bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parameter estimation in a whole-brain network model of epilepsy: comparison of parallel global optimization solvers
Authors: Penas David R. , Hashemi Meysam , Jirsa Viktor K. , Banga Julio R. 
Published: November 2023

AbstractThe Virtual Epileptic Patient (VEP) refers to a computer-based representation of a patient with epilepsy that combines personalized anatomical data with dynamical models of abnormal brain activities. It is capable of generating spatio-temporal seizure patterns that resemble those recorded with invasive methods such as stereoelectro EEG data, allowing for the evaluation of clinical hypotheses before planning surgery. This study highlights the effectiveness of calibrating VEP models using a global optimization approach. The approach utilizes SaCeSS, a cooperative metaheuristic capable of parallel computation, to yield high-quality solutions without requiring excessive computational time. Through extensive benchmarking, our proposal successfully solved a set of different configurations of VEP models, demonstrating better scalability and superior performance against other parallel solvers. These results were further enhanced using a Bayesian optimization framework for hyperparameter tuning, with significant gains in terms of both accuracy and computational cost. Additionally, we added an scalable uncertainty quantification phase after model calibration, and used it to assess the variability in estimated parameters across different problems. Overall, this study has the potential to improve the estimation of pathological brain areas in drug-resistant epilepsy, thereby to inform the clinical decision-making process.Author summaryMotivated by the problem of parameter estimation in a set of whole-brain network models of epilepsy (of increasing complexity), this study addresses the question of choosing a robust global optimization solver that can be accelerated by exploiting parallelism in different infrastructures, from desktop workstations to supercomputers. By leveraging data-driven techniques with robust cooperative global optimization methods, we aim to achieve accurate parameter estimation with reduced reliance on prior information. This is due to the dependency of Bayesian inference on the level of information in the prior, while this approach allows us to quantify uncertainty in the absence of any prior knowledge effectively. In this work, we construct an efficient and accurate method to perform parameter estimation and uncertainty quantification for the VEP model, and we use it to infer the brain regional epileptogenicity from source and sensor level whole-brain data. Of specific interest is the ability of our method to produce inference for high-dimensional state-space models governed by deterministic, stochastic, well-behaved, and stiff differential equations, using only partial observations and sparse encoding from system states to the observation.
Human lncRNAs harbor conserved modules embedded in different sequence contexts
Authors: Ballesio Francesco , Pepe Gerardo , Ausiello Gabriele , Novelletto Andrea , Helmer-Citterich Manuela , Gherardini Pier Federico 
Published: November 2023

AbstractWe analyzed the structure of human long non-coding RNA (lncRNAs) genes to investigate whether the non-coding transcriptome is organized in modular domains, as is the case for protein-coding genes. To this aim, we compared all known human lncRNA exons and identified 340 pairs of exons with high sequence and/or secondary structure similarity but embedded in a dissimilar sequence context. We grouped these pairs in 106 clusters based on their reciprocal similarities. These shared modules are highly conserved between humans and the four great ape species, display evidence of purifying selection and likely arose as a result of recent segmental duplications. Our analysis contributes to the understanding of the mechanisms driving the evolution of the non-coding genome and suggests additional strategies towards deciphering the functional complexity of this class of molecules.Author summaryThe Human genome includes more than 18,000 genes coding for RNAs that are not translated into proteins, called long non-coding RNAs (lncRNA). Mounting evolutionary and experimental evidence shows that a large amount of these RNAs have a specific function, mainly as regulators of a diverse set of biological processes. Here we set out to investigate whether these genes have a modular organization similar to that of protein-coding genes. Accordingly, we compared the sequence of all the exonic regions of human lncRNAs and identified 106 clusters of non-repetitive exonic modules shared between this class of genes. These modules display evidence of purifying selection, are highly conserved between humans and the four great ape species, and may represent distinct functional units that have been shuffled among multiple lncRNA genes, in a manner similar to the exon-shuffling process that is observed in the coding genome.
ARalstonia solanacearumtype III effector alters the actin and microtubule cytoskeleton to promote bacterial virulence in plants
Authors: Hiles Rachel , Rogers Abigail , Jaiswal Namrata , Zhang Weiwei , Butchacas Jules , Merfa Marcus V. , Klass Taylor , Kaser Erica , Jacobs Jonathan M. , Staiger Christopher J. , Helm Matthew , Iyer-Pascuzzi Anjali S. 
Published: November 2023

