bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low-dose kainic acid systemic injection paradigm in mice
Authors: Lawande Niraj V. , Conklin Elisabeth A. , Christian-Hinman Catherine A. 
Published: May 2023

SummaryObjectiveSex differences in epilepsy appear driven in part due to effects of gonadal steroids, with varying results in experimental models based on species, strain, and method of seizure induction. Furthermore, removing a main source of these steroids via gonadectomy may impact seizure characteristics differently in males and females. Repeated low-dose kainic acid (RLDKA) systemic injection paradigms were recently shown to reliably induce status epilepticus (SE) and hippocampal histopathology in C57BL/6J mice. Here, we investigated whether seizure susceptibility in a RLDKA injection protocol exhibits a sex difference, and whether gonadectomy differentially influences response to this seizure induction paradigm in males and females.MethodsAdult C57BL/6J mice were left gonad-intact as controls or gonadectomized (females: ovariectomized, OVX; males: orchidectomized, ORX). At least 2 weeks later, KA was injected i.p. every 30 minutes at 7.5 mg/kg or less until the animal reached SE, defined by at least 5 generalized seizures (GS, Racine stage 3 or higher). Parameters of susceptibility to GS induction, SE development, and mortality rates were quantified.ResultsNo differences in seizure susceptibility or mortality were observed between control males and control females. ORX males exhibited increased susceptibility and reduced latency to both GS and SE, but OVX females exhibited increased susceptibility and reduced latency to SE only. However, ORX males, but not OVX females, exhibited strongly increased seizure-induced mortality.SignificanceThe RLDKA protocol is notable for its efficacy in inducing SE and seizure-induced histopathology in C57BL/6J mice, the background for many transgenic strains in current use in epilepsy research. The present results indicate that this protocol may be beneficial for investigating the effects of gonadal hormone replacement on seizure susceptibility, mortality, and seizure-induced histopathology, and that gonadectomy unmasks sex differences in susceptibility to seizures and mortality not observed in gonad-intact controls.
Concurrent loss of ciliary genesWDR93andCFAP46in phylogenetically distant birds
Authors: Girish Salve Buddhabhushan , Kurian Amia Miriam , Vijay Nagarjun 
Published: May 2023

AbstractThe respiratory system is the primary route of infection for many contagious pathogens. Mucociliary clearance of inhaled pathogens is an important innate defense mechanism sustained by the rhythmic movement of epithelial cilia. To counter host defenses, viral pathogens target epithelial cells and cilia. For instance, the influenza virus modulates the expression ofWDR93, a central ciliary apparatus C1d projection component. Lineage-specific prevalence of such host defense genes results in differential susceptibility. Our comparative analysis of ∼500 vertebrate genomes supports the widespread conservation ofWDR93. However, we identified loss of theWDR93in landfowl, geese, and other phylogenetically-independent bird species. Notably, species withWDR93loss have concurrently lost another C1d component,CFAP46, through large segmental deletions. Understanding the consequences of such gene loss may provide insight into their role in host-pathogen interactions and benefit global pathogen surveillance efforts by prioritizing species missing host defense genes and identifying putative zoonotic reservoirs.
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

AbstractIn 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

AbstractWe 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

AbstractEmotional 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

AbstractHibiscus 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

AbstractDespite 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

AbstractEchinochloa 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

AbstractBiomolecular 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

AbstractThe 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

AbstractTemporal 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

AbstractBackgroundPrevious 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.MethodsWe 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.ResultsWe 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.ConclusionsOverall, 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

AbstractThe 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.