bluuebunny/crossref_metadata_2025 huggingface dataset:
AlphaFold2 captures the conformational landscape of the HAMP signaling domain
Authors: Winski Aleksander , Ludwiczak Jan , Orlowska Malgorzata , Madaj Rafal , Kaminski Kamil , Dunin-Horkawicz Stanislaw
Published: May 2023

In this study, we present a conformational landscape of 5000 AlphaFold2 models of the HAMP domain, a short helical bundle that transduces signals from sensors to effectors in two-component signaling proteins such as sensory histidine kinases and chemoreceptors. The landscape reveals the conformational variability of the HAMP domain, including rotations, shifts, displacements, and tilts of helices, many combinations of which have not been observed in experimental structures. HAMP domains belonging to a single family tend to occupy a defined region of the landscape, even when their sequence similarity is low, suggesting that individual HAMP families have evolved to operate in a specific conformational range. The functional importance of this structural conservation is illustrated by poly-HAMP arrays, in which HAMP domains from families with opposite conformational preferences alternate, consistent with the rotational model of signal transduction. The only poly-HAMP arrays that violate this rule are predicted to be of recent evolutionary origin and structurally unstable. Finally, we identify a family of HAMP domains that are likely to be dynamic due to the presence of a conserved pi-helical bulge. All code associated with this work, including a tool for rapid sequence-based prediction of the rotational state in HAMP domains, is deposited athttps://github.com/labstructbioinf/HAMPpred.
ESMFold Hallucinates Native-Like Protein Sequences
Authors: Jeliazkov Jeliazko R. , del Alamo Diego , Karpiak Joel D.
Published: May 2023

We describe attempts to design protein sequences by inverting the protein structure prediction algorithm ESMFold. State-of-the-art protein structure prediction methods achieve high accuracy by relying on evolutionary patterns derived from either multiple sequence alignments (AlphaFold, RosettaFold) or pretrained protein language models (PLMs; ESMFold, OmegaFold). In principle, by inverting these networks, protein sequences can be designed to fulfill one or more design objectives, such as high prediction confidence, predicted protein binding, or other geometric constraints that can be expressed with loss functions. In practice, sequences designed using an inverted AlphaFold model, termed AFDesign, contain unnatural sequence profiles shown to express poorly, whereas an inverted RosettaFold network has been shown to be sensitive to adversarial sequences. Here, we demonstrate that these limitations do not extend to neural networks that include PLMs, such as ESMFold. Using an inverted ESMFold model, termed ESM-Design, we generated sequences with profiles that are both more native-like and more likely to express than sequences generated using AFDesign, but less likely to express than sequences rescued by the structure-based design method ProteinMPNN. However, the safeguard offered by the PLM came with steep increases in memory consumption, preventing proteins greater than 150 residues from being modeled on a single GPU with 80GB VRAM. During this investigation, we also observed the role played by different sequence initialization schemes, with random sampling of discrete amino acids improving convergence and model quality over any continuous random initialization method. Finally, we showed how this approach can be used to introduce sequence and structure diversification in small proteins such as ubiquitin, while respecting the sequence conservation of active site residues. Our results highlight the effects of architectural differences between structure prediction networks on zero-shot protein design.
Emotional association enhances perceptual memory through amygdalo-cortical inputs during NREM sleep
Authors: Saito Yoshihito , Osako Yuma , Odagawa Maya , Oisi Yasuhiro , Matsubara Chie , Kato Shigeki , Kobayashi Kazuto , Morita Mitsuhiro , Johansen Joshua P. , Murayama Masanori
Published: May 2023

Emotional arousal is thought to enhance the consolidation of associated memories by activating the basolateral amygdala (BLA) and its projections to memory-storing regions1–4. Although the importance of both rapid eye movement (REM) and non-REM (NREM) sleep-state specific BLA activity for emotional memory processing has been proposed5–9, how and when the BLA interacts with other brain regions to enhance memory consolidation remains unclear10. Here, by adding emotional information to a perceptual recognition task that relies on top-down inputs from frontal to sensory cortices, we demonstrated that the BLA not only associates emotional information with perceptual information, but also enhances the retention of associated perceptual memory through BLA-frontal projections. Electrophysiological recordings revealed that emotional association increases the reactivation of coordinated activity across the BLA-frontal-sensory region during NREM sleep, but not during REM sleep. Notably, this inter-regional coordinated reactivation during NREM sleep was entrained to the BLA high-frequency oscillations in the emotional condition, suggesting that the BLA triggers inter-regional interaction. Optogenetic silencing of BLA terminals in the frontal cortex during NREM sleep, but not REM sleep, disrupted the enhanced retention of the perceptual memory, but not the association itself or the emotional component of associative memory. Our results indicate that the inter-regional coordination through the BLA-cortical inputs during NREM sleep is causally required for memory enhancement by emotional arousal.
Genome and transcriptome analyses reveal genes involved in the formation of fine ridges on petal epidermal cells inHibiscus trionum
Authors: Koshimizu Shizuka , Masuda Sachiko , Shibata Arisa , Ishii Takayoshi , Shirasu Ken , Hoshino Atsushi , Arita Masanori
Published: May 2023