AbstractCellular responses to biotic stress frequently involve signaling pathways that are conserved across eukaryotes. These pathways include the cytoskeleton, a proteinaceous network that senses external cues at the cell surface and signals to interior cellular components. During biotic stress, dynamic cytoskeletal rearrangements serve as a platform from which early immune-associated processes are organized and activated. Bacterial pathogens of plants and animals use proteins called type III effectors (T3Es) to interfere with host immune signaling, thereby promoting virulence. We previously found that RipU, a T3E from the soilborne phytobacterial pathogenRalstonia solanacearumK60 (RsK60), co-localizes with the plant cytoskeleton. Here, we show that RipU fromRsK60 (RipUK60) physically associates with both actin and tubulin and disrupts actin and microtubule cytoskeleton organization. We find that pharmacological disruption of the tomato (Solanum lycopersicum) cytoskeleton promotesRsK60 colonization. RipUK60suppresses cell surface-triggered immune responses including flg22-mediated reactive oxygen species (ROS) production and callose deposition. Importantly, tomato plants inoculated withRsK60 lacking RipUK60(ΔripUK60) had reduced wilting symptoms and significantly reduced root colonization when compared to plants inoculated with wild-typeRsK60. Collectively, our data suggest thatRsK60 uses the type III effector RipUK60to remodel cytoskeletal organization, thereby promoting pathogen virulence.
ADR-2 regulates fertility and oocyte fate inC. elegans
Authors: Erdmann Emily A. , Forbes Melanie , Becker Margaret , Perez Sarina , Hundley Heather A. 
Published: November 2023

AbstractRNA binding proteins play essential roles in coordinating germline gene expression and development in all organisms. Here, we report that loss of ADR-2, a member of the Adenosine DeAminase acting on RNA (ADAR) family of RNA binding proteins and the sole adenosine-to-inosine RNA editing enzyme inC. elegans, can improve fertility in multiple genetic backgrounds. First, we show that loss of RNA editing by ADR-2 restores normal embryo production to subfertile animals that transgenically express a vitellogenin (yolk protein) fusion to green fluorescent protein. Using this phenotype, a high-throughput screen was designed to identify RNA binding proteins that when depleted yield synthetic phenotypes with loss ofadr-2. The screen uncovered a genetic interaction between ADR-2 and SQD-1, a member of the heterogenous nuclear ribonucleoprotein (hnRNP) family of RNA binding proteins. Microscopy, reproductive assays, and high-throughput sequencing reveal thatsqd-1is essential for the onset of oogenesis and oogenic gene expression in young adult animals, and that loss ofadr-2can counteract the effects of loss ofsqd-1on gene expression and rescue the switch from spermatogenesis to oogenesis. Together, these data demonstrate that ADR-2 can contribute to the suppression of fertility and suggest novel roles for both RNA editing-dependent and independent mechanisms in regulating embryogenesis.Graphical Abstract:Figure created with BioRender.Article SummaryThe molecular information that controls early development is RNA. Interactions between RNA and RNA binding proteins (RBPs) are critical for successful reproduction across species. In this study, we uncovered two roles for the RBP ADR-2 in regulating reproduction. First, we demonstrate that the RNA editing activity of ADR-2 regulates fertility. Next, we screened over 250 other RBPs revealed a genetic interaction between ADR-2 and SQD-1. Further analysis revealed thatsqd-1is essential for the onset of oogenesis, and an editing-independent function of ADR-2 influences proper germline gene expression and oocyte fate in these animals.
Phenotypic models of drug-drug-gene interactions mediated by cytochrome drug-metabolizing enzymes
Authors: Viviani Roberto , Berres Judith , Stingl Julia C. 
Published: November 2023

