bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic surveillance and molecular evolution of fungicide resistance in European populations of wheat powdery mildew
Authors: Minadakis Nikolaos , Jigisha Jigisha , Cornetti Luca , Kunz Lukas , Müller Marion C. , Torriani Stefano F.F. , Menardo Fabrizio 
Published: November 2024

AbstractFungicides are used in agriculture to manage fungal infections and maintain crop yield and quality. In Europe, their application on cereals increased drastically starting from the mid 1970s, contributing to a significant improvement in yields. However, extensive usage has led to the rapid evolution of resistant pathogen populations within just a few years of fungicide deployment. Here we focus on wheat powdery mildew, a disease caused by the ascomycete fungusBlumeria graminis forma specialis tritici(Bgt). Previous research on Bgt documented the emergence of resistance to different fungicides and identified various resistance mechanisms. Yet, the frequency, distribution, and evolutionary dynamics of fungicide resistance in Bgt populations remain largely unexplored. In this study we leveraged extensive sampling and whole-genome sequencing of Bgt populations in Europe and the Mediterranean to investigate the population genetics and molecular epidemiology of fungicide resistance towards five major fungicide classes. We analyzed gene sequences and copy number variation of eight known fungicide target genes in 415 Bgt isolates sampled between 1980 and 2023. We observed that mutations conferring resistance to various fungicides increased in frequency over time, and had distinct geographic distributions, likely due to diverse deployment of fungicides across different regions. For demethylation inhibitor fungicides we identified multiple independent events of resistance emergence with distinct mutational profiles, and we tracked their rapid spread in the last decades. Overall, we revealed the evolutionary and epidemiological dynamics of fungicide resistance mutations in European Bgt populations. These results underscore the potential of genomic surveillance and population genetics to enhance our understanding of fungicide resistance.
Decoding words during sentence production: Syntactic role encoding and structure-dependent dynamics revealed by ECoG
Authors: Morgan Adam M. , Devinsky Orrin , Doyle Werner K. , Dugan Patricia , Friedman Daniel , Flinker Adeen 
Published: November 2024

AbstractSentence production is the uniquely human ability to transform complex thoughts into strings of words. Despite the importance of this process, language production research has primarily focused on single words. However, it remains a largely untested assumption that the principles of word production generalize to more naturalistic utterances like sentences. Here, we investigate this using high-resolution neurosurgical recordings (ECoG) and an overt production experiment where patients produced six words in isolation (picture naming) and in sentences (scene description). We trained machine learning classifiers to identify the unique brain activity patterns for each word during picture naming, and used these patterns to decode which words patients were processing while they produced sentences. Our findings confirm that words share cortical representations across tasks, but reveal a division of labor within the language network. In sensorimotor cortex, words were consistently activated in the order in which they were said in the sentence. However, in inferior and middle frontal gyri (IFG and MFG), the order in which words were processed depended on the syntactic structure of the sentence. Deeper analysis of this pattern revealed a spatial code for representing a word’s position in the sentence, with subjects selectively encoded in IFG and objects in MFG. Finally, we argue that the processes we observe in prefrontal cortex may impose a subtle pressure on language evolution, explaining why nearly all the world’s languages position subjects before objects.
Discriminative capacity of the 6-item Vision-related Quality of life and Limitations questionnaire (VQL-6)
Authors: Dol Vera Linde , Roelofs Antonius A. J. , Fuermaier Anselm B. M. , Vrijling Anne C. L. , Heutink Joost , Jansonius Nomdo M. 
Published: November 2024

AbstractPurposeThe 6-item Vision-related Quality of life and Limitations questionnaire (VQL-6) is a screening instrument that signals a need for additional low vision care in patients with chronic ophthalmic diseases. This study aims to (1) determine the optimal scoring method for the VQL-6 and (2) evaluate its discriminative capacity for clinical use.MethodsPatients with glaucoma and retina– and cornea-related disorders completed the VQL-6 and participated in an interview designed to distinguish between patients with and without a need of additional care. For the two subscales (general health and quality of life, HQOL, and vision-related limitations, VL) we compared a scoring model with equal item weights to a cross-validated model using regression weights. The optimal scoring method and discriminative capacity of the subscales were determined using receiver operating characteristics (ROC) analysis, with the interview outcome as gold standard. Sensitivities were evaluated at specificities of 90 and 95%.ResultsIn 297 interview assessments, 96 patients (32%) appeared to need additional care. Both scoring models demonstrated very similar area under the ROC curves (AUC). The selected equal weight model yielded an AUC of 0.91 (95% confidence interval 0.87-0.94) for VL and 0.71 (0.65-0.77) for HQOL. For VL, sensitivity was 72 and 64% at 90 and 95% specificity, respectively. Corresponding HQOL sensitivities were 34 and 17%.ConclusionsThe subscale VL shows excellent discriminative capacity and outperformed HQOL. Future studies should explore the feasibility of the VQL-6 in clinical practice.
The effect of oxidative stress on the Adenosine A2a Receptor structure, activity and signalling
Authors: Company-Marin Idoia , Gunner Joseph , Poyner David , Simms John , Pitt Andrew R. , Spickett Corinne M. 
Published: November 2024