Hibiscus trionum, commonly known as the ’Flower of an Hour’, is an easily cultivated plant in the Malvaceae family. The purple base part of its petal exhibits structural color due to the fine ridges on the epidermal cell surface, and the molecular mechanism of ridge formation has been actively investigated. We performed genome sequencing ofH. trionumusing a long-read sequencing technology with transcriptome and pathway analyses to identify candidate genes for fine structure formation. The ortholog ofAtSHINE1, which is involved in the biosynthesis of cuticular wax inArabidopsis thaliana, was significantly overexpressed in the iridescent tissue. In addition, orthologs ofAtCUS2andAtCYP77A, which contribute to cutin synthesis, were also overexpressed. Our results provide important insights into the formation of fine ridges on epidermal cells in plants usingH. trionumas a model.
Electrophysiological Representations of Multivariate Human Emotion Experience
Authors: Liu Jin , Hu Xin , Shen Xinke , Song Sen , Zhang Dan
Published: May 2023

Despite the fact that human daily emotions are co-occurring by nature, most neuroscience studies have primarily adopted a univariate approach to identify the neural representation of emotion (emotion experience within a single emotion category) without adequate consideration to the co-occurrence of different emotions (emotion experience across different emotion categories simultaneously). To investigate the neural representations of multivariate emotion experience, this study employed the inter-situation representational similarity analysis (RSA) method. Researchers used an EEG dataset of 78 participants who watched 28 video clips and rated their experience on eight emotion categories. The EEG-based electrophysiological representation was extracted as the power spectral density (PSD) feature per channel in the five frequency bands. The inter-situation RSA method revealed significant correlations between the multivariate emotion experience ratings and PSD features in the Alpha and Beta bands, primarily over the frontal and parietal-occipital brain regions. The study found the identified EEG representations to be reliable with sufficient situations and participants. Moreover, through a series of ablation analyses, the inter-situation RSA further demonstrated the stability and specificity of the EEG representations for multivariate emotion experience. These findings highlight the importance of adopting a multivariate perspective for a comprehensive understanding of neural representation of human emotion experience.
Telomere-to-telomere genome assembly of an allotetraploid pernicious weed,Echinochloa phyllopogon
Authors: Sato Mitsuhiko P. , Iwakami Satoshi , Fukunishi Kanade , Sugiura Kai , Yasuda Kentaro , Isobe Sachiko , Shirasawa Kenta
Published: May 2023

Echinochloa phyllopogonis an allotetraploid pernicious weed species found in rice fields worldwide that often exhibits resistance to multiple herbicides. An accurate genome sequence is essential to comprehensively understand the genetic basis underlying the traits of this species. Here, the telomere-to-telomere genome sequence ofE. phyllopogonwas presented. Eighteen chromosome sequences spanning 1.0 Gb were constructed using the PacBio highly-fidelity long technology. Of the 18 chromosomes, 12 sequences were entirely assembled into telomere-to-telomere and gap-free contigs, whereas the remaining six sequences were constructed at the chromosomal level with only eight gaps. The sequences were assigned to the A and B genomes with total lengths of 453 and 520 Mb, respectively. Repetitive sequences occupied 42.93% of the A genome and 48.47% of the B genome, although 32,337, and 30,889 high-confidence genes were predicted in the A and B genomes, respectively. This suggested that genome extensions and gene disruptions caused by repeated sequence accumulation often occur in the B genome before polyploidization to establish a tetraploid genome. The highly accurate and comprehensive genome sequence would contribute to elucidating the population structure of this species and could be a milestone in understanding the molecular mechanisms of the pernicious traits and to developing effective weed control strategies to avoid yield loss in rice production.
Single-Molecule FRET Illuminates Structural Subpopulations and Dissects Crucial Molecular Events During Phase Separation of a Prion-Like Low-Complexity Domain
Authors: Joshi Ashish , Walimbe Anuja , Avni Anamika , Rai Sandeep K. , Arora Lisha , Sarkar Snehasis , Mukhopadhyay Samrat
Published: May 2023

Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to be associated with a wide range of cellular functions and dysfunctions. We dissect critical molecular events associated with phase separation of an intrinsically disordered prion-like low-complexity domain of Fused in Sarcoma by performing single-molecule studies that permit us to access the wealth of molecular information that is skewed in conventional ensemble experiments. Our single-molecule FRET experiments reveal the coexistence of two conformationally distinct subpopulations in the monomeric form. Single-droplet single-molecule FRET studies coupled with fluorescence correlation spectroscopy, picosecond time-resolved fluorescence anisotropy, and vibrational Raman spectroscopy indicate that structural unwinding switches intramolecular interactions into intermolecular contacts allowing the formation of a dynamic network within condensates. A disease-related mutation introduces enhanced structural plasticity engendering greater interchain interactions that can accelerate pathological aggregation. Our findings provide key mechanistic underpinnings of sequence-encoded dynamically-controlled structural unzipping resulting in biological phase separation.
Identification of GEFs and GAPS modulating phosphorylation and abundance of Rab10 byLRRK2-G2019Sin neurons
Authors: Fellgett Alison , Sweeney Sean T. , Chawla Sangeeta , Elliott Christopher J. H.
Published: May 2023

The Parkinson ‘s Disease associated kinase LRRK2 is proposed to act through phosphorylation of Rab proteins, most notably Rab10. All Rabs participate in a GTPase cycle, in which GEFs (Guanine nucleotide exchange factors) promote membrane binding, and GAPs (GTPase-activating proteins) promote release into the cytoplasm. LRRK2 is proposed to phosphorylate membrane bound Rab10. The hypothesis is that phosphoRab10 is less sensitive to GAP action and may remain membrane bound. To test how LRRK2 and Rab10 function in the GTPase cycle, we used an immunoblotting strategy in fly brains to show that a putative GEF Crag/DENND4C and three possible GAPs (pollux (plx), GAPcenA and Evi5, orthologs of AS160) interact with LRRK2 controlling the phosphorylation and abundance of Rab10. Crag behaves similarly to a Rab10 GEF and additionally modulates the level of panRab10. Only plx acts as a conventional GAP. GAPcenA seems to act as a GAP for phosphoRab10 more than panRab10. It is likely that Evi5 acts as a GAP for another Rab, possibly Rab11.
Atypical connectome topography and signal flow in temporal lobe epilepsy
Authors: Xie Ke , Royer Jessica , Larivière Sara , Rodriguez-Cruces Raul , Frässle Stefan , Cabalo Donna Gift , Ngo Alexander , DeKraker Jordan , Auer Hans , Tavakol Shahin , Weng Yifei , Abdallah Chifaou , Horwood Linda , Frauscher Birgit , Caciagli Lorenzo , Bernasconi Andrea , Bernasconi Neda , Zhang Zhiqiang , Concha Luis , Bernhardt Boris C.
Published: May 2023

Temporal lobe epilepsy (TLE) is one of the most common pharmaco-resistant epilepsies in adults. While hippocampal pathology is the hallmark of this condition, emerging evidence indicates that brain alterations extend beyond the mesiotemporal epicenter and affect macroscale brain function and cognition. We studied macroscale functional reorganization in TLE, explored structural substrates, and examined cognitive associations. We investigated a multisite cohort of 95 patients with pharmaco-resistant TLE and 95 healthy controls using state-of-the-art multimodal 3T magnetic resonance imaging (MRI). We quantified macroscale functional topographic organization using connectome dimensionality reduction techniques and estimated directional functional flow using generative models of effective connectivity. We observed atypical functional topographies in patients with TLE relative to controls, manifesting as reduced functional differentiation between sensory/motor networks and transmodal systems such as the default mode network, with peak alterations in bilateral temporal and ventromedial prefrontal cortices. TLE-related topographic changes were consistent in all three included sites and reflected reductions in hierarchical flow patterns between cortical systems. Integration of parallel multimodal MRI data indicated that these findings were independent of TLE-related cortical grey matter atrophy, but mediated by microstructural alterations in the superficial white matter immediately beneath the cortex. The magnitude of functional perturbations was robustly associated with behavioral markers of memory function. Overall, this work provides converging evidence for macroscale functional imbalances, contributing microstructural alterations, and their associations with cognitive dysfunction in TLE.
Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes
Authors: Fisher Jennifer L. , Clark Amanda D. , Jones Emma F. , Lasseigne Brittany N.
Published: May 2023

Background

Previous pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters.

Methods

We first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships.

Results

We identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ∼85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community.