AbstractGenetic polymorphisms in drug metabolizing enzymes and drug-drug interactions are major sources of inadequate drug exposure and ensuing adverse effects or insufficient responses. The current challenge in assessing drug-drug gene interactions (DDGI) for the development of precise dose adjustment recommendation systems is to take into account both simultaneously. Here, we analyze the static models of DDGI fromin vivodata and focus on the concept of phenoconversion to model inhibition and genetic polymorphisms jointly. These models are applicable to datasets where pharmacokinetic information is missing and are being used in clinical support systems and consensus dose adjustment guidelines. We show that all such models can be handled by the same formal framework, and that models that differ at first sight are all versions of the same linear phenoconversion model. This model includes the linear pharmacogenetic and inhibition models as special cases. We highlight present challenges in this endeavour and the open issues for future research in developing DDGI models for recommendation systems.
Evaluating the cost-effectiveness of polygenic risk score-stratified screening for abdominal aortic aneurysm
Authors: Kelemen M. , Roychowdhury T. , Danesh J. , Di Angelantonio E. , Inouye M. , O’Sullivan J. , Pennells L. , Sweeting M.J. , Wood A.M. , Harrison S. , Kim L.G. 
Published: November 2023

AbstractAs the heritability of abdominal aortic aneurysm (AAA) is high and AAA partially shares genetic architecture with other cardiovascular diseases, there is interest in whether genetic information could inform AAA screening strategies. Exploiting pleiotropy and meta-analysing summary data from large AAA studies, we constructed a polygenic risk score (PRS) for AAA. Compared with the low PRS tertile, the intermediate and high PRS tertiles had hazard ratios for AAA of 2.13 (95%CI 1.61, 2.82) and 3.70 (95%CI 2.86, 4.80) respectively, after adjusting for known clinical risk factors. Using simulation modelling, we compared PRS- and smoking-stratified screening with inviting men at age 65 and not inviting women (current UK strategy). In a futuristic scenario where genomic information is available on the population, our modelling suggests inviting male current smokers with high PRS earlier than 65 and targeting screening in female smokers with high/intermediate PRS at 65 and 70 respectively, may improve cost-effectiveness.
Improving conversations about Parkinson’s dementia
Authors: Dobreva Ivelina , Thomas Joanne , Marr Anne , O’Connell Ruairiadh , Roche Moïse , Hannaway Naomi , Dore Charlotte , Rose Sian , Liu Ken , Bhome Rohan , Baldwin-Jones Sion , Roberts Janet , Archibald Neil , Alston Duncan , Amar Khaled , Edwards Emma , Foley Jennifer A. , Haunton Victoria J. , Henderson Emily J. , Jha Ashwani , Lindop Fiona , Magee Cathy , Massey Luke , Ruiz-Mendoza Eladia , Mohamed Biju , Patterson Katherine , Ramaswamy Bhanu , Schrag Anette , Silverdale Monty , Suárez-González Aida , Subramanian Indu , Foltynie Tom , Williams-Gray Caroline H. , Yarnall Alison J. , Carroll Camille , Bale Claire , Hugill Cassandra , Weil Rimona S. 
Published: November 2023

AbstractBackgroundPeople with Parkinson’s disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that “nothing can be done about it”. However, open conversations about PD dementia mean that people with the condition can access treatment and support, and are more likely to participate in research aimed at understanding PD dementia.ObjectivesTo co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia.MethodsWe worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources.ResultsWhile most people with PD (70%) and caregivers (81%) shared worries about cognitive changes at the workshops, only 38% and 30% respectively had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals.ConclusionUsing artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.
The how, when, and what of odor valence communication between the olfactory bulb and piriform cortex
Authors: Nordén Frans , Iravani Behzad , Schaefer Martin , Winter Anja L. , Lundqvist Mikael , Arshamian Artin , Lundström Johan N. 
Published: November 2023