AbstractThe adenosine 2a receptor (A2aR) is a G-protein coupled receptor that has important anti-inflammatory effects in response to some agonists and consequently is considered a therapeutic target. Its activity is affected by local membrane lipid environment and presence of certain phospholipid classes, so studies should be conducted using extraction methods such as styrene maleic acid co-polymers (SMA) that retain the local lipids. Currently, little is known about the effect of oxidative stress, which may arise from inflammation, on the A2aR. Therefore it was over-expressed inPichia pastoris, SMA was used to extract the A2aR from cell membranes and its response to ligands was tested in the presence or absence of the radical initiator AAPH or reactive aldehyde acrolein. SMA-extracted A2aR was able to undergo conformational changes, measured by tryptophan fluorescence, in response to its ligands but oxidative treatments had no effect on the structural changes. Similarly, the treatments did not affect temperature-dependent protein unfolding. In contrast, in HEK293 cells expressing the A2aR, oxidative treatments increased cAMP levels in response to the agonist NECA, independently of adenylate cyclase activity. Thus, oxidative stress may be a homeostatic mechanism that abrogates inflammation via the A2aR signalling pathway. (max. 200 words - 194)
Chlamydia trachomatisTmeA promotes pedestal formation through N-WASP and TOCA-1 interactions
Authors: McCullough Alix , Jabeena C.A. , Steiert Brianna , Faris Robert , Weber Mary M. 
Published: November 2024

AbstractChlamydia trachomatis(C.t.) is the causative agent of several human diseases, including the sexually transmitted infection chlamydia and eye infection trachoma. As an obligate intracellular bacterial pathogen, invasion is essential for establishing infection and subsequent pathogenesis. To facilitate invasion,C.t.secretes effector proteins through its type III secretion system (T3SS). These effectors facilitate bacterial entry by manipulating multiple pathways involved in host actin cytoskeletal regulation. Previous studies have demonstrated that the T3SS effector protein TmeA is crucial forC.t.invasion, as it recruits and activates N-WASP. This interaction leads to recruitment and activation of the Arp2/3 complex, promoting cytoskeletal rearrangements at the invasion site to facilitateC.t.uptake. In this study, we define the role of the N-WASP CRIB domain in mediating this interaction, showing that TmeA acts as a functional mimic of Cdc42 in activating N-WASP. Additionally, we identified TOCA-1 as another host protein that directly interacts with TmeA. In other bacterial pathogens, notably EnterohemorrhagicE. coli, N-WASP and TOCA-1 are hijacked to mediate pedestal formation. Using siRNA to knockdown N-WASP and TOCA-1, followed by transmission electron microscopic, we observed that both N-WASP and TOCA-1 are important for inC.t.-mediated pedestal formation. Collectively, these findings reveal a unique mechanism of TmeA-mediated invasion, where direct interactions with N-WASP and TOCA-1 facilitate pedestal formation.ImportanceChlamydia trachomatis(C.t.) is an obligate intracellular bacterial pathogen that poses a significant threat to human health, being associated with various diseases, including chlamydia— the most prevalent bacterial sexually transmitted infection—and trachoma. While Chlamydia infections are often asymptomatic, they can lead to serious complications such as sterility, ectopic pregnancy, and increased risk of cervical and ovarian cancers. Due to its intracellular nature, host cell invasion is essential forC.t.survival. Here, we present new data detailing the binding interactions between theC.t.invasion effector protein TmeA and host cell proteins N-WASP and TOCA-1, demonstrating that both N-WASP and TOCA-1 are involved in pedestal formation duringC.t.invasion. This research advances our understanding of TmeA-mediated host cell invasion, illuminating a key pathway required forC.t.-mediated pathogenesis.
Learning Allosteric Interactions in Gα Proteins from Molecular Dynamics Simulations
Authors: Yu Yiping , Yang Maohua , Wang Wenning 
Published: November 2024