Conclusions

Overall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs.
Did succulents diversify in response to aridity? Evolutionary analyses of major succulent lineages around the world
Authors: Thompson Jamie , Ramírez-Barahona Santiago , Priest Nicholas , Hernández-Hernández Tania
Published: May 2023

The succulent syndrome is one of the most iconic life strategies in angiosperms, maximising water storage through a suite of adaptations to water-scarcity. Though succulence is considered a classic case of convergent evolution driven by shared environmental drivers, we lack a full understanding of whether the timing and drivers of the diversification of succulent lineages are, in fact, concordant. Here we analyse time-calibrated phylogenetic reconstructions of the seven richest lineages of succulents, and study diversification dynamics in relation to abiotic variables. Our analyses reveal different levels of synchronicity and relation with aridity. The impact of atmospheric CO2on succulent macroevolution is varied. While transitions and radiations are especially concentrated in recent time, following a collapse of atmospheric CO2∼15 million years ago, CO2-dependent diversification is not supported in most lineages. With the exception ofEuphorbia, we find that succulence elevates net diversification, though the effects on underlying speciation and extinction disagree. The phylogenetic distribution of transitions to succulence and rate shift increases suggest these phenomena are decoupled, indicating that succulence might not adhere to a classic key innovation model. We discuss that these evolutionary patterns reveal the ecological complexity of the succulent strategy, beyond simplistic interpretations as adaptations towards aridity.
Genetic basis of lineage-specific evolution of fruit traits in hexaploid persimmon
Authors: Horiuchi Ayano , Masuda Kanae , Shirasawa Kenta , Onoue Noriyuki , Matsuzaki Ryusuke , Tao Ryutaro , Kubo Yasutaka , Ushijima Koichiro , Akagi Takashi
Published: May 2023

Frequent polyploidization events in plants have led to the establishment of many lineage-specific traits representing each species. Little is known about the genetic bases for these specific traits in polyploids, presumably due to plant genomic complexity and their difficulties of applying genetic approaches. Hexaploid Oriental persimmon (Diospyros kaki) has evolved specific fruit characters, including wide variations in fruit shapes and astringency. In this study, using whole-genome diploidized/quantitative genotypes from ddRAD-Seq data of 173 persimmon cultivars, we examined their population structures and potential correlations between their structural transitions and variations in nine fruit traits. The population structures of persimmon cultivars were highly randomized and not substantially correlated with the representative fruit traits focused on in this study, except for fruit astringency. With genome-wide association analytic tools considering polyploid alleles, we identified the loci associated with the nine fruit traits; we mainly focused on fruit-shape variations, which have been numerically characterized by principal component analysis of elliptic Fourier descriptors. The genomic regions that putatively underwent selective sweep exhibited no overlap with the loci associated with these persimmon-specific fruit traits. These insights will contribute to understanding of the genetic mechanisms by which fruit traits are independently established, possibly due to polyploidization events.
The Haplotype-resolved Autotetraploid Genome Assembly Provides Insights into the genomic evolution and fruit divergence in Wax apple (Syzygium samarangense(BI.) Merr.et Perry)
Authors: Wei Xiuqing , Chen Min , Zhang Xijuan , Wang Yinghao , Li Liang , Xu Ling , Wang Huanhuan , Jiang Mengwei , Wang Caihui , Zeng Lihui , Xu Jiahui
Published: May 2023

The wax apple (Syzygium samarangense) is an economically important fruit crop with great potential value to human health because it has rich antioxidant substances. Here, we presented one haplotype-resolved autotetraploid genome assembly of the wax apple with size of 1.59 Gb. Comparative genomic analysis revealed three rounds of whole-genome duplication (WGD) events, including two independent WGDs after WGT-γ. Resequencing analysis of 35 accessions partitioned these individuals into two distinct groups, including 28 landraces and seven cultivated species, and several selectively swept genes possibly contributed to fruit growth, includingKRP1-like, IAA17-like, GME-like, andFLACCA-likegenes. Transcriptome analysis in three different varieties during flower and fruit development identified key genes related to fruit size, sugar content, and male sterility. We foundAP2also affects the fruit size by regulating the sepal development in wax apples. The expression of sugar transport-related genes (SWEETs andSUTs) was high in ‘ZY’, likely contributing to a high level of sugar content. Male sterility in ‘Tub’ was associated with tapetal abnormalities due to the decreased expression ofDYT1, TDF1, andAMS, which affects the early tapetum development. The chromosome-scale genome and large-scale transcriptome data presented in this study offer new valuable resources for biological research onS. samarangense, and sheds new light on fruit size control, sugar metabolism, and male sterility regulatory metabolism in wax apple.
RNA structures and dynamics with Å resolution revealed by x-ray free electron lasers
Authors: Zielinski Kara A. , Sui Shuo , Pabit Suzette A. , Rivera Daniel A. , Wang Tong , Hu Qingyue , Kashipathy Maithri M. , Lisova Stella , Schaffer Chris B. , Mariani Valerio , Hunter Mark S. , Kupitz Christopher , Moss Frank R. , Poitevin Frédéric P. , Grant Thomas D. , Pollack Lois
Published: May 2023

