bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep brain stimulation at the basolateral amygdala alters whole-brain connectivity and synchronization and social behaviors ofTbr1deficient mice
Authors: Hsu Tsan-Ting , Huang Tzyy-Nan , Wang Chien-Yao , Hueh Yi-Ping 
Published: July 2023

AbstractAutism spectrum disorders (ASD) are considered neural dysconnectivity syndromes. To better understand ASD and uncover potential treatments, it is imperative to know and dissect the connectivity deficits under conditions of autism. Here, we apply a whole-brain immunostaining and quantification platform to demonstrate impaired structural and functional connectivity and aberrant whole-brain synchronization in aTbr1+/–autism mouse model. We express a channelrhodopsin variant oChIEF fused with Citrine at the basolateral amygdala (BLA) to outline the axonal projections of BLA neurons. By activating the BLA under blue light theta-burst stimulation (TBS), we then evaluate the effect of BLA activation on C-FOS expression at a whole brain level to represent neural activity. We show thatTbr1haploinsufficiency almost completely disrupts contralateral BLA axonal projections and results in mistargeting in both ipsilateral and contralateral hemispheres, thereby globally altering BLA functional connectivity. Based on correlated C-FOS expression among brain regions, we further show thatTbr1deficiency severely disrupts whole-brain synchronization in the absence of salient stimulation.Tbr1+/–and wild-type (WT) mice exhibit opposing responses to TBS-induced amygdalar activation, reducing synchronization in WT mice but enhancing it inTbr1+/–mice. Whole-brain modular organization and inter-module connectivity are also affected by Tbr1 deficiency and amygdalar activation. Following BLA activation by TBS, the synchronizations of the whole brain and the default mode network, a specific subnetwork highly relevant to ASD, are enhanced inTbr1+/–mice, implying a potential ameliorating effect of amygdalar stimulation on brain function. Indeed, TBS-mediated BLA activation increases nose-to-nose social interactions ofTbr1+/–mice, strengthening evidence for the role of amygdalar connectivity in social behaviors. Our high-resolution analytical platform reveals the inter- and intra-hemispheric connectopathies arising from ASD. Our study emphasizes the defective synchronization at a whole-brain scale caused byTbr1deficiency and implies a potential beneficial effect of deep brain stimulation at the amygdala for TBR1-linked autism.
Structural reconstruction of individual filaments in Aβ42 fibril populations assembledin vitroreveal rare species that resembleex vivoamyloid polymorphs from human brains
Authors: Aubrey Liam D. , Lutter Liisa , Fennell Kate , Purton Tracey J. , Ward Natasha , Serpell Louise C. , Xue Wei-Feng 
Published: July 2023

AbstractStructural polymorphism has been demonstrated for bothin vitroandex vivoamyloid fibrils associated with disease. The manner in which different filament structures are assembled from common building blocks remains unclear but the assembly environment is likely to be a key determinant. To address this, three-dimensional reconstruction of individual filament structures was conducted from atomic force microscopy images to map the structural polymorphism landscape of Aβ42amyloid fibril populations formedin vitrounder most frequently used buffer conditions. The data show sensitivity of Aβ42fibril polymorphism to the assembly environment in both the magnitude of heterogeneity and the types of filament species formed. However, some conserved fibril polymorphs were observed across the experimental conditions. Excitingly, by matching individual filament structures to cryo-electron microscopy derived structural data, rare species in these heterogeneous population clouds that show remarkable similarity to Aβ42amyloid polymorphs purified from human patient brains were discovered. These results linkin vitroexperimental approaches with structures formedin vivo, and highlight the polymorph distribution, and the type and magnitude of structural variations within these heterogeneous molecular distributions as important factors in amyloid biology.
Topological data analysis reveals a core heteroblastic program embedded in leaves of grapevine and maracuyá
Authors: Percival Sarah , Chitwood Daniel H. , Husbands Aman Y. 
Published: July 2023