AbstractGα is a key subunit of heterotrimeric guanine-nucleotide-binding regulatory proteins, yet its conformational dynamics are not fully understood. In this study, we developed a Transformer-based graph neural network framework, Dynamic-Mixed Transformer (DMFormer), to investigate conformational dynamics of Gαo. DMFormer achieved an AUC of 0.75 on the training set, demonstrating robustness in distinguishing active and inactive states. The interpretability of the model was enhanced using integrated gradients, identifying the Switch II as a critical motif in stabilizing the active state and revealing distinct movement patterns between GTPase and α-Helix domains. Our findings suggest that the conformational rigidity of the Q205L mutant in the Switch II segment leads to persistent activation. Overall, our study showcases DMFormer as an effective tool for analyzing protein conformational dynamics, offering valuable insights into activation mechanisms of Gα protein.
An intuitive method to visualize Boolean network attractors landscape based on probability distribution from trajectories
Authors: Chong Ket Hing 
Published: November 2024

AbstractMotivationBoolean network modeling is a coarse-grained modeling approach that has been highly valued for its simple abstract representation of biological regulation in molecular network. The simplified ‘On’ and ‘Off’ expression of gene or protein product is a qualitative representation of experimental findings for gene gets turned on or turned off. Boolean network constructed can be analyzed as having point attractor or cyclic attractor; however, current softwares can visualize the Boolean network attractors on a plane and not visualizing Boolean attractors’ landscape in a 3 dimensional view.ResultsHere, we propose an intuitive method to visualize Boolean network attractors land-scape based on probability distributionPof all possible trajectories in the state transition graph. We formulate a quasi-potential valueU= −ln Pthat enables us to plot the Boolean network attractors landscape in 3D. There are two types of attractors in Boolean network: cyclic attractor and point attractor. Our intuitive method can visualize Boolean network in a landscape with point attractor (node labeled with yellow color) and cyclic attractor (node labeled with pink color). In the 3D landscape the attractors are located at the bottom of the directed graphs. The propose method can be applied in the study of networks in general, for example applications in directed graph, social network for popular users or e-commerce store to find favorite products as identified by attractors.Availability and implementationThe source code of Python implementation of the propose method can be downloaded fromBoolean-net-attractor-Land URL link.
Evolution of drug-binding residues in bacterial ribosomes
Authors: Ekemezie Chinenye L. , Chan Lewis I. , Brown Charlotte R. , Helena-Bueno Karla , Williams Tom A. , Melnikov Sergey V. 
Published: November 2024

ABSTRACTRibosomes from certain bacteria possess divergent drug-binding sites compared to those ofEscherichia coli,leading to natural evasion or hypersensitivity to antibiotics. However, in the absence of systematic studies, it is unknown whether this observed divergence is a rare exception or a common occurrence among bacterial species. Here, we address this question by reconstructing the evolutionary history of drug-binding residues of the ribosome from the origin of bacteria to the present day. This analysis reveals the extent of natural diversity of ribosomal drug-binding sites between bacterial species, which may inform the development of species-specific antimicrobials and a more accurate and personalized choice of ribosome-targeting drugs for a given pathogen.
Identification of the Regulatory Elements and Protein Substrates of Lysine Acetoacetylation
Authors: Fu Qianyun , Nguyen Terry , Kumar Bhoj , Azadi Parastoo , Zheng Y. George 
Published: November 2024

AbstractShort chain fatty acylations establish connections between cell metabolism and regulatory pathways. Lysine acetoacetylation (Kacac) was recently identified as a new histone mark. However, regulatory elements, substrate proteins, and epigenetic functions of Kacac remain unknown, hindering further in-depth understanding of acetoacetate modulated (patho)physiological processes. Here, we created a chemo-immunological approach for reliable detection of Kacac, and demonstrated that acetoacetate serves as the primary precursor for histone Kacac. We report the enzymatic addition of the Kacac mark by the acyltransferases GCN5, p300, and PCAF, and its removal by deacetylase HDAC3. Furthermore, we establish acetoacetyl-CoA synthetase (AACS) as a key regulator of cellular Kacac levels. A comprehensive proteomic analysis has identified 139 Kacac sites on 85 human proteins. Bioinformatics analysis of Kacac substrates and RNA-seq data reveal the broad impacts of Kacac on multifaceted cellular processes. These findings unveil pivotal regulatory mechanisms for the acetoacetate-mediated Kacac pathway, opening a new avenue for further investigation into ketone body functions in various pathophysiological states.
Structural context modulates the conformational ensemble of the intrinsically disordered amino terminus of α-synuclein
Authors: Dumarieh Rania , Lagasca Dominique , Krishna Sakshi , Kragelj Jaka , Xiao Yiling , Frederick Kendra K. 
Published: November 2024