RNA macromolecules, like proteins, fold to assume shapes that are intimately connected to their broadly recognized biological functions; however, because of their high charge and dynamic nature, RNA structures are far more challenging to determine. We introduce an approach that exploits the high brilliance of x-ray free electron laser sources to reveal the formation and ready identification of Å scale features in structured and unstructured RNAs. New structural signatures of RNA secondary and tertiary structures are identified through wide angle solution scattering experiments. With millisecond time resolution, we observe an RNA fold from a dynamically varying single strand through a base paired intermediate to assume a triple helix conformation. While the backbone orchestrates the folding, the final structure is locked in by base stacking. In addition to understanding how RNA triplexes form and thereby function as dynamic signaling elements, this new method can vastly increase the rate of structure determination for these biologically essential, but mostly uncharacterized macromolecules.
Characterizing glucokinase variant mechanisms using a multiplexed abundance assay
Authors: Gersing Sarah , Schulze Thea K. , Cagiada Matteo , Stein Amelie , Roth Frederick P. , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus
Published: May 2023

Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms of human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity. We assayed the abundance of 95% of GCK missense and nonsense variants, and found that 43% of hypoactive variants have a decreased cellular abundance. By combining our abundance scores with predictions of protein thermodynamic stability, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.
Identification of the intracellular protein targets of a bio-active clickable half-sandwich iridium complex by chemical proteomics
Authors: Ramos Robin , Karaiskou Anthi , Botuha Candice , Trichet Michaël , Dingli Florent , Forté Jérémy , Lam France , Canette Alexis , Chaumeton Chloé , Salome Murielle , Chenuel Thomas , Bergonzi Céline , Meyer Philippe , Bohic Sylvain , Loew Damarys , Salmain Michèle , Sobczak-Thépot Joëlle
Published: May 2023

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C^N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high affinity targets. Upon iridium complex treatment, HSP90 folding activity was inhibitedin vitroand major cytoskeleton disorganization was observed. We used a wide array of imaging and biochemical methods to validate selected targets and obtain a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity.
Annihilation of action potentials induces electrical coupling between neurons
Authors: Schlötter Moritz , Maret Georg , Kleineidam Christoph J.
Published: May 2023

Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell - Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.
Pro-social and pro-cognitive effects of LIT-001, a novel oxytocin receptor agonist in a neurodevelopmental model of schizophrenia
Authors: Piotrowska Diana , Potasiewicz Agnieszka , Popik Piotr , Nikiforuk Agnieszka
Published: May 2023

Social and cognitive dysfunctions are the most persistent symptoms of schizophrenia. Since oxytocin (OXT) is known to play a role in social functions and modulates cognitive processes, we investigated the effects of a novel, nonpeptide, selective OXT receptor agonist, LIT-001, in a neurodevelopmental model of schizophrenia. Administration of methylazoxymethanol acetate (MAM; 22 mg/kg) on the 17thday of pregnancy is known to cause developmental disturbances of the brain, which lead to schizophrenia-like symptomatology in the offspring. Here, we examined the effects of acutely administered LIT-001 (1, 3, and 10 mg/kg) in MAM-exposed males and females on social behaviour, communication and cognition.

We report that MAM-treated adult male and female rats displayed reduced social behaviour, ultrasonic communication and novel object recognition test performance. LIT-001 partially reversed these deficits, increasing the total social interaction time and the number of ‘happy’ 50 kHz ultrasonic calls in male rats. The compound ameliorated MAM-induced deficits in object discrimination in both sexes.