ABSTRACTLeaves have a single shape. However, embedded in that shape are a multitude of latent shapes arising from evolutionary, developmental, environmental, and other effects. These confounded effects manifest at distinct developmental time points and evolve at different tempos. Here, revisiting datasets comprised of thousands of leaves of vining grapevine (Vitaceae) and maracuyá (Passifloraceae) species, we apply a technique from the mathematical field of topological data analysis to comparatively visualize the structure of heteroblastic effects on leaf shape in each group. Consistent with a morphologically closer relationship, members of the grapevine dataset possess a strong core heteroblasty program with little deviation between species. Remarkably, we found that most members of the maracuyá family also share a core heteroblasty program despite dramatic species-to-species leaf shape differences. This conservation was not detected using traditional analyses. We also identify two morphotypes of maracuyá that deviate from the core structure, suggesting the evolution of new heteroblastic properties in this phylogenetically related sub-group. Our findings illustrate how topological data analysis can be used to disentangle previously confounded developmental and evolutionary effects to visualize latent shapes and hidden relationships, even ones embedded in complex, high-dimensional datasets.
Investigating bacteria-phage interaction dynamics using droplet-based technology
Authors: Nikolic Nela , Anagnostidis Vasileios , Tiwari Anuj , Chait Remy , Gielen Fabrice 
Published: July 2023

ABSTRACTAn alarming rise in antimicrobial resistance worldwide has spurred efforts into the search for alternatives to antibiotic treatments. The use of bacteriophages, bacterial viruses harmless to humans, represents a promising approach with potential to treat bacterial infections (phage therapy). Recent advances in microscopy-based single-cell techniques have allowed researchers to develop new quantitative approaches for assessing the interactions between bacteria and phages, especially the ability of phages to eradicate bacterial pathogen populations. Here we combine droplet microfluidics with fluorescence time-lapse microscopy to characterize the growth and lysis dynamics of the bacteriumEscherichia coliconfined in droplets when challenged with phage. We investigated phages that promote lysis of infectedE. colicells, specifically, a phage species with DNA genome, T7 (Escherichia virus T7) and two phage species with RNA genomes, MS2 (Emesvirus zinderi) and Qβ (Qubevirus durum). Our microfluidic trapping device generated and immobilized picoliter-sized droplets, enabling stable imaging of bacterial growth and lysis in a temperature-controlled setup. Temporal information on bacterial population size was recorded for up to 25 hours, allowing us to determine growth rates of bacterial populations helping us uncover the extent and speed of phage infection. In the long-term, the development of novel microfluidic and single-cell techniques will expedite research towards understanding the genetic and molecular basis of rapid phage-induced lysis, preempting bacterial resistance to phages and ultimately identifying key factors influencing the success of phage therapy.
Brain network reconfiguration during prediction error processing
Authors: Bonna Kamil , Hulme Oliver James , Meder David , Duch Włodzisław , Finc Karolina 
Published: July 2023

AbstractLearning from experience is driven by reward prediction errors—signals that reflect updates to our expectations of reward. Despite numerous studies on neural correlates of reward prediction errors, the question of how large-scale brain networks reconfigure in response to reward prediction error signalling remains open. Here we ask how functional networks change in response to reward prediction errors depending on the context. In our study participants performed the probabilistic reversal learning task in functional magnetic resonance imaging (fMRI) scanner in two experimental contexts: a reward-seeking setting and a punishment-avoiding. We found that the participants’ learning speed depended on the sign of the prediction error but not on the experimental context. Whole-brain network analysis revealed a multi-scale community structure with a separate striatal reward network emerging at a finer topological scale and a ventromedial prefrontal network emerging at a coarser scale. We also found that the integration between large-scale networks increased when switching from positive to negative prediction error events. This pattern of large-scale network reconfiguration aligns with the broad range of research showing increased network integration with increased cognitive demands. Our findings offer a first sketch of how processing reward prediction error affects the functional connectivity of brain-wide networks.
Decrypting the languages of allostery in membrane-bound K-Ras4B using four complementaryin silicoapproaches
Authors: Castelli Matteo , Marchetti Filippo , Osuna Sílvia , F. Oliveira A. Sofia , Mulholland Adrian J. , Serapian Stefano A. , Colombo Giorgio 
Published: July 2023