ABSTRACTRegions of intrinsic disorder play crucial roles in biological systems, yet they often elude characterization by conventional biophysical techniques. To capture conformational distributions across different timescales, we employed a freezing approach coupled with solid-state NMR analysis. Using segmentally isotopically labeled α-synuclein (α-syn), we investigated the conformational preferences of the six alanines, three glycines, and a single site (L8) in the disordered amino terminus under three distinct conditions: in 8 M urea, as a frozen monomer in buffer, and within the disordered regions flanking the amyloid core. The experimental spectra varied significantly among these conditions and deviated from those of a statistical coil. In 8 M urea, monomeric α-syn exhibited the most restricted conformational sampling, rarely accessing chemical shifts characteristic of α-helices or β-strands. In buffer, monomeric α-syn showed broader conformational sampling, favoring α-helical conformations and, to a lesser extent, random coil states. Notably, amino acids in the disordered regions flanking the amyloid core demonstrated the most extensive conformational sampling, with broad peaks encompassing the entire range of possible chemical shifts and a marked preference for highly extended β-strand conformations. Collectively, this work demonstrates that intrinsically disordered regions exhibit distinct conformational preferences, which are influenced not only by the chemical environment but also by the conformations of adjacent protein sequences. The differences in the conformational ensembles of the disordered amino terminus may explain why the monomer and the amyloid form of α-syn interact with different biomolecules inside cells.
Biofunctional coating of synthetic magnetic nanoparticles enables magnetogenetic control of protein functions inside cells
Authors: Kappen Marie , Gemperle Jakub , Secret Emilie , Flesch Julia , Caswell Patrick , Coppey Mathieu , Dahan Maxime , Menager Christine , Liße Domenik , Piehler Jacob 
Published: November 2024

AbstractRemote control of cellular functions via magnetic forces offers unique opportunities in fundamental research and biomedical application. Intracellular delivery of functionalized magnetic nanoparticles (MNP) provides versatile opportunities to assemble signalling platforms for spatiotemporal control by magnetic forces. Such magnetogenetic application, however, has remained highly challenging due to a lack of MNP providing suitable biological, physicochemical and magnetic properties. Here, we achieved single-step surface coating of synthetic maghemite core nanoparticles with green fluo-rescent protein fused to the iron binding site of Mms6 from magnetotactic bacteria. We yielded MNP with intracellular stealth properties (syMagIcS), which could be readily biofunctionalizedin situand translocated within cells via magnetic field gradients. We successfully exploited syMagIcS for spati-otemporal control of Rac1 signalling at the plasma membrane via its guanine nucleotide exchange factor protein TIAM1 and for spatial control of liquid-liquid phase separation using the intrinsically disordered domain of the protein DDX4.
The adolescent frontal cortex shows stronger population-level encoding of information than the adult during a putative sensitive period
Authors: Klinger Madeline E. , Wang Hongli , Tai Lung-Hao , Qü Albert J. , Murphy Mei , Wilbrecht Linda 
Published: November 2024

SummaryAdolescence is considered to be a sensitive period for brain development, but it is not clear how the neocortex functions differently at this stage. We hypothesized that if there is a sensitive period in the dorsomedial prefrontal cortex (dmPFC) during adolescence, then we might find this area shows stronger encoding of task-related information at adolescent ages than at adult ages. To enable optical access to task-related layer 2/3 neural activity in the developing mouse, we imaged mice under a 2-photon microscope while they learned an auditory go/no-go task. We found adolescent mice (postnatal day P30-45) learned the task to criterion faster than adult mice (P60-75). When we compared neural activity in expert mice with comparable performance between the two age groups, we found that a similar fraction of single cells encoded task variables in the two groups. However, task information could be better decoded from the adolescent dmPFC population activity than the adult, even when we controlled for differences in head-fixed running. Adolescents also showed greater noise correlation than adults, and shuffling to remove this noise correlation suggested noise correlation contributed to gain of function in adolescent compared to adult brain. We suggest a working model for an adolescent sensitive period in the frontal association cortex in which greater capacity for distributed encoding of information in the adolescent dmPFC underlies increased sensitivity to experiences that occur at this stage of life.
Dentate Gyrus Norepinephrine Ramping Facilitates Aversive Contextual Processing
Authors: Zhang Eric T. , Saglimbeni Grace S. , Feng Jiesi , Li Yulong , Bruchas Michael R. 
Published: November 2024

AbstractDysregulation in aversive contextual processing is believed to affect several forms of psychopathology, including post-traumatic stress disorder (PTSD). The dentate gyrus (DG) is an important brain region in contextual discrimination and disambiguation of new experiences from prior memories. The DG also receives dense projections from the locus coeruleus (LC), the primary source of norepinephrine (NE) in the mammalian brain, which is active during stressful events. However, how noradrenergic dynamics impact DG-dependent function during contextual discrimination and pattern separation remains unclear. Here, we report that aversive contextual processing in mice is linked to linear elevations in tonic norepinephrine release dynamics within the DG and report that this engagement of prolonged norepinephrine release is sufficient to produce contextual disambiguation, even in the absence of a salient aversive stimulus. These findings suggest that spatiotemporal ramping characteristics of LC-NE release in the DG during stress likely serve an important role in driving contextual processing.