Present results confirm the pro-social activity of LIT-001 and demonstrate its pro-cognitive effects following acute administration.
Lateralized Sensorimotor Evoked Potentials during Visuomotor Transformation in Real and Imagined Movements
Authors: Syrov Nikolay , Yakovlev Lev , Kaplan Alexander , Lebedev Mikhail
Published: May 2023

The neural mechanisms underlying motor preparation have attracted much attention, particularly because of the assertion that they are similar to the mechanisms of motor imagery (MI), a technique widely used in motor rehabilitation and brain-computer interfaces (BCIs). Here we clarified the process of visuomotor transformation for the real and imagined movements by analyzing EEG responses that were time locked to the appearance of visual targets and movement onsets. The experimental task required responding to target stimuli with button presses or imagined button presses while ignoring distractors. We examined how different components of movement-related potentials (MRPs) varied depending on the reaction time (RT) and interpreted the findings in terms of the motor noise accumulation hypothesis. Furthermore, we compared MRPs and event-related desynchronization (ERD) for overt motor actions versus motor imagery. For the MRPs, we distinguished lateralized readiness potentials (LRPs) and reafferent potentials (RAPs). While MRPs were similar for the real and imagined movements, imagery-related potentials were not lateralized. The amplitude of the late potentials that developed during motor imagery at the same time RAPs occurred during real movements was correlated with the amplitude of β-ERD. As such they could have represented sensorimotor activation triggered by the imagery. LRPs that occurred during real movements lasted longer for longer RTs, which is consistent with activity accumulation in the motor cortex prior to overt action onset. LRPs occurred for non-target stimuli, as well, but they were small and short lived. We interpret these results in terms of a visuomotor transformation, where information flows from visual to motor areas and results in a movement, a decision not to move and/or a mental image of a movement. The amplitude of the late positive peak that developed during MI was correlated with the amplitude of the β-ERD. Since the latency of this component was consistent with the timing of RAP, we suggest that it is a non-lateralized RAP-like component associated with sensorimotor activation during kinesthetic MI.
Dual-system free-operant avoidance: extension of a theory
Authors: Perez Omar D. , Dickinson Anthony
Published: May 2023

Our theory of positively reinforced free-operant behavior (Perez & Dickinson, 2020) assumes that responding is controlled by 2 systems. One system is sensitive to the correlation between response and reinforcement rates and controls goal-directed behavior, whereas a habitual system learns by reward prediction error. We present an extension of this theory to the aversive domain that explains why free-operant avoidance responding increases with both the experienced rate of negative reinforcement and the difference between this rate and that programmed by the avoidance schedule. The theory also assumes that the habitual component is reinforced by the acquisition of aversive inhibitory properties by the feedback stimuli generated by responding, which then act as safety signals that reinforce habit performance. Our analysis suggests that the distinction between habitual and goal-directed control of rewarded behavior can also be applied to the aversive domain.
Hierarchical Modelling of Crossing Fibres in the White Matter
Authors: Rafipoor Hossein , Lange Frederik J. , Arthofer Christoph , Cottaar Michiel , Jbabdi Saad
Published: May 2023

While diffusion MRI is typically used to estimate microstructural properties of tissue in volumetric elements (voxels), more specificity can be obtained by separately modelling the properties of individual fibre populations within a voxel. In the context of cross-subjects modelling, these so-called fixel-based analyses require identifying equivalent fibre populations. This is usually done post-hoc, after estimating fibre orientations for individual subjects independently and subsequently matching the fixels between subjects. This approach can fail due to individual differences in fibre orientation distributions.

Here, we introduce a hierarchical framework for fitting crossing fibre models to diffusion MRI data in a population of subjects. This hierarchical setup guarantees that the crossing fibres are consistent by construction and, therefore, comparable across subjects. We propose an expectation-maximisation approach to fit the model, which can scale to large numbers of subjects. This approach produces a crossing-fibre white matter fibre template, which can be used to estimate fibre-specific parameters that are consistent across subjects and, hence, can be used in fixel-based statistical analyses.
Dissociative effects of age on neural differentiation at the category and item level
Authors: Srokova Sabina , Aktas Ayse N. Z. , Koen Joshua D. , Rugg Michael D.
Published: May 2023

Increasing age is associated with age-related neural dedifferentiation, a reduction in the selectivity of neural representations which has been proposed to contribute to cognitive decline in older age. Recent findings indicate that when operationalized in terms of selectivity for different perceptual categories, age-related neural dedifferentiation, and the apparent age-invariant association of neural selectivity with cognitive performance, are largely restricted to the cortical regions typically recruited during scene processing. It is currently unknown whether this category-level dissociation extends to metrics of neural selectivity defined at the level of individual stimulus items. Here, we examined neural selectivity at the category and item levels using multivoxel pattern similarity analysis (PSA) of fMRI data. Healthy young and older male and female adults viewed images of objects and scenes. Some items were presented singly, while others were either repeated or followed by a ‘similar lure’. Consistent with recent findings, category-level PSA revealed robustly lower differentiation in older than younger adults in scene-selective, but not object-selective, cortical regions. By contrast, at the item level, robust age-related declines in neural differentiation were evident for both stimulus categories. Moreover, we identified an age-invariant association between category-level scene-selectivity in the parahippocampal place area and subsequent memory performance, but no such association was evident for item-level metrics. Lastly, category and item-level neural metrics were uncorrelated. Thus, the present findings suggest that age-related category- and item-level dedifferentiation depend on distinct neural mechanisms.