AbstractProteins are evolved molecular machines whose diverse biochemical functions can be dynamically regulated by allostery, through which even faraway protein residues can conformationally communicate. Allostery can express itself in different ways, akin to different “languages”: allosteric control pathways predominating in an unperturbed protein are superseded by others as soon as a perturbation arises—e.g., a mutation—that alters its function (pathologically or not). Accurately modeling these often-unintuitive phenomena could therefore help explain functional changes in a specific protein whenever they are unclear. Unbiased molecular dynamics (MD) simulations are a possibility; however, since allostery can operate at longer timescales than those accessible by MD, simulations require integration with a reliable method able to,e.g., detect regions of incipient allosteric change or likely perturbation pathways. Several methods exist but are typically applied singularly: we argue their joint application, in a “multilingual” approach, could significantly enrich this picture. To prove this, we perform unbiased MD simulations (∼100 µs) of the widely studied, allosterically active oncotarget K-Ras4B, solvated and embedded in a phospholipid membrane, proceeding to decrypt its allostery using four showcase “languages”:Distance Fluctuationanalysis and theShortest Path Mapcapture allosteric communication hotspots at equilibrium;Anisotropic Thermal DiffusionandDynamical Non-Equilibrium MDsimulations assess them once the GTP that oncogenically activates K-Ras4B is, respectively, either superheated or hydrolyzed. “Languages” provide a uniquely articulate, mutually coherent, experimentally consistent picture of allostery in K-Ras4B. At equilibrium, pathways stretch from the membrane-embedded hypervariable region all the way to the active site, touching known flexible allosteric “switches” and proposed pockets. Upon GTP cleavage/perturbation, known to inactivate K-Ras4B, allosteric signals most reverberate on switches and interfaces that recruit effector proteins. Our work highlights the benefits of integrating different allostery detection methods with unbiased MD.
Performance of amplicon and capture based next-generation sequencing approaches for the epidemiological surveillance of Omicron SARS-CoV-2 and other variants of concern
Authors: Daviña-Núñez Carlos , Pérez-Castro Sonia , Cabrera-Alvargonzález Jorge Julio , Rincón-Quintero Anniris , Treinta-Álvarez Ana , Godoy-Diz Montse , Suárez-Luque Silvia , Regueiro-García Benito 
Published: July 2023

AbstractTo control the SARS-CoV-2 pandemic, healthcare systems have focused on ramping up their capacity for epidemiological surveillance through viral whole genome sequencing. In this paper, we tested the performance of two protocols of SARS-CoV-2 nucleic acid enrichment, an amplicon enrichment using different versions of the ARTIC primer panel and a hybrid-capture method using KAPA RNA Hypercap. We focused on the challenge of the Omicron variant sequencing, the advantages of automated library preparation and the influence of the bioinformatic analysis in the final consensus sequence. All 94 samples were sequenced using Illumina iSeq 100 and analysed with two bioinformatic pipelines: a custom-made pipeline and an Illumina-owned pipeline. We were unsuccessful in sequencing six samples using the capture enrichment due to low reads. On the other hand, amplicon dropout and mispriming caused the loss of mutationG21987Aand the erroneous addition of mutationT15521Arespectively using amplicon enrichment. Overall, we found high sequence agreement regardless of method of enrichment, bioinformatic pipeline or the use of automation for library preparation in eight different SARS-CoV-2 variants. Automation and the use of a simple app for bioinformatic analysis can simplify the genotyping process, making it available for more diagnostic facilities and increasing global vigilance.
Ectopical expression of bacterial collagen-like protein supports its role as adhesin in host-parasite coevolution
Authors: Huessy Benjamin , Bumann Dirk , Ebert Dieter 
Published: July 2023