ABSTRACTA core function of the olfactory system is to determine an odor’s valence. The central processing of odor valence is initiated in the olfactory bulb, but the neural mechanisms by which this important information is communicated to, and from, the olfactory cortex (piriform cortex) in humans are not known. To assess communication between the two nodes, we simultaneously measured odor-dependent neural activity in the olfactory bulb and piriform cortex from human participants while obtaining trial-by-trial valence ratings. We determinedwhenvalence information was communicated,whatkind of information was transferred, andhowthe information was transferred (i.e., in which frequency band). Support vector machine learning on the coherence spectrum and frequency-resolved Granger causality were used to identify valence-dependent differences in functional and effective connectivity between the olfactory bulb and piriform cortex. We found that the olfactory bulb communicates odor valence to the piriform cortex in the gamma band shortly after odor onset, while the piriform cortex subsequently feeds valence-related information back to the olfactory bulb in the beta band. Decoding accuracy was better for negative than positive valence, suggesting negative valence superiority. Critically, we replicated these findings in an independent dataset using other odors across a larger perceived valence range. Combined, these results demonstrate that the olfactory bulb and piriform cortex communicate levels of odor pleasantness across multiple frequencies, at specific time-points and in a direction-dependent pattern in accordance with the two-stage model of odor processing. It also provides further evidence that odor valence should be viewed as two perceptual dimensions and not one continuous.
What is Slough? A pilot study to define the proteomic and microbial composition of wound slough and its implications for wound healing
Authors: Townsend Elizabeth C. , Cheong J. Z. Alex , Radzietza Michael , Fritz Blaine , Malone Matthew , Bjarnsholt Thomas , Ousey Karen , Swanson Terry , Schultz Gregory , Gibson Angela L.F. , Kalan Lindsay R. 
Published: November 2023

AbstractSlough is a well-known feature of non-healing wounds. This study aims to determine the proteomic and microbiologic components of slough as well as interrogate the associations between wound slough components and wound healing. Twenty-three subjects with slow-to-heal wounds and visible slough were enrolled. Etiologies included venous stasis ulcers, post-surgical site infections, and pressure ulcers. Patient co-morbidities and wound healing outcome at 3-months post-sample collection was recorded. Debrided slough was analyzed microscopically, through untargeted proteomics, and high-throughput bacterial 16S-ribosomal gene sequencing. Microscopic imaging revealed wound slough to be amorphous in structure and highly variable. 16S-profiling found slough microbial communities to associate with wound etiology and location on the body. Across all subjects, slough largely consisted of proteins involved in skin structure and formation, blood-clot formation, and immune processes. To predict variables associated with wound healing, protein, microbial, and clinical datasets were integrated into a supervised discriminant analysis. This analysis revealed that healing wounds were enriched for proteins involved in skin barrier development and negative regulation of immune responses. While wounds that deteriorated over time started off with a higher baseline Bates-Jensen Wound Assessment Score and were enriched for anerobic bacterial taxa and chronic inflammatory proteins. To our knowledge, this is the first study to integrate clinical, microbiome, and proteomic data to systematically characterize wound slough and integrate it into a single assessment to predict wound healing outcome. Collectively, our findings underscore how slough components can help identify wounds at risk of continued impaired healing and serves as an underutilized biomarker.
Small molecule positive allosteric modulation of homomeric kainate receptors GluK1-3: Development of screening assays and insight into GluK3 structure
Authors: Bay Yasmin , Venskutonytė Raminta , Frantsen Stine M. , Thorsen Thor S. , Musgaard Maria , Frydenvang Karla , Francotte Pierre , Pirotte Bernard , Biggin Philip C. , Kristensen Anders S. , Boesen Thomas , Pickering Darryl S. , Gajhede Michael , Kastrup Jette S. 
Published: November 2023