Significance Statement

Cognitive aging is associated with a decline in the selectivity of the neural responses within cortical regions that respond differentially to distinct perceptual categories (age-related neural dedifferentiation). However, prior research indicates that while scene-related selectivity is reduced in older age and is correlated with cognitive performance independently of age, selectivity for object stimuli is typically not moderated by age or memory performance. Here, we demonstrate that neural dedifferentiation is evident for both scene and object exemplars when it is defined in terms of the specificity of neural representations at the level of individual exemplars. These findings suggest that neural selectivity metrics for stimulus categories and for individual stimulus items depend on different neural mechanisms.
Endogenous recapitulation of Alzheimer’s disease neuropathology through human 3D direct neuronal reprogramming
Authors: Sun Zhao , Kwon Ji-Sun , Ren Yudong , Chen Shawei , Cates Kitra , Lu Xinguo , Walker Courtney K. , Karahan Hande , Sviben Sanja , Fitzpatrick James A J , Valdez Clarissa , Houlden Henry , Karch Celeste M. , Bateman Randall J. , Sato Chihiro , Mennerick Steven J. , Diamond Marc I. , Kim Jungsu , Tanzi Rudolph E. , Holtzman David M. , Yoo Andrew S.
Published: May 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular Aβ deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with β- or γ-secretase inhibitors in LOAD patient-derived neurons and spheroids before Aβ deposit formation significantly lowered Aβ deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed Aβ deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between Aβ accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.
Computationally efficient demographic history inference from allele frequencies with supervised machine learning
Authors: Tran Linh N. , Sun Connie K. , Struck Travis J. , Sajan Mathews , Gutenkunst Ryan N.
Published: May 2023

Inferring past demographic history of natural populations from genomic data is of central concern in many studies across research fields. Previously, our group had developed dadi, a widely used demographic history inference method based on the allele frequency spectrum (AFS) and maximum composite likelihood optimization. However, dadi’s optimization procedure can be computationally expensive. Here, we developed donni (demography optimization via neural network inference), a new inference method based on dadi that is more efficient while maintaining comparable inference accuracy. For each dadi-supported demographic model, donni simulates the expected AFS for a range of model parameters then trains a set of Mean Variance Estimation neural networks using the simulated AFS. Trained networks can then be used to instantaneously infer the model parameters from future input data AFS. We demonstrated that for many demographic models, donni can infer some parameters, such as population size changes, very well and other parameters, such as migration rates and times of demographic events, fairly well. Importantly, donni provides both parameter and confidence interval estimates from input AFS with accuracy comparable to parameters inferred by dadi’s likelihood optimization while bypassing its long and computationally intensive evaluation process. donni’s performance demonstrates that supervised machine learning algorithms may be a promising avenue for developing more sustainable and computationally efficient demographic history inference methods.
Validation of hypermethylated DNA regions found in colorectal cancers as potential aging-independent biomarkers of precancerous colorectal lesions
Authors: Sajibu Sija , Sonder Emanuel , Tiwari Amit , Orjuela Stephany , Parker Hannah R. , The Frans Olivier , Gubler Christoph , Marra Giancarlo , Robinson Mark D.
Published: May 2023

Background

We previously identified 16,772 colorectal cancer-associated hypermethylated DNA regions that were also detectable in precancerous colorectal lesions (preCRCs) and unrelated to normal mucosal aging. We have now conducted a study to validate 990 of these differentially methylated DNA regions (DMR) in a new series of preCRCs.

Methods

We used targeted bisulfite sequencing to validate these 990 potential biomarkers in 59 preCRC tissue samples (41 conventional adenomas, 18 sessile serrated lesions), each with a patient-matched normal mucosal sample. Based on differential DNA methylation tests, a panel of (candidate) DMRs was chosen on a subset of the (our) cohort and validated on the remaining part of our cohort and (two) further publicly available datasets with respect to their stratifying potential between preCRCs and normal mucosa.

Results

Strong statistical significance for the difference in methylation levels was observed across the full set of 990 investigated DMRs. From these, a selected candidate panel of 30 DMRs correctly identified 58/59 tumors (area under the receiver operating curve: 0.998).

