-derived antikinetoplastid compounds (1–3) bind strongly and specifically to the minor groove of AT-DNA and compete with AT-hook 1 for binding. The central core of the molecule is the basis for the observed sequence selectivity of these compounds. These findings provide clues regarding a possible mode of action of DNA minor groove binding compounds that are relevant to major neglected tropical diseases such as leishmaniasis and trypanosomiasis.