AbstractThe kainate receptors GluK1-3 belong to the family of ionotropic glutamate receptors and are essential for fast excitatory neurotransmission in the brain and associated with neurological and psychiatric diseases. How these receptors can be modulated by small molecule agents is not well-understood, especially for GluK3. We show that the positive allosteric modulator BPAM344 can be used to establish robust calcium-sensitive fluorescence-based assays at GluK1-3 for testing agonists, antagonists, and positive allosteric modulators. The EC50of BPAM344 for potentiating the response of 100 µM kainate was determined to 26.3 µM at GluK1, 75.4 µM at GluK2, and 639 µM at GluK3. In the presence of 150 µM BPAM344, domoate was found to be a potent agonist at GluK1 and GluK2 with EC50of 0.77 µM and 1.33 µM, respectively. At GluK3, domoate acts as a very weak agonist or antagonist with IC50of 14.5 µM, in the presence of 500 µM BPAM344 and 100 µM kainate. Using H523A mutated GluK3, we determined the first dimeric structure of the ligand-binding domain by X-ray crystallography, allowing location of BPAM344, zinc, sodium, and chloride ion binding sites at the dimer interface. Molecular dynamics simulations support the stability of the ion sites as well as the involvement of Asp761, Asp790, and Glu797 in binding of zinc ions. Using electron microscopy, we show that in the presence of glutamate and BPAM344, full-length GluK3 adopts a dimer-of-dimers arrangement. This study may contribute to unravelling the potential of kainate receptors as targets for treatment of brain diseases.
Functional integration and segregation during semantic cognition: Evidence across age groups
Authors: Wu Wei , Hoffman Paul 
Published: November 2023

AbstractSemantic cognition is underpinned by ventral anterior temporal lobe (vATL) which encodes knowledge representations and inferior frontal gyri (IFG), which controls activation of knowledge based on the needs of the current context. This core semantic network has been validated in substantial empirical findings in the past. However, it remains unclear how these core semantic areas dynamically communicate with each other to achieve successful semantic processing. Here, we investigated this question by testing functional connectivity in the core semantic network during semantic tasks and whether these connections were affected by cognitive ageing. Compared to a non-semantic executive task, semantic tasks increased the connectivity between left and right IFGs, indicating a bilateral semantic control system. Strengthened connectivity was also found between left IFG and left vATL, and this effect was stronger in the young group. At a whole-brain scale, IFG and vATL increased their coupling with multiple-demand regions during semantic tasks, even though these areas were deactivated relative to non-semantic tasks. This suggests that the domain- general executive network contributes to semantic processing. In contrast, IFG and vATL decreased their interaction with default mode network (DMN) areas during semantic tasks, even though these areas were positively activated by the task. This suggests that DMN areas do not contribute to all semantic tasks: their activation may sometimes reflect automatic retrieval of task-irrelevant memories and associations. Taken together, our study characterized a dynamic connectivity mechanism supporting semantic cognition within and beyond core semantic regions.
BRN1/2 Function in Neocortical Size Determination and Microcephaly
Authors: Barão Soraia , Xu Yijun , Llongueras José P. , Vistein Rachel , Goff Loyal , Nielsen Kristina , Bae Byoung-Il , Smith Richard S. , Walsh Christopher A. , Stein-O’Brien Genevieve , Müller Ulrich 
Published: November 2023

AbstractThe mammalian neocortex differs vastly in size and complexity between mammalian species, yet the mechanisms that lead to an increase in brain size during evolution are not known. We show here that two transcription factors coordinate gene expression programs in progenitor cells of the neocortex to regulate their proliferative capacity and neuronal output in order to determine brain size. Comparative studies in mice, ferrets and macaques demonstrate an evolutionary conserved function for these transcription factors to regulate progenitor behaviors across the mammalian clade. Strikingly, the two transcriptional regulators control the expression of large numbers of genes linked to microcephaly suggesting that transcriptional deregulation as an important determinant of the molecular pathogenesis of microcephaly, which is consistent with the finding that genetic manipulation of the two transcription factors leads to severe microcephaly.