Conclusions

These validated DNA hypermethylation markers can be exploited to develop more accurate noninvasive colorectal tumor screening assays.
Synaptic alterations associated with disrupted sensory encoding in a mouse model of tauopathy
Authors: Meftah Soraya , Cavallini Annalisa , Murray Tracey K. , Jankowski Lukasz , Bose Suchira , Ashby Michael C. , Brown Jonathan T. , Witton Jonathan
Published: May 2023

Synapse loss is currently the best biological correlate of cognitive decline in Alzheimer’s disease and other tauopathies. Synapses seem to be highly vulnerable to tau-mediated disruption in neurodegenerative tauopathies. However, it is unclear how and when this leads to alterations in function in relation to the progression of tauopathy and neurodegeneration. We used the well-characterised rTg4510 mouse model of tauopathy, at 5-6 months and 7-8 months of age, to study the functional impact of cortical synapse loss. The earlier age was used as a model of prodromal tauopathy, with the later age corresponding to more advanced tau pathology and presumed progression of neurodegeneration. Analysis of synaptic protein expression in the somatosensory cortex showed significant reductions in synaptic proteins and NMDA and AMPA receptor subunit expression in rTg4510 mice. Surprisingly,in vitrowhole-cell patch clamp electrophysiology from putative pyramidal neurons in layer 2/3 of the somatosensory cortex suggested no functional alterations in layer 4 to layer 2/3 synaptic transmission at 5-6 months. From these same neurons, however, there were alterations in dendritic structure, with increased branching seen proximal to the soma in rTg4510 neurons. Therefore,in vivowhole-cell patch clamp recordings were utilised to investigate synaptic function and integration in putative pyramidal neurons in layer 2/3 of the somatosensory cortex. These recordings revealed a significant increase in the peak response to synaptically-driven sensory stimulation-evoked activity and a loss of temporal fidelity of the evoked signal to the input stimulus in rTg4510 neurons. Together, these data suggest that loss of synapses, changes in receptor expression, and dendritic restructuring may lead to alterations in synaptic integration at a network level. Understanding of these compensatory processes could identify targets to help delay symptomatic onset within dementia.

Abbreviated summary

Meftah et al. report alterations to synaptic and dendrite properties in the rTg4510 mouse model of tauopathy associated with disrupted synaptic integrationin vivo. Therefore, disrupted synaptic and network integration may be early markers of synapse loss in neurodegenerative tauopathies.
Differential intra-host infection kinetics inAedes aegyptiunderlie superior transmissibility of African relative to Asian Zika virus
Authors: Phengchat Rinyaporn , Pakparnich Phonchanan , Pethrak Chatpong , Pengon Jutharat , Sartsanga Channarong , Chotiwan Nunya , Uppakara Kwanchanok , Suksirisawat Kittitat , Lambrechts Louis , Jupatanakul Natapong
Published: May 2023

Despite numerous studies highlighting the higher transmissibility of the African Zika virus (ZIKV) lineage compared to the Asian lineage in mosquito vectors, little is known about how the viruses interact with different tissues during the early steps of mosquito infection. To address this gap, we aimed to characterize intra-host infection barriers by combining a tissue-level monitoring of infection using plaque assays and a novel quantitative analysis of single-cell level infection kinetics byin situimmunofluorescent staining. Our results revealed that, inAedes aegypti, an African ZIKV strain exhibited a higher replication rate across various tissues than an Asian ZIKV strain. This difference was potentially due to a higher virus production in individual cells, faster spread within tissues, or a combination of both factors. Furthermore, we observed that higher bloodmeal titers resulted in a faster viral spread to neighboring cells suggesting that intra-host infection dynamics depend on inoculum size. We also identified a significant bottleneck during midgut infection establishment for both ZIKV lineages, with only a small percentage of the virus population successfully initiating infection. Finally, thein situimmunofluorescent staining technique enabled the examination of virus infection characteristics in different cell types and revealed heterogeneity in viral replication. Together, these findings demonstrate that differences in intra-host infection kinetics underlie differential transmissibility between African and Asian ZIKV lineages. This information could serve as a starting point to further investigate the underlying mechanisms and ultimately inform the development of alternative control strategies.

Importance

The recent Zika virus (ZIKV) epidemic in the Americas highlights its potential public health threat. While the Asian ZIKV lineage has been identified as the main cause of the epidemic, the African lineage, which has been primarily confined to Africa, has shown evidence of higher transmissibility inAedesmosquitoes. To gain a deeper understanding of this differential transmissibility, our study employed a combination of tissue-level infection kinetics and single-cell level infection kinetics usingin situimmunofluorescent staining. We discovered that the African ZIKV lineage propagates more rapidly and spreads more efficiently within mosquito cells and tissues than its Asian counterpart. This information lays the groundwork for future exploration of the viral and host determinants driving these variations in propagation efficiency.