AbstractFor a profound understanding of the mechanisms of antagonistic coevolution, it is necessary to identify the coevolving genes. The spore-forming bacteriumPasteuria ramosaand its host, the microcrustaceanDaphnia, are a well-characterized paradigm for co-evolution, but the underlying genes remain largely unknown. A genome-wide association study identified a polymorphic carboxy-terminal globular domain ofPasteuriacollagen-like protein 7 (Pcl7) as a candidate mediating parasite attachment and driving its coevolution with the host. SinceP. ramosacannot currently be genetically manipulated, we usedBacillus thuringiensisas a surrogate parasite to express a fusion protein of a Pcl7 carboxy-terminus fromP. ramosaand the amino-terminal domain of aB. thuringiensiscollagen-like protein. MutantB. thuringiensis(Pcl7-Bt) spores but not wild-typeB. thuringiensis(WT-Bt) spores, attached to the same site of susceptible hosts asP. ramosa. Furthermore, Pcl7-Btspores attached readily to host genotypes that were susceptible to theP. ramosaclone that was the origin of the Pcl7 C-terminus, but only slightly to resistant host genotypes. These findings indicated that the fusion protein was properly expressed and folded and demonstrated that indeed the C-terminus of Pcl7 mediates attachment in a host genotype-specific manner. These results provide strong evidence for the involvement of a CLP in the coevolution ofDaphniaandP. ramosaand opens new avenues for genetic epidemiological studies of host-parasite interactions.150-word “Importance” paragraphDuring host-parasite coevolution, hosts evolve to evade the damaging effect of the parasite, while parasites evolve to maximize their benefits by exploiting the host. The genes underlying this coevolution remain largely unknown. For the prime model-system for coevolutionary research, the crustaceanDaphniaand the parasitePasteuria ramosa, collagen-like proteins (CLPs) inPasteuriawere suggested to play a crucial role for host-parasite interactions. Here we report that transferring part of a CLP coding gene from the unculturableP. ramosatoBacillus thuringiensis(Bt), confirmed the function of this protein as a genotype-specific adhesin to the host’s cuticle. Our finding highlights the importance of a CLP in host-parasite interactions and will enable us to explore the population genetic dynamics of coevolution in this system.
Social influences on delayed gratification in New Caledonian crows and Eurasian jays
Authors: Miller Rachael , Davies James , Schiestl Martina , Garcia-Pelegrin Elias , Gray Russell D. , Taylor Alex H. , Clayton Nicola S. 
Published: July 2023

AbstractSelf-control underlies goal-directed behaviour in humans and other animals. Delayed gratification - a measure of self-control - requires the ability to tolerate a delay and/or invest more effort to obtain a reward of higher value over one of lower value, such as food or mates. Social context, in particular, the presence of competitors, may influence delayed gratification. We adapted the ‘rotating-tray’ paradigm, where subjects need to forgo an immediate, lower-quality (i.e. less preferred) reward for a delayed, higher-quality (i.e. more preferred) one, to test social influences on delayed gratification in two corvid species: New Caledonian crows and Eurasian jays. We compared choices for immediate vs. delayed rewards while alone, in the presence of a competitive conspecific and in the presence of a non-competitive conspecific. We found that species differed: jays were more likely to select the immediate, less preferred reward than the crows. We also found that jays were more likely to select the immediate, less preferred reward when a competitor or non-competitor was present than when alone, or when a competitor was present compared to a non- competitor, while the crows selected the delayed, highly preferred reward irrespective of social presence. We discuss our findings in relation to species differences in socio-ecological factors (adult sociality and food caching) and wider implications of social influences on self-control.
Generative and predictive neural networks for the design of functional RNA molecules
Authors: Riley Aidan T. , Robson James M. , Green Alexander A. 
Published: July 2023

ABSTRACTRNA is a remarkably versatile molecule that has been engineered for applications in therapeutics, diagnostics, andin vivoinformation-processing systems. However, the complex relationship between the sequence and structural properties of an RNA molecule and its ability to perform specific functions often necessitates extensive experimental screening of candidate sequences. Here we present a generalized neural network architecture that utilizes thesequenceand structureofRNAmolecules (SANDSTORM) to inform functional predictions. We demonstrate that this approach achieves state-of-the-art performance across several distinct RNA prediction tasks, while learning interpretable abstractions of RNA secondary structure. We paired these predictive models withgenerativeadversarialRNAdesignnetworks (GARDN), allowing the generative modelling of novel mRNA 5’ untranslated regions and toehold switch riboregulators exhibiting a predetermined fitness. This approach enabled the design of novel toehold switches with a 43-fold increase in experimentally characterized dynamic range compared to those designed using classic thermodynamic algorithms. SANDSTORM and GARDN thus represent powerful new predictive and generative tools for the development of diagnostic and therapeutic RNA molecules with improved function.
Differential laboratory passaging of SARS-CoV-2 viral stocks impacts the in vitro assessment of neutralizing antibodies
Authors: Avila-Herrera Aram , Kimbrel Jeffrey A. , Marti Jose Manuel , Thissen James , Saada Edwin A. , Weisenberger Tracy , Arrildt Kathryn T. , Segelke Brent , Allen Jonathan E. , Zemla Adam , Borucki Monica K. 
Published: July 2023

AbstractViral populations in natural infections can have a high degree of sequence diversity, which can directly impact immune escape. However, antibody potency is often tested in vitro with a relatively clonal viral populations, such as laboratory virus or pseudotyped virus stocks, which may not accurately represent the genetic diversity of circulating viral genotypes. This can affect the validity of viral phenotype assays, such as antibody neutralization assays. To address this issue, we tested whether recombinant virus carrying SARS-CoV-2 spike (VSV-SARS-CoV-2-S) stocks could be made more genetically diverse by passage, and if a stock passaged under selective pressure was more capable of escaping monoclonal antibody (mAb) neutralization than unpassaged stock or than viral stock passaged without selective pressures. We passaged VSV-SARS-CoV-2-S four times concurrently in three cell lines and then six times with or without polyclonal antiserum selection pressure. All three of the monoclonal antibodies tested neutralized the viral population present in the unpassaged stock. The viral inoculum derived from serial passage without antiserum selection pressure was neutralized by two of the three mAbs. However, the viral inoculum derived from serial passage under antiserum selection pressure escaped neutralization by all three mAbs. Deep sequencing revealed the rapid acquisition of multiple mutations associated with antibody escape in the VSV-SARS-CoV-2-S that had been passaged in the presence of antiserum, including key mutations present in currently circulating Omicron subvariants. These data indicate that viral stock that was generated under polyclonal antiserum selection pressure better reflects the natural environment of the circulating virus and may yield more biologically relevant outcomes in phenotypic assays.
Ebola Virus VP35 Interacts Non-Covalently with Ubiquitin Chains to Promote Viral Replication Creating New Therapeutic Opportunities
Authors: Rodríguez-Salazar Carlos A. , van Tol Sarah , Mailhot Olivier , Galdino Gabriel , Teruel Natalia , Zhang Lihong , Warren Abbey N. , González-Orozco María , Freiberg Alexander N. , Najmanovich Rafael J. , Giraldo María I. , Rajsbaum Ricardo 
Published: July 2023

AbstractEbolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the co-factor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity that correlated with reduced replication of infectious EBOV. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.Significance StatementEbola virus infection can result in high mortality rates with extreme risk of person-to-person transmission. Sporadic outbreaks in Africa have resulted in thousands of fatal cases, highlighting that there is still insufficient knowledge to develop effective antiviral therapies. Like other viruses, Ebola utilizes the host machinery to replicate. Understanding how viral and host proteins interact can help identifying targets for the rational design of antiviral drugs. Here, we identified interactions between the cellular ubiquitin machinery and the Ebola virus polymerase cofactor protein VP35, which are important for efficient virus replication. We developed an approach to identify and block these virus-host interactions using small chemical compounds, which provides a useful tool to study functional molecular mechanisms and at the same time a potential approach to antiviral therapies.